Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117)

T-K Clarke, M J Adams, G Davies, D M Howard, L S Hall, S Padmanabhan, A D Murray, B H Smith, A Campbell, C Hayward, D J Porteous, I J Deary, A M McIntosh

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Abstract

Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10(-23)). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

Original languageEnglish
Pages (from-to)1376-1384
Number of pages9
JournalMolecular Psychiatry
Volume22
Issue number10
Early online date25 Jul 2017
DOIs
Publication statusPublished - Oct 2017

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Genome-Wide Association Study
Alcohol Drinking
Health
Genes
Single Nucleotide Polymorphism
Neurobiology
Alcohols
Genetic Loci
HDL Cholesterol
Smoking
Genome

Keywords

  • Journal Article

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Clarke, T-K., Adams, M. J., Davies, G., Howard, D. M., Hall, L. S., Padmanabhan, S., ... McIntosh, A. M. (2017). Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117). Molecular Psychiatry, 22(10), 1376-1384. https://doi.org/10.1038/mp.2017.153

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117). / Clarke, T-K; Adams, M J; Davies, G; Howard, D M; Hall, L S; Padmanabhan, S; Murray, A D; Smith, B H; Campbell, A; Hayward, C; Porteous, D J; Deary, I J; McIntosh, A M.

In: Molecular Psychiatry, Vol. 22, No. 10, 10.2017, p. 1376-1384.

Research output: Contribution to journalArticle

Clarke, T-K, Adams, MJ, Davies, G, Howard, DM, Hall, LS, Padmanabhan, S, Murray, AD, Smith, BH, Campbell, A, Hayward, C, Porteous, DJ, Deary, IJ & McIntosh, AM 2017, 'Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117)', Molecular Psychiatry, vol. 22, no. 10, pp. 1376-1384. https://doi.org/10.1038/mp.2017.153
Clarke, T-K ; Adams, M J ; Davies, G ; Howard, D M ; Hall, L S ; Padmanabhan, S ; Murray, A D ; Smith, B H ; Campbell, A ; Hayward, C ; Porteous, D J ; Deary, I J ; McIntosh, A M. / Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117). In: Molecular Psychiatry. 2017 ; Vol. 22, No. 10. pp. 1376-1384.
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abstract = "Alcohol consumption has been linked to over 200 diseases and is responsible for over 5{\%} of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13{\%} (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10(-23)). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.",
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AU - Adams, M J

AU - Davies, G

AU - Howard, D M

AU - Hall, L S

AU - Padmanabhan, S

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N1 - Acknowledgements This research has been conducted using the UK Biobank Resource: application number 4844. We are grateful to the families who took part in GS, the GPs and Scottish School of Primary Care for their help in recruiting them, and the whole GS team that includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award ‘STratifying Resilience and Depression Longitudinally’ (STRADL) Reference 104036/Z/14/Z). We acknowledge with gratitude the financial support received for this work from the Dr Mortimer and Theresa Sackler Foundation. DJP, IJD and AMM are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council is gratefully acknowledged

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N2 - Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10(-23)). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

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