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 Wyss; Jane A. Hoppin; Kathleen C. Barnes; Esteban G. Burchard; W. James Gauderman; Fernando D. Martinez; Benjamin A. Raby; Scott T. Weiss; L. Keoki Williams; Stephanie J. London; Frank D. Gilliland; Dan L. Nicolae; Carole Ober

doi:10.1038/ncomms6965

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 D. Martinez, Benjamin A. Raby, Scott T. Weiss, L. Keoki Williams, Stephanie J. London, Frank D. Gilliland, Dan L. Nicolae, Carole Ober

School of Medicine

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Article number	5965
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms6965
State	Published - Jan 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms6965

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Igartua, C., Myers, R. A., Mathias, R. A., Pino-Yanes, M., Eng, C., Graves, P. E., Levin, A. M., Del-Rio-Navarro, B. E., Jackson, D. J., Livne, O. E., Rafaels, N., Edlund, C. K., Yang, J. J., Huntsman, S., Salam, M. T., Romieu, I., Mourad, R., Gern, J. E., Lemanske, R. F., ... Ober, C. (2015). Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nature communications, 6, Article 5965. https://doi.org/10.1038/ncomms6965

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, FD, 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

@article{7d8a4ec0566d4816897c6549f6cbe9d3,

title = "Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma",

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.",

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

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doi = "10.1038/ncomms6965",

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journal = "Nature communications",

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T1 - Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

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 D.

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 - 2015/1

Y1 - 2015/1

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.

AB - 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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VL - 6

JO - Nature communications

JF - Nature communications

M1 - 5965

ER -

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

Abstract

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