A Genome‐Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos

&NA; Rationale: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome‐wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry. Objectives: Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations. Methods: GWAS of lung function and COPD in Hispanic/Latino participants from a population‐based cohort. We performed replication studies of novel loci in independent studies. Measurements and Main Results: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV1 in ZSWIM7 (rs4791658; P = 4.99 × 10−9) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV1/FVC (P = 9.59 × 10−9) in a region previously identified for COPD‐related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV1, which replicated. A novel locus for FEV1 identified among ever smokers (rs291231; P = 1.92 × 10−8) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 × 10−8) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome‐wide significance level. Conclusions: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.

[1]  Y. Niu,et al.  Histidine and arginine are associated with inflammation and oxidative stress in obese women , 2011, British Journal of Nutrition.

[2]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[3]  Stephen K. Godin,et al.  Evolutionary and Functional Analysis of the Invariant SWIM Domain in the Conserved Shu2/SWS1 Protein Family from Saccharomyces cerevisiae to Homo sapiens , 2015, Genetics.

[4]  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.

[5]  J. D’Armiento,et al.  Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. , 2001, American journal of respiratory and critical care medicine.

[6]  A. Reiner,et al.  A powerful statistical framework for generalization testing in GWAS, with application to the HCHS/SOL , 2017, Genetic epidemiology.

[7]  John P Elder,et al.  Sample design and cohort selection in the Hispanic Community Health Study/Study of Latinos. , 2010, Annals of epidemiology.

[8]  Juan C. Celedón,et al.  Chronic Obstructive Pulmonary Disease in Hispanics. A 9-Year Update. , 2018, American journal of respiratory and critical care medicine.

[9]  I. Petrache,et al.  Pathogenesis of chronic obstructive pulmonary disease. , 2012, The Journal of clinical investigation.

[10]  Y. Wada,et al.  Molecular cloning and structural characterization of the human histidase gene (HAL). , 1995, Genomics.

[11]  F. Gilliland,et al.  New Mexican Hispanic smokers have lower odds of chronic obstructive pulmonary disease and less decline in lung function than non-Hispanic whites. , 2011, American journal of respiratory and critical care medicine.

[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]  W. MacNee,et al.  New paradigms in the pathogenesis of chronic obstructive pulmonary disease I. , 2009, Proceedings of the American Thoracic Society.

[14]  C. Bustamante,et al.  RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference. , 2013, American journal of human genetics.

[15]  R. Ward,et al.  Informativeness of genetic markers for inference of ancestry. , 2003, American journal of human genetics.

[16]  M. Nöthen,et al.  Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis , 2016, Familial Cancer.

[17]  Lloyd E Chambless,et al.  Design and implementation of the Hispanic Community Health Study/Study of Latinos. , 2010, Annals of epidemiology.

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

[19]  A. Stilp,et al.  Meta‐Analysis of Genome‐Wide Association Studies with Correlated Individuals: Application to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) , 2016, Genetic epidemiology.

[20]  A. Churg,et al.  Matrix metalloproteinases in COPD , 2011, European Respiratory Journal.

[21]  Christoph Lange,et al.  Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. , 2014, The Lancet. Respiratory medicine.

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

[23]  T. Tsuji,et al.  DNA damage as a molecular link in the pathogenesis of COPD in smokers , 2012, European Respiratory Journal.

[24]  M. Pembrey,et al.  ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. , 2001, Paediatric and perinatal epidemiology.

[25]  Christoph Lange,et al.  Variants in FAM13A are associated with chronic obstructive pulmonary disease , 2010, Nature Genetics.

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

[27]  Edwin K Silverman,et al.  Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. , 2012, American journal of respiratory and critical care medicine.

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

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

[30]  A. Reiner,et al.  Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits , 2017, PloS one.

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

[32]  S. Redline,et al.  Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models. , 2016, American journal of human genetics.

[33]  J. Brehm,et al.  Chronic obstructive pulmonary disease in Hispanics. , 2008, American journal of respiratory and critical care medicine.

[34]  Qi Yan,et al.  A genome-wide association study of chronic obstructive pulmonary disease in Hispanics. , 2015, Annals of the American Thoracic Society.

[35]  I. Adcock,et al.  Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer , 2011, Thorax.

[36]  H. Ostrer,et al.  Genome-wide patterns of population structure and admixture among Hispanic/Latino populations , 2010, Proceedings of the National Academy of Sciences.

[37]  J. Hankinson,et al.  Standardisation of spirometry , 2005, European Respiratory Journal.

[38]  Kathleen F. Kerr,et al.  Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos. , 2016, American journal of human genetics.

[39]  Lauren S. Mogil,et al.  Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function , 2018, Nature Communications.

[40]  Thomas Lumley,et al.  Prospective study of particulate air pollution exposures, subclinical atherosclerosis, and clinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). , 2012, American journal of epidemiology.

[41]  Peter Kraft,et al.  Quality control and quality assurance in genotypic data for genome‐wide association studies , 2010, Genetic epidemiology.

[42]  J. Hankinson,et al.  Spirometry Reference Equations from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) , 2017, American journal of respiratory and critical care medicine.

[43]  F. Martinez,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. , 2007, American journal of respiratory and critical care medicine.

[44]  D. Rao,et al.  Gene-smoking interactions identify several novel blood pressure loci in the Framingham Heart Study. , 2015, American journal of hypertension.

