Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

Abstract

To identify novel traits associated with alleles known to predispose to alcohol and nicotine use, we conducted a phenome-wide association study (PheWAS) in a large multi-population cohort. We investigated 7688 African-Americans, 1133 Asian-Americans, 14 081 EuropeanAmericans, and 3492 Hispanic-Americans from the Women's Health Initiative, analyzing alleles at the CHRNA3-CHRNA5 locus, ADH1B, and ALDH2 with respect to phenotypic traits related to anthropometric characteristics, dietary habits, social status, psychological traits, reproductive history, health conditions, and nicotine/alcohol use. In ADH1B trans-population meta-analysis and population-specific analysis, we replicated prior associations with drinking behaviors and identified multiple novel phenome-wide significant and suggestive findings related to psychological traits, socioeconomic status, vascular/metabolic conditions, and reproductive health. We then applied Bayesian network learning algorithms to provide insight into the causative relationships of the novel ADH1B associations: ADH1B appears to affect phenotypic traits via both alcohol-mediated and alcohol-independent effects. In an independent sample of 2379 subjects, we also replicated the novel ADH1B associations related to socioeconomic status (household gross income and highest grade finished in school). For CHRNA3-CHRNA5 risk alleles, we replicated association with smoking behaviors, lung cancer, and asthma. There were also novel suggestive CHRNA3-CHRNA5 findings with respect to high-cholesterol-medication use and distrustful attitude. In conclusion, the genetics of alcohol and tobacco use potentially has broader implications on physical and mental health than is currently recognized. In particular, ADH1B may be a gene relevant for the human phenome via both alcohol metabolism-related mechanisms and other alcohol metabolismindependent mechanisms.

The genetic epidemiology of substance use disorder: A review

“…Therefore, PheWAS have the potential to deepen genomic knowledge regarding the range of phenotypic effects associated with GWAS-identified risk alleles. For example, a PheWAS of smoking and alcohol use in 26,394 women replicated prior asosciations between variants in ADH1B and alcohol use (e.g., alcohol servings per week, number of medium servings of wine per day, number of drinks of alcohol) as well as between variants in CHRNA3-CHRNA5 and smoking behaviors (e.g., cigarettes per day, age starte smoking cigarettes regularly; Polimanti, Kranzler & Gelernter, 2016). Further, the combination of PheWAS among affected individuals may also lead to an impoved understanding of SUD as well as other conditions.…”

Polymorphisms in HTR2A and DRD4 Predispose to Smoking and Smoking Quantity

“…In addition to CHRNA5 - CHRNA3 - CHRNB4 loci, which is the international validated loci for smoking quantity and nicotine dependence, [3, 4, 5] the most widely studied gene in the dopaminergic pathway is the dopamine receptor D4, which is encoded by the DRD4 gene; among the most explored genetic variants are the variable number tandem repeat (VNTR), located in exon III of this gene, however, studies that evaluated single nucleotide polymorphisms (SNPs) are scarce [6, 7]. A few studies have explored the association of SNPs in the 5-hydroxytryptamine receptor 2A (HTR2A) gene with nicotine addiction.…”

The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene

“…Although no large genomic investigation has been conducted on RSB, a recent genome-wide association study (GWAS) of age at first sexual intercourse indicated that the onset of sexual activity is genetically correlated to other reproductive and behavioral traits (Day et al, 2016). Our recent phenome-wide association study showed that risk alleles for alcohol-drinking behaviors are associated with reproductive health traits (Polimanti et al, 2016). These data suggest that alcohol use and abuse play a relevant role in RSB.…”