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 European-Americans, 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 metabolism-independent mechanisms.

Figure 1

Manhattan plot of the trans-population meta-analysis including both smoking and alcohol-associated alleles. Red and black lines indicate the phenome-wide and the suggestive significance thresholds (p<1.74*10⁻⁵ and p<1.74*10⁻⁴, respectively). Phenotype abbreviations are defined in Supplementary Table 2. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 2

Phenotypic associations of ADH1B rs1229984 in trans-population meta-analysis (META) and in African (AFR), Asian (ASN), European (EUR), and Hispanic (HISP) samples. In each cell, the correspondent z-score is reported (double underline: phenome-wide significance, p<1.74*10^–5 based on Bonferroni correction for number of traits and markers studied; single underline: suggestive significance, p<1.74*10^–4; bold: nominal significance, p<0.05). The intensity of the cell shading is proportional to the association strength (negative association: red; positive association: green). A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 3

Best causative model of the novel ADH1B rs1229984 phenotype associations identified in WHI cohorts. Phenotype abbreviations are defined in Supplementary Table 2.

Figure 4

Phenotypic associations of CHRNA3–CHRNA5 locus (rs8034191, rs1051730, rs12914385, rs2036527, and rs16969968) in trans-population meta-analysis (META) and in African (AFR), Asian (ASN), European (EUR), and Hispanic (HISP) samples. In each cell, the correspondent z-score is reported (double underline: phenome-wide significance, p<1.74*10^–5 based on Bonferroni correction for number of traits and markers studied; single underline: suggestive significance, p<1.74*10^–4; bold: nominal significance, p<0.05). The intensity of the cell shading is proportional to the association strength (negative association: red; positive association: green). (*) WHI PAGE data set was not available for these markers. A full color version of this figure is available at the Neuropsychopharmacology journal online.