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

D. J. Smith, V. Escott-Price, G. Davies, M. E S Bailey, L. Colodro-Conde, J. Ward, A. Vedernikov, R. Marioni, B. Cullen, D. Lyall, S. P. Hagenaars, D. C M Liewald, M. Luciano, C. R. Gale, S. J. Ritchie, C. Hayward, B. Nicholl, B. Bulik-Sullivan, M. Adams, B. Couvy-Duchesne & 12 others N. Graham, D. Mackay, J. Evans, B. H. Smith, D. J. Porteous, S. E. Medland, N. G. Martin, P. Holmans, A. M. McIntosh, J. P. Pell, I. J. Deary, M. C. O'Donovan

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    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.

    Original languageEnglish
    Pages (from-to)749-757
    Number of pages9
    JournalMolecular Psychiatry
    Volume21
    Issue number6
    Early online date12 Apr 2016
    DOIs
    Publication statusPublished - Jun 2016

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    Genome
    Queensland
    Biomedical Research
    Family Health
    Genome-Wide Association Study
    Major Depressive Disorder
    Scotland
    Neuroticism
    Psychiatry
    Personality
    Meta-Analysis
    Alleles
    Corticotropin-Releasing Hormone Receptors
    Ionotropic Glutamate Receptors
    Chromosomes, Human, Pair 18
    Chromosomes, Human, Pair 8
    Chromosomes, Human, Pair 17
    Chromosomes, Human, Pair 4
    Microtubule-Associated Proteins
    Neurobiology

    Cite this

    Smith, D. J., Escott-Price, V., Davies, G., Bailey, M. E. S., Colodro-Conde, L., Ward, J., ... O'Donovan, M. C. (2016). Genome-wide analysis of over 106  000 individuals identifies 9 neuroticism-associated loci. Molecular Psychiatry, 21(6), 749-757. https://doi.org/10.1038/mp.2016.49
    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. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 6. pp. 749-757.
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    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.",
    author = "Smith, {D. J.} and V. Escott-Price and G. Davies and Bailey, {M. E S} and L. Colodro-Conde and J. Ward and A. Vedernikov and R. Marioni and B. Cullen and D. Lyall and Hagenaars, {S. P.} and Liewald, {D. C M} and M. Luciano and Gale, {C. R.} and Ritchie, {S. J.} and C. Hayward and B. Nicholl and B. Bulik-Sullivan and M. Adams and B. Couvy-Duchesne and N. Graham and D. Mackay and J. Evans and Smith, {B. H.} and Porteous, {D. J.} and Medland, {S. E.} and Martin, {N. G.} and P. Holmans and McIntosh, {A. M.} and Pell, {J. P.} and Deary, {I. J.} and O'Donovan, {M. C.}",
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    Smith, DJ, Escott-Price, V, Davies, G, Bailey, MES, Colodro-Conde, L, Ward, J, Vedernikov, A, Marioni, R, Cullen, B, Lyall, D, Hagenaars, SP, Liewald, DCM, Luciano, M, Gale, CR, Ritchie, SJ, Hayward, C, Nicholl, B, Bulik-Sullivan, B, Adams, M, Couvy-Duchesne, B, Graham, N, Mackay, D, Evans, J, Smith, BH, Porteous, DJ, Medland, SE, Martin, NG, Holmans, P, McIntosh, AM, Pell, JP, Deary, IJ & O'Donovan, MC 2016, 'Genome-wide analysis of over 106  000 individuals identifies 9 neuroticism-associated loci', Molecular Psychiatry, vol. 21, no. 6, pp. 749-757. https://doi.org/10.1038/mp.2016.49

    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.

    In: Molecular Psychiatry, Vol. 21, No. 6, 06.2016, p. 749-757.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Genome-wide analysis of over 106  000 individuals identifies 9 neuroticism-associated loci

    AU - Smith, D. J.

    AU - Escott-Price, V.

    AU - Davies, G.

    AU - Bailey, M. E S

    AU - Colodro-Conde, L.

    AU - Ward, J.

    AU - Vedernikov, A.

    AU - Marioni, R.

    AU - Cullen, B.

    AU - Lyall, D.

    AU - Hagenaars, S. P.

    AU - Liewald, D. C M

    AU - Luciano, M.

    AU - Gale, C. R.

    AU - Ritchie, S. J.

    AU - Hayward, C.

    AU - Nicholl, B.

    AU - Bulik-Sullivan, B.

    AU - Adams, M.

    AU - Couvy-Duchesne, B.

    AU - Graham, N.

    AU - Mackay, D.

    AU - Evans, J.

    AU - Smith, B. H.

    AU - Porteous, D. J.

    AU - Medland, S. E.

    AU - Martin, N. G.

    AU - Holmans, P.

    AU - McIntosh, A. M.

    AU - Pell, J. P.

    AU - Deary, I. J.

    AU - O'Donovan, M. C.

    PY - 2016/6

    Y1 - 2016/6

    N2 - 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.

    AB - 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.

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    Smith DJ, Escott-Price V, Davies G, Bailey MES, Colodro-Conde L, Ward J et al. Genome-wide analysis of over 106  000 individuals identifies 9 neuroticism-associated loci. Molecular Psychiatry. 2016 Jun;21(6):749-757. https://doi.org/10.1038/mp.2016.49