Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma

摘要: Asthma is a complex genetic disease caused by combination of and environmental risk factors. We sought to test classes variants largely missed genome-wide association studies (GWAS), including copy number (CNVs) low-frequency variants, performing whole-genome sequencing (WGS) on 16 individuals from asthma- enriched asthma-depleted families. The samples were obtained an extended 13-generation Hutterite pedigree with reduced heterogeneity due small founding gene pool as result communal lifestyle. sequenced each individual average depth 13-fold, generated comprehensive catalog tested the most severe mutations for asthma. identified validated 1960 CNVs, 19 nonsense or splice-site single nucleotide (SNVs), 18 insertions deletions that out frame. As follow-up, we performed targeted genes in 837 cases 540 controls Puerto Rican ancestry found carry significantly higher burden IL27RA (2.0% controls; 0.23% cases; nominal p=0.004; Bonferroni p=0.21). also genotyped 593 CNVs 1199 individuals. nominally significant (p=0.03; Odds ratio (OR)=3.13) between 6 kbp deletion intron NEDD4L increased this additional 4787 non-Hutterite (nominal p=0.056; OR=1.69). expressed bronchial epithelial cells, conditional knockout lung mice leads inflammation mucus accumulation. Our study represents one early instances applying WGS large component demonstrates how can identify untested GWAS.