Anders Martin Dale

• 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
• Fuhrer, Julian; Shadrin, Alexey; Hughes, Timothy; Parker, Nadine; Hindley, Guy Frederick Lanyon & Frei, Evgeniia [Show all 12 contributors for this article] (2026). Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders. American Journal of Human Genetics. ISSN 0002-9297. p. 1–13. doi: 10.1016/j.ajhg.2026.08.012. Full text in Research Archive
• Koch, Elise; Parker, Nadine; Mohammad, Helin; Lenk, Hasan Cagin; Ystaas, Lars Andreas Rømo & Jaholkowski, Piotr Pawel [Show all 13 contributors for this article] (2026). Genetic overlap between treatment-resistant schizophrenia and smoking initiation. International Journal of Neuropsychopharmacology. ISSN 1461-1457. 29(7). doi: 10.1093/ijnp/pyag035. Full text in Research Archive Show summary

  Background Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior. Objective Here, we aim to identify genetic variants associated with TRS by leveraging overlapping genetic variants with smoking initiation to increase statistical power. Methods We analyzed genome-wide data for TRS and smoking initiation with the conditional/conjunctional false discovery rate (cond/conjFDR) to identify shared loci, and LD score regression to determine genetic correlations. To investigate potential causal effects of shared loci, we performed Mendelian randomization analyses. Shared loci were mapped to genes, which were further investigated for enrichment of drug target genes. Results We observed a significant positive genetic correlation between TRS and smoking initiation (rg = 0.47 P = .0002). Leveraging the genetic overlap between TRS and smoking initiation, we identified four novel loci jointly associated with TRS and smoking initiation. The condFDR results improved polygenic prediction of TRS. Mendelian randomization indicates putative evidence for a causal effect of genetic liability to TRS on smoking initiation. The functional genetic analyses suggest that alpha-1-adrenergic receptors may be involved in the pathophysiology of TRS and possibly related to the efficacy of clozapine versus other antipsychotic drugs. Conclusion In conclusion, our results show that shared genetic mechanisms influence both TRS and smoking behavior, which provide new insights into the biological underpinnings of TRS.

• 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.

• Tesfaye, Markos; Shadrin, Alexey; Parker, Nadine; Jaholkowski, Piotr Pawel; Parekh, Pravesh & Kutrolli, Gleda [Show all 16 contributors for this article] (2026). Comorbidity Alters the Genetic Relationship Between Anxiety Disorders and Major Depression. Biological Psychiatry. ISSN 0006-3223. 100(6), p. 689–698. doi: 10.1016/j.biopsych.2026.04.026. Full text in Research Archive
• Rødevand, Linn Nilsen; Rahman, Mohammad Zillur; Jaholkowski, Piotr Pawel; Parker, Nadine; Valdimarsdóttir, Unnur Anna & Smeland, Olav Bjerkehagen [Show all 14 contributors for this article] (2026). Evidence for overlapping genetic architecture between lifestyle factors and severe mental disorders with different patterns across diagnoses. EBioMedicine. 128. doi: 10.1016/j.ebiom.2026.106304. Full text in Research Archive
• Wang, Xin; Sofer, Tamar; Frei, Oleksandr; Kaplan, Robert; Perreira, Krista M. & Franceschini, Nora [Show all 12 contributors for this article] (2026). Explicitly modeling genetic ancestry to improve polygenic prediction accuracy for height in a large, admixed cohort of US Latinos: Findings from HCHS/SOL. Human Genetics and Genomics Advances (HGG Advances). 7(3). doi: 10.1016/j.xhgg.2026.100597. Full text in Research Archive
• Holen, Børge; Rahman, Mohammad Zillur; Shadrin, Alexey; Icick, Romain; O'Connell, Kevin Sean & Rødevand, Linn [Show all 14 contributors for this article] (2026). Shared genetic variants across substance use disorders implicate common neurobiological pathways, a genome‐wide mixed methods study. BMJ General Psychiatry (GPSYCH). ISSN 2096-5923. 39(2). doi: 10.1002/gps3.70017. Full text in Research Archive Show summary

  ABSTRACT Background Substance use disorders (SUDs) are highly heritable, but the extent of shared and distinct genetic architecture across different SUDs is unclear. Aims To compare the genetic architectures of alcohol use disorder (AUD), cannabis use disorder (CUD) and opioid use disorder (OUD) and to identify shared and unique genetic loci. Methods We analysed large‐scale genome‐wide association study (GWAS) summary statistics from individuals of European ancestry recruited in Europe and the USA. The mixture model MiXeR was used to estimate the unique genetic architecture characteristics of each SUD, including its polygenicity, single nucleotide polymorphism (SNP)‐heritability and discoverability, a measure of the distribution of genetic signal across all causal variants. Pairwise conditional/conjunctional false discovery rate (cond/conjFDR) analyses identified shared loci, followed by biological annotation of implicated genes. Results AUD demonstrated the highest polygenicity, followed by CUD and OUD. SNP‐based heritability was 0.10 for AUD and OUD and 0.01 for CUD. Discoverability was highest for OUD, followed by AUD and CUD. Currently, genome‐wide significant SNPs explain 2.0% of AUD, 0.3% of CUD and 0.2% of OUD variance. Cond/conjFDR identified 39 novel loci for AUD, 10 for CUD and 1 for OUD. Of implicated genes, most were expressed in the brain, including several involved in gamma‐aminobutyric acid and dopaminergic neurotransmission, opioid neurophysiology, myelination, DNA recombination, apoptosis and ubiquitin‐dependent protein catabolism. Conclusions SUDs have polygenic architectures with many shared loci and are similar with regards to some characteristics. However, the level of polygenicity differs across SUDs, with AUD being considerably more polygenic than OUD, whereas CUD is intermediate in terms of its polygenicity. The novel loci implicate genes primarily expressed in the brain, involving a variety of biological functions. The findings expand our view of the aetiology of these disorders, while supporting the hypothesis of a shared set of pleiotropic SUD genes.

• Parker, Nadine; Koch, Elise; Shadrin, Alexey; Fuhrer, Julian; Hindley, Guy F. L. & Stinson, Sara Elizabeth [Show all 15 contributors for this article] (2026). Leveraging the genetics of psychiatric disorders to prioritize potential drug targets and compounds. Neuropsychopharmacology. ISSN 0893-133X. doi: 10.1038/s41386-026-02380-8. Full text in Research Archive
• Moberget, Torgeir; Meer, Dennis van der; Bahrami, Shahram; Roelfs, Daniël; Frei, Oleksandr & Kaufmann, Tobias Herbert [Show all 15 contributors for this article] (2026). The genetic architecture of human cerebellar morphology supports a key role for the cerebellum in human evolution and psychopathology. Communications Biology. 9(1). doi: 10.1038/s42003-026-09664-1. Full text in Research Archive Show summary

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

• Stinson, Sara E.; Shadrin, Alexey; Rahman, Mohammad Zillur; Rødevand, Linn; Broce, Iris J. & Selbæk, Geir [Show all 17 contributors for this article] (2026). Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap. EBioMedicine. 127. doi: 10.1016/j.ebiom.2026.106254. Full text in Research Archive Show summary

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

• Wiström, Erik David; Fuhrer, Julian; Shadrin, Alexey; Fominykh, Vera; O'Connell, Kevin Sean & Jaholkowski, Piotr Pawel [Show all 17 contributors for this article] (2026). Dissecting the genetic relationship between severe mental disorders and autoimmune diseases. Brain, Behavior, and Immunity. ISSN 0889-1591. 133. doi: 10.1016/j.bbi.2025.106249. Full text in Research Archive Show summary

  Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune thyroiditis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes), involving a total of 667,518 cases from 10 genome-wide association studies. While MD was positively genetically correlated with five autoimmune diseases, BD and SCZ were only positively correlated with IBD, suggesting differences in the genetic signal shared with autoimmunity across these mental disorders. A considerable fraction of genetic variants influencing autoimmune diseases (range 17.1–88.4 %) was estimated to overlap with mental disorders; however, this constitutes only a minor part of genetic variants influencing the more polygenic mental disorders. Finally, we identified 172 genetic loci jointly affecting mental disorders and autoimmune diseases, implicating both lipid metabolism and TNF signaling. In conclusion, MD, BD, and SCZ have a small but distinct genetic overlap with autoimmune diseases, which may inform new possible immune targets for treatment in mental illness.

