Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P JMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest P JMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest P JMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

[1]  Claude Bouchard,et al.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance , 2012, Nature Genetics.

[2]  Gary K. Chen,et al.  Meta-analysis identifies common variants associated with body mass index in East Asians , 2012, Nature Genetics.

[3]  Peter Kraft,et al.  Gene-environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes. , 2012, American journal of epidemiology.

[4]  Robert M. Plenge,et al.  Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis , 2011, Nature Genetics.

[5]  K. Nakashima,et al.  [The Rotterdam study]. , 2011, Nihon rinsho. Japanese journal of clinical medicine.

[6]  Christian Gieger,et al.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function , 2011, Nature Genetics.

[7]  Holger Schwender,et al.  Evidence for gene‐environment interaction in a genome wide study of nonsyndromic cleft palate , 2011, Genetic epidemiology.

[8]  Yusuke Nakamura,et al.  Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population , 2011, Nature Genetics.

[9]  M. Arfan Ikram,et al.  The Rotterdam Study: 2012 objectives and design update , 2011, European journal of epidemiology.

[10]  Beate Ritz,et al.  Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee , 2011, PLoS genetics.

[11]  Ryan D. Hernandez,et al.  Meta-analysis of Genome-wide Association Studies of Asthma In Ethnically Diverse North American Populations , 2011, Nature Genetics.

[12]  A. Hudspeth,et al.  A search for factors specifying tonotopy implicates DNER in hair-cell development in the chick's cochlea. , 2011, Developmental biology.

[13]  W. Rathmann,et al.  Cohort profile: the study of health in Pomerania. , 2011, International journal of epidemiology.

[14]  Juan Pablo Lewinger,et al.  Sample size requirements to detect gene‐environment interactions in genome‐wide association studies , 2011, Genetic epidemiology.

[15]  Yang Liu,et al.  Genome-Wide Interaction-Based Association Analysis Identified Multiple New Susceptibility Loci for Common Diseases , 2011, PLoS genetics.

[16]  Josée Dupuis,et al.  Meta‐analysis of gene‐environment interaction: joint estimation of SNP and SNP × environment regression coefficients , 2011, Genetic epidemiology.

[17]  Dennis B. Troup,et al.  NCBI GEO: archive for functional genomics data sets—10 years on , 2010, Nucleic Acids Res..

[18]  J. Stockman.  The Association of Pipe and Cigar Use With Cotinine Levels, Lung Function, and Airflow Obstruction: A Cross-sectional Study , 2011 .

[19]  D. Strachan,et al.  Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. , 2011, The Journal of allergy and clinical immunology.

[20]  Inês Barroso,et al.  Genome-wide association study identifies five loci associated with lung function , 2010, Nature Genetics.

[21]  Peter Kraft,et al.  Genome-Wide Meta-Analysis of Joint Tests for Genetic and Gene-Environment Interaction Effects , 2011, Human Heredity.

[22]  Christian Gieger,et al.  Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies , 2010, Nature Genetics.

[23]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[24]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[25]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[26]  Juan Pablo Lewinger,et al.  Efficient genome-wide association testing of gene-environment interaction in case-parent trios. , 2010, American journal of epidemiology.

[27]  Tariq Ahmad,et al.  Meta-analysis and imputation refines the association of 15q25 with smoking quantity , 2010, Nature Genetics.

[28]  K. Kang,et al.  DNER modulates adipogenesis of human adipose tissue‐derived mesenchymal stem cells via regulation of cell proliferation , 2010, Cell proliferation.

[29]  A. Hofman,et al.  Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function , 2010, Nature Genetics.

[30]  Office on Smoking.  How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General , 2010 .

[31]  Lars Alfredsson,et al.  Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis , 2009, Nature Genetics.

[32]  D. Mannino,et al.  The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. , 2009, American journal of respiratory and critical care medicine.

[33]  P. Tsao,et al.  Notch signaling controls the balance of ciliated and secretory cell fates in developing airways , 2009, Development.

[34]  Laura J. Scott,et al.  Edinburgh Research Explorer Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution , 2022 .

[35]  D. Fitzpatrick,et al.  Long-range regulation at the SOX9 locus in development and disease , 2009, Journal of Medical Genetics.

[36]  D. Melton,et al.  Notch signaling promotes airway mucous metaplasia and inhibits alveolar development , 2009, Development.

[37]  A. Heguy,et al.  Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease. , 2009, American journal of respiratory and critical care medicine.

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

[39]  Scott T. Weiss,et al.  A Genome-Wide Association Study of Pulmonary Function Measures in the Framingham Heart Study , 2009, PLoS genetics.

[40]  K. Lunetta,et al.  Methods in Genetics and Clinical Interpretation Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts , 2010 .

[41]  W. Gauderman,et al.  Gene-environment interaction in genome-wide association studies. , 2008, American journal of epidemiology.

[42]  Monique M. B. Breteler,et al.  The Rotterdam Study: 2016 objectives and design update , 2015, European Journal of Epidemiology.

[43]  A. Zhernakova,et al.  Detecting shared pathogenesis from the shared genetics of immune-related diseases , 2009, Nature Reviews Genetics.

[44]  Andrew D. Johnson,et al.  SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap , 2008, Bioinform..

[45]  M. Eiraku,et al.  Receptor Type Protein Tyrosine Phosphatase-Pleiotrophin Signaling Controls Endocytic Trafficking of DNER That Regulates Neuritogenesis † , 2008 .

[46]  M. Daly,et al.  Estimation of the multiple testing burden for genomewide association studies of nearly all common variants , 2008, Genetic epidemiology.

[47]  M. LeBlanc,et al.  Increasing the power of identifying gene × gene interactions in genome‐wide association studies , 2008, Genetic epidemiology.

