Ida Elken Sønderby

• Korbmacher, Max; Bøen, Rune; Andreassen, Ole; Westlye, Lars Tjelta; Sønderby, Ida Elken & Maximov, Ivan (2026). White matter microstructure differences between 15q11.2 copy number variation carriers and non-carriers in mid-to-late life. Translational Psychiatry. 16, p. 1–8. doi: 10.1038/s41398-026-03962-2. Full text in Research Archive Show summary

  The 15q11.2 BP1-BP2 copy number variant (CNV) has been associated with neurodevelopmental and psychiatric conditions and brain grey matter structure, but its effects on white matter microstructure (WMM) in mid-to-late adulthood to assess long-term neurobiological effects remain unclear. Understanding these effects is important for evaluating long-term neurobiological impacts across the lifespan. WMM parameters were extracted from UK Biobank diffusion magnetic resonance imaging data for 15q11.2 BP1-BP2 deletion (n = 126, mean age: 66 ± 8) and duplication (n = 131, mean age: 64 ± 7) carriers, as well as age- and sex-matched non-carriers (n = 1260 and n = 1310). We used multiple advanced diffusion approaches, extending beyond DTI, providing metrics on various spatial levels comparing the CNV carriers and non-carriers. All metrics were projected on the WM skeleton for further group comparisons. We present various atlas-derived region-level differences between 15q11.2 BP1-BP2 deletion carriers and non-carriers. These differences suggest altered microstructural organization in the corpus callosum, cingulum and hippocampus, uncinate fasciculus, indicated by lower diffusivity and higher fractional anisotropy, kurtosis, axonal water fraction, and intra-neurite volume fraction (absolute standardized effects > 0.22). Most significant differences across multiple diffusion approaches were detected in the corpus callosum. Our findings suggest that during mid- to-late life, WMM in the corpus callosum is affected by 15q11.2 deletion. Different diffusion approaches allowing for microscopic assessments of WM, beyond previous non-microscopic diffusion MRI based assessments, suggest altered axonal density or microstructural organization, potentially reflecting pathological axonal overgrowth and myelination abnormalities, adding explanations for observable developmental and psychiatric differences between deletion carriers and healthy controls.

• Kopal, Jakub; Bakken, N. R.; Parekh, Pravesh; Shadrin, Alexey; Jaholkowski, Piotr Pawel & Ystaas, L. A. R. [Show all 14 contributors for this article] (2026). Early-childhood temperament trajectories map onto transdiagnostic psychiatric risk. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03881-0. Full text in Research Archive
• Ystaas, Lars A.R.; Parekh, Pravesh; Parker, Nadine; Akkouh, Ibrahim Ahmed; Birkenæs, Viktoria & Sønderby, Ida Elken [Show all 12 contributors for this article] (2026). Genetic liability to addiction underlies comorbid bipolar and substance use disorders. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2026.08.008. Full text in Research Archive
• Parekh, Pravesh; Parker, Nadine; Pecheva, Diliana; Frei, Evgeniia; Vaudel, Marc & Smith, Diana M. [Show all 26 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Barak, Eden Nordvold; Kolskår, Knut-Kristian; Dahl, Christine; Alnæs, Dag; Andreassen, Ole & Nærland, Terje [Show all 9 contributors for this article] (2026). Birth Weight and Neurodevelopmental Disorders Across Diagnostic Categories: A Registry-Based Case–Control Study in Clinically Ascertained Samples | Child Psychiatry & Human Development | Springer Nature Link. Child Psychiatry and Human Development. ISSN 0009-398X. doi: 10.1007/s10578-026-02090-8. Full text in Research Archive Show summary

  Increasing prevalence of neurodevelopmental disorders (NDDs) is a growing public health concern. Identifying early risk markers may facilitate earlier intervention and reduce long-term burden. Although birth weight has been widely studied in relation to NDDs, evidence from clinically ascertained samples with single and overlapping diagnoses remains limited. In this case-control study, we compared birth weight between clinically referred individuals with intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) from the Norwegian BUPgen registry (n = 720) and a population-based sample from the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 98,716). Perinatal data were obtained through linkage to the Medical Birth Registry of Norway. Associations were examined using logistic regression adjusted for gestational age, sex, and parental age. Additional analyses assessed interactions by sex and parental age, and birth weight categories. For each 100 g decrease in birth weight, odds significantly increased for the groups any NDD (one or more NDD diagnoses; OR = 1.04) and multiple diagnoses (two or more co-occurring NDDs; OR = 1.07). In diagnosis specific analyses, odds significantly increased for ID (OR = 1.15) and ASD (OR = 1.03). No interactions were observed. In categorical analyses, low birth weight was associated with higher odds of ID (OR = 8.27, p < 0.001), multiple diagnoses (OR = 4.96, p < 0.001), and any NDD (OR = 2.11, p = 0.002). No associations were observed for high birth weight. These findings support low birth weight as an early marker of neurodevelopmental vulnerability across NDD outcomes. Lower birth weight was associated with higher odds of ID, ASD, multiple diagnoses and any NDD, but not ADHD. Associations were strongest and most consistent for ID and comorbid presentations, indicating heterogeneity across diagnostic categories. Increased risk was primarily observed at low birth weight, with no associations for high birth weight. Findings support birth weight as an early marker of neurodevelopmental vulnerability in a clinically ascertained sample.

