Dennis van der Meer

• Parekh, Pravesh; Parker, Nadine; Pecheva, Diliana; Frei, Evgeniia; Vaudel, Marc & Smith, Diana M. [Vis alle 26 forfattere av denne artikkelen] (2026). FEMA-Long: Modeling unstructured covariances for discovery of time-dependent effects in large-scale longitudinal datasets. PLoS Genetics. ISSN 1553-7390. 22(6). doi: 10.1371/journal.pgen.1012184. Fulltekst i vitenarkiv Vis sammendrag

  While linear mixed-effects (LME) models are common for analyzing longitudinal data, most users rely on random intercepts or simple stationary covariance, due to unavailability of computationally tractable solutions. Here, we extend the Fast and Efficient Mixed-Effects Algorithm (FEMA) and present FEMA-Long, a computationally tractable approach to flexibly modeling longitudinal covariance suitable for high-dimensional data. FEMA-Long can: i) model unstructured covariance, ii) model covariates as smooth functions using splines, iii) discover time-dependent effects of covariates with spline interactions, and iv) use these flexible longitudinal modeling strategies to perform longitudinal genome-wide association studies and discover time-dependent genetic effects, in a computationally scalable manner, suitable for high-dimensional data. Through extensive simulations, we show that estimates from FEMA-Long are accurate, while being up to several thousand times faster and with minimal carbon footprint. To show the utility of FEMA-Long for discovering novel biological signal, using data from the Norwegian Mother, Father and Child Cohort Study (MoBa), we performed a longitudinal genome-wide association study with non-linear SNP-by-time interaction on length, weight, and BMI of 68,273 infants with up to six measurements in the first year of life. We found dynamic patterns of random effects including time-varying heritability and genetic correlations, as well as several genetic variants showing time-dependent effects, highlighting the applicability of FEMA-Long to enable novel discoveries.

• Wu, Xiao; Shadrin, Alexey; Blokland, Gabriëlla A.M.; Guloksuz, Sinan; Andreassen, Ole & Linden, David E.J. [Vis alle 7 forfattere av denne artikkelen] (2026). Shared genetic architecture between Alzheimer’s disease and brain morphology. Alzheimer's Research & Therapy. 18. doi: 10.1186/s13195-026-02105-5. Fulltekst i vitenarkiv Vis sammendrag

  Background A hallmark of Late-onset Alzheimer’s disease (LOAD) is brain tissue atrophy across multiple cortical and subcortical regions. However, studies report no significant genetic correlation between LOAD and brain morphology, indicating that the genetic drivers of neurodegeneration are complex. Resolving this shared genetic architecture is key to uncovering the biological mechanisms linking brain morphology to LOAD. Methods We analyzed UK Biobank genotype data (n = 272,513; 57.1 ± 8.0 years; 54.6% female) alongside genome-wide association study summary statistics for LOAD and 89 brain morphological traits. We employed linkage disequilibrium score regression (LDSC), polygenic score (PGS), and Local Analysis of [co]Variant Association (LAVA) to evaluate genetic relationships at the whole-genome and locus level. The extent of polygenic overlap was quantified using bivariate causal mixture modeling (MiXeR), and specific shared loci were identified via conjunctional FDR. Identified loci were mapped to genes and followed by enrichment analyses to characterize the shared biological pathways. Results LDSC and regression analyses revealed no significant global genetic correlations between LOAD and brain morphological traits and no associations between PGS and LOAD proxy scores. In contrast, LAVA identified significant local genetic correlations (both positive and negative) across all LOAD-brain trait pairs. MiXeR analysis further revealed a substantial number of shared genetic variants characterized by mixed effect directions, explaining the lack of global correlation. We identified 183 shared loci mapping to 80 distinct genes. Enrichment analyses indicated that these shared genes are involved in biological processes related to cell differentiation, development, and cellular component organization. Conclusions Our findings provide evidence of extensive polygenic overlap between LOAD and brain morphology, revealing that the absence of global genetic correlation stems from mixed local effect directions. These shared genetic architectures implicate pathways in cellular development and differentiation, providing a molecular framework for understanding the link between brain morphology and LOAD.

• Mufford, Mary S.; Meer, Dennis van der; Baird, C. Lexi; Sun, Delin; LaBar, Kevin S. & Ramesar, Raj [Vis alle 108 forfattere av denne artikkelen] (2026). Shared and specific associations of amygdala nuclei volumes with PTSD symptom domains and childhood trauma: An ENIGMA-PGC PTSD mega-analysis. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03718-w. Fulltekst i vitenarkiv Vis sammendrag

  Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala’s key role in fear conditioning makes it an important focus for investigating the neurobiology of PTSD. However, associations between amygdala volume and PTSD have been inconsistent. The amygdala consists of functionally distinct nuclei. Specific associations between amygdala nuclei volumes and PTSD may account for previous discrepancies between PTSD and whole amygdala volume. This study investigates the associations between amygdala nuclei volumes, PTSD diagnosis, severity, symptom cluster scores, age of onset and childhood trauma. Individuals with a PTSD diagnosis (n = 771) and controls (n = 1 081, 72% trauma-exposed) were sourced from the Enhancing Neuro-Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium (mean age = 32.4 years, (SD = 13 years), 60% male). Nine amygdala nuclei volumes were compared to PTSD diagnosis, age of onset, overall severity, symptom cluster scores (re-experiencing, arousal, and avoidance/emotional numbing), and childhood trauma subscales. Analyses were performed using ordinary least-squares regression, corrected for age, sex, intracranial volume, and whole amygdala volume. PTSD diagnosis was not significantly associated with amygdala nuclei volumes. PTSD severity scores were associated with smaller right lateral nucleus volume (β = −0.26, pBON = 0.01). Smaller right lateral nucleus volume was also associated with re-experiencing (β = −1.01, pBON = 0.04) and arousal (β = −0.9, pBON = 0.04), smaller left paralaminar nucleus volume was associated with re-experiencing (β = −0.1, pBON = 0.04), smaller left corticoamygdaloid transition area volume was associated with avoidance (β = −0.31, pBON = 0.02). Larger left and right central nucleus volumes were significantly associated with childhood physical abuse (β = 0.24, pBON = 9 × 10−3) and neglect (β = 0.29, pBON = 0.04), respectively. Differences in select amygdala nuclei volumes among adults are associated with PTSD severity, symptom cluster scores, and childhood physical abuse and neglect. These findings demonstrate nuclei-specific patterns consistent with their functional roles in fear learning and expression.

• Gurholt, Tiril Pedersen; Beck, Dani; Voldsbekk, Irene; Parker, Nadine; Askeland-Gjerde, Daniel E. & Lange, Ann-Marie Glasø de [Vis alle 13 forfattere av denne artikkelen] (2026). Linking obesity with white matter microstructure highlights the importance of brainstem tracts and sex differences. Brain Communications. 8(1), s. 1–15. doi: 10.1093/braincomms/fcag026. Fulltekst i vitenarkiv Vis sammendrag

  While obesity (body mass index ≥ 30) has been consistently associated with white matter diffusion magnetic resonance imaging (MRI) phenotypes, the contributions of common obesity phenotypes on various diffusion metrics, and the moderating effects of sex and age, require further clarification. This study aims to elucidate these body–brain connections to enhance our understanding of the comorbid link between obesity and body anthropometrics and the brain using a large-scale dataset. We analysed cross-sectional data from 40 040 participants from the UK Biobank (52.2% female; ages 44–83 years) using multiple linear regression to evaluate how obesity and body anthropometrics relate to regional white matter diffusion tensor imaging metrics (fractional anisotropy, axial diffusivity, radial diffusivity, mean diffusivity). We also examined interactions with age and sex. Our analyses revealed significant associations between individual obesity phenotypes (i.e. obesity and body anthropometrics) and diffusion tensor imaging metrics of small effects, with partial correlation coefficient |r| effect sizes ranging from 0.02 to 0.20 for most regions of interest with largest effects in brainstem tracts. We observed more widespread sex-by-obesity phenotypes than age-by-obesity phenotypes interaction effects on diffusion tensor imaging metrics. Our results link obesity and body anthropometrics with white matter phenotypes and suggests that shared body fat-related pathways link physical and brain health that may vary based on sex and age. Understanding these body–brain relationships, and the role of age and sex, could enhance the development and evaluation of targeted, personalized, treatment strategies for brain disorders that co-occur with obesity, although further longitudinal and intervention studies are needed to map the causal dynamics of these associations.

• Sartorius, Alina Marie; Meer, Dennis van der; Shadrin, Alexey; Rokicki, Jaroslav; Campbell, Megan & Winterton, Adriano [Vis alle 11 forfattere av denne artikkelen] (2026). Genetic pathways linking oxytocin-vasotocin hypothalamic subunit architecture with psychiatric and metabolic traits. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03508-4. Fulltekst i vitenarkiv
• Moberget, Torgeir; Meer, Dennis van der; Bahrami, Shahram; Roelfs, Daniël; Frei, Oleksandr & Kaufmann, Tobias Herbert [Vis alle 15 forfattere av denne artikkelen] (2026). The genetic architecture of human cerebellar morphology supports a key role for the cerebellum in human evolution and psychopathology. Communications Biology. 9(1). doi: 10.1038/s42003-026-09664-1. Fulltekst i vitenarkiv Vis sammendrag

  The functional domain of the cerebellum has expanded beyond motor control to also include cognitive and affective functions. In line with this notion, cerebellar volume has increased over recent primate evolution, and cerebellar alterations have been linked to heritable mental disorders. To map the genetic architecture of human cerebellar morphology, we here studied a large imaging genetics sample from the UK Biobank (n discovery = 27,302; n replication: 11,264) with state-of-the art neuroimaging and biostatistics tools. Multivariate GWAS on regional cerebellar MRI features yielded 351 significant genetic loci (226 novel, 94% replicated). Lead SNPs showed positive enrichment for relatively recent genetic mutations over the last 20-40k years (i.e., overlapping the Upper Paleolithic, a period characterized by rapid cultural evolution), while gene level analyses revealed enrichment for human-specific evolution over the last ∼6-8 million years. Finally, we observed genetic overlap with major mental disorders, supporting cerebellar involvement in psychopathology.

• Stinson, Sara E.; Shadrin, Alexey; Rahman, Mohammad Zillur; Rødevand, Linn; Broce, Iris J. & Selbæk, Geir [Vis alle 17 forfattere av denne artikkelen] (2026). Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap. EBioMedicine. 127. doi: 10.1016/j.ebiom.2026.106254. Fulltekst i vitenarkiv Vis sammendrag

  Background: Metabolic dysfunction is a major risk factor for neurodegeneration, yet the genetic architecture linking systemic metabolism to Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear. Methods: We integrated genome-wide association data for 249 circulating metabolites and proglucagon with summary statistics for AD, PD, and cardiometabolic traits. Genetic correlations, polygenic overlap, causal relationships, and shared genetic loci were quantified using linkage disequilibrium score regression, high-definition likelihood, bivariate mixture modelling, Mendelian randomisation, and conjunctional false discovery rate analyses, followed by functional and tissue-specific enrichment analyses. Findings: AD displayed a metabolic-genetic profile aligned with body mass index, type 2 diabetes, coronary artery disease, and stroke, whereas PD exhibited largely opposing patterns (Spearman's rs = −0.26). Mendelian randomization analyses supported causal effects of lipoprotein subclasses, glutamine, and proglucagon on AD risk, with opposite or null effects in PD. Shared loci between metabolites and AD were enriched for lipid metabolism and cholesterol transport, whereas PD-associated loci were enriched for mitochondrial function, vesicle trafficking, and stress-response signalling. Interpretation: AD and PD are shaped by fundamentally distinct metabolic-genetic architectures. Metabolically targeted interventions, particularly those modulating lipid, amino acid, and proglucagon pathways, may require disease-specific and genetically informed strategies for prevention and treatment of neurodegenerative diseases.

• Liu, Hengjian; Hescham, Sarah; Clusmann, Hans; Temel, Yasin & Meer, Dennis van der (2026). Causal Effects Between Neurodegenerative Diseases, Metabolites, and Brain Volume. Current Alzheimer Research. ISSN 1567-2050. doi: 10.2174/0115672050413060251107021634. Fulltekst i vitenarkiv
• Snihirova, Yelyzaveta; Amelsvoort, Therese van; Swillen, Ann; Bree, Marianne van den; Meer, Dennis van der & Harwood, Janet [Vis alle 8 forfattere av denne artikkelen] (2025). Parental Education Predicts Longitudinal IQ Trajectories in 22q11.2 Deletion Syndrome: A Three‐Cohort European Study. Journal of Intellectual Disability Research. ISSN 0964-2633. 69(11), s. 1304–1314. doi: 10.1111/jir.70025. Fulltekst i vitenarkiv Vis sammendrag

  ABSTRACT Background 22q11.2 deletion syndrome (22q11DS) is a genetic disorder characterised by a wide range of physical, cognitive, and psychiatric symptoms. Current knowledge on 22q11DS highlights considerable variation in cognitive outcomes, but the role of environmental factors in shaping these trajectories over time remains poorly understood. Aims This study investigates how environmental factors contribute to variability in intelligence quotient (IQ) among individuals with 22q11DS across three European cohorts. By examining these influences over time, the research aims to identify potential drivers of IQ differences and uncover modifiable factors that may support improved cognitive outcomes in individuals with 22q11DS. Methods Data were collected from 297 individuals with 22q11DS across three European cohorts. Cognitive assessments included full‐scale IQ (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ). Environmental measures encompassed parental education, sleep, stress and substance use, gathered through questionnaires and interviews. Baseline associations between environmental measures and IQ were evaluated with ANOVA at the first assessment. To examine within‐person IQ change across three visits, we used linear mixed‐effects models. Results We found a significant decline in FSIQ, VIQ and PIQ over time, with linear trends observed for all three measures. Parental education, particularly the father's education, explained a significant proportion of the variance of all IQ‐based measures. Conclusions Parental education emerged as a key predictor of IQ, suggesting that socioeconomic factors contribute to cognitive performance variability in individuals with 22q11DS. Even in high‐penetrance genetic variants, such as the 22q11.2 deletion, environmental factors and gene–environment interactions may make significant contributions to the severity of phenotypes.

