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 score4) 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>MAF0.005) 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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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.
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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)