• Dennison, Charlotte A.; Sønderby, Ida Elken; Garcia-Argibay, Miguel; Powell, Victoria; Shakeshaft, Amy & Riglin, Lucy [Show all 13 contributors for this article] (2026). The role of rare copy number variants in early-onset depression. JCPP Advances. doi: 10.1002/jcv2.70128. Full text in Research Archive
• Gurholt, Tiril Pedersen; Beck, Dani; Voldsbekk, Irene; Parker, Nadine; Askeland-Gjerde, Daniel E. & Lange, Ann-Marie Glasø de [Show all 13 contributors for this article] (2026). Linking obesity with white matter microstructure highlights the importance of brainstem tracts and sex differences. Brain Communications. 8(1), p. 1–15. doi: 10.1093/braincomms/fcag026. Full text in Research Archive Show summary

  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.

• Silva, Ana I.; Sønderby, Ida Elken; Kirov, George; Abdellaoui, Abdel; Agartz, Ingrid & Ames, David [Show all 106 contributors for this article] (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), p. 1093–1106. doi: 10.1016/j.bpsc.2025.05.010. Full text in Research Archive Show summary

  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.

• Bergstedt, Jacob; Kõiv, Kadri; Jangmo, Andreas; Haram, Marit; Jaholkowski, Piotr Pawel & Treur, Jorien L. [Show all 21 contributors for this article] (2025). Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases. medRxiv. doi: 10.1101/2025.03.11.25323757. Full text in Research Archive Show summary

  Abstract IMPORTANCE Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN, SETTING, AND PARTICIPANTS Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking. Key Points Question Is genetic liability to specific psychiatric disorders associated with an increased risk of clinically diagnosed cardiometabolic diseases even after adjusting for cross-disorder psychiatric pleiotropy, body mass index, and smoking status? Findings In this study of cohorts in Sweden, Estonia, and Norway, genetic liability to major depressive disorder (MDD) showed stronger associations with cardiometabolic disease (CMD) compared to other psychiatric disorders. Genetic liability to anxiety disorder and PTSD showed associations with CMD that were attenuated when adjusting for cross-disorder psychiatric pleiotropy. Genetic liability to ADHD showed strong associations with obesity and type 2 diabetes that were strongly attenuated when adjusting for body mass index, and smoking status. Genetic liability to schizophrenia showed inverse associations with CMD. Meaning These findings suggest that MDD has a distinctive genetic relationship with CMD compared to other psychiatric disorders and that the well-established phenotypic association between schizophrenia and CMD is not related to genetic factors.

• Hope, Sigrun; Lin, Aihua; Rødevand, Linn; Hübenette, Saira Jameela; Quintana, Daniel & Sønderby, Ida Elken [Show all 17 contributors for this article] (2025). Shared genetic architecture between autism spectrum disorder, loneliness, and social isolation reveals novel genetic loci. Psychiatric Genetics. ISSN 0955-8829. doi: 10.1097/ypg.0000000000000406. Full text in Research Archive Show summary

  Objective: Deficits in social communication and social interaction are core features of autism spectrum disorder (ASD), and studies suggest that loneliness and social isolation are common. ASD has a strong genetic basis, but the genetic architecture and overlap with social phenotypes are not clear. Methods: We analyzed summary statistics from genome-wide association studies on ASD (46 350), loneliness (452 302), and social isolation (288 950), using linkage disequilibrium score regression, local analysis of covariant annotation (LAVA), bivariate causal mixture model (MiXeR), and the conditional/conjunctional false discovery rate (cond/conjFDR). Results: For ASD and social isolation, we found nonsignificant global genetic correlation ( r g = 0.02, P  = 0.8), but LAVA identified 72 genomic regions with bidirectional correlations, and MiXeR estimated that 8.7 k of 13.1 k variants (81%) were shared, of which 53% had concordant effect directions. For ASD and loneliness, we found a positive genetic correlation ( r g = 0.26, P  = 2e-10), LAVA identified 80 genomic regions with bidirectional genetic correlations, and MiXeR suggested that at least 3.8 k variants were shared. We identified nine specific shared genetic loci between ASD and loneliness and eight between ASD and social isolation (conjFDR < 0.05). Of these, 12 loci were novel for ASD. Genes mapped to these loci are involved in γ-aminobutyric acid (GABA), glutamate, calcium, and stress hormone signaling, cerebral glucose transport, TAU-accumulation, and immune function. Conclusion: We found extensive overlap in genetic architecture between ASD, loneliness, and social isolation, with bidirectional effects. By leveraging data for ASD and social traits, we identified 12 novel ASD related genetic loci implicating several genes, thereby elucidating potential pathways underlying their shared genetic architecture.

• Birkenæs, Viktoria; Parekh, Pravesh; Hegemann, Laura Elizabeth; Bakken, Nora Refsum; Frei, Evgeniia & Jaholkowski, Piotr Pawel [Show all 13 contributors for this article] (2025). Youth psychotic experiences: psychometric evaluation and diagnostic associations of the CAPE-16 in adolescents from the Norwegian Mother, Mather and Child Cohort. Journal of Child Psychology and Psychiatry. ISSN 0021-9630. 67(1), p. 27–40. doi: 10.1111/jcpp.70007. Full text in Research Archive Show summary

  Background: Adolescent self-reported psychotic experiences are associated with mental illness and could help guide prevention strategies. Youth report substantially more experiences than adults. However, with large societal changes like the digital revolution and COVID-19 pandemic, existing questionnaires may no longer accurately capture youth experiences. We aimed to determine the ability of the CAPE-16 questionnaire in capturing psychotic experiences across contexts (biological sex and COVID-19 response) and generations, thereby validating important psychometric aspects of the tool in modern adolescents. Methods: We used data from the Norwegian Mother, Father and Child Study (MoBa), a population-based pregnancy cohort. Adolescents responded to the CAPE-16 questionnaire (n = 18,835). For a comparison between age groups, we included adult men from the parent generation who responded to the CAPE-9 (n = 28,793). We investigated the psychometric properties of CAPE-16 through confirmatory factor analyses, measurement invariance testing across biological sex, response before/during the COVID-19 pandemic, and generations (adolescents and fathers), and examined subscale and item-level associations with subsequent registry-based psychiatric diagnoses (average time between CAPE and last registry update: 3.68 ± 1.34 years). Results: Out of 18,835 adolescents, 33.2% reported lifetime psychotic experiences. We confirmed a three-factor structure (paranoia, bizarre thoughts, and hallucinations) and good subscale reliability (ω = .86 and .90). CAPE-16 scores were stable across biological sex and pandemic status. CAPE-9 response patterns were non-invariant across adolescents and adult men, with an item related to digital technology particularly prone to bias. CAPE-16 subscales were associated with subsequent psychiatric diagnoses, especially psychotic disorders. Conclusions: CAPE-16 is a reliable measure of psychotic experiences across sex and a major societal stressor in adolescents. More frequent and distressing experiences increase the risk of subsequent psychiatric diagnoses. Different response patterns between adults and adolescents for items related to digital technology suggest differences in interpretation. Hence, certain items may benefit from revisions.

• Koch, Elise; Smart, Sophie; Einarsson, Guðmundur; Kämpe, Anders; Jonsson, Lina & Alver, Maris [Show all 30 contributors for this article] (2025). Recommendations for defining treatment outcomes in major psychiatric disorders using real-world data. The Lancet Psychiatry. ISSN 2215-0374. 12, p. 457–468. doi: 10.1016/S2215-0366(25)00061-6. Full text in Research Archive
• Meer, Dennis van der; Rahman, Mohammad Zillur; Ottas, Aigar; Parekh, Pravesh; Kutrolli, Gleda & Stinson, Sara Elizabeth [Show all 37 contributors for this article] (2025). Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers. Nature Communications. 16(1). doi: 10.1038/s41467-025-60058-z. Full text in Research Archive Show summary

  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.

• Fraza, Charlotte; Sønderby, Ida Elken; Bøen, Rune; Shi, Yingjie; Beckmann, Christian F. & Marquand, Andre F. (2024). Unraveling the link between CNVs, cognition and individual neuroimaging deviation scores from a population-based reference cohort. Nature Mental Health. 2(12), p. 1451–1463. doi: 10.1038/s44220-024-00322-1. Full text in Research Archive
• Gurholt, Tiril Pedersen; Borda, Miguel Germán; Parker, Nadine; Fominykh, Vera; Kjelkenes, Rikka & Linge, Jennifer [Show all 12 contributors for this article] (2024). Linking sarcopenia, brain structure and cognitive performance: a large-scale UK Biobank study. Brain Communications. 6(2). doi: 10.1093/braincomms/fcae083. Full text in Research Archive Show summary

  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.

• Kopal, Jakub; Kumar, Kuldeep; Shafighi, Kimia; Saltoun, Karin; Modenato, Claudia & Moreau, Clara A. [Show all 30 contributors for this article] (2024). Using rare genetic mutations to revisit structural brain asymmetry. Nature Communications. 15. doi: 10.1038/s41467-024-46784-w. Full text in Research Archive Show summary

  Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

• Beck, Dani; Lange, Ann-Marie Glasø de; Gurholt, Tiril Pedersen; Voldsbekk, Irene; Maximov, Ivan & Subramaniapillai, Sivaniya [Show all 19 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Andersson, Patrik; Linge, Jennifer; Gurholt, Tiril Pedersen; Sønderby, Ida Elken; Hindley, Guy & Andreassen, Ole A. [Show all 7 contributors for this article] (2024). Poor muscle health and cardiometabolic risks associated with antidepressant treatment. Obesity. ISSN 1930-7381. 32(10), p. 1857–1869. doi: 10.1002/oby.24085. Full text in Research Archive
• Koch, Elise Mirjam; Pardiñas, Antonio F.; O'Connell, Kevin Sean; Selvaggi, Pierluigi; Camacho-Collados, Jose & Babic, Aleksandar [Show all 26 contributors for this article] (2024). How real-world data can facilitate the development of precision medicine treatment in psychiatry. Biological Psychiatry. ISSN 0006-3223. 96, p. 543–551. doi: 10.1016/j.biopsych.2024.01.001. Full text in Research Archive Show summary

  Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements—well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms—to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.

• Ivarsdottir, Erna V.; Gudmundsson, Julius; Tragante, Vinicius; Sveinbjornsson, Gardar; Kristmundsdottir, Snaedis & Stacey, Simon N. [Show all 58 contributors for this article] (2024). Gene-based burden tests of rare germline variants identify six cancer susceptibility genes. Nature Genetics. ISSN 1061-4036. 56(11), p. 2422–2433. doi: https:/rdcu.be/dYuc6. Full text in Research Archive
• Szabo, Attila; O'Connell, Kevin Sean; Akkouh, Ibrahim Ahmed; Ueland, Thor; Sønderby, Ida Elken & Hope, Sigrun [Show all 16 contributors for this article] (2024). Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder. Psychiatry Research. ISSN 0165-1781. 342. doi: 10.1016/j.psychres.2024.116245. Full text in Research Archive Show summary

  Background Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified. Methods We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods. Results We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro. Conclusion Our results suggest a role for inflammasome dysregulation in ASD pathophysiology.