• Wu, Xiao; Parekh, Pravesh; Lin, Bochao Danae; Pries, Lotta-Katrin; Guloksuz, Sinan & Rutten, Bart P F [Vis alle 9 forfattere av denne artikkelen] (2025). Exploration of Genetic Overlap of Brain Phenotypes With Schizophrenia: Different Methods Provide Complementary Insights. Schizophrenia Bulletin. ISSN 0586-7614. doi: 10.1093/schbul/sbaf096. Fulltekst i vitenarkiv Vis sammendrag

  Background Genetic studies have shown associations between genetic risk for schizophrenia and brain imaging phenotypes. However, prior studies focused on a single neuroimaging modality and/or employed methods that do not fully elucidate the shared genetic architecture between them, limiting our understanding of their complex genetic relationship. Study Design We used genome-wide association study summary statistics for schizophrenia alongside 37 brain measurements, selected based on adequate SNP-based heritability and representing structural, microstructural, and functional brain features derived from T1, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). These were integrated with a clinical cohort (1065 cases, 1037 controls) to examine the polygenic overlap between schizophrenia and brain measurements. Polygenic overlap was assessed at genome-wide and individual locus levels through linkage disequilibrium score regression, polygenic scoring (PGS), bivariate MiXeR, and conjunctional false discovery rate. Study Results Schizophrenia showed weak genetic correlations with all brain measures (rg = −0.131 to 0.146; PFDR = .069 to .019), and no significant correlation with brain PGS. Nonetheless, a substantial proportion of causal variants with mixed effect direction were shared between schizophrenia and brain traits. Genetic correlations and polygenic scores showed significant positive associations with the proportion of shared variants with concordant effect direction. Additionally, we identified 218 loci shared with schizophrenia in T1, 138 in DTI, and 24 in rs-fMRI measures. Conclusions Our findings indicate shared genetic underpinnings between schizophrenia and brain structure and functional connectivity, emphasizing the necessity for complementary methodologies to investigate the genetic overlap between complex polygenic traits.

• Lin, Bochao Danae; Li, Yunzhi; Goula, Anastasia A.; Chang, Xiao; Grasby, Katrina L. & Medland, Sarah [Vis alle 11 forfattere av denne artikkelen] (2025). Dissecting causal relationships between cortical morphology and neuropsychiatric disorders: a bidirectional Mendelian randomization study. Nature Mental Health. 3(6), s. 613–625. doi: 10.1038/s44220-025-00397-4. Fulltekst i vitenarkiv
• Breddels, Esmee M.; Snihirova, Yelyzaveta; Pishva, Ehsan; Gülöksüz, Sinan; Blokland, Gabriëlla AM & Luykx, Jurjen [Vis alle 10 forfattere av denne artikkelen] (2025). Brain morphology mediating the effects of common genetic risk variants on Alzheimer’s disease. Journal of Alzheimer's Disease Reports. 9. doi: 10.1177/25424823251328300. Fulltekst i vitenarkiv Vis sammendrag

  Background Late-onset Alzheimer's disease (LOAD) has been associated with alterations in the morphology of multiple brain structures, and it is likely that disease mechanisms differ between brain regions. Coupling genetic determinants of LOAD with measures of brain morphology could localize and identify primary causal neurobiological pathways. Objective To determine causal pathways from genetic risk variants of LOAD via brain morphology to LOAD. Methods Mediation and Mendelian randomization (MR) analysis were performed using common genetic variation, T1 MRI and clinical data collected by UK Biobank and Alzheimer's Disease Neuroimaging Initiative. Results Thickness of the entorhinal cortex and the volumes of the hippocampus, amygdala and inferior lateral ventricle mediated the effect of APOE ε4 on LOAD. MR showed that a thinner entorhinal cortex, a smaller hippocampus and amygdala, and a larger volume of the inferior lateral ventricles, increased the risk of LOAD as well as vice versa. Conclusions Combining neuroimaging and genetic data can give insight into the causal neuropathological pathways of LOAD.

• Serin, Emin; Ritter, Kerstin; Schumann, Gunter; Banaschewski, Tobias; Marquand, Andre & Walter, Henrik [Vis alle 91 forfattere av denne artikkelen] (2025). Generating synthetic task-based brain fingerprints for population neuroscience using deep learning. Communications Biology. 8(1). doi: 10.1038/s42003-025-09158-6. Fulltekst i vitenarkiv
• Rokicki, Jaroslav; Campbell, Megan L.; Meer, Dennis van der; Sartorius, Alina Marie; Tesli, Natalia & Jaholkowski, Piotr Pawel [Vis alle 11 forfattere av denne artikkelen] (2025). Brain-based gene expression and corresponding behavioural relevance of risk genes for broad antisocial behaviour. NeuroImage. ISSN 1053-8119. 311. doi: 10.1016/j.neuroimage.2025.121198. Fulltekst i vitenarkiv
• Silva, Ana I.; Sønderby, Ida Elken; Kirov, George; Abdellaoui, Abdel; Agartz, Ingrid & Ames, David [Vis alle 106 forfattere av denne artikkelen] (2025). Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 10(10), s. 1093–1106. doi: 10.1016/j.bpsc.2025.05.010. Fulltekst i vitenarkiv Vis sammendrag

  Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

• Liang, Chen; Yuan, Jiacan; Zhang, Renhe; Tang, Xu; Schumann, Gunter & Hitchen, Esther [Vis alle 89 forfattere av denne artikkelen] (2025). Projecting the morbidity burden of mental and behavioral disorders associated with increasing humid heat in Shanghai. Nature Mental Health. 3(12), s. 1532–1544. doi: 10.1038/s44220-025-00519-y. Fulltekst i vitenarkiv Vis sammendrag

  Residents of low-latitude megacities face growing vulnerability to humid-heat stress under urbanization and global warming, yet limited research has assessed the morbidity burden of mental and behavioral disorders (MBDs) linked to humid-heat exposures in these cities. Here we quantify the hospital admissions of MBDs in Shanghai, a megacity of over 25 million inhabitants, attributable to humid heat, and project future burdens under various greenhouse gas (GHG)-emission and population scenarios. Humid heat drives a higher morbidity burden than high temperature alone, especially in humid-heat nights. Without population change, the humid-heat-related morbidity burden of MBDs would increase by 68.2% (95% empirical confidence interval 56.7%–81.6%) under the highest-GHG-emission scenario by the 2090s, while 8,465 (95% empirical confidence interval 6,928–10,053) cases would be avoided by reducing emissions to the lowest pathway. With projected population decline, the attributable hospital admissions will decrease toward century’s end. These findings highlight the benefit of GHG mitigation in reducing the growing MBD risks posed by extreme humid heat.

• Shadrin, Alexey; Hindley, Guy; Hagen, Espen; Parker, Nadine; Tesfaye, Markos & Jaholkowski, Piotr Pawel [Vis alle 16 forfattere av denne artikkelen] (2025). Distinct patterns of genetic overlap among multimorbidities revealed with trivariate MiXeR. Genome Medicine. 17. doi: 10.1186/s13073-025-01528-3. Fulltekst i vitenarkiv Vis sammendrag

  Background: Multimorbidities are a global health challenge. Accumulating evidence indicates that overlapping genetic architectures underlie comorbid complex human traits and disorders. This can be quantified for a pair of phenotypes using various techniques. Still, the pattern of genetic overlap between three distinct complex phenotypes, which is important for understanding multimorbidities, has not been possible to quantify. Methods: Here, we present and validate the novel trivariate MiXeR tool, which disentangles the pattern of genetic overlap between three complex phenotypes using summary statistics from genome-wide association studies. Our simulations show that trivariate MiXeR can reliably reconstruct different patterns of genetic overlap and estimate the proportions of genetic overlap between three phenotypes. Results: We found substantial genetic overlap between gastro-intestinal and brain diseases supporting a genetic basis of the gut-brain axis—the pattern consistent with pairwise analysis. However, the pattern of genetic overlap between three diverse cardiometabolic and renal health indicators and three immune-linked disorders revealed a much larger genomic component shared between all phenotypes than expected from separate pairwise analyses. This suggests the existence of core pathways underlying distinct but related chronic conditions. Conclusions: Overall, trivariate MiXeR offers a novel and efficient tool for investigating patterns of genetic overlap among three complex phenotypes. This contributes to a better understanding of genetic relationships between complex traits and disorders, potentially providing new insights into the mechanisms underlying common multimorbidities. Trivariate MiXeR is freely available at https://github.com/precimed/mix3r .

• Oppenheimer, Hannah; Shadrin, Alexey; Andersen, Jonas Østerhaug; Schindler, Louise S.; Crestol, Arielle & Andreassen, Ole [Vis alle 10 forfattere av denne artikkelen] (2025). Investigating Shared Cardiovascular Factors and Genetic Overlap of Pregnancy-Related Disorders, Major Depressive Disorder, and Alzheimer’s Disease. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2025.09.018. Fulltekst i vitenarkiv
• Oppenheimer, Hannah; Meer, Dennis van der; Schindler, Louise S.; Crestol, Arielle; Shadrin, Alexey & Andreassen, Ole [Vis alle 9 forfattere av denne artikkelen] (2025). No causal links between estradiol and female’s brain and mental health using Mendelian randomization. Nature Communications. 16(1). doi: 10.1038/s41467-025-65878-7. Fulltekst i vitenarkiv
• Smeland, Olav B.; Kutrolli, Gleda; Bahrami, Shahram; Fominykh, Vera; Parker, Nadine & Fuhrer, Julian [Vis alle 21 forfattere av denne artikkelen] (2025). A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders. Nature Neuroscience. ISSN 1097-6256. 28(12), s. 2439–2450. doi: 10.1038/s41593-025-02090-2. Fulltekst i vitenarkiv Vis sammendrag

  Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

• Lett, Tristram A.; Vaidya, Nilakshi; Jia, Tianye; Polemiti, Elli; Banaschewski, Tobias & Bokde, Arun L. W. [Vis alle 120 forfattere av denne artikkelen] (2025). Framework for Brain-Derived Dimensions of Psychopathology. JAMA psychiatry. ISSN 2168-6238. 82(8), s. 778–778. doi: 10.1001/jamapsychiatry.2025.1246. Fulltekst i vitenarkiv Vis sammendrag

  Importance Psychiatric diagnoses are not defined by neurobiological measures hindering the development of therapies targeting mechanisms underlying mental illness. Research confined to diagnostic boundaries yields heterogeneous biological results, whereas transdiagnostic studies often investigate individual symptoms in isolation. Objective To develop a framework that groups clinical symptoms compatible with ICD-10 and DSM-5 according to their covariation and shared brain mechanisms. Design, Setting, and Participants This diagnostic study was conducted in 2 samples, the population-based Reinforcement-Related Behaviour in Normal Brain Function and Psychopathology (IMAGEN) cohort (longitudinal assessments at 14, 19, and 23 years; study duration from March 2010 to the present) and the cross-diagnostic Brain Network Based Stratification of Mental Illness (STRATIFY)/Earlier Detection and Stratification of Eating Disorders and Comorbid Mental Illnesses (ESTRA) samples (study duration from October 2016 to September 2023). The samples are from 8 clinical research hospitals in Germany, the UK, France, and Ireland. For the population-based IMAGEN study, 794 of 1253 23-year-old participants had complete assessments including complete clinical assessments and neuroimaging data across all time points. For the cross-diagnostic STRATIFY/ESTRA samples, 209 of 485 participants aged 18 to 26 years had complete clinical and neuroimaging data. The sample included healthy control individuals and patients with alcohol use disorder, major depressive disorder, anorexia nervosa, and bulimia nervosa. Exposures Sparse generalized canonical correlation analysis was used to integrate diverse data from clinical symptoms and 7 brain imaging modalities. Main Outcomes and Measures The prediction of symptom features was the main outcome. The model was developed in the training set from the IMAGEN Study at age 23 years (70%), then applied in the remaining holdout test sample (30%), the independent STRATIFY/ESTRA patient sample, and longitudinally in the IMAGEN set. Results In total, 1003 participants were included (425 male and 578 female; mean [SD] age, 22.1 [1.5] years). The reassembly of existing ICD-10 and DSM-5 symptoms revealed 6 cross-diagnostic psychopathology scores. They were consistently associated with multimodal neuroimaging components: excitability and impulsivity (training set: r , 0.26; 95% CI, 0.18-0.33; test set: r , 0.22; 95% CI, 0.10-0.35; STRATIFY/ESTRA set: r , 0.19; 95% CI, 0.07-0.31), depressive mood and distress (training: r , 0.30; 95% CI, 0.20-0.38; test: r , 0.22; 95% CI, 0.09-0.35; STRATIFY/ESTRA: r , 0.19; 95% CI, 0.04-0.33), emotional and behavioral dysregulation (training: r , 0.40; 95% CI, 0.31-0.48; test: r , 0.17; 95% CI, 0.14-0.36; STRATIFY/ESTRA: r , 0.19; 95% CI, 0.06-0.30), stress pathology (training: r , 0.32; 95% CI, 0.19-0.43; test: r , 0.14; 95% CI, 0.05-0.23; STRATIFY/ESTRA: r , 0.12; 95% CI, 0.01-0.22), eating pathology (training: r , 0.34; 95% CI, 0.25-0.42; test: r , 0.26; 95% CI, 0.15-0.37; STRATIFY/ESTRA: r , 0.15; 95% CI, 0.12-0.34), and social fear and avoidance symptoms (training: r , 0.31; 95% CI, 0.25-0.42; test: r , 0.18; 95% CI, 0.15-0.35; STRATIFY/ESTRA: r , 0.12; 95% CI, 0.12-0.33). Conclusion and Relevance In this study, the identification of symptom groups of mental illness robustly defined by precisely characterized brain mechanisms enabled the characterization of dimensions of psychopathology based on quantifiable neurobiological measures.

• Korbmacher, Max; Tranfa, Mario; Pontillo, Giuseppe; Meer, Dennis van der; Wang, Meng-Yun & Andreassen, Ole [Vis alle 8 forfattere av denne artikkelen] (2025). White matter microstructure links with brain, bodily and genetic attributes in adolescence, mid- and late life. NeuroImage. ISSN 1053-8119. 310, s. 1–10. doi: 10.1016/j.neuroimage.2025.121132. Fulltekst i vitenarkiv Vis sammendrag

  Advanced diffusion magnetic resonance imaging (dMRI) allows one to probe and assess brain white matter (WM) organisation and microstructure in vivo. Various dMRI models with different theoretical and practical assumptions have been developed, representing partly overlapping characteristics of the underlying brain biology with potentially complementary value in the cognitive and clinical neurosciences. To which degree the different dMRI metrics relate to clinically relevant geno- and phenotypes is still debated. Hence, we investigate how tract-based and whole WM skeleton parameters from different dMRI approaches associate with clinically relevant and white matter-related phenotypes (sex, age, pulse pressure (PP), body-mass-index (BMI), brain asymmetry) and genetic markers in the UK Biobank (UKB, n=52,140) and the Adolescent Brain Cognitive Development (ABCD) Study (n=5,844). In general, none of the imaging approaches could explain all examined phenotypes, though the approaches were overall similar in explaining variability of the examined phenotypes. Nevertheless, particular diffusion parameters of the used dMRI approaches stood out in explaining some important phenotypes known to correlate with general human health outcomes. A multi-compartment Bayesian dMRI approach provided the strongest WM associations with age, and together with diffusion tensor imaging, the largest accuracy for sex-classifications. We find a similar pattern of metric and tract-dependent asymmetries across datasets, with stronger asymmetries in ABCD data. The magnitude of WM associations with polygenic scores as well as PP depended more on the sample, and likely age, than dMRI metrics. However, kurtosis was most indicative of BMI and potentially of bipolar disorder polygenic scores. We conclude that WM microstructure is differentially associated with clinically relevant pheno- and genotypes at different points in life.

