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Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.

Phil Hyoun LeeiD, Verneri AnttilaiD, Hyejung WoniD, Yen‐Chen Anne FengiD, Jacob RosenthaliD, Zhaozhong ZhuiD, Elliot M. Tucker–DrobiD, Michel Guillaume NivardiD, Andrew David GrotzingeriD, Daniëlle PosthumaiD, Meg M.-J. Wang, Dongmei YuiD, Eli StahliD, Raymond Kenney WaltersiD, Richard AnneyiD, Laramie E. DuncaniD, Sintia Iole BelangeroiD, Jurjen Justin LuykxiD, Henry R. KranzleriD, Anna Keski‐RahkoneniD, Edwin H. CookiD, George KiroviD, Giovanni CoppolaiD, Jaakko A. KaprioiD, Clement C.H. ZaiiD, , Jordan W. SmolleriD

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Abstract

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 a meta-analysis 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. We 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 in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Abstract summary

Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract · CC BY-NC-ND 4.0

Cross-disorder meta-analysis of eight psychiatric GWAS (232,964 cases, 494,162 controls) reports 109 loci shared by two or more disorders and three groups of correlated disorders.

Psychiatric diagnoses share genetic risk, but it has not been clear how many loci are shared, which disorders they link, or whether they push risk in the same direction. Pooling eight disorder GWAS at once gives a map of that shared architecture and separates loci acting on many disorders from those with opposing effects.

Key results

  1. ShownA sizeable set of loci is associated with more than one psychiatric disorder, and a subset acts in opposite directions depending on the disorder.

    109 loci associated with at least two of the eight disorders, 23 of them with effects on four or more disorders, and 11 with antagonistic effects across disorders. · Abstract

  2. SuggestedGenetic correlations among the eight disorders are structured rather than uniform, falling into three groups of mutually related disorders.

    Reported from genetic correlation analysis across the eight disorders; the abstract names no group memberships and gives no correlation estimates or confidence intervals. · Abstract

  3. SuggestedGenes at the pleiotropic loci are characterized as brain-expressed across the lifespan, with expression starting prenatally in the second trimester, and as acting in neurodevelopmental processes.

    Stated as a property of the pleiotropic loci; no enrichment statistics, reference expression dataset or gene-set results are given in the abstract. · Abstract

Methods, data and reproducibility

Genome-wide association results for eight psychiatric disorders were meta-analysed together, genetic correlations between the disorders were estimated to group them, and loci associated with more than one disorder were characterized by the expression and function of nearby genes.

  • Case-control GWAS for eight psychiatric disorders: schizophrenia, bipolar disorder, major depression, autism, ADHD, anorexia nervosa, obsessive-compulsive disorder, Tourette syndrome · human · n = 232,964 cases and 494,162 controls
Limitations (2)
  • Only counts of loci are reported: no effect sizes, genetic correlation values, significance thresholds or per-disorder sample sizes appear in the available text. · noted in this summary
  • Nothing is said about overlap of samples or controls between the contributing GWAS, which matters for both the meta-analysis and the genetic correlation estimates. · noted in this summary

Read this if you work on psychiatric genetics or cross-trait pleiotropy and want a locus-level map of what eight disorder GWAS share.

Citations
47

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