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PLoS One. 2014 Aug 12;9(8):e104396. doi: 10.1371/journal.pone.0104396. eCollection 2014.

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

Author information

1
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
2
Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
3
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
4
Veterans Caribbean Health Care System, San Juan, Puerto Rico, United States of America.
5
Centro de Neumología Pediátrica, San Juan, Puerto Rico, United States of America.
6
Department of Allergy & Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, California, United States of America.
7
Children's Hospital and Research Center Oakland, Oakland, California, United States of America.
8
Bay Area Pediatrics, Oakland, California, United States of America.
9
San Francisco General Hospital, San Francisco, California, and the Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
10
Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States of America.
11
Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States of America; Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
12
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
13
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America; Howard Hughes Medical Institute, Seattle, Washington, United States of America.

Abstract

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.

PMID:
25116239
PMCID:
PMC4130548
DOI:
10.1371/journal.pone.0104396
[Indexed for MEDLINE]
Free PMC Article

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