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Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA‐Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population‐level mapping of average asymmetry was achieved, including an intriguing fronto‐occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi‐dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive–compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders., Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Over the last four years, the ENIGMA‐Laterality Working Group has published six studies of grey matter morphological asymmetry in health and disease, based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. Here we review the findings from these six studies.

Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation ofZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past.

Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further. publishersversion published

Background: Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds. Aims: We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain. Methods: All subjects included for this genome-wide association study ( n=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use Results: Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; β=1.05; p=3.66 × 10−08; n=206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 ( p=1.0 × 10−03) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain. Conclusion: Our findings suggest the involvement of rs78310016 and possibly 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We re-sampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers and right-handers showed average differences of surface area asymmetry within fusiform, anterior insular, anterior-middle-cingulate and precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2 and NME7 – the latter is mutated in left-right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas non-heritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores (PRS) for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. PRS for the two disorders were positively correlated (r=0.08, p=7.13×10−50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each PRS was associated with multivariate brain asymmetry after adjusting for sex, ASD PRS r=0.03, p=2.17×10−9, schizophrenia PRS r=0.04, p=2.61×10−11, but the multivariate patterns were mostly distinct for the two PRS, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both PRS were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risk for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on modest sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last four years, the ENIGMA-Laterality Working Group has published six studies of brain structural asymmetry based on total sample sizes of between roughly 3,500 and 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average brain asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA’s multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for brain asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: Autism Spectrum Disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; Pediatric Obsessive-Compulsive Disorder was associated with altered subcortical asymmetry; Major Depressive Disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.

ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a GWAS on epilepsy (n=12,803 people with epilepsy and 24,218 controls) with that from a GWAS on background EEG (n=8,425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta and theta. We replicated our findings in an independent epilepsy replication dataset (n=4851 people with epilepsy and 20,428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations between genetic generalized epilepsy (GGE) with background EEG oscillations, primarily with the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic work-up of epilepsy.

SummaryGenome-wide association studies have uncovered hundreds of loci associated with psychiatric disorders. Cross-disorder studies are among the prime ramifications of such research. Here, we discuss the methodology of the most widespread methods and their clinical utility with regard to diagnosis, prediction, disease aetiology and treatment in psychiatry.

BACKGROUND: Peripartum depression is a common cause of pregnancy- and postpartum-related morbidity. The production of corticotropin-releasing hormone (CRH) from the placenta alters the profile of hypothalamus-pituitary-adrenal axis hormones and may be associated with postpartum depression. The purpose of this study was to assess, in nondepressed pregnant women, the possible association between CRH levels in pregnancy and depressive symptoms postpartum. METHODS: A questionnaire containing demographic data and the Edinburgh Postnatal Depression Scale (EPDS) was filled in gestational weeks 17 and 32, and 6 week postpartum. Blood samples were collected in week 17 for assessment of CRH. A logistic regression model was constructed, using postpartum EPDS score as the dependent variable and log-transformed CRH levels as the independent variable. Confounding factors were included in the model. Subanalyses after exclusion of study subjects with preterm birth, newborns small for gestational age (SGA), and women on corticosteroids were performed. RESULTS: Five hundred thirty-five women without depressive symptoms during pregnancy were included. Logistic regression showed an association between high CRH levels in gestational week 17 and postpartum depressive symptoms, before and after controlling for several confounders (unadjusted OR = 1.11, 95% CI 1.01-1.22; adjusted OR = 1.13, 95% CI 1.02-1.26; per 0.1 unit increase in log CRH). Exclusion of women with preterm birth and newborns SGA as well as women who used inhalation corticosteroids during pregnancy did not alter the results. CONCLUSIONS: This study suggests an association between high CRH levels in gestational week 17 and the development of postpartum depressive symptoms, among women without depressive symptoms during pregnancy.

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Peripartum depression is a common cause of pregnancy- and postpartum-related morbidity. The production of corticotropin-releasing hormone (CRH) from the placenta alters the profile of hypothalamus-pituitary-adrenal axis hormones and may be associated with postpartum depression. The purpose of this study was to assess, in nondepressed pregnant women, the possible association between CRH levels in pregnancy and depressive symptoms postpartum.A questionnaire containing demographic data and the Edinburgh Postnatal Depression Scale (EPDS) was filled in gestational weeks 17 and 32, and 6 week postpartum. Blood samples were collected in week 17 for assessment of CRH. A logistic regression model was constructed, using postpartum EPDS score as the dependent variable and log-transformed CRH levels as the independent variable. Confounding factors were included in the model. Subanalyses after exclusion of study subjects with preterm birth, newborns small for gestational age (SGA), and women on corticosteroids were performed.Five hundred thirty-five women without depressive symptoms during pregnancy were included. Logistic regression showed an association between high CRH levels in gestational week 17 and postpartum depressive symptoms, before and after controlling for several confounders (unadjusted OR = 1.11, 95% CI 1.01-1.22; adjusted OR = 1.13, 95% CI 1.02-1.26; per 0.1 unit increase in log CRH). Exclusion of women with preterm birth and newborns SGA as well as women who used inhalation corticosteroids during pregnancy did not alter the results.This study suggests an association between high CRH levels in gestational week 17 and the development of postpartum depressive symptoms, among women without depressive symptoms during pregnancy.

The Flinder Sensitive Line (FSL) is a rat strain that displays distinct behavioral and neurochemical features of major depression. Chronic selective serotonin reuptake inhibitors (SSRIs) are able to reverse these symptoms in FSL rats. It is well known that several abnormalities in the serotonergic system have been found in FSL rats, including increased 5-HT brain tissue levels and reduced 5-HT synthesis. SSRIs are known to exert (part of) their effects by desensitization of the 5-HT1A receptor and FSL rats appear to have lower 5-HT1A receptor densities compared with Flinder Resistant Line (FRL) rats. We therefore studied the sensitivity of this receptor on the sexual behavior performance in both FRL and FSL rats. First, basal sexual performance was studied after saline treatment followed by treatment of two different doses of the 5-HT1A receptor agonist ± 8-OH-DPAT. Finally we measured the effect of a 5-HT1A receptor antagonist to check for specificity of the 5-HT1A receptor activation. Our results show that FSL rats have higher ejaculation frequencies compared with FRL rats which do not fit with a more depressive-like phenotype. Moreover FRL rats are more sensitive to effects of ± 8-OH-DPAT upon EL and IF than FSL rats. The blunted response of FSL rats to the effects of ± 8-OH-DPAT may be due to lower densities of 5-HT1A receptors.