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Nicotinic α5 receptor subunit mRNA expression is associated with distant 5′ upstream polymorphisms
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Nicotinic α5 receptor subunit mRNA expression is associated with distant 5′ upstream polymorphisms
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Journal Article
Nicotinic α5 receptor subunit mRNA expression is associated with distant 5′ upstream polymorphisms
2011
Overview
CHRNA5
, encoding the nicotinic
α
5 subunit, is implicated in multiple disorders, including nicotine addiction and lung cancer. Previous studies demonstrate significant associations between promoter polymorphisms and
CHRNA5
mRNA expression, but the responsible sequence variants remain uncertain. To search for
cis
-regulatory variants, we measured allele-specific mRNA expression of
CHRNA5
in human prefrontal cortex autopsy tissues and scanned the
CHRNA5
locus for regulatory variants. A cluster of six frequent single-nucleotide polymorphisms (rs1979905, rs1979906, rs1979907, rs880395, rs905740, and rs7164030), in complete linkage disequilibrium (LD), fully account for a >2.5-fold allelic expression difference and a fourfold increase in overall
CHRNA5
mRNA expression. This proposed enhancer region resides more than 13 kilobases upstream of the
CHRNA5
transcription start site. The same upstream variants failed to affect
CHRNA5
mRNA expression in peripheral blood lymphocytes, indicating tissue-specific gene regulation. Other promoter polymorphisms were also correlated with overall
CHRNA5
mRNA expression in the brain, but were inconsistent with allelic mRNA expression ratios, a robust and proximate measure of
cis
-regulatory variants. The enhancer region and the nonsynonymous polymorphism rs16969968 generate three main haplotypes that alter the risk of developing nicotine dependence. Ethnic differences in LD across the
CHRNA5
locus require consideration of upstream enhancer variants when testing clinical associations.
Publisher
Springer International Publishing,Nature Publishing Group
Subject
5' Untranslated Regions - genetics
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Enhancer Elements, Genetic - genetics
/ Fundamental and applied biological sciences. Psychology
/ General aspects. Genetic counseling
/ Genetics of eukaryotes. Biological and molecular evolution
/ Humans
/ Molecular and cellular biology
/ Nerve Tissue Proteins - genetics
/ Nerve Tissue Proteins - metabolism
/ Polymorphism, Single Nucleotide - genetics
/ Prefrontal Cortex - metabolism
/ Promoter Regions, Genetic - genetics
/ Receptors, Nicotinic - genetics
/ Receptors, Nicotinic - metabolism
