title: Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.
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.
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: V
authors.identifier: 0000-0003-1784-5483
authors.initials: V
authors.lastname: Escott-Price
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: G
authors.initials: G
authors.lastname: Davies
authors.affiliation: School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: M E S
authors.initials: ME
authors.lastname: Bailey
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Colodro-Conde
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ward
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: A
authors.initials: A
authors.lastname: Vedernikov
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.|QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.|Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: R
authors.initials: R
authors.lastname: Marioni
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: B
authors.initials: B
authors.lastname: Cullen
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: D
authors.initials: D
authors.lastname: Lyall
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Hagenaars
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: D C M
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: M
authors.initials: M
authors.lastname: Luciano
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.|MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Gale
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Ritchie
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: B
authors.initials: B
authors.lastname: Nicholl
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Bulik-Sullivan
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: M
authors.identifier: 0000-0002-3599-6018
authors.initials: M
authors.lastname: Adams
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Couvy-Duchesne
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: N
authors.initials: N
authors.lastname: Graham
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: D
authors.initials: D
authors.lastname: Mackay
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Evans
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Division of Population Health Sciences, University of Dundee, Dundee, UK.
authors.forename: B H
authors.initials: BH
authors.lastname: Smith
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: S E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: P
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Pell
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: I J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D000483:Alleles; D001008:Anxiety Disorders / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics; D003865:Major Depressive Disorder / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D000075384:Neuroticism; D020641:Polymorphism, Single Nucleotide; D011793:Queensland; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D012606:Scotland; D006113:United Kingdom; D044465:White People / Q000235:genetics