Resequencing candidate genes implicates rare variants in asthma susceptibility

Dara G. Torgerson, Daniel Capurso, Rasika A. Mathias, Penelope E. Graves, Ryan D. Hernandez, Terri H. Beaty, Eugene R. Bleecker, Benjamin A. Raby, Deborah A. Meyers, Kathleen C. Barnes, Scott T. Weiss, Fernando Martinez, Dan L. Nicolae, Carole Ober

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Abstract

Common variation in over 100 genes has been implicated in the risk of developing asthma, but the contribution of rare variants to asthma susceptibility remains largely unexplored. We selected nine genes that showed the strongest signatures of weak purifying selection from among 53 candidate asthma-associated genes, and we sequenced the coding exons and flanking noncoding regions in 450 asthmatic cases and 515 nonasthmatic controls. We observed an overall excess of p values <0.05 (p = 0.02), and rare variants in four genes (AGT, DPP10, IKBKAP, and IL12RB1) contributed to asthma susceptibility among African Americans. Rare variants in IL12RB1 were also associated with asthma susceptibility among European Americans, despite the fact that the majority of rare variants in IL12RB1 were specific to either one of the populations. The combined evidence of association with rare noncoding variants in IL12RB1 remained significant (p = 3.7 × 10 -4) after correcting for multiple testing. Overall, the contribution of rare variants to asthma susceptibility was predominantly due to noncoding variants in sequences flanking the exons, although nonsynonymous rare variants in DPP10 and in IL12RB1 were associated with asthma in African Americans and European Americans, respectively. This study provides evidence that rare variants contribute to asthma susceptibility. Additional studies are required for testing whether prioritizing genes for resequencing on the basis of signatures of purifying selection is an efficient means of identifying novel rare variants that contribute to complex disease.

Original languageEnglish (US)
Pages (from-to)273-281
Number of pages9
JournalAmerican Journal of Human Genetics
Volume90
Issue number2
DOIs
StatePublished - Feb 10 2012

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Asthma
Genes
African Americans
Exons
Population

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Torgerson, D. G., Capurso, D., Mathias, R. A., Graves, P. E., Hernandez, R. D., Beaty, T. H., ... Ober, C. (2012). Resequencing candidate genes implicates rare variants in asthma susceptibility. American Journal of Human Genetics, 90(2), 273-281. https://doi.org/10.1016/j.ajhg.2012.01.008

Resequencing candidate genes implicates rare variants in asthma susceptibility. / Torgerson, Dara G.; Capurso, Daniel; Mathias, Rasika A.; Graves, Penelope E.; Hernandez, Ryan D.; Beaty, Terri H.; Bleecker, Eugene R.; Raby, Benjamin A.; Meyers, Deborah A.; Barnes, Kathleen C.; Weiss, Scott T.; Martinez, Fernando; Nicolae, Dan L.; Ober, Carole.

In: American Journal of Human Genetics, Vol. 90, No. 2, 10.02.2012, p. 273-281.

Research output: Contribution to journalArticle

Torgerson, DG, Capurso, D, Mathias, RA, Graves, PE, Hernandez, RD, Beaty, TH, Bleecker, ER, Raby, BA, Meyers, DA, Barnes, KC, Weiss, ST, Martinez, F, Nicolae, DL & Ober, C 2012, 'Resequencing candidate genes implicates rare variants in asthma susceptibility', American Journal of Human Genetics, vol. 90, no. 2, pp. 273-281. https://doi.org/10.1016/j.ajhg.2012.01.008
Torgerson DG, Capurso D, Mathias RA, Graves PE, Hernandez RD, Beaty TH et al. Resequencing candidate genes implicates rare variants in asthma susceptibility. American Journal of Human Genetics. 2012 Feb 10;90(2):273-281. https://doi.org/10.1016/j.ajhg.2012.01.008
Torgerson, Dara G. ; Capurso, Daniel ; Mathias, Rasika A. ; Graves, Penelope E. ; Hernandez, Ryan D. ; Beaty, Terri H. ; Bleecker, Eugene R. ; Raby, Benjamin A. ; Meyers, Deborah A. ; Barnes, Kathleen C. ; Weiss, Scott T. ; Martinez, Fernando ; Nicolae, Dan L. ; Ober, Carole. / Resequencing candidate genes implicates rare variants in asthma susceptibility. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 2. pp. 273-281.
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