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. Stevens & 26 others Laura 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

128 Citations (Scopus)

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 (US)
Pages (from-to)3125-3135
Number of pages11
JournalHuman Molecular Genetics
Volume18
Issue number16
DOIs
StatePublished - 2009

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Tobacco Use Disorder
Lung Neoplasms
Amino Acids
Messenger RNA
Alleles
Chromosomes, Human, Pair 15
Nicotinic Receptors
Gene Expression

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Wang, J. C., Cruchaga, C., Saccone, N. L., Bertelsen, S., Liu, P., Budde, J. P., ... 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

Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. / Wang, Jen C.; Cruchaga, Carlos; Saccone, Nancy L.; Bertelsen, Sarah; Liu, Pengyuan; Budde, John P.; Duan, Weimin; Fox, Louis; Grucza, Richard A.; Kern, Jason; Mayo, Kevin; Reyes, Oliver; Rice, John; Saccone, Scott F.; Spiegel, Noah; Steinbach, Joseph H.; Stitzel, Jerry A.; Anderson, Marshall W.; You, Ming; Stevens, Victoria L.; Bierut, Laura J.; Goate, Alison M.; Breslau, N.; Culverhouse, R.; Hatsukami, D.; Hinrichs, A.; Johnson, Eric; Vikis, Haris; Lu, Yan; Wang, Yian; Yang, Ping; Pinney, Susan M.; Petersen, Gloria M.; de Andrade, Mariza; Schwartz, Ann G.; Gazdar, Adi; Gaba, Colette; Mandal, Diptasri; Kupert, Elena; Lee, Juwon; Seminara, Daniela; Fain, Pamela R.; Minna, John; Bailey-Wilson, Joan E.; Li, Yafang; Amos, Christopher I.

In: Human Molecular Genetics, Vol. 18, No. 16, 2009, p. 3125-3135.

Research output: Contribution to journalArticle

Wang, JC, Cruchaga, C, Saccone, NL, Bertelsen, S, Liu, P, Budde, JP, Duan, W, Fox, L, Grucza, RA, Kern, J, Mayo, K, Reyes, O, Rice, J, Saccone, SF, Spiegel, N, Steinbach, JH, Stitzel, JA, Anderson, MW, You, M, Stevens, VL, Bierut, LJ, Goate, AM, Breslau, N, Culverhouse, R, Hatsukami, D, Hinrichs, A, Johnson, E, Vikis, H, Lu, Y, Wang, Y, Yang, P, Pinney, SM, Petersen, GM, de Andrade, M, Schwartz, AG, Gazdar, A, Gaba, C, Mandal, D, Kupert, E, Lee, J, Seminara, D, Fain, PR, Minna, J, Bailey-Wilson, JE, Li, Y & Amos, CI 2009, 'Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5', Human Molecular Genetics, vol. 18, no. 16, pp. 3125-3135. https://doi.org/10.1093/hmg/ddp231
Wang, Jen C. ; Cruchaga, Carlos ; Saccone, Nancy L. ; Bertelsen, Sarah ; Liu, Pengyuan ; Budde, John P. ; Duan, Weimin ; Fox, Louis ; Grucza, Richard A. ; Kern, Jason ; Mayo, Kevin ; Reyes, Oliver ; Rice, John ; Saccone, Scott F. ; Spiegel, Noah ; Steinbach, Joseph H. ; Stitzel, Jerry A. ; Anderson, Marshall W. ; You, Ming ; Stevens, Victoria L. ; Bierut, Laura J. ; Goate, Alison M. ; Breslau, N. ; Culverhouse, R. ; Hatsukami, D. ; Hinrichs, A. ; Johnson, Eric ; Vikis, Haris ; Lu, Yan ; Wang, Yian ; Yang, Ping ; Pinney, Susan M. ; Petersen, Gloria M. ; de Andrade, Mariza ; Schwartz, Ann G. ; Gazdar, Adi ; Gaba, Colette ; Mandal, Diptasri ; Kupert, Elena ; Lee, Juwon ; Seminara, Daniela ; Fain, Pamela R. ; Minna, John ; Bailey-Wilson, Joan E. ; Li, Yafang ; Amos, Christopher I. / Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 16. pp. 3125-3135.
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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.",
author = "Wang, {Jen C.} and Carlos Cruchaga and Saccone, {Nancy L.} and Sarah Bertelsen and Pengyuan Liu and Budde, {John P.} and Weimin Duan and Louis Fox and Grucza, {Richard A.} and Jason Kern and Kevin Mayo and Oliver Reyes and John Rice and Saccone, {Scott F.} and Noah Spiegel and Steinbach, {Joseph H.} and Stitzel, {Jerry A.} and Anderson, {Marshall W.} and Ming You and Stevens, {Victoria L.} and Bierut, {Laura J.} and Goate, {Alison M.} and N. Breslau and R. Culverhouse and D. Hatsukami and A. Hinrichs and Eric Johnson and Haris Vikis and Yan Lu and Yian Wang and Ping Yang and Pinney, {Susan M.} and Petersen, {Gloria M.} and {de Andrade}, Mariza and Schwartz, {Ann G.} and Adi Gazdar and Colette Gaba and Diptasri Mandal and Elena Kupert and Juwon Lee and Daniela Seminara and Fain, {Pamela R.} and John Minna and Bailey-Wilson, {Joan E.} and Yafang Li and Amos, {Christopher I.}",
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T1 - Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5

AU - Wang, Jen C.

AU - Cruchaga, Carlos

AU - Saccone, Nancy L.

AU - Bertelsen, Sarah

AU - Liu, Pengyuan

AU - Budde, John P.

AU - Duan, Weimin

AU - Fox, Louis

AU - Grucza, Richard A.

AU - Kern, Jason

AU - Mayo, Kevin

AU - Reyes, Oliver

AU - Rice, John

AU - Saccone, Scott F.

AU - Spiegel, Noah

AU - Steinbach, Joseph H.

AU - Stitzel, Jerry A.

AU - Anderson, Marshall W.

AU - You, Ming

AU - Stevens, Victoria L.

AU - Bierut, Laura J.

AU - Goate, Alison M.

AU - Breslau, N.

AU - Culverhouse, R.

AU - Hatsukami, D.

AU - Hinrichs, A.

AU - Johnson, Eric

AU - Vikis, Haris

AU - Lu, Yan

AU - Wang, Yian

AU - Yang, Ping

AU - Pinney, Susan M.

AU - Petersen, Gloria M.

AU - de Andrade, Mariza

AU - Schwartz, Ann G.

AU - Gazdar, Adi

AU - Gaba, Colette

AU - Mandal, Diptasri

AU - Kupert, Elena

AU - Lee, Juwon

AU - Seminara, Daniela

AU - Fain, Pamela R.

AU - Minna, John

AU - Bailey-Wilson, Joan E.

AU - Li, Yafang

AU - Amos, Christopher I.

PY - 2009

Y1 - 2009

N2 - 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.

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