• O'Connell, Kevin Sean; Adolfsson, Rolf; Andlauer, Till F.M.; Bauer, Michael; Baune, Bernhaud & Biernacka, Joanna M. [Show all 52 contributors for this article] (2025). New Genomics Discoveries Across the Bipolar Disorder Spectrum Implicate Neurobiological and Developmental Pathways. Biological Psychiatry. ISSN 0006-3223. 98(4), p. 302–310. doi: 10.1016/j.biopsych.2025.05.020. Full text in Research Archive Show summary

  Bipolar disorder (BD) is a highly heritable mental disorder that affects millions of people worldwide. Our understanding of the genetic etiology and biological processes that underlie BD have greatly increased in recent years. Extensive progress has been made in identifying common variant signals for BD, and the polygenic score from the latest genome-wide association study (GWAS) may provide some clinical utility if combined with other risk factors for BD. The role of rare variation in BD remains to be determined, although genes annotated to common variant loci are shown to be enriched for rare variation. BD subtypes have been shown to differ in their genetic architecture, and as such, genetic studies across the subtypes of the BD spectrum will identify subtype-specific signals and reveal subtype-specific biological mechanisms. Despite this, subtype-specific GWAS sample sizes have not increased at the same rate as BD cases, and more concerted efforts are required to obtain this information for participants included in future BD GWASs. Moreover, assessment of culture, geography, and other systematic differences that may impact patient assessment will be necessary to ensure accurate inclusion of diverse ancestral groups and global representation in genetic studies of BD moving forward.

• Shen, Jie; Valentim, Wander; Friligkou, Eleni; Overstreet, Cassie; Choi, Karmel W. & Koller, Dora [Show all 245 contributors for this article] (2025). Shared genetic architecture of posttraumatic stress disorder with cardiovascular imaging, risk, and diagnoses. Nature Communications. 16(1). doi: 10.1038/s41467-025-60487-w. Full text in Research Archive Show summary

  Patients with post-traumatic stress disorder face increased cardiovascular risk. This study examines shared genetic regions between post-traumatic stress disorder and 246 cardiovascular conditions across electronic health records, 82 cardiac imaging, and health behaviors defined by Life’s Essential 8. Post-traumatic stress disorder is genetically correlated with cardiovascular diagnoses in 33 regions, imaging traits in 4 regions, and health behaviors in 44 regions. Potentially shared causal variants between post-traumatic stress disorder and 17 cardiovascular conditions were observed in 11 regions. Subsequent observational analysis in AllofUS cohort showed post-traumatic stress disorder is associated with 13 diagnoses even after accounting for socioeconomic factors and depression. Genetically regulated proteome expression in brain and blood tissues identified 33 blood and 122 brain genes shared between the two conditions, revealing neuronal, immune, metabolic, and calcium-related mechanisms, with several genes as targets for existing drugs. These findings exhibit shared risk loci and genes are involved in tissue-specific mechanisms.

• Makowski, Carolina; Shafiei, Golia; Martinho, Megan; Hagler, Donald J.; Pecheva, Diliana & Dale, Anders [Show all 9 contributors for this article] (2025). Multivariate patterns linking brain microstructure to temperament and behavior in adolescent eating disorders. Molecular Psychiatry. ISSN 1359-4184. 30(11), p. 5326–5337. doi: 10.1038/s41380-025-03117-7. Full text in Research Archive Show summary

  Eating disorders (EDs) are multifaceted psychiatric disorders characterized by varying behaviors, traits, and cognitive profiles driving symptom heterogeneity and severity. Non-invasive neuroimaging studies have been critical to elucidate the neurobiological circuitry involved in ED-related behaviors, but often focused on a limited set of regions of interest and/or symptoms. The current study harnesses multivariate methods to map microstructural and morphometric patterns across the entire brain to multiple domains of behavior and symptomatology in adolescents with EDs. Diffusion-weighted images, modeled with restriction spectrum imaging, were analyzed for 91 adolescents with an ED and 48 healthy controls. Partial least squares analysis was applied to map 38 behavioral measures (encompassing cognition, temperament, and ED symptoms) to restricted diffusion in white matter tracts and subcortical structures across 65 regions of interest. The first significant latent variable explained 46.9% of the covariance between microstructure and behavior. This latent variable retained a significant brain-behavior correlation in held-out data, where an ‘undercontrolled’ behavioral profile (e.g., higher emotional dysregulation, novelty seeking; lower effortful control and interoceptive awareness) was linked to increased restricted diffusion across white matter tracts, particularly those joining frontal, limbic, and thalamic regions. Individually-derived brain and behavior scores for this latent variable were higher in individuals with binge-purge symptoms, compared to those with only restrictive eating symptoms. Findings demonstrate the value of applying multivariate modeling to the array of brain-behavior relationships inherent to the clinical presentation of EDs, and their relevance for providing a neurobiologically-informed model for future clinical subtyping and prediction efforts.

• Pineiro, Didac Vidal; Sørensen, Øystein; Strømstad, Marie Lorentsen; Amlien, Inge; Baaré, William & Bartrés-Faz, David [Show all 74 contributors for this article] (2025). Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change. Nature Communications. 16(1). doi: 10.1038/s41467-025-66354-y. Full text in Research Archive Show summary

  Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer’s Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whethermemory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reachingmoderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

• Takamiya, Akihiro; Riemer, Frank; Erchinger, Vera Jane; Korbmacher, Max; Bartsch, Hauke & Ousdal, Olga Therese [Show all 12 contributors for this article] (2025). Acute and transient change in brain water content induced by a single electroconvulsive therapy session. Brain Stimulation. ISSN 1935-861X. 18(6), p. 2008–2015. doi: 10.1016/j.brs.2025.10.021. Full text in Research Archive Show summary

  Background While electroconvulsive therapy (ECT) is the most effective treatment for severe depression, there is a concern regarding its potential adverse effects on the brain. It is unclear whether a single ECT session (i.e., an electrically induced seizure) leads to physiological microstructural changes or causes lasting adverse biological effects. Methods This study examined longitudinal changes in multishell diffusion MRI-derived metrics in 25 individuals with depression, with scans acquired 2 h before and after their first ECT session. Follow-up scans were collected within 14 days and 6 months after the last ECT session. To control for potential confounding effects of anesthesia and repeated measurements, two additional groups were included: 16 individuals undergoing short-acting anesthesia and 16 healthy controls without interventions. A multicompartment model was applied to explore extracellular free water and intracellular/extracellular compartments. Results Whole-brain voxel-wise analyses identified increased extracellular free water in bilateral periventricular and subcortical regions surrounding the hippocampus, with minimal involvement of cortical regions, following a single ECT session. These changes were not observed in either control group, and were not associated with post-ictal reorientation time (r = 0.11, p = 0.92). Follow-up assessments confirmed that the alterations in tissue free water resolved within 14 days. Conclusions A single ECT-induced seizure induces a transient increase in extracellular water content without evidence of cytotoxic edema indicative of cellular injury. Our findings suggest that ECT-related brain water shifts are reversible and unlikely to reflect permanent damage to brain tissue.

• Koch, Elise; Shadrin, Alexey; Parker, Nadine; Lock, Siobhan K.; Smith, Robert Løvsletten & Frei, Oleksandr [Show all 11 contributors for this article] (2025). Polygenic overlap with granulocyte counts identifies novel loci for clozapine metabolism and clozapine-induced agranulocytosis. Neuropsychopharmacology. ISSN 0893-133X. 50, p. 947–955. doi: 10.1038/s41386-025-02054-x. Full text in Research Archive Show summary

  While clozapine is the most effective antipsychotic drug, its use is limited due to hematological adverse effects involving the reduction of granulocyte counts with potential life-threatening agranulocytosis. It is not yet possible to predict or prevent the risk of agranulocytosis, and the mechanisms are unknown but likely related to clozapine metabolism. Genome-wide association studies (GWASs) of clozapine metabolism and clozapine-induced agranulocytosis have identified few genetic loci. We used the largest available GWAS summary statistics of clozapine metabolism (clozapine-to-norclozapine ratio) and clozapine-induced agranulocytosis, applying the conditional false discovery rate (condFDR) method to increase power for genetic discovery by conditioning on granulocyte counts variants. To investigate potential causal effects of shared loci, we performed Mendelian Randomization analyses. After conditioning on granulocyte counts, we identified two novel loci associated with clozapine-to-norclozapine ratio. These loci were significantly associated with clozapine metabolism in a validation sample of 392 clozapine-treated individuals. For clozapine-induced agranulocytosis, five loci were identified after conditioning on granulocyte counts. These five loci were significantly associated with reduced granulocyte counts in a small independent sample of clozapine-treated individuals. Genetic liability to slow clozapine metabolism (high clozapine-to-norclozapine ratio) showed evidence of a causal effect on reduced neutrophil counts, and genetic liability to low neutrophil counts exhibited weak evidence of a causal effect on clozapine-induced agranulocytosis. Our findings of shared genetic variants associated with clozapine metabolism and granulocyte counts may form the basis for developing prediction models for clozapine-induced agranulocytosis.

