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

Catarina D. Campbell, Kiana Mohajeri, Maika Malig, Fereydoun Hormozdiari, Benjamin Nelson, Gaixin Du, Kristen M. Patterson, Celeste Eng, Dara G. Torgerson, Donglei Hu, Catherine Herman, Jessica X. Chong, Arthur Ko, Brian O'Roak, Niklas Krumm, Laura Vives, Choli Lee, Lindsey A. Roth, William Rodriguez-Cintron, Jose Rodriguez-SantanaEmerita Brigino-Buenaventura, Adam Davis, Kelley Meade, Michael A. LeNoir, Shannon Thyne, Daniel J. Jackson, James E. Gern, Robert F. Lemanske, Jay Shendure, Mark Abney, Esteban G. Burchard, Carole Ober, Evan E. Eichler

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere104396
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - Aug 12 2014
Externally publishedYes

Fingerprint

founder effect
asthma
Asthma
Genes
Genome
genome
Population
Genome-Wide Association Study
genes
odds ratio
Odds Ratio
mutation
Gene Pool
Gene Knockout Techniques
Frameshift Mutation
Mutation
Inborn Genetic Diseases
Genetic Heterogeneity
genetic disorders
gene targeting

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Campbell, C. D., Mohajeri, K., Malig, M., Hormozdiari, F., Nelson, B., Du, G., ... Eichler, E. E. (2014). Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. PLoS One, 9(8), [e104396]. https://doi.org/10.1371/journal.pone.0104396

Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. / Campbell, Catarina D.; Mohajeri, Kiana; Malig, Maika; Hormozdiari, Fereydoun; Nelson, Benjamin; Du, Gaixin; Patterson, Kristen M.; Eng, Celeste; Torgerson, Dara G.; Hu, Donglei; Herman, Catherine; Chong, Jessica X.; Ko, Arthur; O'Roak, Brian; Krumm, Niklas; Vives, Laura; Lee, Choli; Roth, Lindsey A.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose; Brigino-Buenaventura, Emerita; Davis, Adam; Meade, Kelley; LeNoir, Michael A.; Thyne, Shannon; Jackson, Daniel J.; Gern, James E.; Lemanske, Robert F.; Shendure, Jay; Abney, Mark; Burchard, Esteban G.; Ober, Carole; Eichler, Evan E.

In: PLoS One, Vol. 9, No. 8, e104396, 12.08.2014.

Research output: Contribution to journalArticle

Campbell, CD, Mohajeri, K, Malig, M, Hormozdiari, F, Nelson, B, Du, G, Patterson, KM, Eng, C, Torgerson, DG, Hu, D, Herman, C, Chong, JX, Ko, A, O'Roak, B, Krumm, N, Vives, L, Lee, C, Roth, LA, Rodriguez-Cintron, W, Rodriguez-Santana, J, Brigino-Buenaventura, E, Davis, A, Meade, K, LeNoir, MA, Thyne, S, Jackson, DJ, Gern, JE, Lemanske, RF, Shendure, J, Abney, M, Burchard, EG, Ober, C & Eichler, EE 2014, 'Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma', PLoS One, vol. 9, no. 8, e104396. https://doi.org/10.1371/journal.pone.0104396
Campbell, Catarina D. ; Mohajeri, Kiana ; Malig, Maika ; Hormozdiari, Fereydoun ; Nelson, Benjamin ; Du, Gaixin ; Patterson, Kristen M. ; Eng, Celeste ; Torgerson, Dara G. ; Hu, Donglei ; Herman, Catherine ; Chong, Jessica X. ; Ko, Arthur ; O'Roak, Brian ; Krumm, Niklas ; Vives, Laura ; Lee, Choli ; Roth, Lindsey A. ; Rodriguez-Cintron, William ; Rodriguez-Santana, Jose ; Brigino-Buenaventura, Emerita ; Davis, Adam ; Meade, Kelley ; LeNoir, Michael A. ; Thyne, Shannon ; Jackson, Daniel J. ; Gern, James E. ; Lemanske, Robert F. ; Shendure, Jay ; Abney, Mark ; Burchard, Esteban G. ; Ober, Carole ; Eichler, Evan E. / Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. In: PLoS One. 2014 ; Vol. 9, No. 8.
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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.",
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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

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.

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