Background: Alcohol and tobacco use are moderately heritable behaviors (h2 ≈ 0.50), and genome-wide association studies (GWAS) have identified a large number of associated loci. Though the majority of findings map to intergenic regions of the genome, GWAS heritability is known to be enriched at expression quantitative trait loci (eQTLs). Therefore, identifying relevant gene and tissue expression for GWAS loci may inform our understanding of disease mechanisms underlying these signals. In the current study, we tested whether GWAS-associated variants for alcohol and tobacco use colocalized with variants associated with nearby gene expression (cis-eQTLs).
Methods: Summary statistics for variants with minor allele frequency (MAF) > 0.001 were obtained from the most recent GSCAN meta-analyses of drinks per week (DPW), smoking initiation (SI), age of smoking initiation (AI), cigarettes smoked per day (CPD), and smoking cessation (SC) in a sample of European-ancestry individuals (N = 618,489 - 2,669,029, depending on the phenotype). Fine-mapped summary statistics for variants with MAF ≥ 0.01 were obtained from eQTL mapping in 49 tissues as part of the GTEx consortium v8 release. After assigning GWAS variants to approximately LD-independent blocks across the genome, colocalization analyses were conducted using the Bayesian hierarchical test, fastENLOC, for all 5 GWAS trait x 49 tissue pairs.
Results: After correction for multiple testing, a number of independent gene loci (DPW = 151; SI = 374; AI = 2; CPD = 18; and SC = 37) were found to have regional colocalization probabilities (RCPs) > 0.80, indicative of regions that likely harbor a shared causal variant for both the molecular and behavioral trait. These signals were present in brain and non-brain tissues and included several candidate genes previously associated with smoking and psychiatric phenotypes, such as CHRNA2 and SYT3. When aggregated across all tissues, the median proportion of loci with a suggestive RCP > 0.50 overlapping with a GW-significant variant ranged from 17%-40%, depending on the trait.
Discussion: Common variants associated with alcohol and tobacco use exhibit colocalization with variants influencing tissue-specific gene expression, though these patterns occur generally and do not appear to be specific to brain tissues. Relatively smaller sample sizes for eQTL mapping in brain tissues may have limited power to detect shared causal variation in the current study. Future investigations might test for colocalization with eQTL data from phenotype-relevant postmortem brain tissues or conduct additional functional studies to validate select candidate loci.