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

Wednesday,2015-08-26 11:25 America/Los_Angeles — zdrager
TitleRare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.
Publication TypeJournal Article
Year of Publication2016
AuthorsOlfson, E, Saccone, NL, Johnson, EO, Chen, L-S, 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, J-C, Ware, EB, Wilson, G, Yao, J, Zhao, W, Breslau, N, Hatsukami, D, Stitzel, JA, Rice, J, Goate, A, Bierut, LJ
JournalMol Psychiatry
Volume21
Issue5
Pagination601-7
Date Published2016 May
ISSN1476-5578
Abstract<p>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.</p>
DOI10.1038/mp.2015.105
Alternate JournalMol. Psychiatry
PubMed ID26239294
PubMed Central IDPMC4740321
Grant List5RC2HL102419 / HL / NHLBI NIH HHS / United States
CA047988 / CA / NCI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
F30 AA023685 / AA / NIAAA NIH HHS / United States
F30AA023685 / AA / NIAAA NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
HHSN268201100004C / WH / WHI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201300046C / HL / NHLBI NIH HHS / United States
HHSN268201300047C / HL / NHLBI NIH HHS / United States
HHSN268201300048C / HL / NHLBI NIH HHS / United States
HHSN268201300049C / HL / NHLBI NIH HHS / United States
HHSN268201300050C / HL / NHLBI NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
HL043851 / HL / NHLBI NIH HHS / United States
HL054457 / HL / NHLBI NIH HHS / United States
HL054464 / HL / NHLBI NIH HHS / United States
HL054481 / HL / NHLBI NIH HHS / United States
HL071917 / HL / NHLBI NIH HHS / United States
HL080467 / HL / NHLBI NIH HHS / United States
HL103010 / HL / NHLBI NIH HHS / United States
HL118305 / HL / NHLBI NIH HHS / United States
HL119443 / HL / NHLBI NIH HHS / United States
HL54471 / HL / NHLBI NIH HHS / United States
HL54472 / HL / NHLBI NIH HHS / United States
HL54473 / HL / NHLBI NIH HHS / United States
HL54495 / HL / NHLBI NIH HHS / United States
HL54496 / HL / NHLBI NIH HHS / United States
HL54497 / HL / NHLBI NIH HHS / United States
HL54509 / HL / NHLBI NIH HHS / United States
HL54515 / HL / NHLBI NIH HHS / United States
HL87660 / HL / NHLBI NIH HHS / United States
K08 DA030398 / DA / NIDA NIH HHS / United States
K08 DA030398 / DA / NIDA NIH HHS / United States
K08 DA032680 / DA / NIDA NIH HHS / United States
N01 HC085079 / HC / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
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R01 HL103612 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL118305 / HL / NHLBI NIH HHS / United States
R01 HL118305 / HL / NHLBI NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 NS041558 / NS / NINDS NIH HHS / United States
R01AG023629 / AG / NIA NIH HHS / United States
R01DA025888 / DA / NIDA NIH HHS / United States
R01DK089256 / DK / NIDDK NIH HHS / United States
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R01HL068986 / HL / NHLBI NIH HHS / United States
R01HL071051 / HL / NHLBI NIH HHS / United States
R01HL071205 / HL / NHLBI NIH HHS / United States
R01HL071250 / HL / NHLBI NIH HHS / United States
R01HL071251 / HL / NHLBI NIH HHS / United States
R01HL071252 / HL / NHLBI NIH HHS / United States
R01HL071258 / HL / NHLBI NIH HHS / United States
R01HL071259 / HL / NHLBI NIH HHS / United States
R01HL085251 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
R01HL087652 / HL / NHLBI NIH HHS / United States
R01HL103612 / HL / NHLBI NIH HHS / United States
R01HL105756 / HL / NHLBI NIH HHS / United States
R01HL118305 / HL / NHLBI NIH HHS / United States
R01HL120393 / HL / NHLBI NIH HHS / United States
R01HL55673 / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
R21 HL123677 / HL / NHLBI NIH HHS / United States
R21HL123677 / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
T32 GM007200 / GM / NIGMS NIH HHS / United States
T32GM07200 / GM / NIGMS NIH HHS / United States
TL1 TR000449 / TR / NCATS NIH HHS / United States
TL1TR000449 / TR / NCATS NIH HHS / United States
U01 HL054457 / HL / NHLBI NIH HHS / United States
U01 HL054464 / HL / NHLBI NIH HHS / United States
U01 HL054471 / HL / NHLBI NIH HHS / United States
U01 HL054473 / HL / NHLBI NIH HHS / United States
U01 HL054481 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
U01HL080295 / HL / NHLBI NIH HHS / United States
U01HL54473 / HL / NHLBI NIH HHS / United States
U10 AA008401 / AA / NIAAA NIH HHS / United States
U10 HL054471 / HL / NHLBI NIH HHS / United States
U10 HL054472 / HL / NHLBI NIH HHS / United States
U10 HL054481 / HL / NHLBI NIH HHS / United States
U10 HL054495 / HL / NHLBI NIH HHS / United States
U10 HL054496 / HL / NHLBI NIH HHS / United States
U10 HL054497 / HL / NHLBI NIH HHS / United States
U10 HL054509 / HL / NHLBI NIH HHS / United States
U10AA008401 / AA / NIAAA NIH HHS / United States
U19 CA148127 / CA / NCI NIH HHS / United States
U19CA148172 / CA / NCI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
UL1 TR000448 / TR / NCATS NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
UL1TR000040 / TR / NCATS NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
UL1TR000448 / TR / NCATS NIH HHS / United States

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