• Wiström, Erik David; O'Connell, Kevin Sean; Koch, Elise; Jaholkowski, Piotr Pawel; Hindley, Guy & Steen, Nils Eiel [Show all 14 contributors for this article] (2025). The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6. Journal of Affective Disorders Reports. 20, p. 1–10. doi: 10.1016/j.jadr.2025.100889. Full text in Research Archive Show summary

  Background: Immune dysregulation may contribute to the pathophysiology of major depressive disorder (MDD). Here we aimed to identify genetic architecture jointly associated with MDD, white blood cell (WBC) count and interleukin 6 (IL-6) levels. Methods: Using genome-wide association studies summary statistics on MDD (330,173 cases and 727,595 controls), WBC counts (nmax = 563,946) and IL-6 (n = 52,654), we performed linkage disequilibrium (LD) score regression, bivariate causal mixture model (MiXeR), conjunctional false discovery rate (conjFDR) and Mendelian randomization (MR) analyses. Additionally, we used an independent MDD dataset (9,582 cases and 84,670 controls) from the Norwegian Mother, Father and Child Cohort Study for polygenic risk score (PRS) analyses. Findings: We found a significant positive genetic correlation (rg = 0.22) between MDD and IL-6. MiXeR estimates indicated substantial differences in the polygenicity of MDD (13.7K variants), WBC subgroups (0.8K-1.8K variants), and IL-6 (0.2K variants), with 10.1 %-31.4 % of the variants influencing WBC subgroups overlapping with MDD. We identified MDD risk loci shared with basophils (8), eosinophils (17), lymphocytes (23), monocytes (14), neutrophils (20), and total WBC counts (20), as well as two loci shared between MDD and IL-6, at conjFDR <0.05. PRS analysis showed a weak, but significantly increased risk for MDD dependent on monocyte count. Limitations: The analyses only included European ancestry samples, and the causal genes associated with the identified genetic loci were not experimentally validated. Conclusions: MDD shares genetic underpinnings with immune system components, which implicates immune-mediated pathways in the pathophysiology of MDD. However, this connection may only be relevant for a minority of patients.

• Icick, Romain; Shadrin, Alexey; Holen, Børge; Karadag, Naz; Parker, Nadine & O'Connell, Kevin Sean [Show all 20 contributors for this article] (2025). Identification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder. Nature Mental Health. 3(2), p. 253–265. doi: 10.1038/s44220-024-00353-8. Full text in Research Archive Show summary

  Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies can provide new evidence regarding the etiology of AUD. We report a multi-ancestry genome-wide association study focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals (102,079 cases; European, 75,583; African, 20,689 (mostly African American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent). Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci (105 variants) were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes, which show altered expression in brain regions relevant for AUD (striatum, hypothalamus and prefrontal cortex) and encode potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting that they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically relevant comorbidities.

• 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.

• Roelfs, Daniel; Meer, Dennis van der; Alnæs, Dag; Frei, Oleksandr; Shadrin, Alexey & Loughnan, Robert [Show all 11 contributors for this article] (2024). Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders. Nature Mental Health. 2(2), p. 189–199. doi: 10.1038/s44220-023-00190-1. Full text in Research Archive
• Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey; Meer, Dennis van der; Akdeniz, Bayram Cevdet & Hagen, Espen [Show all 50 contributors for this article] (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature Genetics. ISSN 1061-4036. 56(6), p. 1310–1318. doi: 10.1038/s41588-024-01771-1. Full text in Research Archive
• He, Qiang; Wang, Wenjing; Xu, Dingkang; Xiong, Yang; Tao, Chuanyuan & You, Chao [Show all 185 contributors for this article] (2024). Potential causal association between gut microbiome and posttraumatic stress disorder. Translational Psychiatry. 14(1). doi: 10.1038/s41398-024-02765-7. Full text in Research Archive Show summary

  Background The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). Methods The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the MiBioGen consortium. As to PTSD, the Freeze 2 datasets were originated from the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD), and the replicated datasets were obtained from FinnGen consortium. Single nucleotide polymorphisms meeting MR assumptions were selected as instrumental variables. The inverse variance weighting (IVW) method was employed as the main approach, supplemented by sensitivity analyses to evaluate potential pleiotropy and heterogeneity and ensure the robustness of the MR results. We also performed reverse MR analyses to explore PTSD’s causal effects on the relative abundances of specific features of the gut microbiome. Results In Freeze 2 datasets from PGC-PTSD, eight bacterial traits revealed a potential causal association between gut microbiome and PTSD (IVW, all P < 0.05). In addition, Genus.Dorea and genus.Sellimonas were replicated in FinnGen datasets, in which eight bacterial traits revealed a potential causal association between gut microbiome and the occurrence of PTSD. The heterogeneity and pleiotropy analyses further supported the robustness of the IVW findings, providing additional evidence for their reliability. Conclusion Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms.

• Tong, Michelle W.; Yu, Hon J.; Andreassen, Maren Marie Sjaastad; Loubrie, Stephane; Rodríguez-Soto, Ana E. & Seibert, Tyler [Show all 8 contributors for this article] (2024). Longitudinal registration of T<inf>1</inf>-weighted breast MRI: A registration algorithm (FLIRE) and clinical application. Magnetic Resonance Imaging. ISSN 0730-725X. 113. doi: 10.1016/j.mri.2024.110222. Full text in Research Archive
• Nievergelt, Caroline M.; Maihofer, Adam X.; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W. & Coleman, Jonathan R. I. [Show all 235 contributors for this article] (2024). Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nature Genetics. ISSN 1061-4036. 56, p. 792–808. doi: 10.1038/s41588-024-01707-9. Full text in Research Archive Show summary

  Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

• Parker, Nadine; Cheng, Weiqiu; Hindley, Guy; O'Connell, Kevin Sean; Karthikeyan, Sandeep & Holen, Børge [Show all 19 contributors for this article] (2023). Genetic Overlap Between Global Cortical Brain Structure, C-Reactive Protein, and White Blood Cell Counts. Biological Psychiatry. ISSN 0006-3223. 95(1). doi: 10.1016/j.biopsych.2023.06.008. Full text in Research Archive Show summary

  Background For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). Methods Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. Results Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (rg_surface_area = −0.13, false discovery rate–corrected p = 4.17 × 10−3; rg_thickness = −0.13, false discovery rate–corrected p = 4.00 × 10−2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. Conclusions The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.

• Wang, Lu; Heffner, Caleb; Vong, Keng loi; Barrows, Chelsea; Ha, Yoo-Jin & Lee, Sangmoon [Show all 20 contributors for this article] (2023). TMEM161B modulates radial glial scaffolding in neocortical development. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(4). doi: 10.1073/pnas.2209983120. Full text in Research Archive Show summary

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

• Andreassen, Maren Marie Sjaastad; Loubrie, Stephane; Tong, Michelle W.; Fang, Lauren; Seibert, Tyler & Wallace, Anne M. [Show all 15 contributors for this article] (2023). Restriction spectrum imaging with elastic image registration for automated evaluation of response to neoadjuvant therapy in breast cancer. Frontiers in Oncology. 13. doi: 10.3389/fonc.2023.1237720. Full text in Research Archive Show summary

  Purpose: Dynamic contrast-enhanced MRI (DCE) and apparent diffusion coefficient (ADC) are currently used to evaluate treatment response of breast cancer. The purpose of the current study was to evaluate the three-component Restriction Spectrum Imaging model (RSI3C), a recent diffusion-weighted MRI (DWI)-based tumor classification method, combined with elastic image registration, to automatically monitor breast tumor size throughout neoadjuvant therapy. Experimental design: Breast cancer patients (n=27) underwent multi-parametric 3T MRI at four time points during treatment. Elastically-registered DWI images were used to generate an automatic RSI3C response classifier, assessed against manual DCE tumor size measurements and mean ADC values. Predictions of therapy response during treatment and residual tumor post-treatment were assessed using non-pathological complete response (non-pCR) as an endpoint. Results: Ten patients experienced pCR. Prediction of non-pCR using ROC AUC (95% CI) for change in measured tumor size from pre-treatment time point to early-treatment time point was 0.65 (0.38-0.92) for the RSI3C classifier, 0.64 (0.36-0.91) for DCE, and 0.45 (0.16-0.75) for change in mean ADC. Sensitivity for detection of residual disease post-treatment was 0.71 (0.44-0.90) for the RSI3C classifier, compared to 0.88 (0.64-0.99) for DCE and 0.76 (0.50-0.93) for ADC. Specificity was 0.90 (0.56-1.00) for the RSI3C classifier, 0.70 (0.35-0.93) for DCE, and 0.50 (0.19-0.81) for ADC. Conclusion: The automatic RSI3C classifier with elastic image registration suggested prediction of response to treatment after only three weeks, and showed performance comparable to DCE for assessment of residual tumor post-therapy. RSI3C may guide clinical decision-making and enable tailored treatment regimens and cost-efficient evaluation of neoadjuvant therapy of breast cancer.

