Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
2013 Dec
received 2013/01/11
revised 2013/06/21
accepted 2013/08/14
aheadofprint 2013/11/01
entrez 2013/11/05 06:00
pubmed 2013/11/05 06:00
medline 2014/05/13 06:00
Stephens SH Stephens Sarah H SH Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States of America.
Hartz SM Hartz Sarah M SM
Hoft NR Hoft Nicole R NR
Saccone NL Saccone Nancy L NL
Corley RC Corley Robin C RC
Hewitt JK Hewitt John K JK
Hopfer CJ Hopfer Christian J CJ
Breslau N Breslau Naomi N
Coon H Coon Hilary H
Chen X Chen Xiangning X
Ducci F Ducci Francesca F
Dueker N Dueker Nicole N
Franceschini N Franceschini Nora N
Frank J Frank Josef J
Han Y Han Younghun Y
Hansel NN Hansel Nadia N NN
Jiang C Jiang Chenhui C
Korhonen T Korhonen Tellervo T
Lind PA Lind Penelope A PA
Liu J Liu Jason J
Lyytikäinen LP Lyytikäinen Leo-Pekka LP
Michel M Michel Martha M
Shaffer JR Shaffer John R JR
Short SE Short Susan E SE
Sun J Sun Juzhong J
Teumer A Teumer Alexander A
Thompson JR Thompson John R JR
Vogelzangs N Vogelzangs Nicole N
Vink JM Vink Jacqueline M JM
Wenzlaff A Wenzlaff Angela A
Wheeler W Wheeler William W
Yang BZ Yang Bao-Zhu BZ
Aggen SH Aggen Steven H SH
Balmforth AJ Balmforth Anthony J AJ
Baumeister SE Baumeister Sebastian E SE
Beaty TH Beaty Terri H TH
Benjamin DJ Benjamin Daniel J DJ
Bergen AW Bergen Andrew W AW
Broms U Broms Ulla U
Cesarini D Cesarini David D
Chatterjee N Chatterjee Nilanjan N
Chen J Chen Jingchun J
Cheng YC Cheng Yu-Ching YC
Cichon S Cichon Sven S
Couper D Couper David D
Cucca F Cucca Francesco F
Dick D Dick Danielle D
Foroud T Foroud Tatiana T
Furberg H Furberg Helena H
Giegling I Giegling Ina I
Gillespie NA Gillespie Nathan A NA
Gu F Gu Fangyi F
Hall AS Hall Alistair S AS
Hällfors J Hällfors Jenni J
Han S Han Shizhong S
Hartmann AM Hartmann Annette M AM
Heikkilä K Heikkilä Kauko K
Hickie IB Hickie Ian B IB
Hottenga JJ Hottenga Jouke Jan JJ
Jousilahti P Jousilahti Pekka P
Kaakinen M Kaakinen Marika M
Kähönen M Kähönen Mika M
Koellinger PD Koellinger Philipp D PD
Kittner S Kittner Stephen S
Konte B Konte Bettina B
Landi MT Landi Maria-Teresa MT
Laatikainen T Laatikainen Tiina T
Leppert M Leppert Mark M
Levy SM Levy Steven M SM
Mathias RA Mathias Rasika A RA
McNeil DW McNeil Daniel W DW
Medland SE Medland Sarah E SE
Montgomery GW Montgomery Grant W GW
Murray T Murray Tanda T
Nauck M Nauck Matthias M
North KE North Kari E KE
Paré PD Paré Peter D PD
Pergadia M Pergadia Michele M
Ruczinski I Ruczinski Ingo I
Salomaa V Salomaa Veikko V
Viikari J Viikari Jorma J
Willemsen G Willemsen Gonneke G
Barnes KC Barnes Kathleen C KC
Boerwinkle E Boerwinkle Eric E
Boomsma DI Boomsma Dorret I DI
Caporaso N Caporaso Neil N
Edenberg HJ Edenberg Howard J HJ
Francks C Francks Clyde C
Gelernter J Gelernter Joel J
Grabe HJ Grabe Hans Jörgen HJ
Hops H Hops Hyman H
Jarvelin MR Jarvelin Marjo-Riitta MR
Johannesson M Johannesson Magnus M
Kendler KS Kendler Kenneth S KS
Lehtimäki T Lehtimäki Terho T
Magnusson PK Magnusson Patrik K E PK
Marazita ML Marazita Mary L ML
Marchini J Marchini Jonathan J
Mitchell BD Mitchell Braxton D BD
Nöthen MM Nöthen Markus M MM
Penninx BW Penninx Brenda W BW
Raitakari O Raitakari Olli O
Rietschel M Rietschel Marcella M
Rujescu D Rujescu Dan D
Samani NJ Samani Nilesh J NJ
Schwartz AG Schwartz Ann G AG
Shete S Shete Sanjay S
Spitz M Spitz Margaret M
Swan GE Swan Gary E GE
Völzke H Völzke Henry H
Veijola J Veijola Juha J
Wei Q Wei Qingyi Q
Amos C Amos Chris C
Cannon DS Cannon Dale S DS
Grucza R Grucza Richard R
Hatsukami D Hatsukami Dorothy D
Heath A Heath Andrew A
Johnson EO Johnson Eric O EO
Kaprio J Kaprio Jaakko J
Madden P Madden Pamela P
Martin NG Martin Nicholas G NG
Stevens VL Stevens Victoria L VL
Weiss RB Weiss Robert B RB
Kraft P Kraft Peter P
Bierut LJ Bierut Laura J LJ
Ehringer MA Ehringer Marissa A MA
TITLE: Genetic epidemiology
ISOABBREVIATION: Genet. Epidemiol.
