Journal Article

Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in <i>CHRNA5</i>

Jen C. Wang, Carlos Cruchaga, Nancy L. Saccone, Sarah Bertelsen, Pengyuan Liu, John P. Budde, Weimin Duan, Louis Fox, Richard A. Grucza, Jason Kern, Kevin Mayo, Oliver Reyes, John Rice, Scott F. Saccone, Noah Spiegel, Joseph H. Steinbach, Jerry A. Stitzel, Marshall W. Anderson, Ming You, Victoria L. Stevens, Laura J. Bierut and Alison M. Goate

in Human Molecular Genetics

Volume 18, issue 16, pages 3125-3135
Published in print August 2009 | ISSN: 0964-6906
Published online May 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp231
Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5

Show Summary Details

Preview

Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.

Journal Article.  7507 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.