Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans

E. Olfson, N. L. Saccone, E. O. Johnson, L. S. Chen, R. Culverhouse, Kimberly Doheny, S. M. Foltz, L. Fox, S. M. Gogarten, S. Hartz, K. Hetrick, C. C. Laurie, B. Marosy, N. Amin, D. Arnett, R. G. Barr, T. M. Bartz, S. Bertelsen, I. B. Borecki, M. R. BrownD. I. Chasman, C. M. Van Duijn, M. F. Feitosa, E. R. Fox, N. Franceschini, O. H. Franco, M. L. Grove, X. Guo, A. Hofman, S. L.R. Kardia, A. C. Morrison, S. K. Musani, B. M. Psaty, D. C. Rao, A. P. Reiner, K. Rice, P. M. Ridker, L. M. Rose, U. M. Schick, K. Schwander, A. G. Uitterlinden, D. Vojinovic, J. C. Wang, E. B. Ware, G. Wilson, J. Yao, W. Zhao, N. Breslau, D. Hatsukami, J. A. Stitzel, J. Rice, A. Goate, L. J. Bierut

Research output: Contribution to journalArticle

Abstract

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score≥4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)≥0.05), aggregate low frequency variants (0.05>MAF≥0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10 -11; African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Original languageEnglish (US)
Pages (from-to)601-607
Number of pages7
JournalMolecular psychiatry
Volume21
Issue number5
DOIs
StatePublished - May 1 2016

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Tobacco Use Disorder
African Americans
Odds Ratio
Gene Frequency
Meta-Analysis
Exome
Nicotinic Receptors
Nicotine
Lung Neoplasms
Logistic Models
Smoking

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. / Olfson, E.; Saccone, N. L.; Johnson, E. O.; Chen, L. S.; Culverhouse, R.; Doheny, Kimberly; Foltz, S. M.; Fox, L.; Gogarten, S. M.; Hartz, S.; Hetrick, K.; Laurie, C. C.; Marosy, B.; Amin, N.; Arnett, D.; Barr, R. G.; Bartz, T. M.; Bertelsen, S.; Borecki, I. B.; Brown, M. R.; Chasman, D. I.; Van Duijn, C. M.; Feitosa, M. F.; Fox, E. R.; Franceschini, N.; Franco, O. H.; Grove, M. L.; Guo, X.; Hofman, A.; Kardia, S. L.R.; Morrison, A. C.; Musani, S. K.; Psaty, B. M.; Rao, D. C.; Reiner, A. P.; Rice, K.; Ridker, P. M.; Rose, L. M.; Schick, U. M.; Schwander, K.; Uitterlinden, A. G.; Vojinovic, D.; Wang, J. C.; Ware, E. B.; Wilson, G.; Yao, J.; Zhao, W.; Breslau, N.; Hatsukami, D.; Stitzel, J. A.; Rice, J.; Goate, A.; Bierut, L. J.

In: Molecular psychiatry, Vol. 21, No. 5, 01.05.2016, p. 601-607.

