Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

Abstract

Pulmonary function is an easily measurable and reliable index of the physiological state of the lungs and airways 1 . Pulmonary function also predicts mortality in the general population, even among people who have never smoked (never-smokers) who have only modestly reduced pulmonary function and no respiratory symptoms 2,3 . The peak level of pulmonary function attained in early adulthood and its subsequent decline with age are likely influenced by genetic and environmental factors. Tobacco smoking is a major environmental cause of accelerated decline in pulmonary function with age. Other inhaled pollutants also appear to contribute. Familial aggregation studies suggest a genetic contribution to lung function, with heritability estimates exceeding 40% 4,5 , but little is known about the specific genetic factors involved. A relatively uncommon deficiency of α1-antitrypsin is the only established genetic risk factor for accelerated decline in pulmonary function and for development of chronic obstructive pulmonary disease (COPD), especially in smokers 4,6 . However, α1-antitrypsin accounts for little of the population variability in pulmonary function 4 . Candidate gene studies suggest that other genetic variants may influence the time course of pulmonary function and its decline in relation to smoking, but these putative genetic risk factors remain unknown 4 .Forced expiratory volume in the first second (FEV 1 ) and its ratio to forced vital capacity (FEV 1 /FVC) are two clinically relevant pulmonary function measures. Although both FEV 1 and FVC are influenced by lung size and can be reduced by restrictive lung diseases, obstructive lung disease leads to proportionately greater reduction in FEV 1 than FVC. Therefore, reduced FEV 1 /FVC, an indicator of airflow obstruction that is independent of lung size, is the primary criterion for defining an obstructive ventilatory defect 1 . Whereas low FEV 1 /FVC indicates the presence of airflow obstruction, FEV 1 is used to classify the severity and follow the progression of obstructive lung disease over time 5,7,8 .The first genome-wide association study (GWAS) for pulmonary function evaluating 70,987 SNPs in about 1,220 Framingham Heart Study (FHS) participants revealed no genome-wide significant loci 9 . Recently, a GWAS of FEV 1 /FVC using 2,540,223 SNPs in 7,691 FHS participants identified several SNPs on chromosome 4q31 near HHIP with genome-wide significance 10 . A GWAS of COPD 11 also implicated the HHIP region along with CHRNA3-CHRNA5 on chromosome 15, a region previously associated with nicotine dependence 12,13 .We conducted meta-analyses of GWAS results for a cross-sectional analysis of pulmonary function (FEV 1 /FVC and FEV 1 ) in 20,890 individuals of European ancestry from four Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 14 studies: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), FHS and Rotterdam Study (RS-I and RS-II). Given that cigarette smoking is a major risk factor for pulmonary fun...

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…Importantly, the Charge consortium again using a large discovery population of 20,890 subjects also showed genome wide association with FEV1 at the INTS12/GSTCD/NPNT locus as well as describing additional signals (Hancock et al, 2010). This region encompasses genes Intergrator Complex Subunit 12 (INTS12), GSTCD and nephronectin (NPNT).…”

“…Hancock and colleagues study found the most significant association to involve SNP rs17331332 located near NPNT (P = 4.00 x 10 -10 ) ( Table 1) (Hancock et al, 2010;Repapi et al, 2010). To date, seven meta-analyses of GWAS have now been completed and identified SNP associations with FEV1 and/or FEV1 decline (Hancock et al, 2012;Hancock et al, 2010;Repapi et al, 2010;Soler ArtigasLoth, et al, 2011;Tang et al, 2014;Wain L, 2015).…”

“…The first two of these studies was the SpiroMeta and Charge consortium studies that investigate FEV1 and FEV1/FVC and were published as back to back papers in 2010 (Hancock et al, 2010;Repapi et al, 2010). These studies had large discovery and replication samples.…”

“…To date, seven meta-analyses of GWAS have now been completed and identified SNP associations with FEV1 and/or FEV1 decline (Hancock et al, 2012;Hancock et al, 2010;Repapi et al, 2010;Soler ArtigasLoth, et al, 2011;Tang et al, 2014;Wain L, 2015).…”

“…Receptor gene was found associated with FEV1/FVC in 2 meta-analyses (Hancock et al, 2010;Repapi et al, 2010). AGER encodes RAGE, a multiligand receptor implicated in homeostasis, development, inflammation and diseases including diabetes, Alzheimer's and COPD (Bierhaus & Nawroth, 2009;Cheng et al, 2013;Ferhani et al, 2010;Hofmann et al, 2002;Hori et al, 1995;Sparvero et al, 2009;Wu, Ma, Nicholson, & Black, 2011;Yan et al, 1996).…”