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.
Keywords: GWAS; Psychiatric genetics; cross-disorder genetics; functional genomics; gene expression; genetic architecture; genetic correlation; neurodevelopment; pleiotropy; psychiatric disorders.
Copyright © 2019 Elsevier Inc. All rights reserved.
Identification of Risk Loci With Shared Effects on Five Major Psychiatric Disorders: A Genome-Wide AnalysisCross-Disorder Group of the Psychiatric Genomics Consortium. Lancet 381 (9875), 1371-1379. PMID 23453885.National Institute of Mental Health.
Multivariate Analysis of Genome-Wide Data to Identify Potential Pleiotropic Genes for Five Major Psychiatric Disorders Using MetaCCAX Jia et al. J Affect Disord 242, 234-243. PMID 30212762. - Meta-AnalysisThe metaCCA method identified novel variants associated with psychiatric disorders by effectively incorporating information from different GWAS datasets. Our analyses may …
Identifying Common Genome-Wide Risk Genes for Major Psychiatric TraitsS Liu et al. Hum Genet 139 (2), 185-198. PMID 31813014.Major psychiatric traits are genetically inter-correlated with one another, but it not well known which genes play pleiotropic effects across different traits. We curated …
Transdiagnostic Neuroimaging in Psychiatry: A ReviewSA Mitelman. Psychiatry Res 277, 23-38. PMID 30639090. - ReviewTransdiagnostic approach has a long history in neuroimaging, predating its recent ascendance as a paradigm for new psychiatric nosology. Various psychiatric disorders hav …
Specific and Common Genes Implicated Across Major Mental Disorders: A Review of Meta-Analysis StudiesJM Gatt et al. J Psychiatr Res 60, 1-13. PMID 25287955. - ReviewMajor efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental heal …
Cited by 1 PubMed Central articles
The P Factor: Genetic Analyses Support a General Dimension of Psychopathology in Childhood and AdolescenceAG Allegrini et al. J Child Psychol Psychiatry 61 (1), 30-39. PMID 31541466.Diverse forms of psychopathology generally load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across chi …