• Gurholt, Tiril Pedersen; Elvsåshagen, Torbjørn; Bahrami, Shahram; Rahman, Mohammad Zillur; Shadrin, Alexey & Askeland-Gjerde, Daniel E. [Show all 13 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Akdeniz, Bayram Cevdet; Frei, Oleksandr; Hagen, Espen; Filiz, Tahir Tekin; Karthikeyan, Sandeep & Pasman, Joëlle [Show all 18 contributors for this article] (2024). COSGAP: COntainerized Statistical Genetics Analysis Pipelines. Bioinformatics Advances. 4(1). doi: 10.1093/bioadv/vbae067. Full text in Research Archive Show summary

  The collection and analysis of sensitive data in large-scale consortia for statistical genetics is hampered by multiple challenges, due to their non-shareable nature. Time-consuming issues in installing software frequently arise due to different operating systems, software dependencies, and limited internet access. For federated analysis across sites, it can be challenging to resolve different problems, including format requirements, data wrangling, setting up analysis on high-performance computing (HPC) facilities, etc. Easier, more standardized, automated protocols and pipelines can be solutions to overcome these issues. We have developed one such solution for statistical genetic data analysis using software container technologies. This solution, named COSGAP: “COntainerized Statistical Genetics Analysis Pipelines,” consists of already established software tools placed into Singularity containers, alongside corresponding code and instructions on how to perform statistical genetic analyses, such as genome-wide association studies, polygenic scoring, LD score regression, Gaussian Mixture Models, and gene-set analysis. Using provided helper scripts written in Python, users can obtain auto-generated scripts to conduct the desired analysis either on HPC facilities or on a personal computer. COSGAP is actively being applied by users from different countries and projects to conduct genetic data analyses without spending much effort on software installation, converting data formats, and other technical requirements.

• Kopal, Jakub; Kumar, Kuldeep; Saltoun, Karin; Modenato, Claudia; Moreau, Clara A. & Martin-Brevet, Sandra [Show all 32 contributors for this article] (2023). Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence. Nature Human Behaviour. doi: 10.1038/s41562-023-01541-9. Full text in Research Archive
• Bøen, Rune; Kaufmann, Tobias Herbert; Meer, Dennis van der; Frei, Oleksandr; Agartz, Ingrid & Ames, David [Show all 53 contributors for this article] (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), p. 147–160. doi: 10.1016/j.biopsych.2023.08.018. Full text in Research Archive Show summary

  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.

• Oddsson, Asmundur; Sulem, Patrick; Sveinbjornsson, Gardar; Arnadottir, Gudny A.; Steinthorsdottir, Valgerdur & Halldorsson, Gisli H. [Show all 54 contributors for this article] (2023). Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nature Communications. 14(1). doi: 10.1038/s41467-023-38951-2. Full text in Research Archive Show summary

  Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

• Kumar, Kuldeep; Modenato, Claudia; Moreau, Clara; Ching, Christopher R.K.; Harvey, Annabelle & Martin-Brevet, Sandra [Show all 41 contributors for this article] (2023). Subcortical Brain Alterations in Carriers of Genomic Copy Number Variants. American Journal of Psychiatry. ISSN 0002-953X. 180(9), p. 685–698. doi: 10.1176/appi.ajp.20220304. Full text in Research Archive
• Bøen, Rune; Kaufmann, Tobias; Frei, Oleksandr; Meer, Dennis van der; Djurovic, Srdjan & Andreassen, Ole [Show all 9 contributors for this article] (2023). No signs of neurodegenerative effects in 15q11.2 BP1-BP2 copy number variant carriers in the UK Biobank. Translational Psychiatry. 13:61, p. 1–6. doi: 10.1038/s41398-023-02358-w. Full text in Research Archive Show summary

  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.

• Birkenæs, Viktoria; Bakken, Nora Refsum; Frei, Evgeniia; Jaholkowski, Piotr Pawel; Smeland, Olav Bjerkehagen & Woldeyohannes, Markos Tesfaye [Show all 15 contributors for this article] (2023). Psychometric Properties and Diagnostic Associations of the Short-Form Community Assessment of Psychic Experiences in a Population-Based Sample of 29 021 Adult Men. Schizophrenia Bulletin. ISSN 0586-7614. 49(5), p. 1229–1238. doi: 10.1093/schbul/sbad074. Full text in Research Archive Show summary

  Abstract Background and Hypothesis Around 5%–7% of the adult population are estimated to have lifetime psychotic experiences (PEs), which are associated with psychosis risk. PEs assessed with Community Assessment of Psychic Experiences (CAPE) are associated with psychosis but also non-psychotic disorders, which could be partly explained by CAPE indirectly capturing emotional symptoms. We investigated the psychometric properties of a shorter version, CAPE-9, and whether CAPE-9 scores are associated with lifetime psychotic or non-psychotic mental disorders after controlling for current anxiety and depressive symptoms. Design CAPE-9 questionnaire data were obtained from 29 021 men (42.4 ± 5.6 yrs.) from the Norwegian Mother, Father, and Child Cohort Study. We investigated CAPE-9 reliability and factor structure. Logistic regression was used to test effects of current anxiety and depressive symptoms (SCL-12) on associations between CAPE-9 scores and psychiatric diagnoses. Results CAPE-9 fit a previously reported 3-factor structure and showed good reliability. Twenty-six percent reported at least one lifetime PE. CAPE-9 scores were significantly associated with most psychiatric disorders (schizophrenia, depression, bipolar disorder, substance abuse, anxiety, trauma-related disorders, and ADHD). After controlling for concurrent emotional symptoms, only associations with schizophrenia (OR = 1.29; 95% CI = 1.18–1.38) and trauma-related disorders (OR = 1.09; CI = 1.02–1.15) remained significant. Conclusions CAPE-9 showed good psychometric properties in this large population-based adult male sample, and PEs were more clearly associated with psychotic disorders after controlling for current emotional symptoms. These results support the use of the short CAPE-9 as a cost-effective tool for informing public health initiatives and advancing our understanding of the dimensionality of psychosis.

