Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

David M. Howard (Corresponding Author), Lynsey S Hall, Jonathan D. Hafferty, Yanni Zeng, Mark James Adams, Toni-Kim Clarke, David J. Porteous, Reka Nagy, Caroline Hayward, Blair H. Smith, Alison D. Murray, Niamh M. Ryan, Kathryn L. Evans, Chris S. Haley, Ian J. Deary, Pippa A. Thomson, Andrew M. McIntosh

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Abstract

Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.
Original languageEnglish
Article number1263
JournalTranslational Psychiatry
Volume7
Early online date30 Nov 2017
DOIs
Publication statusPublished - 2017

Fingerprint

Major Depressive Disorder
Scotland
Haplotypes
Genome
Cognition
Butyrylcholinesterase
Meta-Analysis
Aptitude
D-Amino-Acid Oxidase
Genes
Family Health
Genome-Wide Association Study
Longitudinal Studies
Alzheimer Disease
Genotype
Proteins

Keywords

  • haplotype association analysis
  • cognition
  • intelligence
  • IQ Generation Scotland
  • UK Biobank
  • English Longitudinal Study of Aging

Cite this

Howard, D. M., Hall, L. S., Hafferty, J. D., Zeng, Y., Adams, M. J., Clarke, T-K., ... McIntosh, A. M. (2017). Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank. Translational Psychiatry, 7, [1263]. https://doi.org/10.1038/s41398-017-0010-9

Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank. / Howard, David M. (Corresponding Author); Hall, Lynsey S; Hafferty, Jonathan D.; Zeng, Yanni; Adams, Mark James; Clarke, Toni-Kim; Porteous, David J.; Nagy, Reka; Hayward, Caroline; Smith, Blair H.; Murray, Alison D.; Ryan, Niamh M.; Evans, Kathryn L.; Haley, Chris S.; Deary, Ian J.; Thomson, Pippa A.; McIntosh, Andrew M.

In: Translational Psychiatry, Vol. 7, 1263, 2017.

Research output: Contribution to journalArticle

Howard, DM, Hall, LS, Hafferty, JD, Zeng, Y, Adams, MJ, Clarke, T-K, Porteous, DJ, Nagy, R, Hayward, C, Smith, BH, Murray, AD, Ryan, NM, Evans, KL, Haley, CS, Deary, IJ, Thomson, PA & McIntosh, AM 2017, 'Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank', Translational Psychiatry, vol. 7, 1263. https://doi.org/10.1038/s41398-017-0010-9
Howard, David M. ; Hall, Lynsey S ; Hafferty, Jonathan D. ; Zeng, Yanni ; Adams, Mark James ; Clarke, Toni-Kim ; Porteous, David J. ; Nagy, Reka ; Hayward, Caroline ; Smith, Blair H. ; Murray, Alison D. ; Ryan, Niamh M. ; Evans, Kathryn L. ; Haley, Chris S. ; Deary, Ian J. ; Thomson, Pippa A. ; McIntosh, Andrew M. / Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank. In: Translational Psychiatry. 2017 ; Vol. 7.
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abstract = "Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.",
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AU - Adams, Mark James

AU - Clarke, Toni-Kim

AU - Porteous, David J.

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AU - Smith, Blair H.

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N2 - Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.

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KW - haplotype association analysis

KW - cognition

KW - intelligence

KW - IQ Generation Scotland

KW - UK Biobank

KW - English Longitudinal Study of Aging

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VL - 7

JO - Translational Psychiatry

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