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; K. 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. Brown; D. 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

doi:10.1038/mp.2015.105

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, K. 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

College of Public Health

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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 language	English
Pages (from-to)	601-607
Number of pages	7
Journal	Molecular Psychiatry
Volume	21
Issue number	5
DOIs	https://doi.org/10.1038/mp.2015.105
State	Published - May 1 2016

Bibliographical note

Publisher Copyright:
© 2016 Macmillan Publishers Limited.

Funding

This work was supported by the National Institutes of Health: grant numbers T32GM07200, UL1TR000448, TL1TR000449 and F30AA023685 to EO; grant numbers K08 DA030398 and R01 DA038076 to LC; and grant number U19CA148172 to LJB. Grant number R01 HL118305 from the National Institutes of Health supported the replication analyses. Grants and contracts from the National Institutes of Health supported the following studies and groups: COGEND (P01CA89392), AAND (R01DA025888), CIDR (HHSN268201100011I), ARIC (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, U01HG004402, HHSN268200625226C, UL1RR025005, 5RC2HL102419), CHS (HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL085251, R01HL068986, R01AG023629, UL1TR000124, DK063491), COGA (U10AA008401), FamHS (R01HL118305, R01DK089256), GENOA (HL054464, HL054457, HL054481, HL071917, NS041558, HL87660, HL119443, HL118305), HyperGEN (HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, R01HL55673, R01HL055673, R01HL118305, U01HL54473, R01HL055673, R01HL118305), JHS (HSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, HL103010, HL118305), MESA (N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, UL1TR000040, UL1RR025005, R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259, UL1RR025005, N02HL64278, UL1TR000124, DK063491), WGHS (HL043851, HL080467, CA047988), WHI (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, R21HL123677, R01HL118305). Erasmus Rucphen Family Study was supported by the following grants: European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947); European Community's Seventh Framework Program (FP7/2007-2013, HEALTH-F4-2007- 201413); Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043); ZonMw grant (project 91111025). Rotterdam Study was supported by Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study was also funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810 and Netherlands Consortium for Healthy Ageing (NCHA). Please see Supplementary Materials for acknowledgements listed by study.

Funders	Funder number
AAND	R01DA025888
ARIC	HHSN268200625226C, UL1RR025005, HHSN268201100006C, R01HL59367, HHSN268201100005C, HHSN268201100008C, HHSN268201100007C, U01HG004402, HHSN268201100009C, HHSN268201100011C, HHSN268201100010C, R01HL087641, 5RC2HL102419, HHSN268201100012C, R01HL086694
CIDR	HHSN268201100011I
COGA	HHSN268201300048C, U10AA008401, NS041558, HL54509, R01HL118305, HL87660, R01HL55673, HHSN268201300050C, HL054481, HL103010, HL054464, HL54515, R01HL055673, HHSN268201300049C, HL119443, R01DK089256, HHSN268201300047C, HL071917, HL054457, U01HL54473, HL54472, HL54473, HL54495, HL54496, HL54497, HSN268201300046C, HL54471
European Commission FP6 STRP	018947, LSHG-CT-2006-01947
European Community's Seventh Framework Program
FP7/2007	HEALTH-F4-2007- 201413
Colorado Mesa University	N01HC95160, N01HC95161, N01HC95162, N01HC95163, R01HL071252, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, R01HL071051, N01HC95169, R01HL071250, N01HC95159, R01HL071251, UL1TR000040, N02HL64278, R01HL071258, R01HL071259
NWO-RFBR	047.017.043
Netherlands Organisation of Scientific Research NWO Investments
Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research
Research Institute for Diseases in the Elderly	RIDE2
WGHS	HL043851, HL080467, CA047988
National Institutes of Health (NIH)	U19CA148172, K08 DA030398, T32GM07200, P01CA89392, F30AA023685, TL1TR000449, UL1TR000448, R01 HL118305, R01 DA038076
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)	R01HL071205
National Heart, Lung, and Blood Institute (NHLBI)
Women's Health Initiative	HHSN268201100004C, HHSN268201100003C, HHSN271201100004C, HHSN268201100002C, HHSN268201100046C, HHSN268201100001C, R21HL123677
Women's Health Initiative
Carolinas HealthCare System	UL1TR000124, R01AG023629, HHSN268200800007C, N01HC55222, N01HC85081, U01HL080295, N01HC85082, R01HL105756, N01HC85080, HHSN268201200036C, N01HC85086, R01HL068986, N01HC85083, R01HL120393, N01HC85079, DK063491, R01HL085251, R01HL103612, R01HL087652
Carolinas HealthCare System
ZonMw Memorabel	91111025
ZonMw Memorabel
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	050-060-810
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mp.2015.105

Cite this

Olfson, E., Saccone, N. L., Johnson, E. O., Chen, L. S., Culverhouse, R., Doheny, K., 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., ... Bierut, L. J. (2016). Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Molecular Psychiatry, 21(5), 601-607. https://doi.org/10.1038/mp.2015.105

@article{9a7915c92d694ae280f16787e1ef8bb7,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

year = "2016",

month = may,

day = "1",

doi = "10.1038/mp.2015.105",

language = "English",

volume = "21",

pages = "601--607",

number = "5",

}

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

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, K.

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

Abstract

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