• Lin, Bochao Danae; Pries, Lotta-Katrin; Arias-Magnasco, Angelo; Klingenberg, Boris; Linden, David E.J. & Blokland, Gabriëlla A.M. [Vis alle 10 forfattere av denne artikkelen] (2025). Exposome-Wide Gene-By-Environment Interaction Study of Psychotic Experiences in the UK Biobank. Biological Psychiatry: Global Open Science. 5(3). doi: 10.1016/j.bpsgos.2025.100460. Fulltekst i vitenarkiv Vis sammendrag

  Background A previous study successfully identified 148 of 23,098 exposures associated with any psychotic experiences (PEs) in the UK Biobank using an exposome-wide association study (XWAS). Furthermore, research has shown that the polygenic risk score for schizophrenia (PRS-SCZ) is associated with PEs. However, the interaction of these exposures with PRS-SCZ remains unknown. Method To systematically investigate possible gene-by-environment interactions underlying PEs through data-driven agnostic analyses, we conducted 1) conditional XWAS adjusting for PRS-SCZ to estimate the main effects of the exposures and of PRS-SCZ, 2) exposome-wide interaction study (XWIS) to estimate multiplicative and additive interactions between PRS-SCZ and exposures, and 3) correlation analyses between PRS-SCZ and exposures. The study included 148,502 participants from the UK Biobank. Results In the conditional XWAS models, significant effects of PRS-SCZ and 148 exposures on PEs remained statistically significant. In the XWIS model, we found significant multiplicative (multiplicative scale, 1.23; 95% CI, 1.10–1.37; p = 4.0 × 10−4) and additive (relative excess risk due to interaction, 0.55; 95% CI, 0.32–0.77; synergy index, 0.22; 95% CI, 0.14–0.30; and attributable proportion, 1.59; 95% CI, 1.30–1.91; all ps < .05/148) interactions of PRS-SCZ and the variable serious medical conditions/disability with PEs. We additionally identified 6 additive gene-by-environment interactions for mental distress, help-/treatment-seeking behaviors (3 variables), sadness, and sleep problems. In the correlation test focused on 7 exposures that exhibited significant interactions with PRS-SCZ, nonsignificant or small (r < 0.04) gene-by-environment correlations were observed. Conclusions These findings reveal evidence for gene-by-environment interactions underlying PEs and suggest that intertwined pathways of genetic vulnerability and exposures may contribute to psychosis risk.

• Meer, Dennis van der; Hindley, Guy; Shadrin, Alexey; Smeland, Olav Bjerkehagen; Parker, Nadine & Dale, Anders M. [Vis alle 8 forfattere av denne artikkelen] (2025). Mapping the Genetic Landscape of Psychiatric Disorders With the MiXeR Toolset. Biological Psychiatry. ISSN 0006-3223. 98(6), s. 455–465. doi: 10.1016/j.biopsych.2025.02.886. Fulltekst i vitenarkiv Vis sammendrag

  Psychiatric disorders have complex genetic architectures with substantial genetic overlap across conditions, which may partially explain their high levels of comorbidity. This presents significant challenges to research. Genome-wide association studies (GWASs) have uncovered hundreds of loci associated with single disorders, but the genetic landscape of psychiatric disorders has remained largely obscure. Moving beyond the conventional infinitesimal model, uni-, bi-, and trivariate MiXeR tools, applied to GWAS summary statistics, has enabled us to more comprehensively describe the genetic architecture of complex disorders and traits and their overlap. Furthermore, the GSA-MiXeR tool improves biological interpretation of GWAS findings to better elucidate causal mechanisms. Here, we outline the methodology that underlies the MiXeR tools together with instructions for their optimal use. We review results from studies that have investigated the genetic architecture of psychiatric disorders and their overlap using the MiXeR toolset. These studies have revealed generally high polygenicity and low discoverability among psychiatric disorders, particularly in contrast to somatic disorders. There is also pervasive genetic overlap across psychiatric disorders and behavioral traits, while their overlap with somatic traits is smaller, consistent with differences in polygenicity. Finally, GSA-MiXeR has quantified the contribution of gene sets to the heritability of psychiatric disorders, prioritizing small, biologically coherent gene sets. Together, these findings have implications for our understanding of the complex relationships between psychiatric disorders and related traits. MiXeR tools have provided new insights into the genetic architecture of psychiatric disorders, generating a better understanding of their underlying biological mechanisms and potential for clinical utility.

• Askeland-Gjerde, Daniel E.; Westlye, Lars Tjelta; Andersson, Patrik; Korbmacher, Max; Lange, Ann-Marie Glasø de & Meer, Dennis van der [Vis alle 10 forfattere av denne artikkelen] (2025). Mediation Analyses Link Cardiometabolic Factors and Liver Fat With White Matter Hyperintensities and Cognitive Performance: A UK Biobank Study. Biological Psychiatry: Global Open Science. 5(4). doi: 10.1016/j.bpsgos.2025.100488. Fulltekst i vitenarkiv Vis sammendrag

  Background Liver fat is associated with cardiometabolic disease, cerebrovascular disease, and dementia. Cerebrovascular disease, most often cerebral small vessel disease, identified by magnetic resonance imaging as white matter hyperintensities (WMHs) often contributes to dementia. However, liver fat’s role in the relationship between cardiometabolic risk, WMHs, and cognitive performance is unclear. Methods In the UK Biobank cohort (N = 32,461, 52.6% female; mean age 64.2 ± 7.7 years; n = 23,354 in the cognitive performance subsample), we used linear regression to investigate associations between cardiometabolic factors measured at baseline and liver fat, WMHs, and cognitive performance measured at follow-up, which was 9.3 ± 2.0 years later on average. We used structural equation modeling to investigate whether liver fat mediated associations between cardiometabolic factors and WMHs and whether WMHs mediated associations between liver fat and cognitive performance. Results Nearly all cardiometabolic factors were significantly associated with liver fat (|r| range = 0.03–0.41, p = 3.4 × 10−8 to 0) and WMHs (|r| = 0.04–0.15, p = 5.8 × 10−13 to 7.0 × 10−159) in regression models. Liver fat was associated with WMHs (r = 0.11, p = 4.3 × 10−82) and cognitive performance (r = −0.03, p = 1.6 × 10−7). Liver fat mediated the associations between cardiometabolic factors and WMHs (|βmediation| = 0.003–0.027, pmediation = 1.9 × 10−8 to 0), and WMHs mediated the associations between liver fat and cognitive performance (βmediation = −0.01, pmediation = 0). Conclusions Our findings indicate that liver fat mediates associations between cardiometabolic factors and WMHs and that WMHs mediate the association between liver fat and cognitive performance. This suggests that liver fat may be important for understanding the effects of cardiometabolic factors on cerebrovascular disease and cognitive function. Experimental studies are warranted to determine relevant targets for preventing vascular-driven cognitive impairment.

• Korbmacher, Max; Vidal-Piñeiro, Didac; Wang, Mengyun; Meer, Dennis van der; Wolfers, Thomas & Nakua, Hajer [Vis alle 10 forfattere av denne artikkelen] (2025). Cross-Sectional Brain Age Assessments Are Limited in Predicting Future Brain Change. Human Brain Mapping. ISSN 1065-9471. 46(6), s. 1–12. doi: 10.1002/hbm.70203. Fulltekst i vitenarkiv Vis sammendrag

  The concept of brain age (BA) describes an integrative imaging marker of brain health, often suggested to reflect aging processes. However, the degree to which cross-sectional MRI features, including BA, reflect past, ongoing, and future brain changes across different tissue types from macro- to microstructure remains controversial. Here, we use multimodal imaging data of 39,325 UK Biobank participants, aged 44–82 years at baseline and 2,520 follow-ups within 1.12–6.90 years to examine BA changes and their relationship to anatomical brain changes. We find insufficient evidence to conclude that BA reflects the rate of brain aging. However, modality-specific differences in brain ages reflect the state of the brain, highlighting diffusion and multimodal MRI brain age as potentially useful cross-sectional markers.

• Tamnes, Christian Krog; Dahl, Andreas; Meer, Dennis van der; Agartz, Ingrid; Alnæs, Dag & Andreassen, Ole [Vis alle 13 forfattere av denne artikkelen] (2025). Relationships between wellbeing polygenic scores, brain structure, and psychopathology in children. Personality and Individual Differences. ISSN 0191-8869. 246. doi: 10.1016/j.paid.2025.113313. Fulltekst i vitenarkiv Vis sammendrag

  Wellbeing is shaped by an interplay of genetic and environmental factors and is associated with both health and functioning. It remains unclear whether genetic influences on wellbeing are linked to brain structure and, in turn, early-life psychopathology. Here, we investigated associations between wellbeing polygenic scores (PGS), magnetic resonance imaging (MRI)-derived measures of brain structure, and parent-reported measures of child psychopathology in a large cross-sectional sample of children from the Adolescent Brain Cognitive Development (ABCD) Study (n = 8844; 8.9–11.0 years old). Preregistered analyses revealed no significant associations between wellbeing PGS and regional cortical thickness or subcortical volumes and only a small negative association with surface area of the parahippocampal cortex (β = −0.03, p = .002), while an exploratory analysis identified a small positive association with intracranial volume (ICV; β = 0.04, p < .001). Preregistered analyses showed small negative associations between wellbeing PGS and general psychopathology (β = −0.09, p < .001) and both internalizing (β = −0.09, p < .001) and externalizing problems (β = −0.07, p < .001). ICV partially mediated the relationships between wellbeing PGS and psychopathology, accounting for 1.3–3.3 % of these relationships. The findings suggest that while wellbeing PGS have limited associations with regional brain structure in children, they exhibit small protective effects against psychopathology.

• Meer, Dennis van der; Rahman, Mohammad Zillur; Ottas, Aigar; Parekh, Pravesh; Kutrolli, Gleda & Stinson, Sara Elizabeth [Vis alle 37 forfattere av denne artikkelen] (2025). Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers. Nature Communications. 16(1). doi: 10.1038/s41467-025-60058-z. Fulltekst i vitenarkiv Vis sammendrag

  Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants. We investigated rare variation through whole exome sequencing gene burden tests, analysed the role of body mass index through Mendelian randomization, and performed genome-wide interaction analyses with sex. We discovered 15,585 loci summed over the univariate GWAS, with high pleiotropy across markers, linked to a wide range of disorders. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. 31 loci interacted with sex, mapped to genes involved in cholesterol processing. The findings offer insights into the genetic architecture of circulating metabolites, revealing pleiotropic loci, highlighting the role of rare variation, and uncovering sex-specific molecular mechanisms of lipid metabolism.

• Roelfs, Daniel; Meer, Dennis van der; Alnæs, Dag; Frei, Oleksandr; Shadrin, Alexey & Loughnan, Robert [Vis alle 11 forfattere av denne artikkelen] (2024). Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders. Nature Mental Health. 2(2), s. 189–199. doi: 10.1038/s44220-023-00190-1. Fulltekst i vitenarkiv
• Gurholt, Tiril Pedersen; Borda, Miguel Germán; Parker, Nadine; Fominykh, Vera; Kjelkenes, Rikka & Linge, Jennifer [Vis alle 12 forfattere av denne artikkelen] (2024). Linking sarcopenia, brain structure and cognitive performance: a large-scale UK Biobank study. Brain Communications. 6(2). doi: 10.1093/braincomms/fcae083. Fulltekst i vitenarkiv Vis sammendrag

  Sarcopenia refers to age-related loss of muscle mass and function and is related to impaired somatic and brain health, including cognitive decline and Alzheimer’s disease. However, the relationships between sarcopenia, brain structure and cognition are poorly understood. Here, we investigate the associations between sarcopenic traits, brain structure and cognitive performance. We included 33 709 UK Biobank participants (54.2% female; age range 44–82 years) with structural and diffusion magnetic resonance imaging, thigh muscle fat infiltration (n = 30 561) from whole-body magnetic resonance imaging (muscle quality indicator) and general cognitive performance as indicated by the first principal component of a principal component analysis across multiple cognitive tests (n = 22 530). Of these, 1703 participants qualified for probable sarcopenia based on low handgrip strength, and we assigned the remaining 32 006 participants to the non-sarcopenia group. We used multiple linear regression to test how sarcopenic traits (probable sarcopenia versus non-sarcopenia and percentage of thigh muscle fat infiltration) relate to cognitive performance and brain structure (cortical thickness and area, white matter fractional anisotropy and deep and lower brain volumes). Next, we used structural equation modelling to test whether brain structure mediated the association between sarcopenic and cognitive traits. We adjusted all statistical analyses for confounders. We show that sarcopenic traits (probable sarcopenia versus non-sarcopenia and muscle fat infiltration) are significantly associated with lower cognitive performance and various brain magnetic resonance imaging measures. In probable sarcopenia, for the included brain regions, we observed widespread significant lower white matter fractional anisotropy (77.1% of tracts), predominantly lower regional brain volumes (61.3% of volumes) and thinner cortical thickness (37.9% of parcellations), with |r| effect sizes in (0.02, 0.06) and P-values in (0.0002, 4.2e−29). In contrast, we observed significant associations between higher muscle fat infiltration and widespread thinner cortical thickness (76.5% of parcellations), lower white matter fractional anisotropy (62.5% of tracts) and predominantly lower brain volumes (35.5% of volumes), with |r| effect sizes in (0.02, 0.07) and P-values in (0.0002, 1.9e−31). The regions showing the most significant effect sizes across the cortex, white matter and volumes were of the sensorimotor system. Structural equation modelling analysis revealed that sensorimotor brain regions mediate the link between sarcopenic and cognitive traits [probable sarcopenia: P-values in (0.0001, 1.0e−11); muscle fat infiltration: P-values in (7.7e−05, 1.7e−12)]. Our findings show significant associations between sarcopenic traits, brain structure and cognitive performance in a middle-aged and older adult population. Mediation analyses suggest that regional brain structure mediates the association between sarcopenic and cognitive traits, with potential implications for dementia development and prevention.

