Meta-analysis and imputation refines the association of 15q25 with smoking quantity
Open accessAbstract
Smoking is a leading global cause of disease and mortality. 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.
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The strongest finding for smoking behavior is an association of smoking quantity with a cluster of nicotinic receptor genes (CHRNA5-CHRNA3-CHRNB4) with an effect size corresponding to one cigarette per day.
“The strongest finding is an association of smoking quantity with a cluster of nicotinic receptor genes (CHRNA5-CHRNA3-CHRNB4) with an effect size corresponding to one cigarette per day, and there may be several independent associations. 104”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [104]
There may be several independent associations to the nicotinic receptor gene cluster for smoking quantity.
“The strongest finding is an association of smoking quantity with a cluster of nicotinic receptor genes (CHRNA5-CHRNA3-CHRNB4) with an effect size corresponding to one cigarette per day, and there may be several independent associations. 104”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [104]
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- Authors
- The Wellcome Trust Case Control Consortium, Liu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., Wareham, N. J., Zhao, J. H., Loos, R. J. F., Barroso, I., Khaw, K.-T., Grundy, S., Barter, P., Mahley, R., Kesaniemi, A., McPherson, R., Vincent, J. B., Strauss, J., Kennedy, J. L., Farmer, A., McGuffin, P., Day, R., Matthews, K., Bakke, P., Gulsvik, A., Lucae, S., Ising, M., Brueckl, T., Horstmann, S., Wichmann, H.-E., Rawal, R., Dahmen, N., Lamina, C., Polasek, O., Zgaga, L., Huffman, J., Campbell, S., Kooner, J., Chambers, J. C., Burnett, M. S., Devaney, J. M., Pichard, A. D., Kent, K. M., Satler, L., Lindsay, J. M., Waksman, R., Epstein, S., Wilson, J. F., Wild, S. H., Campbell, H., Vitart, V., Reilly, M. P., Li, M., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H. H., Rader, D. J., Franke, A., Wittig, M., Schäfer, A., Uda, M., Terracciano, A., Xiao, X., Busonero, F., Scheet, P., Schlessinger, D., Clair, D. S., Rujescu, D., Abecasis, G. R., Grabe, H. J., Teumer, A., Völzke, H., Petersmann, A., John, U., Rudan, I., Hayward, C., Wright, A. F., Kolcic, I., Wright, B. J., Thompson, J. R., Balmforth, A. J., Hall, A. S., Samani, N. J., Anderson, C. A., Ahmad, T., Mathew, C. G., Parkes, M., Satsangi, J., Caulfield, M., Munroe, P. B., Farrall, M., Dominiczak, A., Worthington, J., Thomson, W., Eyre, S., Barton, A., Mooser, V., Francks, C., & Marchini, J.
- Affiliations
- University of Oxford (GB)
- GlaxoSmithKline (Italy) (IT)
- GlaxoSmithKline (United States) (US)
- Imperial College London (GB)
- University of Pennsylvania (US)
- University of Lausanne (CH)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- The University of Texas Southwestern Medical Center (US)
- The Heart Research Institute (AU)
- University of California, San Francisco (US)
- Ottawa Heart Institute (CA)
- Centre for Addiction and Mental Health (CA)
- King's College London (GB)
- University of Dundee (GB)
- University of Bergen (NO)
- Max Planck Institute of Psychiatry (DE)
- Helmholtz Munich (DE)
- Johannes Gutenberg University Mainz (DE)
- Innsbruck Medical University (AT)
- University of Edinburgh (GB)
- Institute of Genetics and Cancer (GB)
- MedStar Washington Hospital Center (US)
- Children's Hospital of Philadelphia (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Institute of Genetic and Biomedical Research (IT)
- National Institute on Aging (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Aberdeen (GB)
- Ludwig-Maximilians-Universität München (DE)
- University of Michigan (US)
- Universität Greifswald (DE)
- Universitätsmedizin Greifswald (DE)
- University of Split (HR)
- University of Leicester (GB)
- University of Leeds (GB)
- Peninsula College of Medicine and Dentistry (GB)
- Guy's Hospital (GB)
- Addenbrooke's Hospital (GB)
- Western General Hospital (GB)
- Queen Mary University of London (GB)
- Centre for Human Genetics (GB)
- Western Infirmary (GB)
- University of Manchester (GB)
- Corresponding author
- Francks, Clyde
- Marchini, Jonathan
- ORCID
- Tozzi, Federica
- Waterworth, Dawn M
- Pillai, Sreekumar G
- Muglia, Pierandrea
- Middleton, Lefkos
- Berrettini, Wade
- Yuan, Xin
- Waeber, Gérard
- Preisig, Martin
- Wareham, Nicholas J
- Zhao, Jing Hua
- Loos, Ruth J F
- Barroso, Inês
- Khaw, Kay-Tee
- Grundy, Scott
- Mahley, Robert
- McPherson, Ruth
- Vincent, John B
- Kennedy, James L
- McGuffin, Peter
- Matthews, Keith
- Lucae, Susanne
- Wichmann, H-Erich
- Rawal, Rajesh
- Lamina, Claudia
- Zgaga, Lina
- Huffman, Jennifer
- Kooner, Jaspal
- Chambers, John C
- Devaney, Joseph M
- Waksman, Ron
- Wilson, James F
- Wild, Sarah H
- Reilly, Muredach P
- Li, Mingyao
- Qu, Liming
- Matthai, William
- Hakonarson, Hakon H
- Rader, Daniel J
- Wittig, Michael
- Uda, Manuela
- Terracciano, Antonio
- Xiao, Xiangjun
- Busonero, Fabio
- Scheet, Paul
- Schlessinger, David
- Rujescu, Dan
- Abecasis, Gonçalo R
- Grabe, Hans Jörgen
- Teumer, Alexander
- Völzke, Henry
- Petersmann, Astrid
- John, Ulrich
- Rudan, Igor
- Hayward, Caroline
- Hall, Alistair S
- Samani, Nilesh J
- Anderson, Carl A
- Mathew, Christopher G
- Parkes, Miles
- Caulfield, Mark
- Munroe, Patricia B
- Farrall, Martin
- Dominiczak, Anna
- Worthington, Jane
- Thomson, Wendy
- Barton, Anne
- Mooser, Vincent
- Francks, Clyde
- Marchini, Jonathan
- Venue
- Nature Genetics
- Published
- 2010-04-25
- Volume
- 42
- Issue
- 5
- Pages
- 436-440
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3612983
- OpenAlex
- W2122791877
- Cited by
- 614
- References
- 39
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 15 · 2022: 21 · 2021: 30 · 2020: 23 · 2019: 29 · 2018: 44 · 2017: 40 · 2016: 59 · 2015: 64 · 2014: 59 · 2013: 47 · 2012: 72
- FWCI
- 6.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Site cant be reached (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Funders
- GlaxoSmithKline
- University of Oxford
- National Institutes of Health (Z99 AG999999, 5t32ag000196-20)
- National Institute on Aging (T32-AG000196, R99 AG999999, ZIAAG000196, Z01AG000196)
- National Institute on Drug Abuse (R01DA025201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- smoking quantity, CHRNA5, CHRNA3, CHRNB4, neuronal nicotinic acetylcholine receptors, fine mapping, genetic association, imputation, promoter
- MeSH terms
- Adult, Aged, Alleles, Chromosome Mapping, Chromosomes, Human, Pair 15, Female, Genetic Markers, Humans, Male, Middle Aged, Models, Genetic, Neurons, Receptors, Nicotinic, Smoking, Cohort Studies, Genome, Human, Polymorphism, Single Nucleotide
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