YEAR: 2013
ISSN: 1098-2272
ISSNTYPE: Electronic
MEDLINETA: Genet Epidemiol
COUNTRY: United States
ISSNLINKING: 0741-0395
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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090532 Wellcome Trust United Kingdom
K01 DA19498 NIDA NIH HHS United States
K01 DA24758 NIDA NIH HHS United States
K02 AA018755 NIAAA NIH HHS United States
K02 AA018755 NIAAA NIH HHS United States
K02 DA021237 NIDA NIH HHS United States
K05 AA017688 NIAAA NIH HHS United States
K07 CA118412 NCI NIH HHS United States
K08 DA032680 NIDA NIH HHS United States
K08 DA032680 NIDA NIH HHS United States
K99R00 DA023549 NIDA NIH HHS United States
KL2 RR024994 NCRR NIH HHS United States
KL2 RR024994 NCRR NIH HHS United States
KL2 TR000450 NCATS NIH HHS United States
N01-AG-1-2109 NIA NIH HHS United States
N01-PC35146 NCI NIH HHS United States
P01 AG005842 NIA NIH HHS United States
P01 CA089392 NCI NIH HHS United States
P01 CA089392 NCI NIH HHS United States
P30 CA016672 NCI NIH HHS United States
P30 DK-072488 NIDDK NIH HHS United States
P60 DA011015 NIDA NIH HHS United States
R01 AA017535 NIAAA NIH HHS United States
R01 AA07535 NIAAA NIH HHS United States
R01 AA07728 NIAAA NIH HHS United States
R01 AA11330 NIAAA NIH HHS United States
R01 AA11998 NIAAA NIH HHS United States
R01 AA13320 NIAAA NIH HHS United States
R01 AA14041 NIAAA NIH HHS United States
R01 AA17688 NIAAA NIH HHS United States
R01 CA060691 NCI NIH HHS United States
R01 CA87895 NCI NIH HHS United States
R01 DA012690 NIDA NIH HHS United States
R01 DA012854 NIDA NIH HHS United States
R01 DA021913 NIDA NIH HHS United States
R01 DA026911 NIDA NIH HHS United States
R01 DA03706 NIDA NIH HHS United States
R01 DA12690 NIDA NIH HHS United States
R01 DA12849 NIDA NIH HHS United States
R01 DA12854 NIDA NIH HHS United States
R01 DE012101 NIDCR NIH HHS United States
R01 DE12101 NIDCR NIH HHS United States
R01 NS45012 NINDS NIH HHS United States
R01AA13321 NIAAA NIH HHS United States
R01HL089651-01 NHLBI NIH HHS United States
R21 DA027070 NIDA NIH HHS United States
R21 DA027070 NIDA NIH HHS United States
R24 HD041020 NICHD NIH HHS United States
T32 AG000186 NIA NIH HHS United States
U01 DA020830 NIDA NIH HHS United States
U01 DA02830 NIDA NIH HHS United States
U01 HG004436 NHGRI NIH HHS United States
U01 HG004738 NHGRI NIH HHS United States
U01 NS069208 NINDS NIH HHS United States
UL1 TR000448 NCATS NIH HHS United States
UL1RR024992 NCRR NIH HHS United States
Age of Onset
Cotinine metabolism
Female metabolism
Genetic Loci genetics
Genetic Predisposition to Disease genetics
Humans genetics
Internationality genetics
Linkage Disequilibrium genetics
Male genetics
Multigene Family genetics
Nerve Tissue Proteins genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
Receptors, Nicotinic genetics
Smoking genetics
Tobacco Use Disorder genetics
0 CHRNA5 protein, human
0 CHRNB4 protein, human
0 Nerve Tissue Proteins
0 Receptors, Nicotinic
0 nicotinic receptor subunit alpha3
K5161X06LL Cotinine
PMC3947535 NLM