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

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 previo...

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Main 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 E, Martin, N G, Holmans, P, McIntosh, A M, Pell, J P, Deary, I J, O'Donovan, M C
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879189/

id	pubmed-4879189
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spelling	pubmed-48791892016-06-02 Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci 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 E Martin, N G Holmans, P McIntosh, A M Pell, J P Deary, I J O'Donovan, M C Immediate Communication 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. Nature Publishing Group 2016-06 2016-04-12 /pmc/articles/PMC4879189/ /pubmed/27067015 http://dx.doi.org/10.1038/mp.2016.49 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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 E Martin, N G Holmans, P McIntosh, A M Pell, J P Deary, I J O'Donovan, M C
spellingShingle	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 E Martin, N G Holmans, P McIntosh, A M Pell, J P Deary, I J O'Donovan, M C Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
author_facet	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 E Martin, N G Holmans, P McIntosh, A M Pell, J P Deary, I J O'Donovan, M C
author_sort	Smith, D J
title	Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
title_short	Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
title_full	Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
title_fullStr	Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
title_full_unstemmed	Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
title_sort	genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci
description	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.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879189/
_version_	1613583782250545152

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

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