• Beck, Dani; Lange, Ann-Marie Glasø de; Gurholt, Tiril Pedersen; Voldsbekk, Irene; Maximov, Ivan & Subramaniapillai, Sivaniya [Vis alle 19 forfattere av denne artikkelen] (2024). Dissecting unique and common variance across body and brain health indicators using age prediction. Human Brain Mapping. ISSN 1065-9471. 45(6). doi: 10.1002/hbm.26685. Fulltekst i vitenarkiv Vis sammendrag

  Ageing is a heterogeneous multisystem process involving different rates of decline in physiological integrity across biological systems. The current study dissects the unique and common variance across body and brain health indicators and parses inter-individual heterogeneity in the multisystem ageing process. Using machine-learning regression models on the UK Biobank data set (N = 32,593, age range 44.6–82.3, mean age 64.1 years), we first estimated tissue-specific brain age for white and gray matter based on diffusion and T1-weighted magnetic resonance imaging (MRI) data, respectively. Next, bodily health traits, including cardiometabolic, anthropometric, and body composition measures of adipose and muscle tissue from bioimpedance and body MRI, were combined to predict ‘body age’. The results showed that the body age model demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. The correlation between body age and brain age predictions was 0.62 for the T1 and 0.64 for the diffusion-based model, indicating a degree of unique variance in brain and bodily ageing processes. Bayesian multilevel modelling carried out to quantify the associations between health traits and predicted age discrepancies showed that higher systolic blood pressure and higher muscle-fat infiltration were related to older-appearing body age compared to brain age. Conversely, higher hand-grip strength and muscle volume were related to a younger-appearing body age. Our findings corroborate the common notion of a close connection between somatic and brain health. However, they also suggest that health traits may differentially influence age predictions beyond what is captured by the brain imaging data, potentially contributing to heterogeneous ageing rates across biological systems and individuals.

• Sartorius, Alina Marie; Rokicki, Jaroslav; Birkeland, Siri; Bettella, Francesco; Barth, Claudia & Lange, Ann-Marie Glasø de [Vis alle 17 forfattere av denne artikkelen] (2024). An evolutionary timeline of the oxytocin signaling pathway. Communications Biology. 7(1). doi: 10.1038/s42003-024-06094-9. Fulltekst i vitenarkiv Vis sammendrag

  Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are ‘modern’. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, ‘mya’), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are ‘ancient’, meaning their emergence dates back to cellular organisms and opisthokonta (3500–1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as ‘medium-aged’. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

• Knol, Maria J.; Poot, Raymond A.; Evans, Tavia E.; Satizabal, Claudia L.; Mishra, Aniket & Sargurupremraj, Muralidharan [Vis alle 304 forfattere av denne artikkelen] (2024). Genetic variants for head size share genes and pathways with cancer. Cell Reports Medicine. 5(5). doi: 10.1016/j.xcrm.2024.101529. Fulltekst i vitenarkiv
• Korbmacher, Max; Meer, Dennis van der; Beck, Dani; Askeland-Gjerde, Daniel E.; Eikefjord, Eli Nina Hølleland & Lundervold, Arvid [Vis alle 9 forfattere av denne artikkelen] (2024). Distinct Longitudinal Brain White Matter Microstructure Changes and Associated Polygenic Risk of Common Psychiatric Disorders and Alzheimer's Disease in the UK Biobank. Biological Psychiatry: Global Open Science. 4(4). doi: 10.1016/j.bpsgos.2024.100323. Fulltekst i vitenarkiv Vis sammendrag

  Background: During the course of adulthood and aging, white matter (WM) structure and organization are characterized by slow degradation processes such as demyelination and shrinkage. An acceleration of such aging processes has been linked to the development of a range of diseases. Thus, an accurate description of healthy brain maturation, particularly in terms of WM features, is fundamental to the understanding of aging. Methods: We used longitudinal diffusion magnetic resonance imaging to provide an overview of WM changes at different spatial and temporal scales in the UK Biobank (UKB) (n = 2678; agescan 1 = 62.38 ± 7.23 years; agescan 2 = 64.81 ± 7.1 years). To examine the genetic overlap between WM structure and common clinical conditions, we tested the associations between WM structure and polygenic risk scores for the most common neurodegenerative disorder, Alzheimer’s disease, and common psychiatric disorders (unipolar and bipolar depression, anxiety, obsessive-compulsive disorder, autism, schizophrenia, attention-deficit/hyperactivity disorder) in longitudinal (n = 2329) and cross-sectional (n = 31,056) UKB validation data. Results: Our findings indicate spatially distributed WM changes across the brain, as well as distributed associations of polygenic risk scores with WM. Importantly, brain longitudinal changes reflected genetic risk for disorder development better than the utilized cross-sectional measures, with regional differences giving more specific insights into gene-brain change associations than global averages. Conclusions: We extend recent findings by providing a detailed overview of WM microstructure degeneration on different spatial levels, helping to understand fundamental brain aging processes. Further longitudinal research is warranted to examine aging-related gene-brain associations.

• Tissink, E.P.; Shadrin, Alexey; Meer, Dennis van der; Parker, Nadine; Hindley, Guy & Roelfs, Daniel [Vis alle 18 forfattere av denne artikkelen] (2024). Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study. Nature Communications. 15. doi: 10.1038/s41467-024-46817-4. Fulltekst i vitenarkiv Vis sammendrag

  Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N = 34,029) and ABCD Study (N = 8607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI in a genome-wide association study (GWAS) with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition.

• Karadag, Naz; Hagen, Espen; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Rahman, Mohammad Zillur [Vis alle 18 forfattere av denne artikkelen] (2024). Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology. Neurology: Genetics. 10(3). doi: 10.1212/NXG.0000000000200143. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives: Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences. Methods: We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples. Results: The epilepsies (2.4 k–2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples. Discussion: Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.

• Tesfaye, Markos; Jaholkowski, Piotr Pawel; Shadrin, Alexey; Meer, Dennis van der; Hindley, Guy & Holen, Børge [Vis alle 18 forfattere av denne artikkelen] (2024). Identification of novel genomic loci for anxiety symptoms and extensive genetic overlap with psychiatric disorders. Psychiatry and Clinical Neurosciences. ISSN 1323-1316. 78(12), s. 783–791. doi: 10.1111/pcn.13742. Fulltekst i vitenarkiv Vis sammendrag

  Aims: Anxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders. Methods: We included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders. Results: Anxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k–11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD (n=47), BIP (n=33), SCZ (n=71), ADHD (n=20), and ASD (n=5). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci. Conclusions: Anxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

• Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey; Meer, Dennis van der; Akdeniz, Bayram Cevdet & Hagen, Espen [Vis alle 50 forfattere av denne artikkelen] (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature Genetics. ISSN 1061-4036. 56(6), s. 1310–1318. doi: 10.1038/s41588-024-01771-1. Fulltekst i vitenarkiv
• García-Marín, Luis M.; Campos, Adrian I.; Diaz-Torres, Santiago; Rabinowitz, Jill A.; Ceja, Zuriel & Mitchell, Brittany L. [Vis alle 190 forfattere av denne artikkelen] (2024). Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries. Nature Genetics. ISSN 1061-4036. 56(11), s. 2333–2344. doi: 10.1038/s41588-024-01951-z. Fulltekst i vitenarkiv
• Karadag, Naz; Hagen, Espen; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Rahman, Mohammad Zillur [Vis alle 19 forfattere av denne artikkelen] (2024). Unraveling the shared genetics of common epilepsies and general cognitive ability. Seizure. ISSN 1059-1311. 122, s. 105–112. doi: 10.1016/j.seizure.2024.09.016. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Cognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown. Methods We investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes ‘all epilepsy’, focal epilepsies and genetic generalized epilepsies (GGE), as well as specific subtypes. We functionally annotated the identified loci using several biological resources and validated the results in independent samples. Results Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ‘all epilepsy’, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k – 2.9k variants). The other epilepsy phenotypes were insufficiently powered for MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ‘all epilepsy’, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ‘all epilepsy’ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 3.62 × 10–7; ‘all epilepsy’: p = 2.58 × 10–3). Conclusion Our study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

• Korbmacher, Max; Meer, Dennis van der; Beck, Dani; Lange, Ann-Marie Glasø de; Eikefjord, Eli Nina Hølleland & Lundervold, Arvid [Vis alle 9 forfattere av denne artikkelen] (2024). Brain asymmetries from mid- to late life and hemispheric brain age. Nature Communications. 15. doi: 10.1038/s41467-024-45282-3. Fulltekst i vitenarkiv Vis sammendrag

  The human brain demonstrates structural and functional asymmetries which have implications for ageing and mental and neurological disease development. We used a set of magnetic resonance imaging (MRI) metrics derived from structural and diffusion MRI data in N=48,040 UK Biobank participants to evaluate age-related differences in brain asymmetry. Most regional grey and white matter metrics presented asymmetry, which were higher later in life. Informed by these results, we conducted hemispheric brain age (HBA) predictions from left/right multimodal MRI metrics. HBA was concordant to conventional brain age predictions, using metrics from both hemispheres, but offers a supplemental general marker of brain asymmetry when setting left/right HBA into relationship with each other. In contrast to WM brain asymmetries, left/right discrepancies in HBA are lower at higher ages. Our findings outline various sex-specific differences, particularly important for brain age estimates, and the value of further investigating the role of brain asymmetries in brain ageing and disease development.

• Goldblatt, Ran; Holz, Nathalie; Tate, Garrett W.; Sherman, Kari; Ghebremicael, Selamawit & Bhuyan, Soumitra S. [Vis alle 95 forfattere av denne artikkelen] (2024). Linking neuroimaging and mental health data from the ABCD Study to UrbanSat measurements of macro environmental factors. Nature Mental Health. 2(11), s. 1285–1297. doi: 10.1038/s44220-024-00318-x. Fulltekst i vitenarkiv
• Gurholt, Tiril Pedersen; Elvsåshagen, Torbjørn; Bahrami, Shahram; Rahman, Mohammad Zillur; Shadrin, Alexey & Askeland-Gjerde, Daniel E. [Vis alle 13 forfattere av denne artikkelen] (2024). Large-scale brainstem neuroimaging and genetic analyses provide new insights into the neuronal mechanisms of hypertension. Human Genetics and Genomics Advances (HGG Advances). 6(1). doi: 10.1016/j.xhgg.2024.100392. Fulltekst i vitenarkiv Vis sammendrag

  While brainstem regions are central regulators of blood pressure, the neuronal mechanisms underlying their role in hypertension remain poorly understood. Here, we investigated the structural and genetic relationships between global and regional brainstem volumes and blood pressure. We used magnetic resonance imaging data from n = 32,666 UK Biobank participants, and assessed the association of volumes of the whole brainstem and its main regions with blood pressure. We applied powerful statistical genetic tools, including bivariate causal mixture modeling (MiXeR) and conjunctional false discovery rate (conjFDR), to non-overlapping genome-wide association studies of brainstem volumes (n = 27,034) and blood pressure (n = 321,843) in the UK Biobank cohort. We observed negative associations between the whole brainstem and medulla oblongata volumes and systolic blood and pulse pressure, and positive relationships between midbrain and pons volumes and blood pressure traits when adjusting for the whole brainstem volume (all partial correlation coefficients ∣r∣ effects between 0.03 and 0.05, p ≤ 0.0042). We observed the largest genetic overlap for the whole brainstem, sharing 77% of its trait-influencing variants with blood pressure. We identified 65 shared loci between brainstem volumes and blood pressure traits and mapped these to 71 genes, implicating molecular pathways linked to sympathetic nervous system development, metal ion transport, and vascular homeostasis. The present findings support a link between brainstem structures and blood pressure and provide insights into their shared genetic underpinnings. The overlapping genetic architectures and mapped genes offer mechanistic information about the roles of brainstem regions in hypertension.

• Wootton, Olivia; Shadrin, Alexey; Bjella, Thomas; Smeland, Olav Bjerkehagen; Meer, Dennis van der & Frei, Oleksandr [Vis alle 11 forfattere av denne artikkelen] (2024). Genomic insights into the shared and distinct genetic architecture of cognitive function and schizophrenia. Scientific Reports. 14(1). doi: 10.1038/s41598-024-66085-y. Fulltekst i vitenarkiv Vis sammendrag

  Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.

• Korbmacher, Max; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Beck, Dani; Eikefjord, Eli Nina & Lundervold, Arvid [Vis alle 9 forfattere av denne artikkelen] (2023). Brain‐wide associations between white matter and age highlight the role of fornix microstructure in brain ageing. Human Brain Mapping. ISSN 1065-9471. 44, s. 4101–4119. doi: 10.1002/hbm.26333. Fulltekst i vitenarkiv Vis sammendrag

  Unveiling the details of white matter (WM) maturation throughout ageing is a fundamental question for understanding the ageing brain. In an extensive comparison of brain age predictions and age-associations of WM features from different diffusion approaches, we analyzed UK Biobank diffusion magnetic resonance imaging (dMRI) data across midlife and older age (N = 35,749, 44.6–82.8 years of age). Conventional and advanced dMRI approaches were consistent in predicting brain age. WM-age associations indicate a steady microstructure degeneration with increasing age from midlife to older ages. Brain age was estimated best when combining diffusion approaches, showing different aspects of WM contributing to brain age. Fornix was found as the central region for brain age predictions across diffusion approaches in complement to forceps minor as another important region. These regions exhibited a general pattern of positive associations with age for intra axonal water fractions, axial, radial diffusivities, and negative relationships with age for mean diffusivities, fractional anisotropy, kurtosis. We encourage the application of multiple dMRI approaches for detailed insights into WM, and the further investigation of fornix and forceps as potential biomarkers of brain age and ageing.