Research output: Contribution to journalArticle

Olfson, E, Saccone, NL, Johnson, EO, Chen, LS, Culverhouse, R, Doheny, K, Foltz, SM, Fox, L, Gogarten, SM, Hartz, S, Hetrick, K, Laurie, CC, Marosy, B, Amin, N, Arnett, D, Barr, RG, Bartz, TM, Bertelsen, S, Borecki, IB, Brown, MR, Chasman, DI, Van Duijn, CM, Feitosa, MF, Fox, ER, Franceschini, N, Franco, OH, Grove, ML, Guo, X, Hofman, A, Kardia, SLR, Morrison, AC, Musani, SK, Psaty, BM, Rao, DC, Reiner, AP, Rice, K, Ridker, PM, Rose, LM, Schick, UM, Schwander, K, Uitterlinden, AG, Vojinovic, D, Wang, JC, Ware, EB, Wilson, G, Yao, J, Zhao, W, Breslau, N, Hatsukami, D, Stitzel, JA, Rice, J, Goate, A & Bierut, LJ 2016, 'Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans', Molecular psychiatry, vol. 21, no. 5, pp. 601-607. https://doi.org/10.1038/mp.2015.105
Olfson, E. ; Saccone, N. L. ; Johnson, E. O. ; Chen, L. S. ; Culverhouse, R. ; Doheny, Kimberly ; Foltz, S. M. ; Fox, L. ; Gogarten, S. M. ; Hartz, S. ; Hetrick, K. ; Laurie, C. C. ; Marosy, B. ; Amin, N. ; Arnett, D. ; Barr, R. G. ; Bartz, T. M. ; Bertelsen, S. ; Borecki, I. B. ; Brown, M. R. ; Chasman, D. I. ; Van Duijn, C. M. ; Feitosa, M. F. ; Fox, E. R. ; Franceschini, N. ; Franco, O. H. ; Grove, M. L. ; Guo, X. ; Hofman, A. ; Kardia, S. L.R. ; Morrison, A. C. ; Musani, S. K. ; Psaty, B. M. ; Rao, D. C. ; Reiner, A. P. ; Rice, K. ; Ridker, P. M. ; Rose, L. M. ; Schick, U. M. ; Schwander, K. ; Uitterlinden, A. G. ; Vojinovic, D. ; Wang, J. C. ; Ware, E. B. ; Wilson, G. ; Yao, J. ; Zhao, W. ; Breslau, N. ; Hatsukami, D. ; Stitzel, J. A. ; Rice, J. ; Goate, A. ; Bierut, L. J. / Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. In: Molecular psychiatry. 2016 ; Vol. 21, No. 5. pp. 601-607.
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abstract = "The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstr{\"o}m Test for Nicotine Dependence score≥4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)≥0.05), aggregate low frequency variants (0.05>MAF≥0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10 -11; African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.",
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TY - JOUR

T1 - Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans

AU - Olfson, E.

AU - Saccone, N. L.

AU - Johnson, E. O.

AU - Chen, L. S.

AU - Culverhouse, R.

AU - Doheny, Kimberly

AU - Foltz, S. M.

AU - Fox, L.

AU - Gogarten, S. M.

AU - Hartz, S.

AU - Hetrick, K.

AU - Laurie, C. C.

AU - Marosy, B.

AU - Amin, N.

AU - Arnett, D.

AU - Barr, R. G.

AU - Bartz, T. M.

AU - Bertelsen, S.

AU - Borecki, I. B.

AU - Brown, M. R.

AU - Chasman, D. I.

AU - Van Duijn, C. M.

AU - Feitosa, M. F.

AU - Fox, E. R.

AU - Franceschini, N.

AU - Franco, O. H.

AU - Grove, M. L.

AU - Guo, X.

AU - Hofman, A.

AU - Kardia, S. L.R.

AU - Morrison, A. C.

AU - Musani, S. K.

AU - Psaty, B. M.

AU - Rao, D. C.

AU - Reiner, A. P.

AU - Rice, K.

AU - Ridker, P. M.

AU - Rose, L. M.

AU - Schick, U. M.

AU - Schwander, K.

AU - Uitterlinden, A. G.

AU - Vojinovic, D.

AU - Wang, J. C.

AU - Ware, E. B.

AU - Wilson, G.

AU - Yao, J.

AU - Zhao, W.

AU - Breslau, N.

AU - Hatsukami, D.

AU - Stitzel, J. A.

AU - Rice, J.

AU - Goate, A.

AU - Bierut, L. J.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score≥4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)≥0.05), aggregate low frequency variants (0.05>MAF≥0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10 -11; African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

AB - The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score≥4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)≥0.05), aggregate low frequency variants (0.05>MAF≥0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10 -11; African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

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