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

Pubmed ID: 26239294

Pubmed Central ID: PMC4740321

Journal: Molecular psychiatry

Publication Date: May 1, 2016

MeSH Terms: Humans, Male, Adult, Female, Genetic Predisposition to Disease, Middle Aged, Nerve Tissue Proteins, Receptors, Nicotinic, Tobacco Use Disorder, Genetic Variation, White People, Black or African American

Grants: HHSN268200800007C, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, R01 AG023629, U01 HL080295, N01 HC085079, N01 HC085081, N01 HC085083, N01 HC095159, UL1 TR000124, UL1TR000124, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C, RC2 HL103010, R01AG023629, U01HL080295, UL1RR025005, R01HL59367, UL1 RR025005, R01HL087641, R01HL086694, P30 DK063491, RC2 HL102419, 5RC2HL102419, HHSN268201300049C, HHSN268201300048C, HHSN268201300047C, HHSN268201300050C, HHSN268201300046C, R01 HL087652, R01 HL105756, R01HL105756, R01HL087652, R01HL103612, UM1 CA182913, R01 HL103612, R01 HL120393, R01 HL068986, DK063491, R01 HL117078, CA047988, R01 CA047988, R01 HL080467, HL080467, U10 HL054472, R01 NS041558, R01HL085251, N01HC95163, U01 HL054471, F30AA023685, U19 CA148127, U01HL54473, U10 HL054497, N01HC95161, U10AA008401, HL054481, N01HC95167, R01 HL071251, U10 HL054509, R01 HL071917, R01 HL071259, R21HL123677, N01 HC095167, HL118305, R01 HL071252, HL87660, R01 HL087660, U19CA148172, N01HC95159, K08 DA030398, R01 HL085251, P01 CA089392, R01 DA038076, N01 HC095161, R01 HL071250, R01 DA025888, N01HC95162, N02 HL64278, N01 HC095164, HL103010, N01HC95166, N01 HC095166, HL54515, N01 HC095160, HL54497, R01HL071252, U01 HL054464, P01CA89392, HL071917, R01 DA026911, R01 HL119443, R01HL071205, R01 HL118305, R01DA025888, K08 DA032680, U10 HL054481, R01 HL071051, N01HC95169, T32 GM007200, R01HL068986, R01HL055673, T32GM07200, HL054464, UL1TR000448, N01HC95165, HL54496, U01 HL054457, N01 HC095169, UL1TR000040, HL54473, HL054457, N01 HC095165, UL1 TR000448, NS041558, TL1TR000449, R01DK089256, R21 HL123677, R01 DK089256, TL1 TR000449, R01HL55673, N01HC95164, R01 HL071205, N01 HC095168, U01 HL054481, N01HC95160, UL1 TR000040, U10 AA008401, U10 HL054495, N01HC95168, N01 HC095163, R01HL071259, U10 HL054496, U10 HL054471, HL54495, R01HL071251, R01HL118305, N01 HC095162, R01HL071258, HL119443, R01HL071051, R01 HL071258, HL54471, HL54509, R01 HL055673, R01HL071250, U01 HL054473, F30 AA023685, R01HL120393, HL54472, HHSN268201100009I, HHSN268201100005G, HHSN268201100008I, HHSN268201100011I, HHSN268201100005I, HHSN268201100007I, HHSN268201100001I, HHSN268201100002I, HHSN268201100004I, R01 HL043851, N02HL64278, R01 HL077612, U01 HL054472, U01 HL054496, UC2 HL103010, U10 HL054464, U01 HL054497, U01 HL054509, U10 HL054457, U10 HL054473, U01 HL054495, R01 AG055406

Authors: Arnett D, Franco OH, Hofman A, Rice J, Psaty BM, Guo X, Amin N, Ridker PM, Reiner AP, Uitterlinden AG, Morrison AC, Franceschini N, van Duijn CM, Schick UM, Chasman DI, Grove ML, Musani SK, Rice K, Feitosa MF, Borecki IB, Zhao W, Kardia SL, Barr RG, 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, Bartz TM, Bertelsen S, Brown MR, Fox ER, Rao DC, Rose LM, Schwander K, Vojinovic D, Wang JC, Ware EB, Wilson G, Yao J, Breslau N, Hatsukami D, Stitzel JA, Goate A, Bierut LJ

Cite As: 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 SL, 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. Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Mol Psychiatry 2016 May;21(5):601-7. Epub 2015 Aug 4.

Studies:

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.