Meta-analysis and imputation refines the association of 15q25 with smoking quantity

被引：490

作者：

Liu, Jason Z. ^{[1
]}

Tozzi, Federica ^{[2
]}

Waterworth, Dawn M. ^{[3
]}

Pillai, Sreekumar G. ^{[3
]}

Muglia, Pierandrea ^{[2
]}

Middleton, Lefkos ^{[4
]}

Berrettini, Wade ^{[5
]}

Knouff, Christopher W. ^{[6
]}

Yuan, Xin ^{[3
]}

Waeber, Gerard ^{[7
,8
]}

Vollenweider, Peter ^{[7
,8
]}

Preisig, Martin ^{[7
,9
]}

Wareham, Nicholas J. ^{[10
]}

Zhao, Jing Hua ^{[10
]}

Loos, Ruth J. F. ^{[10
]}

Barroso, Ines ^{[11
]}

Khaw, Kay-Tee ^{[12
]}

Grundy, Scott ^{[13
]}

Barter, Philip ^{[14
]}

Mahley, Robert ^{[15
,16
]}

Kesaniemi, Antero ^{[17
,18
]}

McPherson, Ruth ^{[19
]}

Vincent, John B. ^{[20
]}

Strauss, John ^{[20
]}

Kennedy, James L. ^{[20
]}

Farmer, Anne ^{[21
]}

McGuffin, Peter ^{[21
]}

Day, Richard ^{[22
]}

Matthews, Keith ^{[22
]}

Bakke, Per ^{[23
]}

Gulsvik, Amund ^{[23
]}

Lucae, Susanne ^{[24
]}

Ising, Marcus ^{[24
]}

Brueckl, Tanja ^{[24
]}

Horstmann, Sonja ^{[24
]}

Wichmann, H-Erich ^{[25
,26
,27
]}

Rawal, Rajesh ^{[25
]}

Dahmen, Norbert ^{[28
]}

Lamina, Claudia ^{[25
,29
]}

Polasek, Ozren ^{[30
]}

Zgaga, Lina ^{[31
]}

Huffman, Jennifer ^{[32
]}

Campbell, Susan ^{[32
]}

Kooner, Jaspal ^{[33
]}

Chambers, John C. ^{[34
]}

Burnett, Mary Susan ^{[35
]}

Devaney, Joseph M. ^{[35
]}

Pichard, Augusto D. ^{[35
]}

Kent, Kenneth M. ^{[35
]}

Satler, Lowell ^{[35
]}

机构：

[1] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[2] GlaxoSmithKline, Div Genet, Verona, Italy

[3] GlaxoSmithKline, Div Genet, Upper Merion, PA USA

[4] Univ London Imperial Coll Sci Technol & Med, Div Neurosci & Mental Hlth, London SW7 2AZ, England

[5] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA

[6] GlaxoSmithKline, Div Genet, Res Triangle Pk, NC USA

[7] Univ Lausanne, Univ Hosp Ctr, Lausanne, Switzerland

[8] Univ Lausanne, Dept Internal Med, Lausanne, Switzerland

[9] Univ Lausanne, Dept Psychiat, Lausanne, Switzerland

[10] Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England

[11] Wellcome Trust Sanger Inst, Hinxton, England

[12] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[13] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA

[14] Heart Res Inst, Sydney, NSW, Australia

[15] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94143 USA

[16] Amer Hosp, Istanbul, Turkey

[17] Univ Oulu, Dept Internal Med, SF-90220 Oulu, Finland

[18] Univ Oulu, Bioctr Oulu, SF-90220 Oulu, Finland

[19] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada

[20] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada

[21] Kings Coll London, Inst Psychiat, Genet & Dev Psychiat Ctr, Med Res Council Social, London, England

[22] Univ Dundee, Div Med Sci, Ctr Neurosci, Dundee, Scotland

[23] Univ Bergen, Inst Med, Bergen, Norway

[24] Max Planck Inst Psychiat, D-80804 Munich, Germany

[25] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[26] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[27] Univ Munich, Klinikum Grosshadern, D-80804 Munich, Germany

[28] Johannes Gutenberg Univ Mainz, Psychiat Klin & Poliklin, Mainz, Germany

[29] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria

[30] Univ Zagreb, Sch Med, Sch Publ Hlth, Zagreb 41000, Croatia

[31] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[32] MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[33] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[34] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol, London, England

[35] Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA

[36] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA

[37] Univ Penn, Inst Translat Med & Therapeut, Sch Med, Philadelphia, PA 19104 USA

[38] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[39] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[40] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy

[41] NIA, Baltimore, MD USA

[42] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[43] Univ Aberdeen, Dept Mental Hlth, Aberdeen, Scotland

[44] Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-80804 Munich, Germany

[45] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[46] Ernst Moritz Arndt Univ Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany

[47] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[48] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany

[49] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[50] Ernst Moritz Arndt Univ Greifswald, Dept Epidemiol & Social Med, Greifswald, Germany

来源：

NATURE GENETICS | 2010年 / 42卷 / 05期

关键词：

GENOME-WIDE ASSOCIATION; LUNG-CANCER; NICOTINE DEPENDENCE; SUSCEPTIBILITY LOCUS; RISK-FACTORS; GENES;

D O I：

10.1038/ng.572

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Smoking is a leading global cause of disease and mortality(1). We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

引用

页码：436 / U75

页数：7

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