[show abstract][hide abstract] ABSTRACT: Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/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 FEV(1) and FEV(1)/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 FEV(1)/FVC or FEV(1) 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.
[show abstract][hide abstract] ABSTRACT: Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
American Journal of Respiratory and Critical Care Medicine 07/2012; 186(7):622-32. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function.
We conducted the first genome-wide association study on the age-related decrease in FEV(1) and its ratio to forced vital capacity (FVC) stratified a priori by asthma status.
Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV(1) and FEV(1)/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study).
Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV(1) decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV(1)/FVC ratio decrease in asthmatic participants (P = 5.3 × 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline.
Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.
The Journal of allergy and clinical immunology 03/2012; 129(5):1218-28. · 9.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
[show abstract][hide abstract] ABSTRACT: Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
[show abstract][hide abstract] ABSTRACT: To cite this article: Hancock DB, Håberg SE, Furu K, Whitworth KW, Nafstad P, Nystad W, London SJ. Oral contraceptive pill use before pregnancy and respiratory outcomes in early childhood. Pediatr Allergy Immunol 2011; 22: 528–536.AbstractBackground: Oral contraceptive pills (OCPs) are often used soon before, and sometimes during, pregnancy. A few studies have suggested that OCP use before pregnancy may increase risks for childhood respiratory outcomes, but data are inconclusive. No studies have analyzed the two types of OCPs, estrogen-progestin combined pills and progestin-only pills, separately.Methods: In the Norwegian Mother and Child Cohort Study (MoBa), we prospectively examined associations of OCP use before pregnancy, by type, with lower respiratory tract infections in 60,225 children followed to 6 months old, lower respiratory tract infections and wheezing in 42,520 children followed to 18 months old, and asthma in 24,472 children followed to 36 months old. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) crudely and with adjustment for a wide range of potential confounders.Result: Combined pills were used much more commonly than progestin-only pills. Taking combined pills before pregnancy was not associated with lower respiratory tract infections, wheezing, or asthma. Progestin-only pill use in the year before pregnancy had a slight positive association with wheezing at 6–8 months old [adjusted OR (95% CI) = 1.19 (1.05–1.34)].Conclusion: Our finding that combined pill use before pregnancy was not related to respiratory outcomes should provide reassurance to the vast majority of mothers using OCPs before becoming pregnant. The small association with progestin-only pill use and early respiratory outcomes may reflect uncontrolled confounding or other bias. Nonetheless, it does suggest that these two types of pills should be examined separately in future analyses of respiratory and other childhood outcomes.
[show abstract][hide abstract] ABSTRACT: Meta-analyses of genome-wide association studies are often based on imputed single nucleotide polymorphism (SNP) data, because component studies were genotyped using different platforms. One would like to include case-parent triad studies along with case-control studies in such meta-analyses. However, there are no published methods for estimating relative risks from imputed data for case-parent triad studies. The authors propose a method for estimating the relative risk for a variant SNP allele based on a log-additive model. Their simulations first confirm that the proposed method performs well with genotyped SNP data. As an empirical test of the method's behavior with imputed SNPs, the authors then apply it to chromosome 22 data from the Mexico City Childhood Asthma Study (1998-2003). For chromosome 22, the authors had data on 7,293 SNPs that were both genotyped and imputed using the software MACH, which relies on linkage disequilibrium with nearby SNPs. Correlation between estimated relative risks based on the actual genotypes and those based on the imputed genotypes was remarkably high (r(2) = 0.95), validating this method of relative risk estimation for the case-parent study design. This method should be useful to investigators who wish to conduct meta-analyses using imputed SNP data from both case-parent triad and case-control studies.
American journal of epidemiology 02/2011; 173(5):553-9. · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is growing interest in the study of gene-environment interactions in the context of genome-wide association studies (GWASs). These studies will likely require meta-analytic approaches to have sufficient power.
We describe an approach for meta-analysis of a joint test for genetic main effects and gene-environment interaction effects. Using simulation studies based on a meta-analysis of five studies (total n = 10,161), we compare the power of this test to the meta-analysis of marginal test of genetic association and the meta-analysis of standard 1 d.f. interaction tests across a broad range of genetic main effects and gene-environment interaction effects.
We show that the joint meta-analysis is valid and can be more powerful than classical meta-analytic approaches, with a potential gain of power over 50% compared to the marginal test. The standard interaction test had less than 1% power in almost all the situations we considered. We also show that regardless of the test used, sample sizes far exceeding those of a typical individual GWAS will be needed to reliably detect genes with subtle gene-environment interaction patterns.
The joint meta-analysis is an attractive approach to discover markers which may have been missed by initial GWASs focusing on marginal marker-trait associations.
Human Heredity 01/2010; 70(4):292-300. · 1.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
[show abstract][hide abstract] ABSTRACT: More than 200 asthma candidate genes have been examined in human association studies or identified with knockout mouse approaches. However, many have not been systematically replicated in human populations, especially those containing a large number of tagging single nucleotide polymorphisms (SNPs).
We comprehensively evaluated the association of previously implicated asthma candidate genes with childhood asthma in a Mexico City population.
From the literature, we identified candidate genes with at least 1 positive report of association with asthma phenotypes in human subjects or implicated in asthma pathogenesis using knockout mouse experiments. We performed a genome-wide association study in 492 asthmatic children aged 5 to 17 years and both parents using the Illumina HumanHap 550v3 BeadChip. Separate candidate gene analyses were performed for 2933 autosomal SNPs in the 237 selected genes by using the log-linear method with a log-additive risk model.
Sixty-one of the 237 genes had at least 1 SNP with a P value of less than .05 for association with asthma. The 9 most significant results were observed for rs2241715 in the gene encoding TGF-beta1 (TGFB1; P = 3.3 x 10(-5)), rs13431828 and rs1041973 in the gene encoding IL-1 receptor-like 1 (IL1RL1; P = 2 x 10(-4) and 3.5 x 10(-4)), 5 SNPs in the gene encoding dipeptidyl-peptidase 10 (DPP10; P = 1.6 x 10(-4) to 4.5 x 10(-4)), and rs17599222 in the gene encoding cytoplasmic FMR1 interacting protein 2 (CYFIP2; P = 4.1 x 10(-4)). False discovery rates were less than 0.1 for all 9 SNPs. Multimarker analysis identified TGFB1, IL1RL1, the gene encoding IL-18 receptor 1 (IL18R1), and DPP10 as the genes most significantly associated with asthma.
This comprehensive analysis of literature-based candidate genes suggests that SNPs in several candidate genes, including TGFB1, IL1RL1, IL18R1, and DPP10, might contribute to childhood asthma susceptibility in a Mexican population.
The Journal of allergy and clinical immunology 11/2009; 125(2):321-327.e13. · 9.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case-parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10x10(-6) in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79x10(-7)). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.
[show abstract][hide abstract] ABSTRACT: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 x 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.