Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry

Jen Chyong Wang, Noah Spiegel, Sarah Bertelsen, Nhung Le, Nicholas McKenna, John P. Budde, Oscar Harari, Manav Kapoor, Andrew Brooks, Dana Hancock, Jay Tischfield, Tatiana Foroud, Laura J. Bierut, Joe Henry Steinbach, Howard Edenberg, Bryan J. Traynor, Alison M. Goate

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere80204
JournalPLoS One
Volume8
Issue number11
DOIs
StatePublished - Nov 26 2013

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ancestry
Genes
Multigene Family
Messenger RNA
Alleles
multigene family
substance abuse
Population
alleles
Frontal Lobe
Substance-Related Disorders
Linkage Disequilibrium
Nicotinic Receptors
Gene expression
Haplotypes
linkage disequilibrium
haplotypes
risk factors
Gene Expression
genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wang, J. C., Spiegel, N., Bertelsen, S., Le, N., McKenna, N., Budde, J. P., ... Goate, A. M. (2013). Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry. PLoS One, 8(11), [e80204]. https://doi.org/10.1371/journal.pone.0080204

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; Traynor, Bryan J.; Goate, Alison M.

In: PLoS One, Vol. 8, No. 11, e80204, 26.11.2013.

Research output: Contribution to journalArticle

Wang, JC, Spiegel, N, Bertelsen, S, Le, N, McKenna, N, Budde, JP, Harari, O, Kapoor, M, Brooks, A, Hancock, D, Tischfield, J, Foroud, T, Bierut, LJ, Steinbach, JH, Edenberg, H, Traynor, BJ & Goate, AM 2013, 'Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry', PLoS One, vol. 8, no. 11, e80204. https://doi.org/10.1371/journal.pone.0080204
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 ; Traynor, Bryan J. ; Goate, Alison M. / Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry. In: PLoS One. 2013 ; Vol. 8, No. 11.
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