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

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. StevensLaura J. Bierut, Alison M. Goate, N. Breslau, R. Culverhouse, D. Hatsukami, A. Hinrichs, Eric Johnson, Haris Vikis, Yan Lu, Yian Wang, Ping Yang, Susan M. Pinney, Gloria M. Petersen, Mariza de Andrade, Ann G. Schwartz, Adi Gazdar, Colette Gaba, Diptasri Mandal, Elena Kupert, Juwon Lee, Daniela Seminara, Pamela R. Fain, John Minna, Joan E. Bailey-Wilson, Yafang Li, Christopher I. Amos

Research output: Contribution to journalArticle

135 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3125-3135
Number of pages11
JournalHuman molecular genetics
Volume18
Issue number16
DOIs
StatePublished - Aug 6 2009

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    Wang, J. C., Cruchaga, C., Saccone, N. L., Bertelsen, S., Liu, P., Budde, J. P., Duan, W., Fox, L., Grucza, R. A., Kern, J., Mayo, K., Reyes, O., Rice, J., Saccone, S. F., Spiegel, N., Steinbach, J. H., Stitzel, J. A., Anderson, M. W., You, M., ... Amos, C. I. (2009). Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Human molecular genetics, 18(16), 3125-3135. https://doi.org/10.1093/hmg/ddp231