Insight Into Nicotine and Alcohol Use Through Genetic Association Meta-Analyses

Abstract

Alcohol and tobacco use are leading causes of mortality worldwide and increases risk of many medical diseases. Twin studies routinely find that alcohol and tobacco use are heritable but large genome-wide association studies (GWAS) have only found a handful of reproducible associated single nucleotide polymorphisms (SNPs) due to the large sample sizes that are needed to find these variants with small effects. The heritability derived from these SNPs are also far from the heritability estimated from twin studies, generally under 10%, much less than the 30-60% typically found in twin studies. In this research, we aim to better understand the biology of substance use by finding more genetic variants associated with alcohol and tobacco use as well as addressing this discrepancy in heritability (commonly termed “missing heritability”). In the first study, we performed the largest GWAS meta-analysis to date with 1.2 million participants with European ancestry and discovered 566 conditionally independent variants in 406 loci. In the second study, we performed an exome meta-analysis to search for rare variants that may explain the missing heritability. We found no significant rare variants but replicated many common variants from the GWAS meta-analysis. In the last study, we constructed a polygenic risk score using the results from the GWAS meta-analysis and tested for association with endophenotypes associated with substance use. We found no significant association between any of our substance use PRS and endophenotypes. Future research should explore more diverse samples to discover any ancestry-specific variants that may affect alcohol and nicotine use.