Genome-wide analysis of over 106000 individuals identifies 9 neuroticism-associated loci

被引：149

作者：

Smith, D. J. ^{[1
]}

Escott-Price, V. ^{[2
]}

Davies, G. ^{[3
]}

Bailey, M. E. S. ^{[4
]}

Colodro-Conde, L. ^{[5
]}

Ward, J. ^{[1
]}

Vedernikov, A. ^{[2
]}

Marioni, R. ^{[3
,5
,6
]}

Cullen, B. ^{[1
]}

Lyall, D. ^{[1
]}

Hagenaars, S. P. ^{[3
]}

Liewald, D. C. M. ^{[3
]}

Luciano, M. ^{[3
]}

Gale, C. R. ^{[3
,7
]}

Ritchie, S. J. ^{[3
]}

Hayward, C. ^{[6
,8
]}

Nicholl, B. ^{[1
]}

Bulik-Sullivan, B. ^{[9
,10
,11
,12
]}

Adams, M. ^{[13
]}

Couvy-Duchesne, B. ^{[5
]}

Graham, N. ^{[1
]}

Mackay, D. ^{[1
]}

Evans, J. ^{[1
]}

Smith, B. H. ^{[8
,14
]}

Porteous, D. J. ^{[3
,8
,15
]}

Medland, S. E. ^{[5
]}

Martin, N. G. ^{[5
]}

Holmans, P. ^{[2
]}

McIntosh, A. M. ^{[3
,8
,13
]}

Pell, J. P. ^{[1
]}

Deary, I. J. ^{[3
,8
]}

O'Donovan, M. C. ^{[2
]}

机构：

[1] Univ Glasgow, Inst Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland

[2] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

[3] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[4] Univ Glasgow, Sch Life Sci, Coll Med Vet & Life Sci, Glasgow G12 8RZ, Lanark, Scotland

[5] QIMR Berghofer Med Res Inst, Herston, Qld, Australia

[6] Univ Edinburgh, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[7] Univ Southampton, Southampton Gen Hosp, Lifecourse Epidemiol Unit, MRC, Southampton, Hants, England

[8] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland

[9] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[10] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[11] Harvard Univ, Sch Med, Boston, MA USA

[12] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA

[13] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland

[14] Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland

[15] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland

来源：

MOLECULAR PSYCHIATRY | 2016年 / 21卷 / 06期

基金：

澳大利亚研究理事会; 英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

MAJOR DEPRESSIVE DISORDER; COMMON SNPS EXPLAIN; PERSONALITY DIMENSIONS; GENETIC-VARIATION; SEX-DIFFERENCES; MOOD DISORDERS; PROTEIN; HERITABILITY; TRAITS; METAANALYSIS;

D O I：

10.1038/mp.2016.49

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 similar to 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 x 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 similar to 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.

引用

页码：749 / 757

页数：9

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