Abstract
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Highlights
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk
Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P 1⁄4 4.31 Â 10 À 6; OR 1⁄4 1.25; MAF 1⁄4 1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P 1⁄4 7.81 Â 10 À 8 and 4.09 Â 10 À 8, respectively) and MTHFR in the African ancestry sample (P 1⁄4 1.72 Â 10 À 6)
Heritability estimates indicate that approximately half the variation in risk is attributable to genetic factors[1,2,3]; yet, the common variants identified by genome-wide association studies (GWAS) account for very little of the genetic risk[4,5,6,7]
Summary
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Heritability estimates indicate that approximately half the variation in risk is attributable to genetic factors[1,2,3]; yet, the common variants identified by genome-wide association studies (GWAS) account for very little of the genetic risk[4,5,6,7] This so-called ‘missing heritability’ in asthma and other common diseases has been attributed to many potential causes that generally fall into two categories[8]. We begin to address the first limitation of GWAS by investigating the role of rare (minor allele frequency (MAF) o1%) and low-frequency (MAF 1–5%) variants in asthma We conducted this meta-analysis study in the largest ethnically diverse sample of asthma cases, non-asthmatic controls and case– parent trios, which include 13 studies[4,10,11] from 8 groups of investigators who compose the EVE Consortium on Asthma Genetics[4,10]. We report an association in Latinos and in the combined sample with functional variants in GSDMB, a gene at the 17q12–21 asthma locus[4,5,12,13,14], which is attributed to a putatively damaging common missense mutation
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