The CHRNA5/CHRNA3/CHRNB4 Nicotinic Receptor Regulome: Genomic Architecture, Regulatory Variants, and Clinical Associations.

Functionally related genes often cluster into a genome region under coordinated regulation, forming a local regulome. To understand regulation of the CHRNA5/CHRNA3/CHRNB4 nicotinic receptor gene cluster, we integrate large-scale RNA expression data (brain and peripheral) from GTEx (Genotype Tissue Expression), clinical associations (GRASP), and linkage disequilibrium data (1000 Genomes) to find candidate SNPs representing independent regulatory variants. CHRNA3, CHRNA5, CHRNB4 mRNAs, and a well-expressed CHRNA5 antisense RNA (RP11-650L12.2) are co-expressed in many human tissues, suggesting common regulatory elements. The CHRNA5 enhancer haplotype tagged by rs880395 not only increases CHRNA5 mRNA expression in all tissues, but also enhances RP11-650L12.2 and CHRNA3 expression, suggesting DNA looping to multiple promoters. However, in nucleus accumbens and putamen, but not other brain regions, CHRNA3 expression associates uniquely with a haplotype tagged by rs1948 (located in the CHRNB4 3'UTR). Haplotype/diplotype analysis of rs880395 and rs1948 plus rs16969968 (a nonsynonymous CHRNA5 risk variant) in GWAS (COGEND, UW-TTURC, SAGE) yields a nicotine dependence risk profile only partially captured by rs16969968 alone. An example of local gene clusters, this nicotinic regulome is controlled by complex genetic variation, with broad implications for interpreting GWAS.