Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

Catherine Igartua, Rachel A. Myers, Rasika A. Mathias, Maria Pino-Yanes, Celeste Eng, Penelope E. Graves, Albert M. Levin, Blanca E. Del-Rio-Navarro, Daniel J. Jackson, Oren E. Livne, Nicholas Rafaels, Christopher K. Edlund, James J. Yang, Scott Huntsman, Muhammad T. Salam, Isabelle Romieu, Raphael Mourad, James E. Gern, Robert F. Lemanske, Annah WyssJane A. Hoppin, Kathleen C. Barnes, Esteban G. Burchard, W. James Gauderman, Fernando Martinez, Benjamin A. Raby, Scott T. Weiss, L. Keoki Williams, Stephanie J. London, Frank D. Gilliland, Dan L. Nicolae, Carole Ober

Research output: Contribution to journalArticle

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Abstract

Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10'6 OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81 × 10'8 and 4.09 × 10'8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10'6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the €missing heritability € of asthma.

Original languageEnglish (US)
Article number5965
JournalNature Communications
Volume6
DOIs
StatePublished - 2015

Fingerprint

asthma
DNA sequences
Asthma
deoxyribonucleic acid
Genes
low frequencies
Hispanic Americans
genes
loci
Missense Mutation
mutations
African Americans
proportion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Igartua, C., Myers, R. A., Mathias, R. A., Pino-Yanes, M., Eng, C., Graves, P. E., ... Ober, C. (2015). Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nature Communications, 6, [5965]. https://doi.org/10.1038/ncomms6965

Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. / Igartua, Catherine; Myers, Rachel A.; Mathias, Rasika A.; Pino-Yanes, Maria; Eng, Celeste; Graves, Penelope E.; Levin, Albert M.; Del-Rio-Navarro, Blanca E.; Jackson, Daniel J.; Livne, Oren E.; Rafaels, Nicholas; Edlund, Christopher K.; Yang, James J.; Huntsman, Scott; Salam, Muhammad T.; Romieu, Isabelle; Mourad, Raphael; Gern, James E.; Lemanske, Robert F.; Wyss, Annah; Hoppin, Jane A.; Barnes, Kathleen C.; Burchard, Esteban G.; Gauderman, W. James; Martinez, Fernando; Raby, Benjamin A.; Weiss, Scott T.; Williams, L. Keoki; London, Stephanie J.; Gilliland, Frank D.; Nicolae, Dan L.; Ober, Carole.

In: Nature Communications, Vol. 6, 5965, 2015.

Research output: Contribution to journalArticle

Igartua, C, Myers, RA, Mathias, RA, Pino-Yanes, M, Eng, C, Graves, PE, Levin, AM, Del-Rio-Navarro, BE, Jackson, DJ, Livne, OE, Rafaels, N, Edlund, CK, Yang, JJ, Huntsman, S, Salam, MT, Romieu, I, Mourad, R, Gern, JE, Lemanske, RF, Wyss, A, Hoppin, JA, Barnes, KC, Burchard, EG, Gauderman, WJ, Martinez, F, Raby, BA, Weiss, ST, Williams, LK, London, SJ, Gilliland, FD, Nicolae, DL & Ober, C 2015, 'Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma', Nature Communications, vol. 6, 5965. https://doi.org/10.1038/ncomms6965
Igartua, Catherine ; Myers, Rachel A. ; Mathias, Rasika A. ; Pino-Yanes, Maria ; Eng, Celeste ; Graves, Penelope E. ; Levin, Albert M. ; Del-Rio-Navarro, Blanca E. ; Jackson, Daniel J. ; Livne, Oren E. ; Rafaels, Nicholas ; Edlund, Christopher K. ; Yang, James J. ; Huntsman, Scott ; Salam, Muhammad T. ; Romieu, Isabelle ; Mourad, Raphael ; Gern, James E. ; Lemanske, Robert F. ; Wyss, Annah ; Hoppin, Jane A. ; Barnes, Kathleen C. ; Burchard, Esteban G. ; Gauderman, W. James ; Martinez, Fernando ; Raby, Benjamin A. ; Weiss, Scott T. ; Williams, L. Keoki ; London, Stephanie J. ; Gilliland, Frank D. ; Nicolae, Dan L. ; Ober, Carole. / Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. In: Nature Communications. 2015 ; Vol. 6.
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AU - Igartua, Catherine

AU - Myers, Rachel A.

AU - Mathias, Rasika A.

AU - Pino-Yanes, Maria

AU - Eng, Celeste

AU - Graves, Penelope E.

AU - Levin, Albert M.

AU - Del-Rio-Navarro, Blanca E.

AU - Jackson, Daniel J.

AU - Livne, Oren E.

AU - Rafaels, Nicholas

AU - Edlund, Christopher K.

AU - Yang, James J.

AU - Huntsman, Scott

AU - Salam, Muhammad T.

AU - Romieu, Isabelle

AU - Mourad, Raphael

AU - Gern, James E.

AU - Lemanske, Robert F.

AU - Wyss, Annah

AU - Hoppin, Jane A.

AU - Barnes, Kathleen C.

AU - Burchard, Esteban G.

AU - Gauderman, W. James

AU - Martinez, Fernando

AU - Raby, Benjamin A.

AU - Weiss, Scott T.

AU - Williams, L. Keoki

AU - London, Stephanie J.

AU - Gilliland, Frank D.

AU - Nicolae, Dan L.

AU - Ober, Carole

PY - 2015

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N2 - Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10'6 OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81 × 10'8 and 4.09 × 10'8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10'6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the €missing heritability € of asthma.

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