[45]  D. Strachan,et al.  Childhood chest illness and the rate of decline of adult lung function between ages 35 and 45 years. , 2007, American journal of respiratory and critical care medicine.

[46]  Alexander Hanbo Li,et al.  Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. , 2015, Circulation. Cardiovascular genetics.

[47]  Sarah C. Nelson,et al.  Improved imputation accuracy in Hispanic/Latino populations with larger and more diverse reference panels: applications in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). , 2016, Human molecular genetics.

[48]  J. Wedzicha,et al.  Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. , 2017, American journal of respiratory and critical care medicine.

[49]  Chronic obstructive pulmonary disease among adults--United States, 2011. , 2012, MMWR. Morbidity and mortality weekly report.

[50]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

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

[52]  Benjamin M. Smith,et al.  Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study. , 2014, American journal of respiratory and critical care medicine.

[53]  J L Hankinson,et al.  Spirometric reference values from a sample of the general U.S. population. , 1999, American journal of respiratory and critical care medicine.

[54]  D. Strachan,et al.  Early influences on adult lung function in two national British cohorts , 2007, Archives of Disease in Childhood.

[55]  Qian S. Zhang,et al.  ASAFE: ancestry-specific allele frequency estimation , 2016, Bioinform..

[56]  Cesar G Victora,et al.  Cohort Profile Update: The 1982 Pelotas (Brazil) Birth Cohort Study , 2015, International journal of epidemiology.

[57]  Lorna M. Lopez,et al.  Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation , 2015, Nature Communications.

[58]  Sina A. Gharib,et al.  Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function , 2012, PLoS genetics.

[59]  Jiaquan Xu,et al.  Deaths: preliminary data for 2008. , 2010, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

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

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

[62]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[63]  P. Stenvinkel,et al.  Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality. , 2008, The American journal of clinical nutrition.

[64]  N. Laird,et al.  The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility. , 2011, American journal of respiratory cell and molecular biology.

[65]  J. Riley,et al.  Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD. , 2012, Molecular bioSystems.

[66]  Blair H. Smith,et al.  Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function. , 2011, American journal of respiratory and critical care medicine.

[67]  M. Feldman,et al.  Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation , 2008 .

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

[69]  G. Washko,et al.  Obstructive lung disease in Mexican Americans and non-Hispanic whites: an analysis of diagnosis and survival in the National Health and Nutritional Examination Survey III Follow-up Study. , 2014, Chest.

[70]  M. Tobin,et al.  APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema , 2013, European Respiratory Journal.

[71]  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.

[72]  Christian Gieger,et al.  Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets , 2017, Nature Genetics.

[73]  N. Siafakas,et al.  DNA Damage Due to Oxidative Stress in Chronic Obstructive Pulmonary Disease (COPD) , 2012, International journal of molecular sciences.

[74]  S. J. Sadler,et al.  Cloning and expression of rat histidase. Homology to two bacterial histidases and four phenylalanine ammonia-lyases. , 1990, The Journal of biological chemistry.

[75]  C. Victora,et al.  Cohort profile: the 1982 Pelotas (Brazil) birth cohort study. , 2006, International journal of epidemiology.

[76]  Y. Lussier,et al.  Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing. , 2016, Translational research : the journal of laboratory and clinical medicine.

[77]  L. Wain,et al.  Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank , 2015, The Lancet. Respiratory medicine.

[78]  Harry J de Koning,et al.  Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis , 2017, Nature Genetics.

[79]  Junjie Chen,et al.  Cellular senescence and DNA repair. , 2006, Experimental cell research.

[80]  J. Hankinson,et al.  Interpretative strategies for lung function tests , 2005, European Respiratory Journal.

[81]  R. Kaplan,et al.  Pulmonary Disease and Age at Immigration among Hispanics. Results from the Hispanic Community Health Study/Study of Latinos. , 2016, American journal of respiratory and critical care medicine.

[82]  R. Kaplan,et al.  Local Ancestry Inference in a Large US-Based Hispanic/Latino Study: Hispanic Community Health Study/Study of Latinos (HCHS/SOL) , 2016, G3: Genes, Genomes, Genetics.

[83]  Sina A. Gharib,et al.  Multiethnic meta-analysis identifies new loci for pulmonary function , 2017, bioRxiv.

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

[85]  Jaakko Kaprio,et al.  Genetic and environmental factors in health-related behaviors: studies on Finnish twins and twin families. , 2002, Twin research : the official journal of the International Society for Twin Studies.

[86]  J. Celedón,et al.  Asthma in Hispanics. , 2006, American journal of respiratory and critical care medicine.

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

[88]  J. Brehm,et al.  Native American ancestry, lung function, and COPD in Costa Ricans. , 2014, Chest.

[89]  J. Yates,et al.  Sws1 is a conserved regulator of homologous recombination in eukaryotic cells , 2006, The EMBO journal.

[90]  Lorna M. Lopez,et al.  Genome-wide association analysis identifies six new loci associated with forced vital capacity , 2014, Nature Genetics.

[91]  N. Day,et al.  Abdominal obesity and respiratory function in men and women in the EPIC-Norfolk Study, United Kingdom. , 2004, American journal of epidemiology.

[92]  J. Marchini,et al.  Genotype Imputation with Thousands of Genomes , 2011, G3: Genes | Genomes | Genetics.