• Xu, Jiayuan; Liu, Nana; Polemiti, Elli; Garcia-Mondragon, Liliana; Tang, Jie & Liu, Xiaoxuan [Vis alle 88 forfattere av denne artikkelen] (2023). Effects of urban living environments on mental health in adults. Nature Medicine. ISSN 1078-8956. 29, s. 1456–1467. doi: 10.1038/s41591-023-02365-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Urban-living individuals are exposed to many environmental factors that may combine and interact to influence mental health. While individual factors of an urban environment have been investigated in isolation, no attempt has been made to model how complex, real-life exposure to living in the city relates to brain and mental health, and how this is moderated by genetic factors. Using the data of 156,075 participants from the UK Biobank, we carried out sparse canonical correlation analyses to investigate the relationships between urban environments and psychiatric symptoms. We found an environmental profile of social deprivation, air pollution, street network and urban land-use density that was positively correlated with an affective symptom group ( r  = 0.22, P perm  &lt; 0.001), mediated by brain volume differences consistent with reward processing, and moderated by genes enriched for stress response, including CRHR1 , explaining 2.01% of the variance in brain volume differences. Protective factors such as greenness and generous destination accessibility were negatively correlated with an anxiety symptom group ( r  = 0.10, P perm  &lt; 0.001), mediated by brain regions necessary for emotion regulation and moderated by EXD3 , explaining 1.65% of the variance. The third urban environmental profile was correlated with an emotional instability symptom group ( r  = 0.03, P perm  &lt; 0.001). Our findings suggest that different environmental profiles of urban living may influence specific psychiatric symptom groups through distinct neurobiological pathways.

• Campbell, Megan L.; Dalvie, Shareefa; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Frei, Oleksandr [Vis alle 9 forfattere av denne artikkelen] (2023). Distributed Genetic Effects of the Corpus Callosum Subregions Suggest Links to Neuropsychiatric Disorders and Related Traits. Acta Neuropsychiatrica. ISSN 0924-2708. doi: 10.1017/neu.2023.32. Fulltekst i vitenarkiv Vis sammendrag

  Background: The corpus callosum (CC) is a brain structure with a high heritability and potential role in psychiatric disorders. However, the genetic architecture of the CC and the genetic link with psychiatric disorders remain largely unclear. We investigated the genetic architectures of the volume of the CC and its subregions and the genetic overlap with psychiatric disorders. Methods: We applied multivariate genome-wide association study (GWAS) to genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank, aiming to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) obtained by FreeSurfer 7.1. Multivariate GWAS was run combining all subregions, co-varying for relevant variables. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression (LDSC) was used to determine Single nucleotide polymorphism (SNP)-based heritability of total CC volume and volumes of its subregions as well as their genetic correlations with relevant psychiatric traits. Results: We identified 70 independent loci with distributed effects across the five subregions of the CC (p < 5 × 10−8). Additionally, we identified 33 significant loci in the anterior subregion, 23 in the mid-anterior, 29 in the central, 7 in the mid-posterior and 56 in the posterior subregion. Gene-set analysis revealed 156 significant genes contributing to volume of the CC subregions (p < 2.6 × 10−6). LDSC estimated the heritability of CC to (h2SNP = 0.38, SE = 0.03) and subregions ranging from 0.22 (SE = 0.02) to 0.37 (SE = 0.03). We found significant genetic correlations of total CC volume with bipolar disorder (BD, rg = −0.09, SE = 0.03; p = 5.9 × 10−3) and drinks consumed per week (rg = −0.09, SE = 0.02; p = 4.8 × 10−4), and volume of the mid-anterior subregion with BD (rg = −0.12, SE = 0.02; p = 2.5 × 10−4), major depressive disorder (MDD) (rg = −0.12, SE = 0.04; p = 3.6 × 10−3), drinks consumed per week (rg = −0.13, SE = 0.04; p = 1.8 × 10−3) and cannabis use (rg = −0.09, SE = 0.03; p = 8.4 × 10−3). Conclusions: Our results demonstrate that the CC has a polygenic architecture implicating multiple genes and show that CC subregion volumes are heritable. We found that distinct genetic factors are involved in the development of anterior and posterior subregions, consistent with their divergent functional specialisation. Significant genetic correlation between volumes of the CC and BD, drinks per week, MDD and cannabis consumption subregion volumes with psychiatric traits is noteworthy and deserving of further investigation.

• Bøen, Rune; Kaufmann, Tobias Herbert; Meer, Dennis van der; Frei, Oleksandr; Agartz, Ingrid & Ames, David [Vis alle 53 forfattere av denne artikkelen] (2023). Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers. Biological Psychiatry. ISSN 0006-3223. 95(2), s. 147–160. doi: 10.1016/j.biopsych.2023.08.018. Fulltekst i vitenarkiv Vis sammendrag

  Background Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

• Meer, Dennis van der; Cheng, Weiqiu; Rokicki, Jaroslav; Fernandez-Cabello, Sara; Shadrin, Alexey & Smeland, Olav Bjerkehagen [Vis alle 19 forfattere av denne artikkelen] (2023). Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation. Schizophrenia Bulletin. ISSN 0586-7614. 50(2), s. 327–338. doi: 10.1093/schbul/sbad140. Fulltekst i vitenarkiv Vis sammendrag

  Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.

• Mufford, Mary S.; Meer, Dennis van der; Kaufmann, Tobias Herbert; Frei, Oleksandr; Ramesar, Raj & Thompson, Paul M. [Vis alle 11 forfattere av denne artikkelen] (2023). The Genetic Architecture of Amygdala Nuclei. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2023.06.022. Fulltekst i vitenarkiv Vis sammendrag

  Background Whereas genetic variants influencing total amygdala volume have been identified, the genetic architecture of its distinct nuclei has yet to be explored. We aimed to investigate whether increased phenotypic specificity through nuclei segmentation aids genetic discoverability and elucidates the extent of shared genetic architecture and biological pathways with related disorders. Methods T1-weighted brain magnetic resonance imaging scans (N = 36,352, 52% female) from the UK Biobank were segmented into 9 amygdala nuclei with FreeSurfer (version 6.1). Genome-wide association analyses were performed on the entire sample, a European-only subset (n = 31,690), and a generalization (transancestry) subset (n = 4662). We estimated single nucleotide polymorphism–based heritability; derived polygenicity, discoverability, and power estimates; and investigated genetic correlations and shared loci with psychiatric disorders. Results The heritability of the nuclei ranged from 0.17 to 0.33. Across the whole amygdala and the nuclei volumes, we identified 28 novel genome-wide significant (padj < 5 × 10−9) loci in the European analysis, with significant en masse replication for the whole amygdala and central nucleus volumes in the generalization analysis, and we identified 10 additional candidate loci in the combined analysis. The central nucleus had the highest statistical power for discovery. The significantly associated genes and pathways showed unique and shared effects across the nuclei, including immune-related pathways. Shared variants were identified between specific nuclei and autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, bipolar disorder, and schizophrenia. Conclusions Through investigation of amygdala nuclei volumes, we have identified novel candidate loci in the neurobiology of amygdala volume. These nuclei volumes have unique associations with biological pathways and genetic overlap with psychiatric disorders.

• Hindley, Guy Frederick Lanyon; Shadrin, Alexey; Meer, Dennis van der; Parker, Nadine; Cheng, Weiqiu & O'Connell, Kevin Sean [Vis alle 23 forfattere av denne artikkelen] (2023). Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy. Nature Human Behaviour. 7, s. 1584–1600. doi: 10.1038/s41562-023-01630-9. Fulltekst i vitenarkiv
• Makowski, Carolina; Wang, Hao; Srinivasan, Anjali; Qi, Anna; Qiu, Yuqi & Meer, Dennis van der [Vis alle 11 forfattere av denne artikkelen] (2023). Larger cerebral cortex is genetically correlated with greater frontal area and dorsal thickness. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(11). doi: 10.1073/pnas.2214834120. Fulltekst i vitenarkiv Vis sammendrag

  Human cortical expansion has occurred non-uniformly across the brain. We assessed the genetic architecture of cortical global expansion and regionalization by comparing two sets of genome-wide association studies of 24 cortical regions with and without adjustment for global measures (i.e., total surface area, mean cortical thickness) using a genetically informed parcellation in 32,488 adults. We found 393 and 756 significant loci with and without adjusting for globals, respectively, where 8% and 45% loci were associated with more than one region. Results from analyses without adjustment for globals recovered loci associated with global measures. Genetic factors that contribute to total surface area of the cortex particularly expand anterior/frontal regions, whereas those contributing to thicker cortex predominantly increase dorsal/frontal-parietal thickness. Interactome-based analyses revealed significant genetic overlap of global and dorsolateral prefrontal modules, enriched for neurodevelopmental and immune system pathways. Consideration of global measures is important in understanding the genetic variants underlying cortical morphology.

• Bøen, Rune; Kaufmann, Tobias; Frei, Oleksandr; Meer, Dennis van der; Djurovic, Srdjan & Andreassen, Ole [Vis alle 9 forfattere av denne artikkelen] (2023). No signs of neurodegenerative effects in 15q11.2 BP1-BP2 copy number variant carriers in the UK Biobank. Translational Psychiatry. 13:61, s. 1–6. doi: 10.1038/s41398-023-02358-w. Fulltekst i vitenarkiv Vis sammendrag

  The 15q11.2 BP1-BP2 copy number variant (CNV) is associated with altered brain morphology and risk for atypical development, including increased risk for schizophrenia and learning difficulties for the deletion. However, it is still unclear whether differences in brain morphology are associated with neurodevelopmental or neurodegenerative processes. This study derived morphological brain MRI measures in 15q11.2 BP1-BP2 deletion (n = 124) and duplication carriers (n = 142), and matched deletion-controls (n = 496) and duplication-controls (n = 568) from the UK Biobank study to investigate the association with brain morphology and estimates of brain ageing. Further, we examined the ageing trajectory of age-affected measures (i.e., cortical thickness, surface area, subcortical volume, reaction time, hand grip strength, lung function, and blood pressure) in 15q11.2 BP1-BP2 CNV carriers compared to non-carriers. In this ageing population, the results from the machine learning models showed that the estimated brain age gaps did not differ between the 15q11.2 BP1-BP2 CNV carriers and non-carriers, despite deletion carriers displaying thicker cortex and lower subcortical volume compared to the deletion-controls and duplication carriers, and lower surface area compared to the deletion-controls. Likewise, the 15q11.2 BP1-BP2 CNV carriers did not deviate from the ageing trajectory on any of the age-affected measures examined compared to non-carriers. Despite altered brain morphology in 15q11.2 BP1-BP2 CNV carriers, the results did not show any clear signs of apparent altered ageing in brain structure, nor in motor, lung or heart function. The results do not indicate neurodegenerative effects in 15q11.2 BP1-BP2 CNV carriers.

• Wang, Lu; Heffner, Caleb; Vong, Keng loi; Barrows, Chelsea; Ha, Yoo-Jin & Lee, Sangmoon [Vis alle 20 forfattere av denne artikkelen] (2023). TMEM161B modulates radial glial scaffolding in neocortical development. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(4). doi: 10.1073/pnas.2209983120. Fulltekst i vitenarkiv Vis sammendrag

  Significance Neocortical folding (i.e., gyrification) is a fundamental evolutionary mechanism allowing the expansion of cortical surface area and increased cognitive function. Increased gyrification has been correlated with intelligence across species but has been difficult to study molecularly in non-gyrated animal models. Here we identify a role for TMEM161B in human gyrification, establishing cellular polarity and structural integrity of radial glial fibers of the developing brain. Abstract TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

• Schumann, Gunter; Andreassen, Ole; Banaschewski, Tobias; Calhoun, Vince D.; Clinton, Nicholas & Desrivieres, Sylvane [Vis alle 30 forfattere av denne artikkelen] (2023). Addressing Global Environmental Challenges to Mental Health Using Population Neuroscience: A Review. JAMA psychiatry. ISSN 2168-6238. 80(10), s. 1066–1074. doi: 10.1001/jamapsychiatry.2023.2996. Fulltekst i vitenarkiv
• Lindseth, Linn Renate Sjøveian; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Agartz, Ingrid; Westlye, Lars Tjelta & Tamnes, Christian Krog [Vis alle 7 forfattere av denne artikkelen] (2023). Associations between reproductive history, hormone use, APOE ε4 genotype and cognition in middle- to older-aged women from the UK Biobank. Frontiers in Aging Neuroscience. 14:1014605, s. 1–13. doi: 10.3389/fnagi.2022.1014605. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Relative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimer’s disease. While women’s health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence women’s cognition later in life. Methods: We investigated the associations between reproductive history, exogenous hormone use, apolipoprotein (APOE) ε4 genotype and cognition in 221,124 middle- to older-aged (mean age 56.2 ± 8.0 years) women from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function. Results: A longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen’s d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition. Discussion: Our findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d = 0.1). More research targeting the long-term effects of female-specific factors on cognition and age-related neurocognitive disorders including Alzheimer’s disease is crucial for a better understanding of women’s brain health and to support women’s health care.

• Roelfs, Daniel; Frei, Oleksandr; Meer, Dennis van der; Tissink, Elleke; Shadrin, Alexey & Alnæs, Dag [Vis alle 9 forfattere av denne artikkelen] (2023). Shared genetic architecture between mental health and the brain functional connectome in the UK Biobank. BMC Psychiatry. 23(1). doi: 10.1186/s12888-023-04905-7. Fulltekst i vitenarkiv Vis sammendrag

  Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45–82 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population.

• Kjelkenes, Rikka; Wolfers, Thomas; Alnæs, Dag; Meer, Dennis van der; Pedersen, Mads Lund & Dahl, Andreas [Vis alle 12 forfattere av denne artikkelen] (2023). Mapping Normative Trajectories of Cognitive Function and Its Relation to Psychopathology Symptoms and Genetic Risk in Youth. Biological Psychiatry: Global Open Science. 3(2), s. 255–263. doi: 10.1016/j.bpsgos.2022.01.007. Fulltekst i vitenarkiv Vis sammendrag

  Background Adolescence hosts a sharp increase in the incidence of mental disorders. The prodromal phases are often characterized by cognitive deficits that predate disease onset by several years. Characterization of cognitive performance in relation to normative trajectories may have value for early risk assessment and monitoring. Methods Youth aged 8 to 21 years (N = 6481) from the Philadelphia Neurodevelopmental Cohort were included. Performance scores from a computerized neurocognitive battery were decomposed using principal component analysis, yielding a general cognitive score. Items reflecting various aspects of psychopathology from self-report questionnaires and collateral caregiver information were decomposed using independent component analysis, providing individual domain scores. Using normative modeling and Bayesian statistics, we estimated normative trajectories of cognitive function and tested for associations between cognitive deviance and psychopathological domain scores. In addition, we tested for associations with polygenic scores for mental and behavioral disorders often involving cognition, including schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, and Alzheimer’s disease. Results More negative normative cognitive deviations were associated with higher general psychopathology burden and domains reflecting positive and prodromal psychosis, attention problems, norm-violating behavior, and anxiety. In addition, better performance was associated with higher joint burden of depression, suicidal ideation, and negative psychosis symptoms. The analyses revealed no evidence for associations with polygenic scores. Conclusions Our results show that cognitive performance is associated with general and specific domains of psychopathology in youth. These findings support the close links between cognition and psychopathology in youth and highlight the potential of normative modeling for early risk assessment.