• Meer, Dennis van der; Gurholt, Tiril Pedersen; Sønderby, Ida Elken; Shadrin, Alexey; Hindley, Guy Frederick Lanyon & Rahman, Zillur [Show all 18 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Granerud, Guro; Elvsåshagen, Torbjørn; Arntzen, Erik; Juhasz, Katalin; Emilsen, Nina Merete & Sønderby, Ida Elken [Show all 8 contributors for this article] (2022). A family study of symbolic learning and synaptic plasticity in autism spectrum disorder. Frontiers in Human Neuroscience. 16. doi: 10.3389/fnhum.2022.950922. Full text in Research Archive Show summary

  The current study presents a male with autism spectrum disorder (ASD) and a 3q29 deletion, and three healthy first-degree relatives. Our magnetic resonance imaging (MRI) dataset included a healthy control subset. We describe a comprehensive multimodal approach, including equivalence class formation, neurocognitive testing, MRI, and electroencephalography (EEG)-based cortical plasticity, which can provide new insights into sociocommunicative and learning impairments and neural underpinnings in ASD. On neurocognitive testing, the proband showed reduced processing speed, attending behavior, and executive function. He required more training trials in equivalence class training compared with family members and exhibited impaired priming of words compared with priming with images. The proband had smaller intracranial volume and surface area and a larger visual evoked potential (VEP) C1 amplitude than family members and intact long-term potentiation (LTP)-like visual cortex plasticity. Together, these results suggest that 3q29 deletion-related ASD is associated with impaired problem-solving strategies in complex socio-communicative and learning tasks, smaller intracranial and surface area, altered VEP amplitude, and normal LTP-like visual cortex plasticity. Further studies are needed to clarify whether this multimodal approach can be used to identify ASD subgroups with distinct neurobiological alterations and to uncover mechanisms underlying sociocommunicative and learning impairments. Lay Summary: We studied learning, brain activity, and brain structure in a person with autism and a genetic aberration, and his close relatives. Compared with relatives, the person with autism required more training for learning, and visual learning was better than verbal learning. This person had some changes in the activity of the visual cortex, and the size and the surface area of the brain were reduced. Knowledge about learning and brain mechanisms is valuable for the development of training programs for individuals with autism.

• Gurholt, Tiril Pedersen; Kaufmann, Tobias; Frei, Oleksandr; Alnæs, Dag; Haukvik, Unn Kristin H. & Meer, Dennis van der [Show all 17 contributors for this article] (2021). Population-based body–brain mapping links brain morphology with anthropometrics and body composition. Translational Psychiatry. doi: 10.1038/s41398-021-01414-7. Full text in Research Archive Show summary

  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 [Show all 13 contributors for this article] (2021). Association between complement component 4A expression, cognitive performance and brain imaging measures in UK Biobank. Psychological Medicine. ISSN 0033-2917. p. 1–11. doi: 10.1017/S0033291721000179. Full text in Research Archive Show summary

  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 [Show all 76 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Sønderby, Ida Elken; Ching, Christopher R. K.; Thomopoulos, Sophia I.; Meer, Dennis van der; Sun, Daqiang & Villalon-Reina, Julio E. [Show all 52 contributors for this article] (2021). Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs. Human Brain Mapping. ISSN 1065-9471. 43(1), p. 470–499. doi: 10.1002/hbm.25354. Full text in Research Archive Show summary

  The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype-first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

• Modenato, Claudia; Martin-Brevet, Sandra; Moreau, Clara; Rodriguez-Herreros, Borja; Kumar, Kuldeep & Draganski, Bogdan [Show all 8 contributors for this article] (2021). Lessons learned from neuroimaging studies of copy number variants: A systematic review. Biological Psychiatry. ISSN 0006-3223. 90(9), p. 596–610. doi: 10.1016/j.biopsych.2021.05.028. Full text in Research Archive Show summary

  Pathogenic copy number variants (CNVs) and aneuploidies alter gene dosage and are associated with neurodevelopmental psychiatric disorders such as autism spectrum disorder and schizophrenia. Brain mechanisms mediating genetic risk for neurodevelopmental psychiatric disorders remain largely unknown, but there is a rapid increase in morphometry studies of CNVs using T1-weighted structural magnetic resonance imaging. Studies have been conducted one mutation at a time, leaving the field with a complex catalog of brain alterations linked to different genomic loci. Our aim was to provide a systematic review of neuroimaging phenotypes across CNVs associated with developmental psychiatric disorders including autism and schizophrenia. We included 76 structural magnetic resonance imaging studies on 20 CNVs at the 15q11.2, 22q11.2, 1q21.1 distal, 16p11.2 distal and proximal, 7q11.23, 15q11-q13, and 22q13.33 (SHANK3) genomic loci as well as aneuploidies of chromosomes X, Y, and 21. Moderate to large effect sizes on global and regional brain morphometry are observed across all genomic loci, which is in line with levels of symptom severity reported for these variants. This is in stark contrast with the much milder neuroimaging effects observed in idiopathic psychiatric disorders. Data also suggest that CNVs have independent effects on global versus regional measures as well as on cortical surface versus thickness. Findings highlight a broad diversity of regional morphometry patterns across genomic loci. This heterogeneity of brain patterns provides insight into the weak effects reported in magnetic resonance imaging studies of cognitive dimension and psychiatric conditions. Neuroimaging studies across many more variants will be required to understand links between gene function and brain morphometry.

