Meta‐Analysis of Genetic Influences on Initial Alcohol Sensitivity. (28th October 2018)

• Record Type: Journal Article
• Authors: Edwards, Alexis C.; Deak, Joseph D.; Gizer, Ian R.; Lai, Dongbing; Chatzinakos, Chris; Wilhelmsen, Kirk P.; Lindsay, Jonathan; Heron, Jon; Hickman, Matthew; Webb, Bradley T.; Bacanu, Silviu‐Alin; Foroud, Tatiana M.; Kendler, Kenneth S.; Dick, Danielle M.; Schuckit, Marc A.
• Is Part Of: Alcoholism. Volume 42:Number 12(2018)
• Page Start: 2349
• Page End: 2359
• Publication Date: 2018-10-28
• Subjects: Avon Longitudinal Study of Parents and Children -- Genetics -- Genome‐Wide Association Studies -- Heritability -- Initial Alcohol Sensitivity -- Self‐Rating of the Effects of Alcohol; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.13896
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract : Background: 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. Methods: 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. Results: 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 h SNP 2 = 0.19 (SE = 0.10), though this was driven by 1 sample ( N = 3, 683, h SNP 2 = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed. Conclusions: 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. Abstract : Initial sensitivity to alcohol is associated with later problematic alcohol‐related outcomes. The current study found evidence of aggregate genetic influences on initial sensitivity, though no individual SNP met genome‐wide significance criteria. Further analyses suggest that the biology of initial sensitivity may diverge from that of other alcohol outcomes. As with other complex traits, how initial sensitivity is assessed is likely critical to the identification of robust genetic signals.