• Korbmacher, Max; Gurholt, Tiril Pedersen; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Beck, Dani & Eikefjord, Eli Nina [Vis alle 10 forfattere av denne artikkelen] (2023). Bio-psycho-social factors’ associations with brain age: a large-scale UK Biobank diffusion study of 35,749 participants. Frontiers in Psychology. 14. doi: 10.3389/fpsyg.2023.1117732. Fulltekst i vitenarkiv Vis sammendrag

  Kontrollert for godkjenning av Elise Davis-Keaveny

• Reas, Emilie T.; Shadrin, Alexey; Frei, Oleksandr; Motazedi, Ehsan; McEvoy, Linda & Bahrami, Shahram [Vis alle 22 forfattere av denne artikkelen] (2023). Improved multimodal prediction of progression from MCI to Alzheimer's disease combining genetics with quantitative brain MRI and cognitive measures. Alzheimer's & Dementia. ISSN 1552-5260. 19(11), s. 5151–5158. doi: 10.1002/alz.13112. Fulltekst i vitenarkiv Vis sammendrag

  Introduction There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD). Methods Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS. Results The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau. Discussion The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment.

• Meer, Dennis van der; Gurholt, Tiril Pedersen; Sønderby, Ida Elken; Shadrin, Alexey; Hindley, Guy Frederick Lanyon & Rahman, Zillur [Vis alle 18 forfattere av denne artikkelen] (2022). The link between liver fat and cardiometabolic diseases is highlighted by genome-wide association study of MRI-derived measures of body composition. Communications Biology. 5(1). doi: 10.1038/s42003-022-04237-4. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Obesity and associated morbidities, metabolic associated fatty liver disease (MAFLD) included, constitute some of the largest public health threats worldwide. Body composition and related risk factors are known to be heritable and identification of their genetic determinants may aid in the development of better prevention and treatment strategies. Recently, large-scale whole-body MRI data has become available, providing more specific measures of body composition than anthropometrics such as body mass index. Here, we aimed to elucidate the genetic architecture of body composition, by conducting genome-wide association studies (GWAS) of these MRI-derived measures. We ran both univariate and multivariate GWAS on fourteen MRI-derived measurements of adipose and muscle tissue distribution, derived from scans from 33,588 White European UK Biobank participants (mean age of 64.5 years, 51.4% female). Through multivariate analysis, we discovered 100 loci with distributed effects across the body composition measures and 241 significant genes primarily involved in immune system functioning. Liver fat stood out, with a highly discoverable and oligogenic architecture and the strongest genetic associations. Comparison with 21 common cardiometabolic traits revealed both shared and specific genetic influences, with higher mean heritability for the MRI measures (h 2  = .25 vs. .13, p  = 1.8x10 −7 ). We found substantial genetic correlations between the body composition measures and a range of cardiometabolic diseases, with the strongest correlation between liver fat and type 2 diabetes (r g  = .49, p  = 2.7x10 −22 ). These findings show that MRI-derived body composition measures complement conventional body anthropometrics and other biomarkers of cardiometabolic health, highlighting the central role of liver fat, and improving our knowledge of the genetic architecture of body composition and related diseases.

• Fan, Chun Chieh; Loughnan, Robert; Makowski, Carolina; Pecheva, Diliana; Chen, Chi-Hua & Hagler, Donald J. [Vis alle 12 forfattere av denne artikkelen] (2022). Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain. Nature Communications. 13(1). doi: 10.1038/s41467-022-30110-3. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.

• Nerland, Stener; Stokkan, Therese; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne; Richard, Geneviève & Beck, Dani [Vis alle 11 forfattere av denne artikkelen] (2022). A comparison of intracranial volume estimation methods and their cross-sectional and longitudinal associations with age. Human Brain Mapping. ISSN 1065-9471. doi: 10.1002/hbm.25978. Fulltekst i vitenarkiv Vis sammendrag

  Intracranial volume (ICV) is frequently used in volumetric magnetic resonance imaging (MRI) studies, both as a covariate and as a variable of interest. Findings of associations between ICV and age have varied, potentially due to differences in ICV estimation methods. Here, we compared five commonly used ICV estimation methods and their associations with age. T1-weighted cross-sectional MRI data was included for 651 healthy individuals recruited through the NORMENT Centre (mean age = 46.1 years, range = 12.0–85.8 years) and 2410 healthy individuals recruited through the UK Biobank study (UKB, mean age = 63.2 years, range = 47.0–80.3 years), where longitudinal data was also available. ICV was estimated with FreeSurfer (eTIV and sbTIV), SPM12, CAT12, and FSL. We found overall high correlations across ICV estimation method, with the lowest observed correlations between FSL and eTIV (r = .87) and between FSL and CAT12 (r = .89). Widespread proportional bias was found, indicating that the agreement between methods varied as a function of head size. Body weight, age, sex, and mean ICV across methods explained the most variance in the differences between ICV estimation methods, indicating possible confounding for some estimation methods. We found both positive and negative cross-sectional associations with age, depending on dataset and ICV estimation method. Longitudinal ICV reductions were found for all ICV estimation methods, with annual percentage change ranging from −0.293% to −0.416%. This convergence of longitudinal results across ICV estimation methods offers strong evidence for age-related ICV reductions in mid- to late adulthood.

• Bahrami, Shahram; Nordengen, Kaja; Shadrin, Alexey; Frei, Oleksandr; Meer, Dennis van der & Dale, Anders [Vis alle 9 forfattere av denne artikkelen] (2022). Distributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders. Nature Communications. 13(1). doi: 10.1038/s41467-022-31086-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Despite its major role in complex human functions across the lifespan, most notably navigation, learning and memory, much of the genetic architecture of the hippocampal formation is currently unexplored. Here, through multivariate genome-wide association analysis in volumetric data from 35,411 white British individuals, we reveal 177 unique genetic loci with distributed associations across the hippocampal formation. We identify genetic overlap with eight brain disorders with typical onset at different stages of life, where common genes suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.

• Snihirova, Yelyzaveta; Linden, David E. J.; Amelsvoort, Therese van & Meer, Dennis van der (2022). Environmental Influences on the Relation between the 22q11.2 Deletion Syndrome and Mental Health: A Literature Review. Genes. 13(11). doi: 10.3390/genes13112003. Fulltekst i vitenarkiv Vis sammendrag

  22q11.2 deletion syndrome (22q11DS) is a clinically heterogeneous genetic syndrome, associated with a wide array of neuropsychiatric symptoms. The clinical presentation is likely to be influenced by environmental factors, yet little is known about this. Here, we review the available research literature on the role of the environment in 22q11DS. We find that within-patient design studies have mainly investigated the role of parental factors, stress, and substance use, reporting significant effects of these factors on the clinical profile. Case-control studies have been less successful, with almost no reports of significant moderating effects of the environment. We go on to hypothesize which specific environmental measures are most likely to interact with the 22q11 deletion, based on the genes in this region and their involvement in molecular pathways. We end by discussing potential reasons for the limited findings so far, including modest sample sizes and limited availability of environmental measures, and make recommendations how to move forward.

• Norbom, Linn Christin Bonaventure; Hanson, Jamie; Meer, Dennis van der; Ferschmann, Lia; Røysamb, Espen & Soest, Tilmann von [Vis alle 10 forfattere av denne artikkelen] (2022). Parental socioeconomic status is linked to cortical microstructure and language abilities in children and adolescents. Developmental Cognitive Neuroscience. ISSN 1878-9293. 56. doi: 10.1016/j.dcn.2022.101132. Fulltekst i vitenarkiv Vis sammendrag

  Gradients in parental socioeconomic status (SES) are closely linked to important life outcomes in children and adolescents, such as cognitive abilities, school achievement, and mental health. Parental SES may also influence brain development, with several magnetic resonance imaging (MRI) studies reporting associations with youth brain morphometry. However, MRI signal intensity metrics have not been assessed, but could offer a microstructural correlate, thereby increasing our understanding of SES influences on neurobiology. We computed a parental SES score from family income, parental education and parental occupation, and assessed relations with cortical microstructure as measured by T1w/T2w ratio (n = 504, age = 3–21 years). We found negative age-stabile relations between parental SES and T1w/T2w ratio, indicating that youths from lower SES families have higher ratio in widespread frontal, temporal, medial parietal and occipital regions, possibly indicating a more developed cortex. Effect sizes were small, but larger than for conventional morphometric properties i.e. cortical surface area and thickness, which were not significantly associated with parental SES. Youths from lower SES families had poorer language related abilities, but microstructural differences did not mediate these relations. T1w/T2w ratio appears to be a sensitive imaging marker for further exploring the association between parental SES and child brain development.

• Fernandez-Cabello, Sara; Alnæs, Dag; Meer, Dennis van der; Dahl, Andreas; Holm, Madelene Christin & Kjelkenes, Rikka [Vis alle 12 forfattere av denne artikkelen] (2022). Associations between brain imaging and polygenic scores of mental health and educational attainment in children aged 9–11. NeuroImage. ISSN 1053-8119. 263. doi: 10.1016/j.neuroimage.2022.119611. Fulltekst i vitenarkiv Vis sammendrag

  Psychiatric disorders are highly heritable and polygenic, and many have their peak onset in late childhood and adolescence, a period of tremendous changes. Although the neurodevelopmental antecedents of mental illness are widely acknowledged, research in youth population cohorts is still scarce, preventing our progress towards the early characterization of these disorders. We included 7,124 children (9–11 years old) from the Adolescent Brain and Cognitive Development Study to map the associations of structural and diffusion brain imaging with common genetic variants and polygenic scores for psychiatric disorders and educational attainment. We used principal component analysis to derive imaging components, and calculated their heritability. We then assessed the relationship of imaging components with genetic and clinical psychiatric risk with univariate models and Canonical correlation analysis (CCA). Most imaging components had moderate heritability. Univariate models showed limited evidence and small associations of polygenic scores with brain structure at this age. CCA revealed two significant modes of covariation. The first mode linked higher polygenic scores for educational attainment with less externalizing problems and larger surface area. The second mode related higher polygenic scores for schizophrenia, bipolar disorder, and autism spectrum disorder to higher global cortical thickness, smaller white matter volumes of the fornix and cingulum, larger medial occipital surface area and smaller surface area of lateral and medial temporal regions. While cross-validation suggested limited generalizability, our results highlight the potential of multivariate models to better understand the transdiagnostic and distributed relationships between mental health and brain structure in late childhood.

• Loughnan, Robert J.; Shadrin, Alexey; Frei, Oleksandr; Meer, Dennis van der; Zhao, Weiqi & Palmer, Clare E. [Vis alle 12 forfattere av denne artikkelen] (2022). Generalization of cortical MOSTest genome-wide associations within and across samples. NeuroImage. ISSN 1053-8119. 263. doi: 10.1016/j.neuroimage.2022.119632. Fulltekst i vitenarkiv Vis sammendrag

  Genome-Wide Association studies have typically been limited to univariate analysis in which a single outcome measure is tested against millions of variants. Recent work demonstrates that a Multivariate Omnibus Statistic Test (MOSTest) is well powered to discover genomic effects distributed across multiple phenotypes. Applied to cortical brain MRI morphology measures, MOSTest has resulted in a drastic improvement in power to discover loci when compared to established approaches (min-P). One question that arises is how well these discovered loci replicate in independent data. Here we perform 10 times cross validation within 34,973 individuals from UK Biobank for imaging measures of cortical area, thickness and sulcal depth (>1,000 dimensionality for each). By deploying a replication method that aggregates discovered effects distributed across multiple phenotypes, termed PolyVertex Score (MOSTest-PVS), we demonstrate a higher replication yield and comparable replication rate of discovered loci for MOSTest (# replicated loci: 242–496, replication rate: 96–97%) in independent data when compared with the established min-P approach (# replicated loci: 26–55, replication rate: 91–93%). An out-of-sample replication of discovered loci was conducted with a sample of 4,069 individuals from the Adolescent Brain Cognitive Development® (ABCD) study, who are on average 50 years younger than UK Biobank individuals. We observe a higher replication yield and comparable replication rate of MOSTest-PVS compared to min-P. This finding underscores the importance of using well-powered multivariate techniques for both discovery and replication of high dimensional phenotypes in Genome-Wide Association studies.

• Meer, Dennis van der & Kaufmann, Tobias (2022). Mapping the genetic architecture of cortical morphology through neuroimaging: progress and perspectives. Translational Psychiatry. 12(1). doi: 10.1038/s41398-022-02193-5. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Cortical morphology is a key determinant of cognitive ability and mental health. Its development is a highly intricate process spanning decades, involving the coordinated, localized expression of thousands of genes. We are now beginning to unravel the genetic architecture of cortical morphology, thanks to the recent availability of large-scale neuroimaging and genomic data and the development of powerful biostatistical tools. Here, we review the progress made in this field, providing an overview of the lessons learned from genetic studies of cortical volume, thickness, surface area, and folding as captured by neuroimaging. It is now clear that morphology is shaped by thousands of genetic variants, with effects that are region- and time-dependent, thereby challenging conventional study approaches. The most recent genome-wide association studies have started discovering common genetic variants influencing cortical thickness and surface area, yet together these explain only a fraction of the high heritability of these measures. Further, the impact of rare variants and non-additive effects remains elusive. There are indications that the quickly increasing availability of data from whole-genome sequencing and large, deeply phenotyped population cohorts across the lifespan will enable us to uncover much of the missing heritability in the upcoming years. Novel approaches leveraging shared information across measures will accelerate this process by providing substantial increases in statistical power, together with more accurate mapping of genetic relationships. Important challenges remain, including better representation of understudied demographic groups, integration of other ‘omics data, and mapping of effects from gene to brain to behavior across the lifespan.

