title: The CHRNA5/CHRNA3/CHRNB4 Nicotinic Receptor Regulome: Genomic Architecture, Regulatory Variants, and Clinical Associations.
abstract: 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.
authors.affiliation: Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.|Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Barrie
authors.affiliation: Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hartmann
authors.affiliation: Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Sung-Ha
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: John T
authors.initials: JT
authors.lastname: Frater
authors.affiliation: University of Lodz, Lodz, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Seweryn
authors.affiliation: Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.affiliation: Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D005786:Gene Expression Regulation; D056726:Genetic Association Studies / Q000379:methods; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D011978:Receptors, Nicotinic / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D014029:Tobacco Use Disorder / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human
keywords: eQTL; functional genomics; gene expression; genetic association studies; genetic variation; human; nicotinic receptor subunit; regulome; smoking