There are approximately 50 variants spanning ∼83 kb within and flanking the CHRNA5-A3-B4 gene cluster and the adjacent PSMA4 gene that are highly correlated (D′≥0.9; r2≥0.7) with the variants (i.e. rs3841324, rs588765, rs880395) associated with CHRNA5 mRNA levels in populations of European ancestry (Table S1). It is not clear which of these variants directly affect CHRNA5 mRNA expression. Because populations of African ancestry have reduced linkage disequilibrium (LD) patterns across this gene cluster (http://hapmap.ncbi.nlm.nih.gov) (Table S1), the contrasting genetic architecture in Africans and Europeans can be leveraged to identify the functional variation most tightly linked to differences in CHRNA5 mRNA expression. A previous study using quantitative allele specific gene expression in prefrontal cortex tissue from 59 Caucasians and 14 African Americans reported a cluster of 6 highly correlated SNPs located ∼13.5 kb upstream of the CHRNA5 gene that accounted for the variability in mRNA expression [23]. Differential allelic expression of CHRNA5 was also detected in normal lung tissue and in lung adenocarcinoma; two single nucleotide polymorphisms (rs55853698 and rs55781567) in the 5′UTR of CHRNA5 were associated with significant imbalance in
