Meta‐Analysis of Genetic Influences on Initial Alcohol Sensitivity

Alexis C Edwards, Joseph Deak, Ian Gizer, Dongbing Lai, Chris Chatzinakos, Kirk Wilhelmsen, J. Lindsay, Matthew Hickman, Jon Heron, Matt Hickman, Bradley T Webb, Silviu-Alin Bacanu, Tatiana Foroud, Kenneth S Kendler, Danielle M Dick, Marc A Schuckit

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Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported.

We conducted a meta‐analysis of 2 population‐based genome‐wide association studies of the Self‐Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)‐based heritability and conducted a series of secondary aggregate genetic analyses.

No individual locus reached genome‐wide significance. Gene and set based analyses, both overall and using tissue‐specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta‐analysis of SNP‐based heritability resulted in a modest estimate of = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed.

Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings.
Original languageEnglish
Pages (from-to)2349-2359
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Issue number12
Early online date1 Oct 2018
Publication statusPublished - Dec 2018


  • Avon Longitudinal Study of Parents and Children
  • Genetics
  • Genome-Wide Association Studies
  • Heritability
  • Initial Alcohol Sensitivity
  • Self-Rating of the Effects of Alcohol


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