title: Exploration of a Polygenic Risk Score for Alcohol Consumption: A Longitudinal Analysis from the ALSPAC Cohort.
abstract: BACKGROUND
  Uncertainty remains about the true extent by which alcohol consumption causes a number of health outcomes. Genetic variants, or combinations of variants built into a polygenic risk score (PGRS), can be used in an instrumental variable framework to assess causality between a phenotype and disease outcome of interest, a method known as Mendelian randomisation (MR). We aimed to identify genetic variants involved in the aetiology of alcohol consumption, and develop a PGRS for alcohol.
  
  
  METHODS
  Repeated measures of alcohol consumption from mothers and their offspring were collected as part of the Avon Longitudinal Study of Parents and Children. We tested the association between 89 SNPs (identified from either published GWAS data or from functional literature) and repeated measures of alcohol consumption, separately in mothers (from ages 28-48) and offspring (from ages 15-21) who had ever reported drinking. We modelled log units of alcohol using a linear mixed model and calculated beta coefficients for each SNP separately. Cross-validation was used to determine an allelic score for alcohol consumption, and the AVENGEME algorithm employed to estimate variance of the trait explained.
  
  
  RESULTS
  Following correction for multiple testing, one SNP (rs1229984) showed evidence for association with alcohol consumption (β = -0.177, SE = 0.042, p = <0.0001) in the mothers. No SNPs showed evidence for association in the offspring after correcting for multiple testing. The optimal allelic score was generated using p-value cut offs of 0.5 and 0.05 for the mothers and offspring respectively. These scores explained 0.3% and 0.7% of the variance.
  
  
  CONCLUSIONS
  Our PGRS explains a modest amount of the variance in alcohol consumption and larger sample sizes would be required to use our PGRS in an MR framework.
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol (IEU), University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
authors.forename: Michelle
authors.identifier: http://orcid.org/0000-0002-1849-8543
authors.initials: M
authors.lastname: Taylor
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol (IEU), University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Simpkin
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol (IEU), University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Haycock
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol (IEU), University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Luisa
authors.initials: L
authors.lastname: Zuccolo
mesh_terms: D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult