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

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 × 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.

Inês Barroso | Lowell Satler | Paul Scheet | Alexander Teumer | Lefkos Middleton | Henry Völzke | William Matthai | Vincent Mooser | Igor Rudan | Xiangjun Xiao | Jing Hua Zhao | Christopher G Mathew | Nilesh J Samani | Andre Franke | Keith Matthews | Harry Campbell | David Schlessinger | Nicholas J Wareham | Tariq Ahmad | Caroline Hayward | Muredach P Reilly | Norbert Dahmen | Lina Zgaga | Gérard Waeber | Jack Satsangi | Wendy Thomson | Arne Schäfer | Jaspal Kooner | Ruth McPherson | Jonathan Marchini | Peter McGuffin | Martin Farrall | Fabio Busonero | Pierandrea Muglia | Antonio Terracciano | Anne Barton | John Strauss | Claudia Lamina | Michael Wittig | John C Chambers | Miles Parkes | Astrid Petersmann | Hans Jörgen Grabe | Kay-Tee Khaw | Anne Farmer | Ozren Polasek | Jennifer Huffman | Amund Gulsvik | Liming Qu | Gonçalo R Abecasis | Ron Waksman | Veronique Vitart | Ivana Kolcic | Carl A Anderson | Benjamin J. Wright | Peter Vollenweider | Rajesh Rawal | Susanne Lucae | Jane Worthington | Mary Susan Burnett | Alan F Wright | Per Bakke | J. Marchini | G. Abecasis | D. Rujescu | P. Muglia | C. Francks | D. Clair | H. Hakonarson | J. Vincent | Mingyao Li | D. Schlessinger | N. Samani | A. Farmer | P. McGuffin | A. Balmforth | A. Hall | J. Thompson | M. Parkes | J. Satsangi | C. Mathew | A. Dominiczak | P. Munroe | M. Caulfield | M. Farrall | A. Barton | S. Eyre | W. Thomson | Jane Worthington | A. Gulsvik | U. John | H. Völzke | P. Scheet | S. Grundy | M. Reilly | D. Rader | H. Wichmann | M. Uda | S. Wild | M. Preisig | R. Mahley | B. Wright | Arne S Schäfer | A. Terracciano | C. Anderson | I. Rudan | N. Wareham | V. Mooser | P. Bakke | P. Barter | R. Wilensky | H. Grabe | A. Petersmann | A. Teumer | N. Dahmen | J. Kennedy | A. Franke | A. Wright | R. McPherson | J. Kooner | I. Barroso | C. Hayward | I. Kolčić | O. Polašek | V. Vitart | H. Campbell | P. Vollenweider | G. Waeber | James F. Wilson | J. Chambers | L. Middleton | K. Matthews | R. Rawal | F. Busonero | R. Loos | K. Khaw | M. Burnett | S. Epstein | J. Zhao | K. Kent | A. Pichard | L. Zgaga | D. Waterworth | C. Lamina | S. Pillai | Xin Yuan | W. Berrettini | R. Waksman | Tariq Ahmad | J. Huffman | M. Wittig | Xiangjun Xiao | F. Tozzi | J. Strauss | R. Day | S. Lucae | M. Ising | L. Qu | Jason Z. Liu | J. Devaney | Susan Campbell | J. Lindsay | C. Knouff | Daniel J Rader | Marcus Ising | James L Kennedy | Ulrich John | John B Vincent | Sreekumar G Pillai | Susan Campbell | James F Wilson | Anthony J Balmforth | H-Erich Wichmann | Steve Eyre | Dawn M Waterworth | Scott Grundy | Sarah H Wild | Patricia B Munroe | Manuela Uda | Ruth J F Loos | Dan Rujescu | Mingyao Li | Alistair S Hall | Martin Preisig | Federica Tozzi | Clyde Francks | Mark Caulfield | Augusto D Pichard | Kenneth M Kent | Wade Berrettini | Richard Day | A. Kesaniemi | T. Brueckl | S. Horstmann | Lowell Satler | W. Matthai | Anna Dominiczak | John R Thompson | Xin Yuan | Jason Z Liu | Christopher W Knouff | Philip Barter | Robert Mahley | Antero Kesaniemi | Tanja Brueckl | Sonja Horstmann | Joseph M Devaney | Joseph M Lindsay | Stephen Epstein | Robert Wilensky | Hakon H Hakonarson | David St Clair | Benjamin J Wright | A. Barton | R. Loos | A. Wright | J. Kennedy | R. Waksman

[1]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[2]  C. Gieger,et al.  Sequence variants at CHRNB 3 – CHRNA 6 and CYP 2 A 6 affect smoking behavior , 2010 .

