The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function

Ward, J. et al. (2020) The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function. Molecular Psychiatry, 25(11), pp. 3091-3099. (doi: 10.1038/s41380-019-0439-8) (PMID:31168069) (PMCID:PMC7116257)

Abstract

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Daniel and Cullen, Dr Breda and O'Donovan, Professor Michael and Graham, Dr Nicholas and Ferguson, Ms Amy and Lyall, Dr Laura and Bailey, Dr Mark and Ward, Dr Joey and Johnston, Ms Keira and Pell, Professor Jill and Lyall, Dr Donald and Strawbridge, Dr Rona
• Authors: Ward, J., Tunbridge, E. M., Sandor, C., Lyall, L. M., Ferguson, A., Strawbridge, R. J., Lyall, D. M., Cullen, B., Graham, N., Johnston, K. J.A., Webber, C., Escott-Price, V., O'Donovan, M., Pell, J. P., Bailey, M. E.S., Harrison, P. J., and Smith, D. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > General Practice and Primary Care; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Molecular Psychiatry
• Publisher: Nature Research
• ISSN: 1359-4184
• ISSN (Online): 1476-5578
• Published Online: 05 June 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Molecular Psychiatry 25(11): 3091-3099
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
63234	5	MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16	George Baillie	Medical Research Council (MRC)	MR/K501335/1	MVLS GRADUATE SCHOOL
302131	0	Understanding the excess risk of cardiometabolic disease in individuals with serious mental illness	Jill Pell	Medical Research Council (MRC)	MR/S003061/1	HW - Public Health
302957	0	Mental Health Data Pathfinder	Daniel Smith	Medical Research Council (MRC)	MC_PC_17217	HW - Mental Health and Wellbeing