• Thompson, Paul M.; Jahanshad, Neda; Ching, Christopher R.K.; Salminen, Lauren E.; Thomopoulos, Sophia I. & Bright, Joanna [Show all 170 contributors for this article] (2020). ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. Translational Psychiatry. 10:100, p. 1–28. doi: 10.1038/s41398-020-0705-1. Full text in Research Archive Show summary

  This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

• Grasby, Katrina L.; Jahanshad, Neda; Painter, Jodie N; Colodro-Conde, Lucía; Bralten, Janita & Hibar, DP [Show all 50 contributors for this article] (2020). The genetic architecture of the human cerebral cortex. Science. ISSN 0036-8075. 367(6484). doi: 10.1126/science.aay6690. Full text in Research Archive Show summary

  INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.

• Hofer, Edith; Roshchupkin, Gennady V.; Adams, Hieab H H; Knol, Maria J.; Lin, Honghuang & Li, Shuo [Show all 51 contributors for this article] (2020). Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults. Nature Communications. 11. doi: 10.1038/s41467-020-18367-y. Full text in Research Archive Show summary

  Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

• Palomera, Aldo Còrdova; Meer, Dennis van der; Kaufmann, Tobias; Bettella, Francesco; Wang, Yunpeng & Alnæs, Dag [Show all 40 contributors for this article] (2020). Genetic control of variability in subcortical and intracranial volumes. Molecular Psychiatry. ISSN 1359-4184. p. 1–8. doi: 10.1038/s41380-020-0664-1. Full text in Research Archive Show summary

  Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8–89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

• Meer, Dennis van der; Sønderby, Ida Elken; Kaufmann, Tobias; Walters, G. Bragi; Abdellaoui, Abdel & Ames, David [Show all 132 contributors for this article] (2019). Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition. JAMA psychiatry. ISSN 2168-6238. doi: 10.1001/jamapsychiatry.2019.3779. Full text in Research Archive Show summary

  IMPORTANCE: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. OBJECTIVE: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. MAIN OUTCOMES AND MEASURES: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2 , sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. RESULTS: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. CONCLUSIONS AND RELEVANCE: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders

• Gudmundsson, Ólafur Ó.; Walters, Gudmundur Bragi; Ingason, Andrés; Johansson, Stefan; Zayats, Tetyana & Athanasiu, Lavinia [Show all 27 contributors for this article] (2019). Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder. Translational Psychiatry. 9, p. 1–9. doi: 10.1038/s41398-019-0599-y. Full text in Research Archive Show summary

  Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

• Stokowy, Tomasz; Polushina, Tatiana; Sønderby, Ida Elken; Karlsson, Robert; Giddaluru, Sudheer & Hellard, Stephanie Le [Show all 12 contributors for this article] (2018). Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes. Scientific Reports. 8(6915), p. 1–8. doi: 10.1038/s41598-018-25280-4. Full text in Research Archive Show summary

  Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We established a set of 117 myelination genes by database searches and manual curation. We used a combination of GWAS (SCZ_N = 35,476; CTRL_N = 46,839), exome chip (SCZ_N = 269; CTRL_N = 336) and exome sequencing data (SCZ_N = 2,527; CTRL_N = 2,536) from schizophrenia cases and healthy controls to examine common and rare variants. We found that a subset of lipid-related genes was nominally associated with schizophrenia (p = 0.037), but this signal did not survive multiple testing correction (FWER = 0.16) and was mainly driven by the SREBF1 and SREBF2 genes that have already been linked to schizophrenia. Further analysis demonstrated that the lowest nominal p-values were p = 0.0018 for a single common variant (rs8539) and p = 0.012 for burden of rare variants (LRP1 gene), but none of them survived multiple testing correction. Our findings suggest that variation in myelination-related genes is not a major risk factor for schizophrenia.

• Hughes, Timothy; Sønderby, Ida Elken; Polushina, Tatiana; Hansson, Lars Johan Axel; Holmgren, Asbjørn & Athanasiu, Lavinia [Show all 24 contributors for this article] (2018). Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder. Translational Psychiatry. 8(210), p. 1–10. doi: 10.1038/s41398-018-0175-x. Full text in Research Archive Show summary

  Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis p-values: 6.8E–05 for bipolar disorder and 8.2E–04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E–05 for schizophrenia and 9.8E–04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3´s association with bipolar disorder.

