Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

Smith, D.J. et al. (2016) Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci. Molecular Psychiatry, 21(6), pp. 749-757. (doi:10.1038/mp.2016.49) (PMID:27067015)

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Abstract

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form’s Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ~15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10−15) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ~1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel and Nicholl, Dr Barbara and Evans, Professor Jonathan and Cullen, Dr Breda and Ritchie, Dr Stuart and Mackay, Dr Daniel and Graham, Mr Nicholas and Bailey, Dr Mark and Ward, Mr Joey and Pell, Professor Jill and Lyall, Dr Donald
Authors: Smith, D.J., Escott-Price, V., Davies, G., Bailey, M.E.S., Colodro-Conde, L., Ward, J., Vedernikov, A., Marioni, R., Cullen, B., Lyall, D., Hagenaars, S.P., Liewald, D.C.M., Luciano, M., Gale, C.R., Ritchie, S.J., Hayward, C., Nicholl, B., Bulik-Sullivan, B., Adams, M., Couvy-Duchesne, B., Graham, N., Mackay, D., Evans, J., Smith, B.H., Porteous, D.J., Medland, S., Martin, N.G., Holmans, P., McIntosh, A.M., Pell, J.P., Deary, I.J., and O'Donovan, M.C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > General Practice and Primary Care
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Molecular Psychiatry
Publisher:Nature Publishing Group
ISSN:1359-4184
ISSN (Online):1476-557
Copyright Holders:Copyright © 2016 Nature Publishing Group
First Published:First published in Molecular Psychiatry 21(6): 749-757
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
381721Generation ScotlandAnna DominiczakScottish Executive Health Department (SEHHD-CSO)CZD/16/6RI CARDIOVASCULAR & MEDICAL SCIENCES