TY - JOUR
T1 - Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma
AU - Campbell, Catarina D.
AU - Mohajeri, Kiana
AU - Malig, Maika
AU - Hormozdiari, Fereydoun
AU - Nelson, Benjamin
AU - Du, Gaixin
AU - Patterson, Kristen M.
AU - Eng, Celeste
AU - Torgerson, Dara G.
AU - Hu, Donglei
AU - Herman, Catherine
AU - Chong, Jessica X.
AU - Ko, Arthur
AU - O'Roak, Brian J.
AU - Krumm, Niklas
AU - Vives, Laura
AU - Lee, Choli
AU - Roth, Lindsey A.
AU - Rodriguez-Cintron, William
AU - Rodriguez-Santana, Jose
AU - Brigino-Buenaventura, Emerita
AU - Davis, Adam
AU - Meade, Kelley
AU - LeNoir, Michael A.
AU - Thyne, Shannon
AU - Jackson, Daniel J.
AU - Gern, James E.
AU - Lemanske, Robert F.
AU - Shendure, Jay
AU - Abney, Mark
AU - Burchard, Esteban G.
AU - Ober, Carole
AU - Eichler, Evan E.
PY - 2014/8/12
Y1 - 2014/8/12
N2 - Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.
AB - Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.
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U2 - 10.1371/journal.pone.0104396
DO - 10.1371/journal.pone.0104396
M3 - Article
C2 - 25116239
AN - SCOPUS:84905913420
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 8
M1 - e104396
ER -