• Bahrami, Shahram; Nordengen, Kaja; Shadrin, Alexey; Frei, Oleksandr; Meer, Dennis van der & Dale, Anders [Show all 9 contributors for this article] (2022). Distributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders. Nature Communications. 13(1). doi: 10.1038/s41467-022-31086-w. Full text in Research Archive Show summary

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

• Loughnan, Robert J.; Shadrin, Alexey; Frei, Oleksandr; Meer, Dennis van der; Zhao, Weiqi & Palmer, Clare E. [Show all 12 contributors for this article] (2022). Generalization of cortical MOSTest genome-wide associations within and across samples. NeuroImage. ISSN 1053-8119. 263. doi: 10.1016/j.neuroimage.2022.119632. Full text in Research Archive Show summary

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

• Cheng, Weiqiu; Meer, Dennis van der; Parker, Nadine; Hindley, Guy Frederick Lanyon; O'Connell, Kevin Sean & Wang, Yunpeng [Show all 20 contributors for this article] (2022). Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-022-01751-z. Full text in Research Archive Show summary

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

• Hindley, Guy Frederick Lanyon; O'Connell, Kevin Sean; Rahman, Zillur; Frei, Oleksandr; Bahrami, Shahram & Shadrin, Alexey [Show all 17 contributors for this article] (2022). The shared genetic basis of mood instability and psychiatric disorders: A cross-trait genome-wide association analysis. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 189(6), p. 207–218. doi: 10.1002/ajmg.b.32907. Full text in Research Archive Show summary

  Recent genome-wide association studies of mood instability (MOOD) have found significant positive genetic correlation with major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. GWAS summary statistics for schizophrenia (SCZ, n = 105,318), bipolar disorder (BIP, n = 413,466), DEP (n = 450,619), attention-deficit hyperactivity disorder (ADHD, n = 53,293), and MOOD (n = 363,705) were analyzed using the bivariate causal mixture model and conjunctional false discovery rate methods. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg = 0.10–0.62). Of 10.4 K genomic variants influencing MOOD, 4 K–9.4 K influenced psychiatric disorders. Furthermore, MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25. Fifty-three jointly associated loci were overlapping across two or more disorders, seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, “synapse organization.” The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions may relate to differences in the core clinical features of each disorder.

• Hindley, Guy; Frei, Oleksandr; Shadrin, Alexey; Cheng, Weiqiu; O'Connell, Kevin Sean & Icick, Romain [Show all 17 contributors for this article] (2022). Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation. American Journal of Psychiatry. ISSN 0002-953X. 179(11), p. 833–843. doi: 10.1176/appi.ajp.21101051. Full text in Research Archive
• Makowski, Carolina; Meer, Dennis van der; Dong, Weixiu; Wang, Hao; Wu, Yan & Zou, Jingjing [Show all 18 contributors for this article] (2022). Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases. Science. ISSN 0036-8075. 375(6580). doi: 10.1126/science.abe8457. Full text in Research Archive
• Huynh-Le, Minh-Phuong; Karunamuni, Roshan; Fan, Chun Chieh; Asona, Lui; Thompson, Wesley Kurt & Martinez, Maria Elena [Show all 75 contributors for this article] (2022). Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score. Prostate Cancer and Prostatic Diseases. ISSN 1365-7852. 25(4), p. 755–761. doi: 10.1038/s41391-022-00497-7. Full text in Research Archive Show summary

  Abstract Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. Methods In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. Results The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43–15.16] in ProtecT, 7.07 [6.58–7.60] in African ancestry, 10.31 [9.58–11.11] in Asian ancestry, and 11.18 [10.34–12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11–0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15–0.22) and 0.26 (0.19–0.33), respectively. Conclusions We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

• Akdeniz, Bayram Cevdet; Frei, Oleksandr; Shadrin, Alexey; Vetrov, Dmitry; Kropotov, Dmitry & Dale, Anders [Show all 8 contributors for this article] (2022). Finemap-MiXeR: A variational Bayesian approach for genetic finemapping. BioRxiv. ISSN 0362-4331. Full text in Research Archive
• Loughnan, Robert; Ahern, Jonathan; Tompkins, Cherisse; Palmer, Clare E.; Iversen, John & Thompson, Wesley Kurt [Show all 12 contributors for this article] (2022). Association of Genetic Variant Linked to Hemochromatosis with Brain Magnetic Resonance Imaging Measures of Iron and Movement Disorders. JAMA Neurology. ISSN 2168-6149. 79(9), p. 919–928. doi: 10.1001/jamaneurol.2022.2030. Full text in Research Archive
• Besser, Alexandra H.; Fang, Lauren K.; Tong, Michelle W.; Andreassen, Maren Marie Sjaastad; Ojeda-Fournier, Haydee & Conlin, Christopher C. [Show all 14 contributors for this article] (2022). Tri-Compartmental Restriction Spectrum Imaging Breast Model Distinguishes Malignant Lesions from Benign Lesions and Healthy Tissue on Diffusion-Weighted Imaging. Cancers. 14(13). doi: 10.3390/cancers14133200. Full text in Research Archive Show summary

  Diffusion-weighted MRI (DW-MRI) offers a potential adjunct to dynamic contrast-enhanced MRI to discriminate benign from malignant breast lesions by yielding quantitative information about tissue microstructure. Multi-component modeling of the DW-MRI signal over an extended b-value range (up to 3000 s/mm2) theoretically isolates the slowly diffusing (restricted) water component in tissues. Previously, a three-component restriction spectrum imaging (RSI) model demonstrated the ability to distinguish malignant lesions from healthy breast tissue. We further evaluated the utility of this three-component model to differentiate malignant from benign lesions and healthy tissue in 12 patients with known malignancy and synchronous pathology-proven benign lesions. The signal contributions from three distinct diffusion compartments were measured to generate parametric maps corresponding to diffusivity on a voxel-wise basis. The three-component model discriminated malignant from benign and healthy tissue, particularly using the restricted diffusion C1 compartment and product of the restricted and intermediate diffusion compartments (C1 and C2). However, benign lesions and healthy tissue did not significantly differ in diffusion characteristics. Quantitative discrimination of these three tissue types (malignant, benign, and healthy) in non-pre-defined lesions may enhance the clinical utility of DW-MRI in reducing excessive biopsies and aiding in surveillance and surgical evaluation without repeated exposure to gadolinium contrast.

• Icick, Romain; Shadrin, Alexey; Holen, Børge; Karadag, Naz; Lin, Aihua & Hindley, Guy [Show all 17 contributors for this article] (2022). Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings. Neuropsychopharmacology. ISSN 0893-133X. 47, p. 1883–1891. doi: 10.1038/s41386-022-01401-6. Full text in Research Archive
• Bahrami, Shahram; Shadrin, Alexey A.; Frei, Oleksandr; O`Connell, Kevin; Bettella, Francesco & Krull, Florian [Show all 15 contributors for this article] (2021). Genetic loci shared between major depression and intelligence with mixed directions of effect. Nature Human Behaviour. p. 1–9. doi: 10.1038/s41562-020-01031-2. Full text in Research Archive
• Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Chu, Yunhan; Shadrin, Alexey A. & O'Connell, Kevin Sean [Show all 14 contributors for this article] (2021). Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01527-z. Full text in Research Archive Show summary

  Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.

• Shadrin, Alexey A.; Kaufmann, Tobias; Meer, Dennis van der; Palmer, Clare E.; Makowski, Carolina & Loughnan, Robert [Show all 22 contributors for this article] (2021). Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology. NeuroImage. ISSN 1053-8119. 244, p. 1–8. doi: 10.1016/j.neuroimage.2021.118603. Full text in Research Archive Show summary

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

• Huynh-Le, Minh-Phuong; Fan, Chun Chieh; Karunamuni, Roshan A.; Thompson, Wesley K.; Martinez, Maria Elena & Eeles, Rosalind A. [Show all 78 contributors for this article] (2021). Polygenic hazard score is associated with prostate cancer in multi-ethnic populations. Nature Communications. 12(1). doi: 10.1038/s41467-021-21287-0. Full text in Research Archive
• Chaarani, B.; Hahn, S.; Allgaier, N.; Adise, S.; Owens, M.M. & Juliano, A.C. [Show all 193 contributors for this article] (2021). Baseline brain function in the preadolescents of the ABCD Study. Nature Neuroscience. ISSN 1097-6256. 24(8), p. 1176–1186. doi: 10.1038/s41593-021-00867-9. Full text in Research Archive
• Huynh-Le, Minh-Phuong; Karunamuni, Roshan; Fan, Chun-Chieh; Thompson, Wesley K; Muir, Kenneth & Lophatananon, Artitaya [Show all 13 contributors for this article] (2021). Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men. Prostate Cancer and Prostatic Diseases. ISSN 1365-7852. doi: 10.1038/s41391-021-00341-4. Full text in Research Archive
• Pihlstrøm, Lasse; Fan, Chun Chieh; Frei, Oleksandr; Tan, Manuela; Karunamuni, Roshan A. & Blauwendraat, Cornelis [Show all 12 contributors for this article] (2021). Genetic Stratification of Age-Dependent Parkinson's Disease Risk by Polygenic Hazard Score. Movement Disorders. ISSN 0885-3185. doi: 10.1002/mds.28808. Full text in Research Archive Show summary

  Background Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders. Objectives We aimed to develop and validate a polygenic hazard score model in sporadic PD. Methods Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls. Results A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49–4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. Conclusions We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

• Hindley, Guy Frederick Lanyon; Bahrami, Shahram; Steen, Nils Eiel; O'Connell, Kevin Sean; Frei, Oleksandr & Shadrin, Alexey [Show all 13 contributors for this article] (2021). Characterising the shared genetic determinants of bipolar disorder, schizophrenia and risk-taking. Translational Psychiatry. 11:466, p. 1–10. doi: 10.1038/s41398-021-01576-4. Full text in Research Archive Show summary