• Palomera, Aldo Còrdova; Kaufmann, Tobias; Bettella, Francesco; Wang, Yunpeng; Doan, Nhat Trung & Meer, Dennis van der [Show all 12 contributors for this article] (2018). Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories. European Journal of Human Genetics. ISSN 1018-4813. 26(7), p. 1049–1059. doi: 10.1038/s41431-018-0134-2. Full text in Research Archive
• Sønderby, Ida Elken; Gustafsson, Omar; Doan, Nhat Trung; Hibar, Derrek; Martin-Brevet, Sandra & Espeseth, Thomas [Show all 15 contributors for this article] (2018). Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Molecular Psychiatry. ISSN 1359-4184. p. 1–16. doi: 10.1038/s41380-019-0358-8. Full text in Research Archive Show summary

  Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

• Meer, Dennis van der; Rokicki, Jaroslav; Kaufmann, Tobias; Palomera, Aldo Còrdova; Moberget, Torgeir & Alnæs, Dag [Show all 54 contributors for this article] (2018). Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes. Molecular Psychiatry. ISSN 1359-4184. p. 1–13. doi: 10.1038/s41380-018-0262-7. Full text in Research Archive Show summary

  The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

• Athanasiu, Lavinia; Smorr, Lisa-Lena H; Tesli, Martin Steen; Røssberg, Jan Ivar; Sønderby, Ida Elken & Spigset, Olav [Show all 8 contributors for this article] (2015). Genome-wide association study identifies common variants associated with pharmacokinetics of psychotropic drugs. Journal of Psychopharmacology. ISSN 0269-8811. 29(8), p. 884–891. doi: 10.1177/0269881115584469. Full text in Research Archive
• Hughes, Timothy; Hansson, Lars Johan Axel; Sønderby, Ida Elken; Athanasiu, Lavinia; Zuber, Verena & Tesli, Martin Steen [Show all 13 contributors for this article] (2015). A Loss-of-Function Variant in a Minor Isoform of ANK3 Protects Against Bipolar Disorder and Schizophrenia. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2015.09.021. Full text in Research Archive
• Goulart, Luiz Fernando De Souza; Bettella, Franscesco; Sønderby, Ida Elken; Schork, Andrew J.; Thompson, Kurt Wesley & Mattingsdal, Morten [Show all 12 contributors for this article] (2015). MicroRNAs enrichment in GWAS of complex human phenotypes. BMC Genomics. 16:304. doi: 10.1186/s12864-015-1513-5. Full text in Research Archive Show summary

  Background: The genotype information carried by Genome-wide association studies (GWAS) seems to have the potential to explain more of the ‘missing heritability’ of complex human phenotypes, given improved statistical approaches. Several lines of evidence support the involvement of microRNA (miRNA) and other non-coding RNA in complex human traits and diseases. We employed a novel, genetic annotation-informed enrichment method for GWAS that captures more polygenic effects than standard GWAS analysis, to investigate if miRNA-tagging Single Nucleotide Polymorphisms (SNPs) are enriched of associations with 15 complex human phenotypes. We then leveraged the enrichment using a conditional False Discovery Rate (condFDR) approach to assess any improvement in the detection of individual miRNA SNPs associated with the disorders. Results: We found SNPs tagging miRNA transcription regions to be significantly enriched of associations with 10 of 15 phenotypes. The enrichment remained significant after controlling for affiliation to other genomic categories, and was confirmed by replication. Albeit only nominally significant, enrichment was found also in miRNA binding sites for 10 phenotypes out of 15. Leveraging the enrichment in the condFDR framework, we observed a 2-4-fold increase in discovery of SNPs tagging miRNA regions. Conclusions: Our results suggest that miRNAs play an important role in the polygenic architecture of complex human disorders and traits, and therefore that miRNAs are a genomic category that can and should be used to improve gene discovery.

• Zayats, Tetyana; Athanasiu, Lavinia; Sønderby, Ida Elken; Djurovic, Srdjan; Westlye, Lars Tjelta & Tamnes, Christian Krog [Show all 15 contributors for this article] (2015). Genome-wide analysis of attention deficit hyperactivity disorder in Norway. PLOS ONE. 10(4). doi: 10.1371/journal.pone.0122501. Full text in Research Archive Show summary

  Background Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci. Materials and Methods Participants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD. Results In total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28–1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21–1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14–1.66, p=8.31E-04). Conclusion This study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.

• Zai, Clement C; Manchia, M; Sønderby, Ida Elken; Yilmaz, Z.; Luca, Valeria De & Tiwari, AK [Show all 19 contributors for this article] (2015). Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders. World Journal of Biological Psychiatry. ISSN 1562-2975. 16(3), p. 171–179. doi: 10.3109/15622975.2014.953011. Full text in Research Archive
• Finseth, Per Ivar; Sønderby, Ida Elken; Djurovic, Srdjan; Agartz, Ingrid; Malt, Ulrik Fredrik & Melle, Ingrid [Show all 10 contributors for this article] (2014). Association analysis between suicidal behaviour and candidate genes of bipolar disorder and schizophrenia. Journal of Affective Disorders. ISSN 0165-0327. 163, p. 110–114. doi: 10.1016/j.jad.2013.12.018. Full text in Research Archive Show summary

  Background: The present study investigated associations between the strongest joint genetic risk variants for bipolar disorder (BD) and schizophrenia (SCZ) and a history of suicide attempt in patients with BD, SCZ and related psychiatric disorders. Methods: A history of suicide attempt was assessed in a sample of 1009 patients with BD, SCZ and related psychosis spectrum disorders, and associations with the joint genetic risk variants for BD and SCZ (rs2239547 (ITIH3/4-region), rs10994359 (ANK3) and rs4765905 (CACNA1 C)) were investigated. Previously reported susceptibility loci for suicide attempt in BD were also investigated. Associations were tested by logistic regression with Bonferroni correction for multiple testing. Results: The risk allele in rs2239547 (ITIH3/4-region) was significantly associated with a history of suicide attempt (p ¼ 0.01) after multiple testing correction (p threshold o 0.017). The previous suicide attempt susceptibility loci were only nominally associated, but had the same direction of risk in the replication sample (sign test, p ¼ 0.02). Limitations: Relatively small sample size and retrospective clinical assessment. Conclusions: We detected a novel association between suicide attempt and the ITIH3/4-region in a combined group of patients with BD, SCZ and related psychosis spectrum disorders. This may be useful in understanding molecular mechanisms of suicidal behaviour in severe mental disorders, although replication is warranted. Keywords: Suicidal behaviour; Bipolar disorder; Schizophrenia; Candidate gene

• Tesli, Martin Steen; Egeland, Randi; Sønderby, Ida Elken; Haukvik, Unn Kristin H.; Bettella, Franscesco & Hibar, Derrek [Show all 12 contributors for this article] (2013). No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes. Journal of Affective Disorders. ISSN 0165-0327. 151(1), p. 291–297. doi: 10.1016/j.jad.2013.06.008. Full text in Research Archive
• Mattingsdal, Morten; Brown, Andrew; Djurovic, Srdjan; Sønderby, Ida Elken; ALONSO, ANDRES SERVER & Melle, Ingrid [Show all 10 contributors for this article] (2013). Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways. NeuroImage. ISSN 1053-8119. 70, p. 143–149. doi: 10.1016/j.neuroimage.2012.12.035. Full text in Research Archive
• Wirgenes, Katrine Verena; Sønderby, Ida Elken; Haukvik, Unn Kristin H.; Mattingsdal, Morten; Tesli, Martin Steen & Athanasiu, Lavinia [Show all 14 contributors for this article] (2012). TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Translational Psychiatry. 2(e112). doi: 10.1038/tp.2012.39. Full text in Research Archive

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• Birkenæs, Viktoria; Parekh, Pravesh; Andreassen, Ole; Havdahl, Alexandra & Sønderby, Ida Elken (2024). Predicting first-episode psychosis using polygenic risk and longitudinal child and adolescent phenotypes. Full text in Research Archive
• Kopal, Jakub; Kumar, Kuldeep; Shafighi, Kimia; Saltoun, Karin; Modenato, Claudia & Moreau, Clara A. [Show all 30 contributors for this article] (2024). Correction to: Using rare genetic mutations to revisit structural brain asymmetry (Nature Communications, (2024), 15, 1, (2639), 10.1038/s41467-024-46784-w). Nature Communications. 15(1). doi: 10.1038/s41467-024-47545-5. Full text in Research Archive
• Birkenæs, Viktoria; Shadrin, Alexey; Parekh, Pravesh; Frei, Evgeniia; Havdahl, Alexandra & Andreassen, Ole [Show all 7 contributors for this article] (2023). Self-Reported Psychotic Experiences: Does an Unreliable Phenotypic Measure Introduce Bias in Genetic Associations? Full text in Research Archive
• Birkenæs, Viktoria; Shadrin, Alexey; Frei, Evgeniia; Parekh, Pravesh; Jaholkowski, Piotr Pawel & Smeland, Olav Bjerkehagen [Show all 9 contributors for this article] (2023). Genome-Wide Analysis of Self-Reported Psychotic Experiences in the Norwegian Mother, Father, and Child study. Full text in Research Archive
• Akdeniz, Bayram Cevdet; Bøen, Rune; Frei, Oleksandr; Hovig, Eivind; Andreassen, Ole & Sønderby, Ida Elken (2022). LARGE-SCALE ANALYSIS WITH SOFTWARE CONTAINERS IN ENIGMA-CNV–AN INTERNATIONAL WORKING GROUP TO STUDY RECURRENT COPY NUMBER VARIANTS AND BRAIN MEASURES. Neuropsychopharmacology, 2022. Full text in Research Archive
• Sønderby, Ida Elken (2017). The 16p11.2 Distal Copy Number Variant Conveys Dose-Response Effects on Intracranial Volume and Structures of the Basal ganglia: A Mega-Analysis from the Enigma-CNV Working Group. Full text in Research Archive
• Sønderby, Ida Elken (2017). Update, ENIGMA-CNV - from genes to phenotypes to brain structures. Full text in Research Archive
• Sønderby, Ida Elken (2016). Coupling subcortical brain volumes with CNVs: A preliminary mega-analysis in ENIGMA-CNV. Full text in Research Archive
• Córdova-Palomera, Aldo; Bettella, Francesco; Wang, Yunpeng; Doan, Nhat Trung; Alnæs, Dag & Moberget, Torgeir [Show all 11 contributors for this article] (2016). POTENTIAL BRAIN MORPHOLOGY INSTABILITY FEATURES MEDIATING THE ASSOCIATION BETWEEN GENOME-WIDE HOMOZYGOSITY AND ALTERED NEUROCOGNITION. Full text in Research Archive
• Sønderby, Ida Elken (2016). ENIGMA-CNV - a genetics-MR-project - finding the needle in the haystack. Full text in Research Archive
• Sønderby, Ida Elken (2016). Association of subcortical brain volumes with CNVs: A mega-analysis from the ENIGMA-CNV working group. Full text in Research Archive
• Sønderby, Ida Elken (2015). ENIGMA CNV working group: Coupling subcortical brain volumes with CNVs in healthy and patient populations. Full text in Research Archive

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