Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.National Institutes of HealthVoRSUNY DownstatePsychiatry and Behavioral SciencesInstitute for Genomics in HealthN/

Can the twin-exhaust model explain radio jets?

The distinctions between compact cores in various powerful extragalactic sources have proved difficult to interpret. In a few source categories (for example radio galaxies and quasistellar radio sources) extended structure on much larger scales exist; their energy is undoubtedly supplied through the narrow channels that are being increasingly observed and seem to be directed from the compact cores. Continuous production of high-energy plasma in a high-pressure region at the core centre is necessary to account for the energetics and channel structures1. The twin-exhaust mechanism 2 is one means of forming double jets in active galactic nuclei. As originally envisaged , the 'central engine' continuously releases hot gas in the centre of a flat-bottomed potential well formed by the stellar cluster in a galactic centre. This potential well holds a cloud of cooler gas which confines the hot gas in a central cavity. If the cooler gas cloud is flattened (for example, by rotation), buoyancy forces can accelerate the hot gas into two collimated jets via de Laval nozzles. These jets may correspond to the observed radio jets in quasars and radio galaxies, and result in the formation of extended double sources. Here, we combine new results from numerical calculations5 of the Blandford-Rees model, with severe observational and theoretical constraints, to reach conclusions concerning the nature of the allowed flows. In particular, we conclude that high-velocity, high-powered jets cannot be produced in gravitational potentials produced by stellar clusters. However, the more general notion of the twin-exhaust mechanism1, in which the central potential can be cusp-like near a massive black hole, is not ruled out for the high-powered radio sources. Note also that more compex twin-exhaust models (for example, magnetohydrodynamic flows) may lead to less severe constraints

Neurocognitive Allied Phenotypes for Schizophrenia and Bipolar Disorder

Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed

Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

Depression is more frequent among individuals exposed to traumatic events.Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD between individuals reporting and not reporting trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD was greater in participants reporting trauma exposure (24%) than in individuals not reporting trauma exposure taking into account the strong, positive genetic correlation observed between MDD and reported trauma exposure. The genetic correlation between MDD 15 and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8x10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3x10-4). Our results suggest that the genetic contribution to MDD is greater when additional risk factors are present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD