Meta‐Analysis of Genetic Influences on Initial Alcohol Sensitivity

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 two population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated 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 one 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 h2SNP=0.19 (SE=0.10), though this was driven by one sample (N=3683, h2SNP=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.

The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample

“…Individuals with higher SRE‐T scores demonstrate lower level of response to alcohol, potentially via dampening of neural and physiological pathways in response to alcohol (Schuckit, ; Schuckit et al., ). There are currently no published GWAS of SRE‐T, although a meta‐analysis of a related but etiologically distinct trait representing subjective ratings of EtOH during the first 5 times that alcohol was consumed (SRE‐5) did not find loci previously associated with alcohol consumption or dependence to be related to it (Edwards et al., ). Thus, even though SRE is heritable (Kalu et al., ) and related to alcohol consumption, its genetic underpinnings may be quite different from those related to alcohol intake.…”

Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B/Mef2 in Alcohol Sensitivity

“…Higher scores on the SRE have been associated with the development of alcohol use and misuse (Schuckit, ; Schuckit et al., ), suggesting that it has predictive validity for risk of later problematic alcohol consumption. The meta‐analytic single‐nucleotide polymorphism (SNP)‐based heritability estimate ( ) in our previous report (Edwards et al., ) was modest ( = 0.19, SE = 0.10) in the combined ALSPAC and S4S samples. This modest heritability was driven, however, by the ALSPAC sample ( = 0.36, SE = 0.14, p = 0.04); the heritability estimate did not differ from 0 in S4S.…”

“…Participants, aged 15.5, 16.5, and 17.5, were asked to consider the first 5 or so times they consumed alcohol and to report the number of standard drinks (defined in the questionnaire/interview) they consumed before they experienced signs of intoxication. As described previously (Edwards et al., ), responses were winsorized to account for outliers and total scores were derived according to recommendations by Schuckit and colleagues (). The total score was used as a continuous outcome in subsequent GWAS, with sex and ancestry‐informative principal components as covariates.…”

“…We previously reported a meta‐analysis of GWAS on the Self‐Rating of the Effects of Alcohol (SRE) across 2 adolescent‐to‐young adult samples, Avon Longitudinal Study of Parents and Children (ALSPAC) and Spit for Science (S4S) (Edwards et al., ). The SRE (Schuckit et al., ) captures the number of alcoholic drinks needed for respondents to experience intoxication when they first began drinking (i.e., initial sensitivity).…”

Genome‐wide association studies of the self‐rating of effects of ethanol (SRE)

“…Two linkage studies, one using 745 European ancestry individuals (included in this study) and another in American Indians, detected modest evidence of linkage. Recently, a meta‐analysis of genome‐wide association studies (GWAS) of SRE score of the first five times of drinking (SRE‐5) did not identify genome‐wide significant loci . Genetic analyses of the average SRE scores across the three time periods (SRE‐T) have been limited to candidate gene studies .…”