Abstract P101: MEGA Analysis of Alcohol Consumption: The PAGE Study

Abstract

Harmful use of alcohol results in 3.3 million deaths annually and 139 million disability-adjusted life years, and is a risk factor for obesity, hypertension, cardiomyopathy, and stroke. According to the NIAAA, while some minority groups (African Americans and Hispanics) are more likely to abstain from alcohol, those who do drink have higher rates of alcohol consumption and binge drinking. In addition, most genetic studies of alcohol have focused on dependence phenotypes. In populations of European and East Asian ancestry, genes related to alcohol metabolism, including ADH and ALDH , have been identified, and AUTS2 and SLC6A1 have been associated with alcohol consumption. Studies focused on diverse populations are necessary to provide insight into population-specific genetic variability and guide precision screening and intervention efforts. We aim to further efforts in precision medicine using The Multi-Ethnic Genotyping Array (MEGA), a custom array designed to capture genetic variants in minority populations to allow for imputation to low minor allele frequencies (MAF) across ancestries, as well as clinically relevant variants and deep genotyping of previously identified GWAS regions associated with complex diseases. We performed the first discovery study for alcohol traits using MEGA genotype data in African American, Hispanic, Asian, Native Hawaiian, and Native American PAGE participants to discover novel genetic variants influencing alcohol consumption. Our preliminary results focus on non-pregnant women over 21 (N=21,641), with phenotype data on drinks/week in study-specific single variant additive regression models controlling for age, PCs, and study center. Study-specific results were then meta-analyzed in METAL. Four variants on chromosome 8 (R 2 =0.33-0.81) passed our chip-wide significance threshold of p=2.8E-8. Of these, rs115165977 showed the strongest association with drinks/week (beta=1.93, se=0.32, p=1.70E-09). This variant is monomorphic in European and East Asian reference populations, but has a MAF between 0.01-0.03 in non-Asian PAGE populations. Rs115165977 is near ZFPM2 , a gene previously associated with cardiomyopathy that codes for a transcription factor regulating GATA proteins important for heart morphogenesis. This mouse ortholog of ZFPM2 has also been associated with alcohol acceptance and alcohol-induced loss of the righting reflex. Future work will focus on analysis of alcohol consumption using PAGE imputed data in the full sample, as well as fine-mapping known alcohol-related loci typed on the MEGA chip.