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

Article, Preprint English OPEN
Marioni, Riccardo ; O'Donovan, Michael ; Deary, Ian ; Pell, Jill ; Mcintosh, Andrew ; Holmans, Peter ; Martin, Nick ; Medland, Sarah ; Porteous, David ; Smith, Blair ; Evans, Jonathan ; Mackay, Daniel ; Graham, Nicholas ; Smith, Daniel ; Adams, Mark ; Bulik-Sullivan, Brendan ; Nicholl, Barbara ; Hayward, Caroline ; Ritchie, Stuart ; Gale, Catharine ; Luciano, Michelle ; Liewald, David ; Hagenaars, Saskia ; Lyall, Donald ; Cullen, Breda ; Vedernikov, Alexey ; Ward, Joey ; Conde, Lucia ; Bailey, Mark ; Davies, Gail ... view all 32 authors (2016)
  • Publisher: Nature Publishing Group
  • Journal: volume 21, issue 6, pages 749-757 (issn: 1359-4184, eissn: 1476-5578)
  • Related identifiers: doi: 10.1038/mp.2016.177, doi: 10.1038/mp.2016.49, doi: 10.1038/mp.2016.49., doi: 10.1101/032417, pmc: PMC4879189, pmc: PMC5078853
  • Subject: Molecular Biology | bepress|Life Sciences|Biology | /dk/atira/pure/subjectarea/asjc/2700/2738 | Cellular and Molecular Neuroscience | Corrigendum | /dk/atira/pure/subjectarea/asjc/2800/2804 | bepress|Life Sciences|Genetics and Genomics|Genetics | Immediate Communication | /dk/atira/pure/subjectarea/asjc/1300/1312 | QH426 | Psychiatry and Mental health
    mesheuropmc: mental disorders

2\ud Abstract \ud Neuroticism is a personality trait of fundamental \ud importance for psychological wellbeing and public \ud health. It is strongly associated with major depr\ud essive disorder (MDD) and several other psychiatric \ud conditions. Although neuroticism is heritable, attem\ud pts to identify the alleles involved in previous \ud studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis \ud of GWAS of neuroticism which includes 91,370 participants from the UK Biobank cohort, 6,659 \ud participants from the Generation Scotland Scot\ud tish Family Health Study (GS:SFHS) and 8,687 \ud participants from a QIMR Berghofer Medical Research \ud Institute (QIMR) cohort. \ud All participants were \ud assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised \ud (EPQ-R-S) Short Form’s Neuroticism scale. We found a SNP-based heritability estimate for \ud neuroticism of approximately 15% (SE = 0.7%). Meta\ud -analysis identified 9 novel loci associated with \ud neuroticism. The strongest evidence for association was at a locus on chromosome 8 (p = 1.5x10\ud -15\ud ) \ud spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting \ud candidate genes on chromosome 1 (\ud GRIK3,\ud glutamate receptor ionotropic kainate 3), chromosome 4 \ud (\ud KLHL2\ud , Kelch-like protein 2), chromosome 17 (\ud CRHR1,\ud corticotropin-releasing hormone receptor 1 \ud and \ud MAPT,\ud microtubule-associated protein Tau), and on chromosome 18 (\ud CELF4,\ud CUGBP elav-like \ud family member 4). We found no evidence for gene\ud tic differences in the comm\ud on allelic architecture \ud of neuroticism by sex. By comparing our findings \ud with those of the Psychiatric Genetics Consortia, \ud we identified a strong genetic correlation b\ud etween neuroticism and MDD and a less strong but \ud significant genetic correlation with schizophrenia, al\ud though not with bipolar disorder. Polygenic risk \ud scores derived from the primary UK Biobank sample captured about 1% of the variance in \ud neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant \ud alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated \ud within the these cohorts. Th\ud e identification of 9 novel neuroticism-associated loci will drive \ud forward future work on the neurobiology of neuroticism and related phenotypes.
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