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

Research output: Contribution to journalArticle

  • D. J. Smith
  • V. Escott-Price
  • M. E S Bailey
  • L. Colodro-Conde
  • J. Ward
  • A. Vedernikov
  • B. Cullen
  • D. Lyall
  • S. P. Hagenaars
  • D. C M Liewald
  • C. R. Gale
  • S. J. Ritchie
  • B. Nicholl
  • B. Bulik-Sullivan
  • B. Couvy-Duchesne
  • N. Graham
  • D. Mackay
  • J. Evans
  • B. H. Smith
  • S. E. Medland
  • N. G. Martin
  • P. Holmans
  • J. P. Pell
  • M. C. O'Donovan

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Original languageEnglish
Pages (from-to)749-757
JournalMolecular Psychiatry
Issue number6
Early online date12 Apr 2016
Publication statusPublished - Jun 2016


Neuroticism is a personality trait of fundamental importance for psychological wellbeing 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 GWAS of neuroticism which includes 91,370 participants from the UK Biobank cohort, 6,659 participants from the Generation Scotland Scottish 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 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 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. The identification of 9 novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

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