title: Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry.
abstract: Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Jen-Chyong
authors.initials: JC
authors.lastname: Wang
authors.forename: Noah
authors.initials: N
authors.lastname: Spiegel
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Nhung
authors.initials: N
authors.lastname: Le
authors.forename: Nicholas
authors.initials: N
authors.lastname: McKenna
authors.forename: John P
authors.initials: JP
authors.lastname: Budde
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.forename: Manav
authors.initials: M
authors.lastname: Kapoor
authors.forename: Andrew
authors.initials: A
authors.lastname: Brooks
authors.forename: Dana
authors.initials: D
authors.lastname: Hancock
authors.forename: Jay
authors.initials: J
authors.lastname: Tischfield
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Joe Henry
authors.initials: JH
authors.lastname: Steinbach
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D000483:Alleles; D022981:Allelic Imbalance; D044383:Black People / Q000235:genetics*; D005625:Frontal Lobe / Q000378:metabolism; D005786:Gene Expression Regulation; D023061:Gene Order; D005838:Genotype; D006801:Humans; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D059368:RNA Isoforms; D011978:Receptors, Nicotinic / Q000235:genetics*; D038621:Regulatory Sequences, Ribonucleic Acid; D044465:White People / Q000235:genetics*
chemical_list: C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D059368:RNA Isoforms; D011978:Receptors, Nicotinic; D038621:Regulatory Sequences, Ribonucleic Acid