• Rokicki, Jaroslav; Kaufmann, Tobias; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Bahrami, Shahram & Sartorius, Alina [Vis alle 14 forfattere av denne artikkelen] (2022). Oxytocin receptor expression patterns in the human brain across development. Neuropsychopharmacology. ISSN 0893-133X. doi: 10.1038/s41386-022-01305-5. Fulltekst i vitenarkiv
• Motazedi, Ehsan; Cheng, Weiqiu; Thomassen, Jesper Qvist; Frei, Oleksandr; Rongve, Arvid & Athanasiu, Lavinia [Vis alle 30 forfattere av denne artikkelen] (2022). Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations. Journal of Alzheimer's Disease. ISSN 1387-2877. 88(4), s. 1533–1544. doi: 10.3233/JAD-220174. Fulltekst i vitenarkiv Vis sammendrag

  Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

• Cheng, Weiqiu; Meer, Dennis van der; Parker, Nadine; Hindley, Guy Frederick Lanyon; O'Connell, Kevin Sean & Wang, Yunpeng [Vis alle 20 forfattere av denne artikkelen] (2022). Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-022-01751-z. Fulltekst i vitenarkiv Vis sammendrag

  Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74–96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.

• Schindler, Louise S; Subramaniapillai, Sivaniya; Barth, Claudia; Meer, Dennis van der; Pedersen, Mads Lund & Kaufmann, Tobias [Vis alle 18 forfattere av denne artikkelen] (2022). Associations between abdominal adipose tissue, reproductive span, and brain characteristics in post-menopausal women. NeuroImage: Clinical. 36. doi: 10.1016/j.nicl.2022.103239. Fulltekst i vitenarkiv Vis sammendrag

  The menopause transition involves changes in oestrogens and adipose tissue distribution, which may influence female brain health post-menopause. Although increased central fat accumulation is linked to risk of cardiometabolic diseases, adipose tissue also serves as the primary biosynthesis site of oestrogens post-menopause. It is unclear whether different types of adipose tissue play diverging roles in female brain health post-menopause, and whether this depends on lifetime oestrogen exposure, which can have lasting effects on the brain and body even after menopause. Using the UK Biobank sample, we investigated associations between brain characteristics and visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) in 10,251 post-menopausal females, and assessed whether the relationships varied depending on length of reproductive span (age at menarche to age at menopause). To parse the effects of common genetic variation, we computed polygenic scores for reproductive span. The results showed that higher VAT and ASAT were both associated with higher grey and white matter brain age, and greater white matter hyperintensity load. The associations varied positively with reproductive span, indicating more prominent associations between adipose tissue and brain measures in females with a longer reproductive span. The effects were in general small, but could not be fully explained by genetic variation or relevant confounders. Our findings indicate that associations between abdominal adipose tissue and brain health post-menopause may partly depend on individual differences in cumulative oestrogen exposure during reproductive years, emphasising the complexity of neural and endocrine ageing processes in females.

• Frangou, Sophia; Modabbernia, Amirhossein; Williams, Steven C. R.; Papachristou, Efstathios; Doucet, Gaëlle E. & Agartz, Ingrid [Vis alle 63 forfattere av denne artikkelen] (2022). Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years. Human Brain Mapping. ISSN 1065-9471. 43(1), s. 431–451. doi: 10.1002/hbm.25364. Fulltekst i vitenarkiv Vis sammendrag

  Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

• Makowski, Carolina; Meer, Dennis van der; Dong, Weixiu; Wang, Hao; Wu, Yan & Zou, Jingjing [Vis alle 18 forfattere av denne artikkelen] (2022). Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases. Science. ISSN 0036-8075. 375(6580). doi: 10.1126/science.abe8457. Fulltekst i vitenarkiv
• Meer, Dennis van der; Shadrin, Alexey; O'Connell, Kevin Sean; Bettella, Francesco; Djurovic, Srdjan & Wolfers, Thomas [Vis alle 17 forfattere av denne artikkelen] (2022). Boosting Schizophrenia Genetics by Utilizing Genetic Overlap With Brain Morphology. Biological Psychiatry. ISSN 0006-3223. 92(4), s. 291–298. doi: 10.1016/j.biopsych.2021.12.007. Fulltekst i vitenarkiv Vis sammendrag

  Background Schizophrenia is a complex polygenic disorder with subtle, distributed abnormalities in brain morphology. There are indications of shared genetic architecture between schizophrenia and brain measures despite low genetic correlations. Through the use of analytical methods that allow for mixed directions of effects, this overlap may be leveraged to improve our understanding of underlying mechanisms of schizophrenia and enrich polygenic risk prediction outcome. Methods We ran a multivariate genome-wide analysis of 175 brain morphology measures using data from 33,735 participants of the UK Biobank and analyzed the results in a conditional false discovery rate together with schizophrenia genome-wide association study summary statistics of the Psychiatric Genomics Consortium (PGC) Wave 3. We subsequently created a pleiotropy-enriched polygenic score based on the loci identified through the conditional false discovery rate approach and used this to predict schizophrenia in a nonoverlapping sample of 743 individuals with schizophrenia and 1074 healthy controls. Results We found that 20% of the loci and 50% of the genes significantly associated with schizophrenia were also associated with brain morphology. The conditional false discovery rate analysis identified 428 loci, including 267 novel loci, significantly associated with brain-linked schizophrenia risk, with functional annotation indicating high relevance for brain tissue. The pleiotropy-enriched polygenic score explained more variance in liability than conventional polygenic scores across several scenarios. Conclusions Our results indicate strong genetic overlap between schizophrenia and brain morphology with mixed directions of effect. The results also illustrate the potential of exploiting polygenetic overlap between brain morphology and mental disorders to boost discovery of brain tissue–specific genetic variants and its use in polygenic risk frameworks.

• Subramaniapillai, Sivaniya; Suri, Sana; Barth, Claudia; Maximov, Ivan; Voldsbekk, Irene & Meer, Dennis van der [Vis alle 13 forfattere av denne artikkelen] (2022). Sex- and age-specific associations between cardiometabolic risk and white matter brain age in the UK Biobank cohort. Human Brain Mapping. ISSN 1065-9471. 43(12), s. 3759–3774. doi: 10.1002/hbm.25882. Fulltekst i vitenarkiv Vis sammendrag

  Cardiometabolic risk (CMR) factors are associated with accelerated brain aging and increased risk for sex-dimorphic illnesses such as Alzheimer's disease (AD). Yet, it is unknown how CMRs interact with sex and apolipoprotein E-ϵ4 (APOE4), a known genetic risk factor for AD, to influence brain age across different life stages. Using age prediction based on multi-shell diffusion-weighted imaging data in 21,308 UK Biobank participants, we investigated whether associations between white matter Brain Age Gap (BAG) and body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage (BF%), and APOE4 status varied (i) between males and females, (ii) according to age at menopause in females, and (iii) across different age groups in males and females. We report sex differences in associations between BAG and all three CMRs, with stronger positive associations among males compared to females. Independent of APOE4 status, higher BAG (older brain age relative to chronological age) was associated with greater BMI, WHR, and BF% in males, whereas in females, higher BAG was associated with greater WHR, but not BMI and BF%. These divergent associations were most prominent within the oldest group of females (66–81 years), where greater BF% was linked to lower BAG. Earlier menopause transition was associated with higher BAG, but no interactions were found with CMRs. In conclusion, the findings point to sex- and age-specific associations between CMRs and brain age. Incorporating sex as a factor of interest in studies addressing CMR may promote sex-specific precision medicine, consequently improving health care for both males and females.

• Brouwer, Rachel M.; Klein, Marieke; Grasby, Katrina L.; Schnack, Hugo G.; Jahanshad, Neda & Teeuw, Jalmar [Vis alle 200 forfattere av denne artikkelen] (2022). Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nature Neuroscience. ISSN 1097-6256. 25(4), s. 421–432. doi: 10.1038/s41593-022-01042-4. Fulltekst i vitenarkiv
• Pedersen, Mads Lund; Alnæs, Dag; Meer, Dennis van der; Fernandez-Cabello, Sara; Berthet, Pierre Guillaume Raphael & Dahl, Andreas [Vis alle 12 forfattere av denne artikkelen] (2022). Computational Modeling of the n-Back Task in the ABCD Study: Associations of Drift Diffusion Model Parameters to Polygenic Scores of Mental Disorders and Cardiometabolic Diseases. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. doi: 10.1016/j.bpsc.2022.03.012. Fulltekst i vitenarkiv Vis sammendrag

  Background Cognitive dysfunction is common in mental disorders and represents a potential risk factor in childhood. The nature and extent of associations between childhood cognitive function and polygenic risk for mental disorders is unclear. We applied computational modeling to gain insight into mechanistic processes underlying decision making and working memory in childhood and their associations with polygenic risk scores (PRSs) for mental disorders and comorbid cardiometabolic diseases. Methods We used the drift diffusion model to infer latent computational processes underlying decision making and working memory during the n-back task in 3707 children ages 9 to 10 years from the Adolescent Brain Cognitive Development (ABCD) Study. Single nucleotide polymorphism–based heritability was estimated for cognitive phenotypes, including computational parameters, aggregated n-back task performance, and neurocognitive assessments. PRSs were calculated for Alzheimer’s disease, bipolar disorder, coronary artery disease (CAD), major depressive disorder, obsessive-compulsive disorder, schizophrenia, and type 2 diabetes. Results Heritability estimates of cognitive phenotypes ranged from 12% to 38%. Bayesian mixed models revealed that slower accumulation of evidence was associated with higher PRSs for CAD and schizophrenia. Longer nondecision time was associated with higher PRSs for Alzheimer’s disease and lower PRSs for CAD. Narrower decision threshold was associated with higher PRSs for CAD. Load-dependent effects on nondecision time and decision threshold were associated with PRSs for Alzheimer’s disease and CAD, respectively. Aggregated neurocognitive test scores were not associated with PRSs for any of the mental or cardiometabolic phenotypes. Conclusions We identified distinct associations between computational cognitive processes and genetic risk for mental illness and cardiometabolic disease, which could represent childhood cognitive risk factors.

• Roelfs, Daniel; Alnæs, Dag; Frei, Oleksandr; Meer, Dennis van der; Smeland, Olav Bjerkehagen & Andreassen, Ole Andreas [Vis alle 8 forfattere av denne artikkelen] (2021). Phenotypically independent profiles relevant to mental health are genetically correlated. Translational Psychiatry. 11(1). doi: 10.1038/s41398-021-01313-x. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide association studies (GWAS) and family-based studies have revealed partly overlapping genetic architectures between various psychiatric disorders. Given clinical overlap between disorders, our knowledge of the genetic architectures underlying specific symptom profiles and risk factors is limited. Here, we aimed to derive distinct profiles relevant to mental health in healthy individuals and to study how these genetically relate to each other and to common psychiatric disorders. Using independent component analysis, we decomposed self-report mental health questionnaires from 136,678 healthy individuals of the UK Biobank, excluding data from individuals with a diagnosed neurological or psychiatric disorder, into 13 distinct profiles relevant to mental health, capturing different symptoms as well as social and risk factors underlying reduced mental health. Utilizing genotypes from 117,611 of those individuals with White British ancestry, we performed GWAS for each mental health profile and assessed genetic correlations between these profiles, and between the profiles and common psychiatric disorders and cognitive traits. We found that mental health profiles were genetically correlated with a wide range of psychiatric disorders and cognitive traits, with strongest effects typically observed between a given mental health profile and a disorder for which the profile is common (e.g. depression symptoms and major depressive disorder, or psychosis and schizophrenia). Strikingly, although the profiles were phenotypically uncorrelated, many of them were genetically correlated with each other. This study provides evidence that statistically independent mental health profiles partly share genetic underpinnings and show genetic overlap with psychiatric disorders, suggesting that shared genetics across psychiatric disorders cannot be exclusively attributed to the known overlapping symptomatology between the disorders.

• Cheng, Weiqiu; Frei, Oleksandr; Meer, Dennis van der; Wang, Yunpeng; O`Connell, Kevin & Chu, Yunhan [Vis alle 20 forfattere av denne artikkelen] (2021). Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness. JAMA psychiatry. ISSN 2168-6238. 78(9), s. 1020–1030. doi: 10.1001/jamapsychiatry.2021.1435. Fulltekst i vitenarkiv Vis sammendrag

  Importance Schizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive. Objective To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci. Design, Setting, and Participants Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021. Main Outcomes and Measures The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci. Results Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified. Conclusions and Relevance This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

• Monereo-Sánchez, Jennifer; Schram, Miranda T.; Frei, Oleksandr; O'Connell, Kevin Sean; Shadrin, Alexey & Smeland, Olav Bjerkehagen [Vis alle 11 forfattere av denne artikkelen] (2021). Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain. Frontiers in Neuroscience. ISSN 1662-4548. 15, s. 1–9. doi: 10.3389/fnins.2021.653130. Fulltekst i vitenarkiv Vis sammendrag

  Background: Alzheimer’s disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterising their genetic overlap may provide aetiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects. Methods: We applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD ( n = 79,145) and depression ( n = 450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (UKB) (mean age 57.21, 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data. Results: MiXer estimated 98 causal genetic variants overlapping between the 2 disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD ( B = −0.002, p = 9.1 × 10 –4 ) and depression ( B = 0.007, p = 3.2 × 10 –9 ) in the UKB. This SNP was also associated with several regions of the corpus callosum volume anterior ( B &amp;gt; 0.024, p &amp;lt; 8.6 × 10 –4 ), third ventricle volume ventricle ( B = −0.025, p = 5.0 × 10 –6 ), and inferior temporal gyrus surface area ( B = 0.017, p = 5.3 × 10 –4 ). Discussion: Our results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.

• Monereo-Sánchez, Jennifer; Luykx, Jurjen J.; Pinzón-Espinosa, Justo; Richard, Geneviève; Motazedi, Ehsan & Westlye, Lars Tjelta [Vis alle 8 forfattere av denne artikkelen] (2021). Diphtheria And Tetanus Vaccination History Is Associated With Lower Odds of COVID-19 Hospitalization. Frontiers in Immunology. 12, s. 1–7. doi: 10.3389/fimmu.2021.749264. Fulltekst i vitenarkiv Vis sammendrag

  Background COVID-19 is characterized by strikingly large, mostly unexplained, interindividual variation in symptom severity: while some individuals remain nearly asymptomatic, others suffer from severe respiratory failure. Previous vaccinations for other pathogens, in particular tetanus, may partly explain this variation, possibly by readying the immune system. Methods We made use of data on COVID-19 testing from 103,049 participants of the UK Biobank (mean age 71.5 years, 54.2% female), coupled to immunization records of the last ten years. Using logistic regression, covarying for age, sex, respiratory disease diagnosis, and socioeconomic status, we tested whether individuals vaccinated for tetanus, diphtheria or pertussis, differed from individuals that had only received other vaccinations on 1) undergoing a COVID-19 test, 2) being diagnosed with COVID-19, and 3) whether they developed severe COVID-19 symptoms. Results We found that individuals with registered diphtheria or tetanus vaccinations are less likely to develop severe COVID-19 than people who had only received other vaccinations (diphtheria odds ratio (OR)=0.47, p-value=5.3*10 -5 ; tetanus OR=0.52, p-value=1.2*10 -4 ). Discussion These results indicate that a history of diphtheria or tetanus vaccinations is associated with less severe manifestations of COVID-19. These vaccinations may protect against severe COVID-19 symptoms by stimulating the immune system. We note the correlational nature of these results, yet the possibility that these vaccinations may influence the severity of COVID-19 warrants follow-up investigations.