[48]  Ronald P. Stolk,et al.  Universal risk factors for multifactorial diseases-LifeLines : a three-generation population-based study , 2008 .

[49]  L. Liang,et al.  A genome-wide association study of global gene expression , 2007, Nature Genetics.

[50]  Meena Kumari,et al.  Lifecourse influences on health among British adults: effects of region of residence in childhood and adulthood. , 2007, International journal of epidemiology.

[51]  V. Gudnason,et al.  Age, Gene/Environment Susceptibility-Reykjavik Study: multidisciplinary applied phenomics. , 2007, American journal of epidemiology.

[52]  Peter Kraft,et al.  Exploiting Gene-Environment Interaction to Detect Genetic Associations , 2007, Human Heredity.

[53]  Ronald G. Crystal,et al.  Modification of gene expression of the small airway epithelium in response to cigarette smoking , 2006, Journal of Molecular Medicine.

[54]  I. Hall,et al.  Glucocorticoids Increase Repair Potential in a Novel in vitro Human Airway Epithelial Wounding Model , 2006, Journal of Clinical Immunology.

[55]  I. Sayers,et al.  The effect of β2-adrenoceptor agonists on phospholipase C (beta1) signalling in human airway smooth muscle cells , 2006 .

[56]  Masahiko Watanabe,et al.  Impaired cerebellar functions in mutant mice lacking DNER , 2006, Molecular and Cellular Neuroscience.

[57]  S. Rubin,et al.  Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects , 2005, Thorax.

[58]  Wj Gauderman,et al.  QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies , 2006 .

[59]  I. Sayers,et al.  The effect of beta2-adrenoceptor agonists on phospholipase C (beta1) signalling in human airway smooth muscle cells. , 2006, European journal of pharmacology.

[60]  N. Day,et al.  Respiratory function and self-reported functional health: EPIC-Norfolk population study , 2005, European Respiratory Journal.

[61]  U. Ackermann-Liebrich,et al.  SAPALDIA: Methods and participation in the cross-sectional part of the Swiss Study on Air Pollution and Lung Diseases in Adults , 2005, Sozial- und Präventivmedizin.

[62]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[63]  D. Jarvis,et al.  The European Community Respiratory Health Survey II , 1994, European Respiratory Journal.

[64]  B. Hogan,et al.  Differential gene expression in the distal tip endoderm of the embryonic mouse lung. , 2002, Gene expression patterns : GEP.

[65]  R. Kronmal,et al.  Multi-Ethnic Study of Atherosclerosis: objectives and design. , 2002, American journal of epidemiology.

[66]  Carlos G Vanoye,et al.  KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. , 2002, American journal of human genetics.

[67]  M. Omata,et al.  Inward rectifier K(+) current in human bronchial smooth muscle cells: inhibition with antisense oligonucleotides targeted to Kir2.1 mRNA. , 2002, American journal of respiratory cell and molecular biology.

[68]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[69]  J. Deng,et al.  Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[70]  M de Lange,et al.  Are Twins and Singletons Comparable? A Study of Disease-related and Lifestyle Characteristics in Adult Women , 2001, Twin Research.

[71]  W Winkelstein,et al.  Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. , 2000, Chest.

[72]  C. Hawrylowicz,et al.  Regulation of major histocompatibility complex class II antigens on human alveolar macrophages by granulocyte–macrophage colony‐stimulating factor in the presence of glucocorticoids , 1999, Immunology.

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

[74]  Richard R. Behringer,et al.  Sox9 is required for cartilage formation , 1999, Nature Genetics.

[75]  V M Hawthorne,et al.  Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study , 1996, BMJ.

[76]  Sahar Mansour,et al.  Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene , 1994, Nature.

[77]  D. Jarvis,et al.  The European Community Respiratory Health Survey. , 1994, The European respiratory journal.

[78]  P. Rantakallio,et al.  Labour induction policy in hospitals of different levels of specialisation , 1993, British journal of obstetrics and gynaecology.

[79]  R. Kronmal,et al.  The Cardiovascular Health Study: design and rationale. , 1991, Annals of epidemiology.

[80]  Aric Invest.  The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators , 1989 .

[81]  R. Rouse,et al.  The distribution of MHC class I and II antigens on bronchial epithelium. , 1989, The American review of respiratory disease.

[82]  A. Folsom,et al.  The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. , 1989, American journal of epidemiology.

[83]  S B Hulley,et al.  CARDIA: study design, recruitment, and some characteristics of the examined subjects. , 1988, Journal of clinical epidemiology.

[84]  F. Speizer,et al.  Assessment of genetic and nongenetic influences on pulmonary function. A twin study. , 2015, The American review of respiratory disease.

[85]  D. Jacobs,et al.  Recruitment in the Coronary Artery Disease Risk Development in Young Adults (Cardia) Study. , 1987, Controlled clinical trials.

[86]  J. Opitz,et al.  The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al in 1971. , 1983, American journal of medical genetics.

[87]  M. Feinleib,et al.  Genetic and environmental influences on pulmonary function in adult twins. , 2015, The American review of respiratory disease.

[88]  W. Kannel,et al.  The Framingham Offspring Study. Design and preliminary data. , 1975, Preventive medicine.

[89]  A. Shahani.  A Saturated Experiment in Sequential Determination of Operating Conditions , 1970 .

[90]  P. Rantakallio,et al.  Groups at risk in low birth weight infants and perinatal mortality. , 1969, Acta paediatrica Scandinavica.

[91]  W. Kannel,et al.  The Framingham Study An Epidemiological Approach to Coronary Heart Disease , 1966, Circulation.