The shared genetic basis of mood instability and psychiatric disorders: A cross‐trait genome‐wide association analysis

Year: 2022

Type: article

Abstract: ABSTRACT Mood instability (MOOD) is a transdiagnostic phenomenon with a prominent neurobiological basis. Recent genome-wide association studies found significant positive genetic correlation between MOOD and 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. 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 analysed using the bivariate causal mixture model and conjunctional false discovery rate methods to estimate the proportion of shared variants influencing MOOD and each disorder, and identify jointly associated genomic loci. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg=0.10-0.62). Of 10.4K genomic variants influencing MOOD, 4K-9.4K were estimated to influence psychiatric disorders. MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25, with consistent genetic effects in independent samples. Fifty-three jointly associated loci were overlapping across two or more disorders (transdiagnostic), 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 of shared loci suggest divergent effects on corresponding neurobiological mechanisms which may relate to differences in the core clinical features of each disorder.

Source: American Journal of Medical Genetics Part B Neuropsychiatric Genetics

DOI: 10.1002/ajmg.b.32907

Authors: Guy Hindley, Kevin S. O'Connell, Zillur Rahman, Oleksandr Frei, Shahram Bahrami, Alexey Shadrin, Margrethe C. Høegh, Weiqiu Cheng, Naz Karadag, Aihua Lin, Linn Rødevand, Chun C. Fan, Srdjan Djurovic, Trine V. Lagerberg, Anders M. Dale, Olav B. Smeland, Ole A. Andreassen

Institutions: Oslo University Hospital, King's College London, University of Oslo, University of California San Diego, University of Bergen

Language: English

Topic: Genetic Associations and Epidemiology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,450

Funders: Stiftelsen Kristian Gerhard Jebsen, European Commission, Norges Forskningsråd, National Institutes of Health, Horizon 2020 Framework Programme, Medical Research Council, Helse Sør-Øst RHF, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering

OpenAlex ID: W4285590765