  Increased risk-taking is a central component of bipolar disorder (BIP) and is implicated in schizophrenia (SCZ). Risky behaviours, including smoking and alcohol use, are overrepresented in both disorders and associated with poor health outcomes. Positive genetic correlations are reported but an improved understanding of the shared genetic architecture between risk phenotypes and psychiatric disorders may provide insights into underlying neurobiological mechanisms. We aimed to characterise the genetic overlap between risk phenotypes and SCZ, and BIP by estimating the total number of shared variants using the bivariate causal mixture model and identifying shared genomic loci using the conjunctional false discovery rate method. Summary statistics from genome wide association studies of SCZ, BIP, risk-taking and risky behaviours were acquired (n = 82,315–466,751). Genomic loci were functionally annotated using FUMA. Of 8.6–8.7 K variants predicted to influence BIP, 6.6 K and 7.4 K were predicted to influence risk-taking and risky behaviours, respectively. Similarly, of 10.2–10.3 K variants influencing SCZ, 9.6 and 8.8 K were predicted to influence risk-taking and risky behaviours, respectively. We identified 192 loci jointly associated with SCZ and risk phenotypes and 206 associated with BIP and risk phenotypes, of which 68 were common to both risk-taking and risky behaviours and 124 were novel to SCZ or BIP. Functional annotation implicated differential expression in multiple cortical and sub-cortical regions. In conclusion, we report extensive polygenic overlap between risk phenotypes and BIP and SCZ, identify specific loci contributing to this shared risk and highlight biologically plausible mechanisms that may underlie risk-taking in severe psychiatric disorders.

• Andlauer, Till F.M.; Guzman-Parra, José; Streit, Fabian; Strohmaier, Jana; González, Maria José & Flores, Susana Gil [Show all 50 contributors for this article] (2021). Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Molecular Psychiatry. ISSN 1359-4184. 26, p. 1286–1298. doi: 10.1038/s41380-019-0558-2. Full text in Research Archive Show summary

  Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

• Karunamuni, Roshan A.; Huynh-Le, Minh-Phuong; Fan, Chun Chieh; Thompson, Wesley K.; Lui, Asona & Martinez, Maria Elena [Show all 48 contributors for this article] (2021). Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24. Prostate Cancer and Prostatic Diseases. ISSN 1365-7852. doi: 10.1038/s41391-021-00403-7. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Dale, Anders & Andreassen, Ole Andreas (2020). The polygenic architecture of schizophrenia — rethinking pathogenesis and nosology. Nature Reviews Neurology. ISSN 1759-4758. p. 1–14. doi: 10.1038/s41582-020-0364-0. Full text in Research Archive
• Bahrami, Shahram; Steen, Nils Eiel; Shadrin, Alexey A.; O`Connell, Kevin; Frei, Oleksandr & Bettella, Francesco [Show all 13 contributors for this article] (2020). Shared genetic loci between body mass index and major psychiatric disorders: A genome-wide association study. JAMA psychiatry. ISSN 2168-6238. 77(5), p. 503–512. doi: 10.1001/jamapsychiatry.2019.4188. Full text in Research Archive Show summary

  IMPORTANCE People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown. OBJECTIVE To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them. DESIGN, SETTING, AND PARTICIPANTS Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018. MAIN OUTCOMES AND MEASURES The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways. RESULTS Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = −0.11, P = 2.1 × 10−10; BIP: r for genetic = −0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10−10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways. CONCLUSIONS AND RELEVANCE In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones

• Meer, Dennis van der; Frei, Oleksandr; Kaufmann, Tobias; Shadrin, Alexey A.; Devor, Anna & Smeland, Olav Bjerkehagen [Show all 12 contributors for this article] (2020). Understanding the genetic determinants of the brain with MOSTest. Nature Communications. 11:3512, p. 1–9. doi: 10.1038/s41467-020-17368-1. Full text in Research Archive
• Shadrin, Alexey A.; Frei, Oleksandr; Smeland, Olav Bjerkehagen; Bettella, Francesco; O`Connell, Kevin & Gani, Osman [Show all 12 contributors for this article] (2020). Phenotype-specific differences in polygenicity and effect size distribution across functional annotation categories revealed by AI-MiXeR. Bioinformatics. ISSN 1367-4803. doi: 10.1093/bioinformatics/btaa568. Full text in Research Archive Show summary

  Abstract Motivation Determining the relative contributions of functional genetic categories is fundamental to understanding the genetic etiology of complex human traits and diseases. Here, we present Annotation Informed-MiXeR, a likelihood-based method for estimating the number of variants influencing a phenotype and their effect sizes across different functional annotation categories of the genome using summary statistics from genome-wide association studies. Results Extensive simulations demonstrate that the model is valid for a broad range of genetic architectures. The model suggests that complex human phenotypes substantially differ in the number of causal variants, their localization in the genome and their effect sizes. Specifically, the exons of protein-coding genes harbor more than 90% of variants influencing type 2 diabetes and inflammatory bowel disease, making them good candidates for whole-exome studies. In contrast, &amp;lt;10% of the causal variants for schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder are located in protein-coding exons, indicating a more substantial role of regulatory mechanisms in the pathogenesis of these disorders. Availability and implementation The software is available at: https://github.com/precimed/mixer. Supplementary information Supplementary data are available at Bioinformatics online.

• Fan, Chun Chieh; Banks, Sarah J.; Thompson, Wesley K.; Chen, Chi-Hua; McEvoy, Linda K. & Tan, Chin Hong [Show all 14 contributors for this article] (2020). Sex-dependent autosomal effects on clinical progression of Alzheimer's disease. Brain. ISSN 0006-8950. 143(7), p. 2272–2280. doi: 10.1093/brain/awaa164. Full text in Research Archive
• Stahl, Eli A.; Breen, Gerome; Forstner, Andreas J.; McQuillin, Andrew; Ripke, Stephan & Trubetskoy, Vassily [Show all 277 contributors for this article] (2019). Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics. ISSN 1061-4036. 51(5), p. 793–803. doi: 10.1038/s41588-019-0397-8. Full text in Research Archive Show summary

  Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10−4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• Nievergelt, Caroline M.; Maihofer, Adam X.; Klengel, Torsten; Atkinson, Elizabeth G.; Chen, Chia-Yen & Choi, Karmel W. [Show all 179 contributors for this article] (2019). International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature Communications. 10:4558, p. 1–16. doi: 10.1038/s41467-019-12576-w. Full text in Research Archive Show summary

  The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

• Kremen, William S.; Panizzon, Matthew S.; Elman, Jeremy A.; Granholm, Eric L.; Andreassen, Ole Andreas & Dale, Anders [Show all 14 contributors for this article] (2019). Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk. Neurobiology of Aging. ISSN 0197-4580. 83, p. 114–121. doi: 10.1016/j.neurobiolaging.2019.09.001. Full text in Research Archive
• Drange, Ole Kristian; Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Finseth, Per Ivar; Witoelar, Aree & Frei, Oleksandr [Show all 52 contributors for this article] (2019). Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes. Frontiers in Neuroscience. ISSN 1662-4548. 13. doi: 10.3389/fnins.2019.00220. Full text in Research Archive Show summary

  Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect). Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Shadrin, Alexey A.; O`Connell, Kevin; Fan, Chun Chieh & Bahrami, Shahram [Show all 11 contributors for this article] (2019). Discovery of shared genomic loci using the conditional false discovery rate approach. Human Genetics. ISSN 0340-6717. p. 1–10. doi: 10.1007/s00439-019-02060-2. Full text in Research Archive Show summary

  In recent years, genome-wide association study (GWAS) sample sizes have become larger, the statistical power has improved and thousands of trait-associated variants have been uncovered, offering new insights into the genetic etiology of complex human traits and disorders. However, a large fraction of the polygenic architecture underlying most complex phenotypes still remains undetected. We here review the conditional false discovery rate (condFDR) method, a model-free strategy for analysis of GWAS summary data, which has improved yield of existing GWAS and provided novel findings of genetic overlap between a wide range of complex human phenotypes, including psychiatric, cardiovascular, and neurological disorders, as well as psychological and cognitive traits. The condFDR method was inspired by Empirical Bayes approaches and leverages auxiliary genetic information to improve statistical power for discovery of single-nucleotide polymorphisms (SNPs). The cross-trait condFDR strategy analyses separate GWAS data, and leverages overlapping SNP associations, i.e., cross-trait enrichment, to increase discovery of trait-associated SNPs. The extension of the condFDR approach to conjunctional FDR (conjFDR) identifies shared genomic loci between two phenotypes. The conjFDR approach allows for detection of shared genomic associations irrespective of the genetic correlation between the phenotypes, often revealing a mixture of antagonistic and agonistic directional effects among the shared loci. This review provides a methodological comparison between condFDR and other relevant cross-trait analytical tools and demonstrates how condFDR analysis may provide novel insights into the genetic relationship between complex phenotypes.

• Tan, Chin Hong; Bonham, Luke W.; Fan, Chun Chieh; Mormino, Elizabeth C.; Sugrue, Leo P. & Broce, Iris J. [Show all 24 contributors for this article] (2019). Polygenic hazard score, amyloid deposition and Alzheimer's neurodegeneration. Brain. ISSN 0006-8950. 142(2), p. 460–470. doi: 10.1093/brain/awy327. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Bahrami, Shahram; Frei, Oleksandr; Shadrin, Alexey A.; O`Connell, Kevin & Savage, Jeanne E. [Show all 15 contributors for this article] (2019). Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. Molecular Psychiatry. ISSN 1359-4184. p. 1–10. doi: 10.1038/s41380-018-0332-x. Full text in Research Archive Show summary

  Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders associated with cognitive impairment, which is considered a major determinant of functional outcome. Despite this, the etiology of the cognitive impairment is poorly understood, and no satisfactory cognitive treatments exist. Increasing evidence indicates that genetic risk for SCZ may contribute to cognitive impairment, whereas the genetic relationship between BD and cognitive function remains unclear. Here, we combined large genome-wide association study data on SCZ (n = 82,315), BD (n = 51,710), and general intelligence (n = 269,867) to investigate overlap in common genetic variants using conditional false discovery rate (condFDR) analysis. We observed substantial genetic enrichment in both SCZ and BD conditional on associations with intelligence indicating polygenic overlap. Using condFDR analysis, we leveraged this enrichment to increase statistical power and identified 75 distinct genomic loci associated with both SCZ and intelligence, and 12 loci associated with both BD and intelligence at conjunctional FDR < 0.01. Among these loci, 20 are novel for SCZ, and four are novel for BD. Most SCZ risk alleles (61 of 75, 81%) were associated with poorer cognitive performance, whereas most BD risk alleles (9 of 12, 75%) were associated with better cognitive performance. A gene set analysis of the loci shared between SCZ and intelligence implicated biological processes related to neurodevelopment, synaptic integrity, and neurotransmission; the same analysis for BD was underpowered. Altogether, the study demonstrates that both SCZ and BD share genetic influences with intelligence, albeit in a different manner, providing new insights into their genetic architectures.

• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Show all 84 contributors for this article] (2019). Common brain disorders are associated with heritable patterns of apparent aging of the brain. Nature Neuroscience. ISSN 1097-6256. 22(10), p. 1617–1623. doi: 10.1038/s41593-019-0471-7. Full text in Research Archive Show summary

  Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Fan, Chun-Chieh; Shadrin, Alexey A.; Dale, Anders & Andreassen, Ole Andreas (2019). The emerging pattern of shared polygenic architecture of psychiatric disorders, conceptual and methodological challenges. Psychiatric Genetics. ISSN 0955-8829. 29(5), p. 152–159. doi: 10.1097/YPG.0000000000000234. Full text in Research Archive Show summary

  Genome-wide association studies have transformed psychiatric genetics and provided novel insights into the genetic etiology of psychiatric disorders. Two major discoveries have emerged; the disorders are polygenic, with a large number of common variants each with a small effect and many genetic variants influence more than one phenotype, suggesting shared genetic etiology. These concepts have the potential to revolutionize the current classification system with diagnostic categories and facilitate development of better treatments. However, to reach clinical impact, we need larger samples and better analytical tools, as most polygenic factors remain undetected. We here present statistical approaches designed to improve the yield of existing genome-wide association studies for polygenic phenotypes. We review how these tools have informed the current knowledge on the genetic architecture of psychiatric disorders, focusing on schizophrenia, bipolar disorder and major depression, and overlap with psychological and cognitive traits. We discuss application of statistical tools for stratification and prediction.

• 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

• Satizabal, Claudia L.; Adams, Hieab H.H.; Hibar, Derrek; White, Charles C.; Knol, Maria J. & Stein, Jason L. [Show all 289 contributors for this article] (2019). Genetic architecture of subcortical brain structures in 38,851 individuals. Nature Genetics. ISSN 1061-4036. 51, p. 1624–1636. doi: 10.1038/s41588-019-0511-y. Full text in Research Archive Show summary

  Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

• Ousdal, Olga Therese; Argyelan, Miklos; Narr, Katherine L.; Abbott, Christopher; Wade, Benjamin & Vandenbulcke, Mathieu [Show all 34 contributors for this article] (2019). Brain changes induced by electroconvulsive therapy are broadly distributed. Biological Psychiatry. ISSN 0006-3223. 87(5), p. 451–461. doi: 10.1016/j.biopsych.2019.07.010. Full text in Research Archive Show summary

  Background Electroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response. Methods Longitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites. Results Volumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean ± SD of 1.04 ± 1.03% (Cohen’s d = 1.01, p < .001) and the subcortical gray matter volume increased by 1.47 ± 1.05% (d = 1.40, p < .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearman’s rank correlation ρ = −.44, p < .001), while total white matter volume remained unchanged (d = −0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome. Conclusions The findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response.

• Frei, Oleksandr; Holland, Dominic; Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Fan, Chun Chieh & Mæland, Steffen [Show all 12 contributors for this article] (2019). Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation. Nature Communications. 10(1). doi: 10.1038/s41467-019-10310-0. Full text in Research Archive Show summary

  Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.

• Hoogman, Martine; Muetzel, Ryan; Guimãraes, João-Tiago; Shumskaya, Elena; Mennes, Maarten & Zwiers, Marcel P. [Show all 115 contributors for this article] (2019). Brain imaging of the cortex in ADHD: A coordinated analysis of large-scale clinical and population-based samples. American Journal of Psychiatry. ISSN 0002-953X. 176(7), p. 531–542. doi: 10.1176/appi.ajp.2019.18091033. Full text in Research Archive Show summary

  Objective: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. Methods: Cortical thickness and surface area (based on the Desikan–Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). Results: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen’s d=−0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. Conclusions: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Hagen, Espen; Næss, Solveig & Ness, Torbjørn V [Show all 16 contributors for this article] (2019). Alterations in schizophrenia-associated genes can lead to increased power in delta oscillations. Cerebral Cortex. ISSN 1047-3211. 29(2), p. 875–891. doi: 10.1093/cercor/bhy291. Full text in Research Archive Show summary

  Genome-wide association studies have implicated many ion channels in schizophrenia pathophysiology. Although the functions of these channels are relatively well characterized by single-cell studies, the contributions of common variation in these channels to neurophysiological biomarkers and symptoms of schizophrenia remain elusive. Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage-gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta-frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a deficit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia.

• Karunamuni, Roshan A.; White, Nathan S.; Fromm, Annette; Moen, Gunnar; Grüner, Renate & Dale, Anders [Show all 7 contributors for this article] (2019). Improved characterization of cerebral infarction using combined tissue T2 and high b-value diffusion MRI in post-thrombectomy patients: a feasibility study. Acta Radiologica. ISSN 0284-1851. 60(10), p. 1294–1300. doi: 10.1177/0284185118820063. Full text in Research Archive
• Oltedal, Leif; Narr, Katherine L.; Abbott, Christopher; Anand, Amit; Argyelan, Miklos & Bartsch, Hauke [Show all 26 contributors for this article] (2018). Volume of the Human Hippocampus and Clinical Response Following Electroconvulsive Therapy. Biological Psychiatry. ISSN 0006-3223. 84(8), p. 574–581. doi: 10.1016/j.biopsych.2018.05.017. Full text in Research Archive
• Bonham, Luke W.; Karch, Celeste M.; Fan, Chun C.; Tan, Chin; Geier, Ethan G. & Wang, Yunpeng [Show all 25 contributors for this article] (2018). CXCR4 involvement in neurodegenerative diseases. Translational Psychiatry. 8:73, p. 1–10. doi: 10.1038/s41398-017-0049-7. Full text in Research Archive Show summary

  Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

• Fan, Chun Chieh; Smeland, Olav Bjerkehagen; Schork, Andrew J.; Chen, Chi-Hua; Holland, Dominic & Lo, Min-Tzu [Show all 11 contributors for this article] (2018). Beyond heritability: Improving discoverability in imaging genetics. Human Molecular Genetics. ISSN 0964-6906. 27(1), p. R22–R28. doi: 10.1093/hmg/ddy082. Full text in Research Archive
• Erp, Theo G.M. Van; Walton, Esther; Hibar, Derrek; Schmaal, Lianne; Jiang, Wenhao & Glahn, David C. [Show all 151 contributors for this article] (2018). Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2018.04.023. Full text in Research Archive Show summary

  Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11–78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10–87 years; 53% male) assessed with standardized methods at 39 centers worldwide. Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen’s d = −0.530/−0.516) and smaller surface area (left/right hemisphere: Cohen’s d = −0.251/−0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

• Kong, Xiang-Zhen; Mathias, Samuel R.; Guadalupe, Tulio; Agartz, Ingrid; Andreassen, Ole Andreas & Bøen, Erlend [Show all 33 contributors for this article] (2018). Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 115(22), p. E5154–E5163. doi: 10.1073/pnas.1718418115. Full text in Research Archive
• Thunemann, Martin; Lu, Yichen; Liu, Xin; Kılıç, Kıvılcım; Desjardins, Michèle & Vandenberghe, Matthieu [Show all 16 contributors for this article] (2018). Deep 2-photon imaging and artifact-free optogenetics through transparent graphene microelectrode arrays. Nature Communications. 9:2015, p. 1–12. doi: 10.1038/s41467-018-04457-5. Full text in Research Archive Show summary

  Recent advances in optical technologies such as multi-photon microscopy and optogenetics have revolutionized our ability to record and manipulate neuronal activity. Combining optical techniques with electrical recordings is of critical importance to connect the large body of neuroscience knowledge obtained from animal models to human studies mainly relying on electrophysiological recordings of brain-scale activity. However, integration of optical modalities with electrical recordings is challenging due to generation of light-induced artifacts. Here we report a transparent graphene microelectrode technology that eliminates light-induced artifacts to enable crosstalk-free integration of 2-photon microscopy, optogenetic stimulation, and cortical recordings in the same in vivo experiment. We achieve fabrication of crack- and residue-free graphene electrode surfaces yielding high optical transmittance for 2-photon imaging down to ~ 1 mm below the cortical surface. Transparent graphene microelectrode technology offers a practical pathway to investigate neuronal activity over multiple spatial scales extending from single neurons to large neuronal populations.