• Shadrin, Alexey A.; Kaufmann, Tobias; Meer, Dennis van der; Palmer, Clare E.; Makowski, Carolina & Loughnan, Robert [Vis alle 22 forfattere av denne artikkelen] (2021). Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology. NeuroImage. ISSN 1053-8119. 244, s. 1–8. doi: 10.1016/j.neuroimage.2021.118603. Fulltekst i vitenarkiv Vis sammendrag

  Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study®. This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.

• Meer, Dennis van der; Kaufmann, Tobias; Shadrin, Alexey; Makowski, Carolina; Frei, Oleksandr & Roelfs, Daniel [Vis alle 17 forfattere av denne artikkelen] (2021). The genetic architecture of human cortical folding. Science Advances. 7(51), s. 1–9. doi: 10.1126/sciadv.abj9446. Fulltekst i vitenarkiv Vis sammendrag

  The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10−8). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.

• Gurholt, Tiril Pedersen; Kaufmann, Tobias; Frei, Oleksandr; Alnæs, Dag; Haukvik, Unn Kristin H. & Meer, Dennis van der [Vis alle 17 forfattere av denne artikkelen] (2021). Population-based body–brain mapping links brain morphology with anthropometrics and body composition. Translational Psychiatry. doi: 10.1038/s41398-021-01414-7. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Understanding complex body–brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n  = 24,728) and body MRI ( n  = 4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body–brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body–brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies.

• O'Connell, Kevin S.; Sønderby, Ida Elken; Frei, Oleksandr; Meer, Dennis van der; Athanasiu, Lavinia & Smeland, Olav Bjerkehagen [Vis alle 13 forfattere av denne artikkelen] (2021). Association between complement component 4A expression, cognitive performance and brain imaging measures in UK Biobank. Psychological Medicine. ISSN 0033-2917. s. 1–11. doi: 10.1017/S0033291721000179. Fulltekst i vitenarkiv Vis sammendrag

  Background Altered expression of the complement component C4A gene is a known risk factor for schizophrenia. Further, predicted brain C4A expression has also been associated with memory function highlighting that altered C4A expression in the brain may be relevant for cognitive and behavioral traits. Methods We obtained genetic information and performance measures on seven cognitive tasks for up to 329 773 individuals from the UK Biobank, as well as brain imaging data for a subset of 33 003 participants. Direct genotypes for variants (n = 3213) within the major histocompatibility complex region were used to impute C4 structural variation, from which predicted expression of the C4A and C4B genes in human brain tissue were predicted. We investigated if predicted brain C4A or C4B expression were associated with cognitive performance and brain imaging measures using linear regression analyses. Results We identified significant negative associations between predicted C4A expression and performance on select cognitive tests, and significant associations with MRI-based cortical thickness and surface area in select regions. Finally, we observed significant inconsistent partial mediation of the effects of predicted C4A expression on cognitive performance, by specific brain structure measures. Conclusions These results demonstrate that the C4 risk locus is associated with the central endophenotypes of cognitive performance and brain morphology, even when considered independently of other genetic risk factors and in individuals without mental or neurological disorders.

• Sønderby, Ida Elken; Meer, Dennis van der; Moreau, Clara; Kaufmann, Tobias; Walters, G. Bragi & Ellegaard, Maria [Vis alle 76 forfattere av denne artikkelen] (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01213-0. Fulltekst i vitenarkiv Vis sammendrag

  Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

• Dongen, Jenny van; Hagenbeek, Fiona A.; Suderman, Matthew; Roetman, Peter J.; Sugden, Karen & Chiocchetti, Andreas G [Vis alle 51 forfattere av denne artikkelen] (2021). DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan. Molecular Psychiatry. ISSN 1359-4184. 26, s. 2148–2162. doi: 10.1038/s41380-020-00987-x. Fulltekst i vitenarkiv Vis sammendrag

  Abstract DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior ( N  = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10 −7 ; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression ( r  = 0.74, p  = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

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• Meer, Dennis van der; Beck, Dani; Askeland-Gjerde, Daniel E.; Eikefjord, Eli; Lundervold, Arvid & Andreassen, Ole A. [Vis alle 8 forfattere av denne artikkelen] (2024). Distinct longitudinal brain white matter microstructure changes and associated polygenic risk of common psychiatric disorders and Alzheimer’s disease in the UK Biobank. Fulltekst i vitenarkiv
• Meer, Dennis van der; Beck, Dani; Lange, Ann-Marie Glasø de; Eikefjord, Eli Nina Hølleland; Lundervold, Arvid & Andreassen, Ole A. [Vis alle 8 forfattere av denne artikkelen] (2024). Brain asymmetries from mid-to late life and hemispheric brain age. Fulltekst i vitenarkiv
• Norbom, Linn Christin Bonaventure; Hanson, Jamie; Meer, Dennis van der; Ferschmann, Lia; Røysamb, Espen & Soest, Tilmann von [Vis alle 10 forfattere av denne artikkelen] (2023). Erratum to “Parental socioeconomic status is linked to cortical microstructure and language abilities in children and adolescents” [Dev. Cogn. Neurosci. 56C (2022) 101132] (Developmental Cognitive Neuroscience (2022) 56, (S1878929322000755), (10.1016/j.dcn.2022.101132)). Developmental Cognitive Neuroscience. ISSN 1878-9293. 61. doi: 10.1016/j.dcn.2023.101225. Fulltekst i vitenarkiv
• Korbmacher, Max; Gurholt, Tiril Pedersen; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Beck, Dani & Eikefjord, Eli Nina Hølleland [Vis alle 10 forfattere av denne artikkelen] (2023). Brain age estimates from different white matter microstructure features associate concordantly with bio-psycho-social factors. Fulltekst i vitenarkiv
• Korbmacher, Max; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Beck, Dani; Eikefjord, Eli Nina Hølleland & Lundervold, Arvid [Vis alle 9 forfattere av denne artikkelen] (2023). Fornix and forceps are key regions of white matter brain age. Fulltekst i vitenarkiv
• Korbmacher, Max; Gurholt, Tiril Pedersen; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Beck, Dani & Eikefjord, Eli Nina Hølleland [Vis alle 10 forfattere av denne artikkelen] (2023). White matter microstructure is predictive of cardiometabolic health. Fulltekst i vitenarkiv
• Korbmacher, Max; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Beck, Dani; Eikefjord, Eli Nina Hølleland & Lundervold, Arvid [Vis alle 9 forfattere av denne artikkelen] (2023). Regional grey and white matter asymmetry decreases at higher ages. Fulltekst i vitenarkiv
• Korbmacher, Max; Lange, An-Marie Glasø de; Eikefjord, Eli Nina; Meer, Dennis van der; Lundervold, Arvid & Andreassen, Ole A [Vis alle 8 forfattere av denne artikkelen] (2022). Brain-wide associations between white matter and age: fornix microstructure drives brain age. Fulltekst i vitenarkiv
• Maximov, Ivan; Meer, Dennis van der; Lange, Ann-Marie Glasø de; Kaufmann, Tobias; Shadrin, Alexey & Frei, Oleksandr [Vis alle 8 forfattere av denne artikkelen] (2021). YTTRIUM: QC algorithm for the processed diffusion maps in UK Biobank 18608 sample. Fulltekst i vitenarkiv
• Maximov, Ivan; Meer, Dennis van der; Lange, Ann Marie de; Kaufmann, Tobias & Westlye, Lars Tjelta (2021). Probing human cortical microstructure using diffusion MRI: insights from N = 17,646 individuals of the UK Biobank. Fulltekst i vitenarkiv
• Sartorius, Alina Marie; Quintana, Daniel; Westlye, Lars Tjelta & Meer, Dennis van der (2026). Deciphering the oxytocin signaling pathway. An exploratory, open, multi-method approach to understand and annotate a diverse endocrine system. Universitetet i Oslo. Fulltekst i vitenarkiv Vis sammendrag

  The nonapeptide oxytocin is a multifaceted and evolutionarily conserved hormone and neuromodulator. The domains it has been implicated in since its discovery approximately 130 years ago (Howell, 1898; Oliver & Schäfer, 1895) range from galactagogue (I. Ott & Scott, 1910) and uterotonic (Dale, 1906, 1909), over energy and bone metabolic (Colaianni et al., 2014; Leng & Sabatier, 2017), cardiovascular (Gutkowska & Jankowski, 2012), to social (H. K. Caldwell, 2017), cognitive (Brambilla et al., 2016), and psychiatric (Young, 2001). It is predominantly synthesized in the brain within the hypothalamus, where its structurally and functionally related paralog vasotocin (Theofanopoulou et al., 2021) is produced, too (Bethlehem et al., 2013; Brownstein et al., 1980; Buijs et al., 2021; Ivell, 1986; Meyer-Lindenberg et al., 2011). From there, the neuropeptide is released centrally (Landgraf & Neumann, 2004; Leng et al., 2008; Neumann, 2007) and into the periphery via the circulation (Meyer Lindenberg et al., 2011). The mentioned functions are often well conserved across mammals (Bielsky & Young, 2004), in early vertebrates (Goodson, 2005; Gwee et al., 2009), and even in some invertebrate species (Odekunle & Elphick, 2020). However, many of the results in the different domains, mostly but not exclusively, in humans, are marked by inconsistency and unsuccessful replication attempts (Audunsdottir et al., 2024; Brede et al., 2019; Declerck et al., 2020; Kosfeld et al., 2005; Sikich et al., 2021; Thienel et al., 2016), or appear to be highly dependent on (latent) context variables (Bartz et al., 2011; Ford & Young, 2022; Olszewski et al., 2016). More rigorous open science practices could help with reducing questionable research practices, increasing reproducibility and standardizing experimental designs. This indirectly promotes result consistency (Crüwell et al., 2019; Yamada, 2018). At the same time, the oxytocin research field is currently still lacking an overarching theoretical framework. The lack of such an interdisciplinary, comprehensive framework and the persistence of research conceptualized in isolated domains perpetuates heterogeneity in study designs, which leads to heterogeneity in outcomes (Muthukrishna & Henrich, 2019; Winterton, Westlye, et al., 2021). Adopting a more open scientific approach and reiterating on basic questions regarding a phenotype’s evolution, mechanisms, and physiology (Tinbergen, 1963) can aid with developing a comprehensive theory and with homogenizing findings. This in turn may aid with reconciling the scattered landscape of oxytocin research findings. To this end, this doctoral thesis focused on exploring the oxytocin system from the ground up from an evolutionary genetics, imaging genetics, and meta-analytical perspective. A suite of different methods was chosen to represent the broad range of oxytocinergic properties and to cover a variety of ultimate and proximate angles. Open science principles were adopted wherever possible. Potential theoretical frameworks are discussed based on the findings and the reviewed literature. Paper I (Sartorius et al., 2024) assumed a comprehensive evolutionary perspective by delineating the timeline of the oxytocin signaling pathway genes over the course of the past 3.5 billion years using comparative genetics and positive selection analyses. The assigned evolutionary ages of each gene indicated that the majority of the pathway genes were modern (~64%), but that some genes were conserved in species as ancient as descendants of early cellular life. The analyses confirmed that OXT, OXTR, and CD38 emerged with the evolution of jawless and jawed vertebrates 540 – 530 million years ago. Modern oxytocin pathway genes were found to be enriched in muscle tissue and the brain, specifically in fronto cortical regions. In Paper II (Sartorius et al., 2026a), a specific aspect of the oxytocin systems physiology was investigated. The shared genetic architecture between oxytocinergic-vasotocinergic hypothalamus subunits and selected psychiatric/neurodevelopmental and metabolic traits was explored using bivariate mixture models, and subsequently functionally annotated. Moderate-to-extensive genetic overlap was found between all subunits and traits, on average more so between the subunits and psychiatric/neurodevelopmental than metabolic traits. The most extensive overlap, however, was found between the two anterior hypothalamic subunits and systolic blood pressure. The genes were up- and down-regulated in different tissues and enriched in gene sets related to cortical morphology and cognitive impairment. Given the lack of unanimity of study designs investigating and results describing oxytocin’s energy regulatory properties, Paper III (Sartorius et al., 2026b) was set out to synthesize data within this domain. Effects of exogenous oxytocin on caloric intake and appetite in healthy and clinical individuals were collected and pooled in a preregistered living systematic review and meta-analysis. Oxytocin administration was linked to appetite outcomes in some clinical populations, and to caloric intake conditional on the diagnostic group, that is, in patients with obesity. The results in healthy populations were inconclusive, possibly due to low power and high heterogeneity within and between the included studies. Based on these findings and contemporary literature, five different potential theoretical frameworks were explored. This included among other the option that oxytocin could be a behavioral flexibility hormone (Quintana & Guastella, 2020; Walle et al., 2026), that it could be a hormone with the primary function to facilitate successful reproduction (Feldman & Bakermans-Kranenburg, 2017; Insel et al., 1997; Wathes & Swann, 1982), or that the current multifunctionality is rooted in conserved contractile and osmoregulatory properties that diversified during evolution. Beyond that, the clinical utility of the findings was discussed, as well as methodological considerations and future directions. For instance, the quality of invertebrate and vertebrate genomes was addressed together with further open science perspectives. Prospective studies may focus on exploring the ontogenic angle of the oxytocin system, and using the openly shared code and analysis pipelines from the three papers here to, for instance, explore bivariate mixture models with additional ‘social’ traits. To conclude, the findings highlight the complexity of the oxytocin system – which goes beyond sociality – and the breadth of the undertaking of proposing an overarching theoretical framework for it. The results support the notion that the oxytocin signaling pathway is evolutionary conserved and evolved gradually, and that central oxytocin-vasotocin signaling may be connected to psychiatric/neuro developmental and metabolic traits by a shared set of genetic variants. The results also show that the hypothalamic peptide affects appetite in clinical groups, and corroborates that respective studies are underpowered and heterogenous, showcasing again the need for more open science and a unifying theoretical framework. While this thesis neither seeks nor claims to conclusively resolve the mysteries of the oxytocin system, its results aid in better understanding the endocrine system and add to the pool of knowledge to inspire future oxytocin research.

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