[3]  William Wheeler,et al.  Genome-Wide and Candidate Gene Association Study of Cigarette Smoking Behaviors , 2009, PloS one.

[4]  Scott F. Saccone,et al.  Novel genes identified in a high-density genome wide association study for nicotine dependence. , 2007, Human molecular genetics.

[5]  N. Benowitz.  Neurobiology of nicotine addiction: implications for smoking cessation treatment. , 2008, The American journal of medicine.

[6]  P. Muglia,et al.  Genome-wide association study of recurrent major depressive disorder in two European case–control cohorts , 2010, Molecular Psychiatry.

[7]  J. Kooner,et al.  Ethnicity-related differences in left ventricular function, structure and geometry: a population study of UK Indian Asian and European white subjects , 2009, Heart.

[8]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[9]  G. Schwarz.  Estimating the Dimension of a Model , 1978 .

[10]  Scott F. Saccone,et al.  Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. , 2009, Human molecular genetics.

[11]  Manuel A. R. Ferreira,et al.  Practical aspects of imputation-driven meta-analysis of genome-wide association studies. , 2008, Human molecular genetics.

[12]  K. Shianna,et al.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci , 2009, PLoS genetics.

[13]  U. Pastorino,et al.  Transcription Deregulation at the 15q25 Locus in Association with Lung Adenocarcinoma Risk , 2009, Clinical Cancer Research.

[14]  H. Wit.  Faculty Opinions recommendation of Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. , 2008 .

[15]  Vincent Mooser,et al.  The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome , 2008, BMC cardiovascular disorders.

[16]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[17]  Igor Rudan,et al.  Runs of homozygosity in European populations. , 2008, American journal of human genetics.

[18]  Majid Ezzati,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[19]  Alberto Piazza,et al.  Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants , 2009, Nature Genetics.

[20]  Ming D. Li.  Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses , 2008, Human Genetics.

[21]  Ming D. Li.  The genetics of nicotine dependence , 2006, Current psychiatry reports.

[22]  I. Rudan,et al.  Genome-wide association study of biochemical traits in Korcula Island, Croatia. , 2009, Croatian medical journal.

[23]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[24]  David B. Goldstein,et al.  A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia , 2009, PLoS genetics.

[25]  S L Normand,et al.  Meta-analysis: formulating, evaluating, combining, and reporting. , 1999, Statistics in medicine.

[26]  C. Gieger,et al.  KORA-gen - Resource for Population Genetics, Controls and a Broad Spectrum of Disease Phenotypes , 2005 .

[27]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[28]  N. Day,et al.  EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. , 1999, British journal of cancer.

[29]  Jonathan C. Cohen,et al.  Genetic and phenotypic architecture of metabolic syndrome-associated components in dyslipidemic and normolipidemic subjects: the GEMS Study. , 2008, Atherosclerosis.

[30]  Scott F. Saccone,et al.  Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence , 2009, Molecular Psychiatry.

[31]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[32]  Michael Krawczak,et al.  PopGen: Population-Based Recruitment of Patients and Controls for the Analysis of Complex Genotype-Phenotype Relationships , 2006, Public Health Genomics.

[33]  William A. Richardson,et al.  SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout , 2008, Nature Genetics.

[34]  P. Muglia,et al.  α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking , 2008, Molecular Psychiatry.

[35]  Michael Krawczak,et al.  PopGen – Bevölkerungsbasierte Rekrutierung von Patienten und Kontrollen für die Untersuchung komplexer Genotyp-Phänotyp-Beziehungen (PopGen – Population-based Recruitment of Patients and Controls for the Analysis of Complex Genotype-phenotype Relationships) , 2007, it Inf. Technol..

[36]  Ming D. Li,et al.  Genome-wide meta-analyses identify multiple loci associated with smoking behavior , 2010, Nature Genetics.

[37]  G. Abecasis,et al.  Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians , 2006, PLoS genetics.

[38]  John P. A. Ioannidis,et al.  Validating, augmenting and refining genome-wide association signals , 2009, Nature Reviews Genetics.

[39]  U. John,et al.  Study of Health in Pomerania (SHIP): A health examination survey in an east German region: Objectives and design , 2005, Sozial- und Präventivmedizin.

[40]  Robert C. Thompson,et al.  Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry , 2009, Proceedings of the National Academy of Sciences.

[41]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.