Biological Sciences Division
Published August 12, 2014 | Version v1
Journal article Open

Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

Creators

  • 1. University of Washington
  • 2. University of Chicago
  • 3. University of California San Francisco
  • 4. Veterans Caribbean Health Care System
  • 5. Centro de Neumología Pediátrica
  • 6. Kaiser Permanente-Vallejo Medical Center

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

The authors confirm that all data underlying the findings are fully available without restriction. Sequencing data are available under dbGaP accession number phs000599.v1.p1.

Files

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Additional details

Identifiers

DOI
10.1371/journal.pone.0104396
Other
oai:uchicago.tind.io:10859

Funding

American Asthma Foundation
Senior Investigator Award
National Institutes of Health
R01 HL085197
National Institutes of Health
R01 HD21244
National Institutes of Health
P01 HL070831
National Institutes of Health
AI095230
National Institutes of Health
RC2 HL101651
National Institutes of Health
R01-ES015794
National Institutes of Health
U19-AI077439
National Institutes of Health
R01-HL088133
National Institutes of Health
R01-HL078885
National Institutes of Health
R01-HL004464
National Institutes of Health
R01-HL104608
National Institute on Minority Health and Health Disparities
P60MD006902
Flight Attendant Medical Research Institute
Robert Wood Johnson Foundation
Amos Medical Faculty Development Award
Sandler Foundation
American Asthma Foundation
National Institutes of Health
P01-HL070831
National Institutes of Health
UL1TR000427

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics