Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry

Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry

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 express...

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Main Authors: Wang, Jen-Chyong, Spiegel, Noah, Bertelsen, Sarah, Le, Nhung, McKenna, Nicholas, Budde, John P., Harari, Oscar, Kapoor, Manav, Brooks, Andrew, Hancock, Dana, Tischfield, Jay, Foroud, Tatiana, Bierut, Laura J., Steinbach, Joe Henry, Edenberg, Howard J., Traynor, Bryan J., Goate, Alison M.
Format: Online
Language:English
Published: Public Library of Science 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841173/
id pubmed-3841173
recordtype oai_dc
spelling pubmed-38411732013-12-03 Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry Wang, Jen-Chyong Spiegel, Noah Bertelsen, Sarah Le, Nhung McKenna, Nicholas Budde, John P. Harari, Oscar Kapoor, Manav Brooks, Andrew Hancock, Dana Tischfield, Jay Foroud, Tatiana Bierut, Laura J. Steinbach, Joe Henry Edenberg, Howard J. Traynor, Bryan J. Goate, Alison M. Research Article 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. Public Library of Science 2013-11-26 /pmc/articles/PMC3841173/ /pubmed/24303001 http://dx.doi.org/10.1371/journal.pone.0080204 Text en © 2013 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Wang, Jen-Chyong
Spiegel, Noah
Bertelsen, Sarah
Le, Nhung
McKenna, Nicholas
Budde, John P.
Harari, Oscar
Kapoor, Manav
Brooks, Andrew
Hancock, Dana
Tischfield, Jay
Foroud, Tatiana
Bierut, Laura J.
Steinbach, Joe Henry
Edenberg, Howard J.
Traynor, Bryan J.
Goate, Alison M.
spellingShingle Wang, Jen-Chyong
Spiegel, Noah
Bertelsen, Sarah
Le, Nhung
McKenna, Nicholas
Budde, John P.
Harari, Oscar
Kapoor, Manav
Brooks, Andrew
Hancock, Dana
Tischfield, Jay
Foroud, Tatiana
Bierut, Laura J.
Steinbach, Joe Henry
Edenberg, Howard J.
Traynor, Bryan J.
Goate, Alison M.
Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry
author_facet Wang, Jen-Chyong
Spiegel, Noah
Bertelsen, Sarah
Le, Nhung
McKenna, Nicholas
Budde, John P.
Harari, Oscar
Kapoor, Manav
Brooks, Andrew
Hancock, Dana
Tischfield, Jay
Foroud, Tatiana
Bierut, Laura J.
Steinbach, Joe Henry
Edenberg, Howard J.
Traynor, Bryan J.
Goate, Alison M.
author_sort Wang, Jen-Chyong
title Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry
title_short Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry
title_full Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry
title_fullStr Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry
title_full_unstemmed Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry
title_sort cis-regulatory variants affect chrna5 mrna expression in populations of african and european ancestry
description 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.
publisher Public Library of Science
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841173/
_version_ 1612030863109783552

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