• Srinivasan, Saurabh; Bettella, Francesco; Frei, Oleksandr; Hill, W. David; Wang, Yunpeng & Witoelar, Aree [Show all 17 contributors for this article] (2018). Enrichment of genetic markers of recent human evolution in educational and cognitive traits. Scientific Reports. 8:12585, p. 1–9. doi: 10.1038/s41598-018-30387-9. Full text in Research Archive Show summary

  Higher cognitive functions are regarded as one of the main distinctive traits of humans. Evidence for the cognitive evolution of human beings is mainly based on fossil records of an expanding cranium and an increasing complexity of material culture artefacts. However, the molecular genetic factors involved in the evolution are still relatively unexplored. Here, we investigated whether genomic regions that underwent positive selection in humans after divergence from Neanderthals are enriched for genetic association with phenotypes related to cognitive functions. We used genome wide association data from a study of college completion (N = 111,114), one of educational attainment (N = 293,623) and two different studies of general cognitive ability (N = 269,867 and 53,949). We found nominally significant polygenic enrichment of associations with college completion (p = 0.025), educational attainment (p = 0.043) and general cognitive ability (p = 0.015 and 0.025, respectively), suggesting that variants influencing these phenotypes are more prevalent in evolutionarily salient regions. The enrichment remained significant after controlling for other known genetic enrichment factors, and for affiliation to genes highly expressed in the brain. These findings support the notion that phenotypes related to higher order cognitive skills typical of humans have a recent genetic component that originated after the separation of the human and Neanderthal lineages.

• Broce, Iris J.; Tan, Chin Hong; Fan, CC; Jansen, Iris E.; Savage, Jeanne E. & Witoelar, Aree [Show all 34 contributors for this article] (2018). Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathologica. ISSN 0001-6322. doi: 10.1007/s00401-018-1928-6. Full text in Research Archive
• Sowa, Piotr; Harbo, Hanne Flinstad; White, Nathan S.; Celius, Elisabeth Gulowsen; Bartsch, Hauke & Berg-Hansen, Pål [Show all 12 contributors for this article] (2018). Restriction spectrum imaging of white matter and its relation to neurological disability in multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. p. 1–12. doi: 10.1177/1352458518765671. Full text in Research Archive Show summary

  Background: Restriction spectrum imaging (RSI) is a recently introduced magnetic resonance imaging diffusion technique. The utility of RSI in multiple sclerosis (MS) is unknown. Objective: To investigate the association between RSI-derived parameters and neurological disability in MS. Methods: Seventy-seven relapsing-remitting MS patients were scanned with RSI on a 3-Tesla scanner. RSI-derived parameters: fast and slow apparent diffusion coefficient (sADC), fractional anisotropy, restricted fractional anisotropy, neurite density (ND), cellularity, extracellular water fraction and free water fraction were obtained in white matter lesions (WML) and normal appearing white matter (NAWM). Patients were divided into three groups according to their expanded disability status scale (EDSS): with minimal, low and substantial disability (<2.5, 2.5–3 and >3, respectively). Group comparisons and correlation analyses were performed. Results: All tested RSI-derived parameters differed between WML and NAWM (p<0.001 for all pairwise comparisons). The sADC in WML showed largest difference across disability subgroups (ANOVA: F=5.1, η2=0.12 p=0.008). ND in NAWM showed strongest correlation with disability (ϱ=-0.39, p<0.001). Conclusion: The strongest correlation with EDSS of ND obtained in NAWM indicates that processes outside lesions are important for disability in MS. Our study suggests that RSIderived parameters may help understand the “clinico-radiological paradox” and improve disease monitoring in MS.

• Vojinovic, Dina; Adams, Hieab H.; Jian, Xueqiu; Yang, Qiong; Smith, Albert Vernon & Bis, Joshua C. [Show all 91 contributors for this article] (2018). Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. Nature Communications. 9:3945, p. 1–11. doi: 10.1038/s41467-018-06234-w. Full text in Research Archive Show summary

  The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

• Fan, Chun Chieh; Schork, Andrew J.; Brown, Timothy T.; Spencer, Barbara E.; Akshoomoff, Natacha & Chen, Chi-Hua [Show all 16 contributors for this article] (2018). Williams Syndrome neuroanatomical score associates with GTF2IRD1 in large-scale magnetic resonance imaging cohorts: A proof of concept for multivariate endophenotypes. Translational Psychiatry. 8:114(1), p. 1–8. doi: 10.1038/s41398-018-0166-y. Full text in Research Archive Show summary

  Despite great interest in using magnetic resonance imaging (MRI) for studying the effects of genes on brain structure in humans, current approaches have focused almost entirely on predefined regions of interest and had limited success. Here, we used multivariate methods to define a single neuroanatomical score of how William’s Syndrome (WS) brains deviate structurally from controls. The score is trained and validated on measures of T1 structural brain imaging in two WS cohorts (training, n = 38; validating, n = 60). We then associated this score with single nucleotide polymorphisms (SNPs) in the WS hemi-deleted region in five cohorts of neurologically and psychiatrically typical individuals (healthy European descendants, n = 1863). Among 110 SNPs within the 7q11.23 WS chromosomal region, we found one associated locus (p = 5e–5) located at GTF2IRD1, which has been implicated in animal models of WS. Furthermore, the genetic signals of neuroanatomical scores are highly enriched locally in the 7q11.23 compared with summary statistics based on regions of interest, such as hippocampal volumes (n = 12,596), and also globally (SNP-heritability = 0.82, se = 0.25, p = 5e−4). The role of genetic variability in GTF2IRD1 during neurodevelopment extends to healthy subjects. Our approach of learning MRI-derived phenotypes from clinical populations with well-established brain abnormalities characterized by known genetic lesions may be a powerful alternative to traditional region of interest-based studies for identifying genetic variants regulating typical brain development.

• Ringstad, Geir; Valnes, Lars Magnus; Dale, Anders; Pripp, Are Hugo; Vatnehol, Svein Are Sirirud & Emblem, Kyrre Eeg [Show all 8 contributors for this article] (2018). Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. Journal of Clinical Investigation. ISSN 0021-9738. 3(13), p. 1–16. doi: 10.1172/jci.insight.121537. Full text in Research Archive Show summary

  To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.

• Karch, Celeste M.; Wen, Natalie; Fan, Chun C.; Yokoyama, Jennifer S.; Kouri, Naomi & Ross, Owen A. [Show all 21 contributors for this article] (2018). Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. JAMA Neurology. ISSN 2168-6149. 75(7), p. 860–875. doi: 10.1001/jamaneurol.2018.0372. Full text in Research Archive
• Seibert, Tyler M.; Fan, Chun Chieh; Wang, Yunpeng; Zuber, Verena; Karunamuni, Roshan & Parsons, J. Kellogg [Show all 62 contributors for this article] (2018). Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. The BMJ. 360:j5757, p. 1–7. doi: 10.1136/bmj.j5757. Full text in Research Archive Show summary

  Objectives: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Results: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10−16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

• Logue, Mark W.; Panizzon, Matthew S.; Elman, Jeremy A.; Gillespie, Nathan A.; Hatton, Sean N. & Gustavson, Daniel E. [Show all 14 contributors for this article] (2018). Use of an Alzheimer's disease polygenic risk score to identify mild cognitive impairment in adults in their 50s. Molecular Psychiatry. ISSN 1359-4184. p. 1–10. doi: 10.1038/s41380-018-0030-8. Full text in Research Archive
• Li, Yi; Barkovich, Matthew J.; Karch, Celeste M.; Nillo, Ryan M.; Fan, Chun-Chieh & Broce, Iris J. [Show all 25 contributors for this article] (2018). Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex. Scientific Reports. 8:13373, p. 1–10. doi: 10.1038/s41598-018-31075-4. Full text in Research Archive Show summary

  Tuberous sclerosis complex (TSC), a heritable neurodevelopmental disorder, is caused by mutations in the TSC1 or TSC2 genes. To date, there has been little work to elucidate regional TSC1 and TSC2 gene expression within the human brain, how it changes with age, and how it may influence disease. Using a publicly available microarray dataset, we found that TSC1 and TSC2 gene expression was highest within the adult neo-cerebellum and that this pattern of increased cerebellar expression was maintained throughout postnatal development. During mid-gestational fetal development, however, TSC1 and TSC2 expression was highest in the cortical plate. Using a bioinformatics approach to explore protein and genetic interactions, we confirmed extensive connections between TSC1/TSC2 and the other genes that comprise the mammalian target of rapamycin (mTOR) pathway, and show that the mTOR pathway genes with the highest connectivity are also selectively expressed within the cerebellum. Finally, compared to age-matched controls, we found increased cerebellar volumes in pediatric TSC patients without current exposure to antiepileptic drugs. Considered together, these findings suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population.

