Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia

Ward, J. et al. (2017) Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia. Translational Psychiatry, 7, 1264. (doi: 10.1038/s41398-017-0012-7) (PMID:29187730) (PMCID:PMC5802589)

Abstract

Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (rg = 0.60, SE = 0.07, p = 8.95 × 10−17) and a small but significant genetic correlation with both schizophrenia (rg = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (rg = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.

• 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 Mackay, Professor Daniel and Graham, Dr Nicholas and Lyall, Dr Laura and Bailey, Dr Mark and Cavanagh, Professor Jonathan and Ward, Dr Joey and Pell, Professor Jill and Ferguson, Amy and Lyall, Dr Donald and Strawbridge, Dr Rona
• Authors: Ward, J., Strawbridge, R. J., Bailey, M. E.S., Graham, N., Ferguson, A., Lyall, D. M., Cullen, B., Pidgeon, L. M., Cavanagh, J., Mackay, D. F., Pell, J. P., O'Donovan, M., Escott-Price, V., and Smith, D. J.
• College/School: 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 Life Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Translational Psychiatry
• Publisher: Nature Publishing Group
• ISSN: 2158-3188
• ISSN (Online): 2158-3188
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Translational Psychiatry 7:1264
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
63234	1	MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16	Jeremy Mottram	Medical Research Council (MRC)	MR/K501335/1	III - PARASITOLOGY