Polygenic risk for alcohol dependence associates with alcohol consumption, cognitive function and social deprivation in a population-based cohort

Toni-Kim Clarke, Andrew H. Smith, Joel Gelernter, Henry R. Kranzler, Lindsay A. Farrer, Lynsey S. Hall, Ana M. Fernandez-Pujals, Donald J. MacIntyre, Blair H. Smith, Lynne J. Hocking, Sandosh Padmanabhan, Caroline Hayward, Pippa A. Thomson, David J. Porteous, Ian J. Deary, Andrew M. McIntosh

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Alcohol dependence is frequently co-morbid with cognitive impairment. The relationship between these traits is complex as cognitive dysfunction may arise as a consequence of heavy drinking or exist prior to the onset of dependence. In the present study, we tested the genetic overlap between cognitive abilities and alcohol dependence using polygenic risk scores (PGRS). We created two independent PGRS derived from two recent genome-wide association studies (GWAS) of alcohol dependence (SAGE GWAS: n = 2750; Yale-Penn GWAS: n = 2377) in a population-based cohort, Generation Scotland: Scottish Family Health Study (GS:SFHS) (n = 9863). Data on alcohol consumption and four tests of cognitive function [Mill Hill Vocabulary (MHV), digit symbol coding, phonemic verbal fluency (VF) and logical memory] were available. PGRS for alcohol dependence were negatively associated with two measures of cognitive function: MHV (SAGE: P = 0.009, β = -0.027; Yale-Penn: P = 0.001, β = -0.034) and VF (SAGE: P = 0.0008, β = -0.036; Yale-Penn: P = 0.00005, β = -0.044). VF remained robustly associated after adjustment for education and social deprivation; however, the association with MHV was substantially attenuated. Shared genetic variants may account for some of the phenotypic association between cognitive ability and alcohol dependence. A significant negative association between PGRS and social deprivation was found (SAGE: P = 5.2 × 10(-7) , β = -0.054; Yale-Penn: P = 0.000012, β = -0.047). Individuals living in socially deprived regions were found to carry more alcohol dependence risk alleles which may contribute to the increased prevalence of problem drinking in regions of deprivation. Future work to identify genes which affect both cognitive impairment and alcohol dependence will help elucidate biological processes common to both disorders.

Original languageEnglish
Pages (from-to)469-480
Number of pages12
JournalAddiction Biology
Issue number2
Early online date10 Apr 2015
Publication statusPublished - Mar 2016

Bibliographical note


We are grateful to the families who took part in GS:SFHS, the GPs and Scottish School of Primary Care for their help in recruiting them, and the whole GS team, which includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers.

Funded by
Scottish Government Health Department, Chief Scientist Office. Grant Number: CZD/16/6
National Institutes of Health. Grant Numbers: N01-HG-65403, HHSN268200782096C, RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, P50 AA12870, MSTP T32GM07205, CTSA 8UL1TR000142
NIH Genes, Environment and Health Initiative [GEI]. Grant Numbers: U01 HG004422, U01HG004438
Gene Environment Association Studies (GENEVA). Grant Number: U01 HG004446
Collaborative Study on the Genetics of Alcoholism. Grant Number: U10 AA008401
Collaborative Genetic Study of Nicotine Dependence. Grant Number: P01 CA089392
Family Study of Cocaine Dependence. Grant Number: R01 DA013423
National Institute on Alcohol Abuse and Alcoholism
National Institute on Drug Abuse
Dr Mortimer and Theresa Sackler Foundation
Biotechnology and Biological Sciences Research Council (BBSRC)
Medical Research Council (MRC)


  • alcohol dependence
  • cognition
  • environment
  • genetics
  • polygenic
  • social deprivation


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