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

Smith, Daniel J., Escott-Price, Valentina, Davies, Gail, Bailey, Mark E. S., Colodro-Conde, Lucia, Ward, Joey, Vedernikov, Alexey, Marioni, Riccardo, Cullen, Breda, Lyall, Donals, Hagenaars, Saskia P., Liewald, David C. M., Luciano, Michelle, Gale, Catharine R., Ritchie, Stuart J., Hayward, Caroline, Nicholl, Barbara, Bulik-Sullivan, Brendan, Adams, Mark, Couvy-Duchesne, Baptiste, Graham, Nicholas, Mackay, Daniel, Evans, Jonathan, Smith, Blair H., Porteous, David J., Medland, Sarah, Martin, Nick G., Holmans, Peter Alan, McIntosh, Andrew M., Pell, Jill P., Deary, Ian and O'Donovan, Michael Conlon 2016. Genome-wide analysis of over 106,000 individuals identifies 9 neuroticism-associated loci. Molecular Psychiatry 21 (6) , pp. 749-757. 10.1038/mp.2016.49

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Abstract

2 Abstract Neuroticism is a personality trait of fundamental importance for psychological wellbeing and public health. It is strongly associated with major depr essive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attem pts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of GWAS of neuroticism which includes 91,370 participants from the UK Biobank cohort, 6,659 participants from the Generation Scotland Scot tish Family Health Study (GS:SFHS) and 8,687 participants from a QIMR 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 SNP-based heritability estimate for neuroticism of approximately 15% (SE = 0.7%). Meta -analysis identified 9 novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (p = 1.5x10 -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 gene tic differences in the comm on allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation b etween neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, al though not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured about 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 the these cohorts. Th e identification of 9 novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: Q Science > QH Natural history > QH426 Genetics
Publisher: Nature Publishing Group
ISSN: 1359-4184
Funders: UK Biobank, The Wellcome Trust, Medical Research Council, Department of Health, Scottish Government and Northwset Regional Development Agency
Date of First Compliant Deposit: 15 June 2016
Date of Acceptance: 3 March 2016
Last Modified: 13 Apr 2019 03:02
URI: http://orca.cf.ac.uk/id/eprint/87549

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