• Broce, Iris J.; Karch, Celeste M.; Wen, Natalie; Fan, Chun C.; Wang, Yunpeng & Tan, Chin Hong [Show all 29 contributors for this article] (2018). Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Medicine. ISSN 1549-1277. 15:e1002487(1), p. 1–20. doi: 10.1371/journal.pmed.1002487. Full text in Research Archive Show summary

  Background: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLAregion. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

• Zuber, Verena; Jönsson, Erik Gunnar; Frei, Oleksandr; Witoelar, Aree; Thompson, Wesley Kurt & Schork, Andrew J. [Show all 18 contributors for this article] (2018). Identification of shared genetic variants between schizophrenia and lung cancer. Scientific Reports. 674(8), p. 1–8. doi: 10.1038/s41598-017-16481-4. Full text in Research Archive Show summary

  Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.

• Davies, Gail; Lam, Max; Harris, Sarah E.; Trampush, Joey W.; Luciano, Michelle & Hill, W. David [Show all 221 contributors for this article] (2018). Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nature Communications. 9(2098), p. 1–16. doi: 10.1038/s41467-018-04362-x. Full text in Research Archive Show summary

  General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

• Hellard, Stephanie Le; Wang, Yunpeng; Witoelar, Aree; Zuber, Verena; Bettella, Francesco & Hugdahl, Kenneth [Show all 15 contributors for this article] (2017). Identification of gene loci that overlap between schizophrenia and educational attainment. Schizophrenia Bulletin. ISSN 0586-7614. 43(3), p. 654–664. doi: 10.1093/schbul/sbw085. Full text in Research Archive
• Srinivasan, Saurabh; Bettella, Francesco; Hassani, Sahar; Wang, Yunpeng; Witoelar, Aree & Schork, Andrew J. [Show all 13 contributors for this article] (2017). Probing the association between early evolutionary markers and schizophrenia. PLOS ONE. 12:e0169227(1), p. 1–15. doi: 10.1371/journal.pone.0169227. Full text in Research Archive
• Næss, Solveig; Chintaluri, Chaitanya; Ness, Torbjørn Vefferstad; Dale, Anders; Einevoll, Gaute & Wójcik, Daniel K. (2017). Corrected four-sphere head model for EEG signals. Frontiers in Human Neuroscience. 11, p. 1–7. doi: 10.3389/fnhum.2017.00490. Full text in Research Archive Show summary

  The EEG signal is generated by electrical brain cell activity, often described in terms of current dipoles. By applying EEG forward models we can compute the contribution from such dipoles to the electrical potential recorded by EEG electrodes. Forward models are key both for generating understanding and intuition about the neural origin of EEG signals as well as inverse modeling, i.e., the estimation of the underlying dipole sources from recorded EEG signals. Different models of varying complexity and biological detail are used in the field. One such analytical model is the four-sphere model which assumes a four-layered spherical head where the layers represent brain tissue, cerebrospinal fluid (CSF), skull, and scalp, respectively. While conceptually clear, the mathematical expression for the electric potentials in the four-sphere model is cumbersome, and we observed that the formulas presented in the literature contain errors. Here, we derive and present the correct analytical formulas with a detailed derivation. A useful application of the analytical four-sphere model is that it can serve as ground truth to test the accuracy of numerical schemes such as the Finite Element Method (FEM). We performed FEM simulations of the four-sphere head model and showed that they were consistent with the corrected analytical formulas. For future reference we provide scripts for computing EEG potentials with the four-sphere model, both by means of the correct analytical formulas and numerical FEM simulations.

• Hoogman, Martine; Bralten, Janita; Hibar, Derrek; Mennes, Maarten; Zwiers, Marcel P. & Schweren, Lizanne S.J. [Show all 82 contributors for this article] (2017). Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. The Lancet Psychiatry. ISSN 2215-0374. 4(4), p. 310–319. doi: 10.1016/S2215-0366(17)30049-4. Full text in Research Archive

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• Bonham, Luke W.; Oddi, Alexis P.; Escobar, Valerie Drews; Khan, Jared A.; Sauri, Ariel I. & Castruita, Patricia A. [Show all 23 contributors for this article] (2025). A common IFI44L variant strongly predicts clinical trajectories in aging and neurodegeneration. Alzheimer's & Dementia. ISSN 1552-5260. 21(s1). doi: 10.1002/alz70855_104509. Full text in Research Archive Show summary

  Background Dysregulation of the interferon (IFN) response is emerging as a major pathobiological contributor across multiple forms of neurodegeneration, but much less is known about how genetic variation in the IFN pathway modulates the course of neurodegenerative disease. IFN signaling represents a primary cellular mechanism for the antiviral response. Furthermore, both viral infection and vaccination are increasingly recognized for their roles in modifying neurodegenerative disease risk. We hypothesized that common variation in IFN-stimulated gene IFI44L, which is enriched in IFN-responsive immune-cell subsets and strongly associated with vaccine response, would be associated with differences in clinical trajectories in neurodegenerative disease and normal aging. Method We performed longitudinal analyses using linear mixed-effects models on measures of clinical severity and cognitive impairment across four clinical diagnoses and two independent cohorts, including the University of California, San Francisco Memory and Aging Center (MAC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Clinical measures included the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Mini-Mental State Examination. IFI44L rs273259 genotype was measured by whole-genome sequencing (MAC) and Illumina GWAS BeadChips (ADNI). Result After controlling for baseline age, sex, education, APOE ε4 dosage, and self-reported race, IFI44L genotype strongly associated with clinical trajectories in clinically normal (CN) individuals and those with mild cognitive impairment (MCI) in the ADNI cohort, with the rs273259 alternate (G) allele displaying a highly significant, dose-dependent relationship with worse clinical trajectories (for CDR-SB, in CN, p < 2 x 10-16; in MCI, p = 1.1 x 10-6; Figure 1A-B). In the MAC cohort, the alternate allele was also associated with worse CDR-SB trajectories in CN (p = 0.05), frontotemporal dementia (p = 3.9 x 10-10; Figure 1C) and early-onset AD (p = 3.3 x 10-3; Figure 1D). Among subjects with neuropathologically defined frontotemporal lobar degeneration (FTLD) with tau or TDP-43 proteinopathy, IFI44L genotype was associated with clinical trajectories in both subtypes (p = 3.8 x 10-5, FTLD-tau; p = 0.03, FTLD-TDP). Conclusion A common IFI44L variant is significantly associated with clinical trajectories in normal aging and in multiple forms of neurodegenerative disease, confirming an important role for IFN signaling in aging and neurodegeneration (Figure 2).

• Einevoll, Gaute Tomas; Pettersen, Klas Henning; Sæbø, Solve; Stensola, Hanne & Dale, Anders (2023). On neuro-AI. [Internet]. Podcast "Vett og vitenskap". Full text in Research Archive
• Ditmars, Hillary L.; Logue, Mark W.; Toomey, Rosemary; Mckenzie, Ruth E.; Franz, Carol E. & Panizzon, Matthew S. [Show all 27 contributors for this article] (2022). Erratum: Associations Between Depression and Cardiometabolic Health: A 27-Year Longitudinal Study (Cambridge University (2021) DOI: 10.1017/S003329172000505X). Psychological Medicine. ISSN 0033-2917. 52(14), p. 3018–3018. doi: 10.1017/S0033291722003105. Full text in Research Archive
• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Show all 97 contributors for this article] (2020). Publisher Correction: Common brain disorders are associated with heritable patterns of apparent aging of the brain (Nature Neuroscience, (2019), 22, 10, (1617-1623), 10.1038/s41593-019-0471-7). Nature Neuroscience. ISSN 1097-6256. 23(2), p. 295–295. doi: 10.1038/s41593-019-0553-6. Full text in Research Archive
• Davies, Gail; Lam, Max; Harris, Sarah E.; Trampush, Joey W.; Luciano, Michelle & Hill, W. David [Show all 222 contributors for this article] (2019). Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (Nature Communications, (2018), 9, 1, (2098), 10.1038/s41467-018-04362-x). Nature Communications. 10(1). doi: 10.1038/s41467-019-10160-w. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Bahrami, Shahram; Frei, Oleksandr; Shadrin, Alexey A.; Savage, Jeanne E. & Watanabe, Kyoko [Show all 14 contributors for this article] (2018). Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder and intelligence. Full text in Research Archive

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