Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

Blanca E. Himes, Keith Sheppard, Annerose Berndt, Adriana S. Leme, Rachel A. Myers, Christopher R. Gignoux, Albert M. Levin, W. James Gauderman, James J. Yang, Rasika A. Mathias, Isabelle Romieu, Dara G. Torgerson, Lindsey A. Roth, Scott Huntsman, Celeste Eng, Barbara Klanderman, John Ziniti, Jody Senter-Sylvia, Stanley J. Szefler, Robert F. Lemanske & 35 others Robert S. Zeiger, Robert C. Strunk, Fernando D. Martinez, Homer Boushey, Vernon M. Chinchilli, Elliot Israel, David Mauger, Gerard H. Koppelman, Dirkje S. Postma, Maartje A.E. Nieuwenhuis, Judith M. Vonk, John J. Lima, Charles G. Irvin, Stephen P. Peters, Michiaki Kubo, Mayumi Tamari, Yusuke Nakamura, Augusto A. Litonjua, Kelan G. Tantisira, Benjamin A. Raby, Eugene R. Bleecker, Deborah A. Meyers, Stephanie J. London, Kathleen C. Barnes, Frank D. Gilliland, L. Keoki Williams, Esteban G. Burchard, Dan L. Nicolae, Carole Ober, Dawn L. DeMeo, Edwin K. Silverman, Beverly Paigen, Gary Churchill, Steve D. Shapiro, Scott T. Weiss

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.

Original languageEnglish
Article numbere56179
JournalPloS one
Volume8
Issue number2
DOIs
Publication statusPublished - 14-02-2013

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Kv Channel-Interacting Proteins
asthma
Human Genome
Asthma
Genes
Genome-Wide Association Study
genome
mice
genes
proteins
Single Nucleotide Polymorphism
Pulmonary diseases
genome-wide association study
meta-analysis

All Science Journal Classification (ASJC) codes

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

Cite this

Himes, B. E., Sheppard, K., Berndt, A., Leme, A. S., Myers, R. A., Gignoux, C. R., ... Weiss, S. T. (2013). Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene. PloS one, 8(2), [e56179]. https://doi.org/10.1371/journal.pone.0056179
Himes, Blanca E. ; Sheppard, Keith ; Berndt, Annerose ; Leme, Adriana S. ; Myers, Rachel A. ; Gignoux, Christopher R. ; Levin, Albert M. ; Gauderman, W. James ; Yang, James J. ; Mathias, Rasika A. ; Romieu, Isabelle ; Torgerson, Dara G. ; Roth, Lindsey A. ; Huntsman, Scott ; Eng, Celeste ; Klanderman, Barbara ; Ziniti, John ; Senter-Sylvia, Jody ; Szefler, Stanley J. ; Lemanske, Robert F. ; Zeiger, Robert S. ; Strunk, Robert C. ; Martinez, Fernando D. ; Boushey, Homer ; Chinchilli, Vernon M. ; Israel, Elliot ; Mauger, David ; Koppelman, Gerard H. ; Postma, Dirkje S. ; Nieuwenhuis, Maartje A.E. ; Vonk, Judith M. ; Lima, John J. ; Irvin, Charles G. ; Peters, Stephen P. ; Kubo, Michiaki ; Tamari, Mayumi ; Nakamura, Yusuke ; Litonjua, Augusto A. ; Tantisira, Kelan G. ; Raby, Benjamin A. ; Bleecker, Eugene R. ; Meyers, Deborah A. ; London, Stephanie J. ; Barnes, Kathleen C. ; Gilliland, Frank D. ; Williams, L. Keoki ; Burchard, Esteban G. ; Nicolae, Dan L. ; Ober, Carole ; DeMeo, Dawn L. ; Silverman, Edwin K. ; Paigen, Beverly ; Churchill, Gary ; Shapiro, Steve D. ; Weiss, Scott T. / Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene. In: PloS one. 2013 ; Vol. 8, No. 2.
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abstract = "Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.",
author = "Himes, {Blanca E.} and Keith Sheppard and Annerose Berndt and Leme, {Adriana S.} and Myers, {Rachel A.} and Gignoux, {Christopher R.} and Levin, {Albert M.} and Gauderman, {W. James} and Yang, {James J.} and Mathias, {Rasika A.} and Isabelle Romieu and Torgerson, {Dara G.} and Roth, {Lindsey A.} and Scott Huntsman and Celeste Eng and Barbara Klanderman and John Ziniti and Jody Senter-Sylvia and Szefler, {Stanley J.} and Lemanske, {Robert F.} and Zeiger, {Robert S.} and Strunk, {Robert C.} and Martinez, {Fernando D.} and Homer Boushey and Chinchilli, {Vernon M.} and Elliot Israel and David Mauger and Koppelman, {Gerard H.} and Postma, {Dirkje S.} and Nieuwenhuis, {Maartje A.E.} and Vonk, {Judith M.} and Lima, {John J.} and Irvin, {Charles G.} and Peters, {Stephen P.} and Michiaki Kubo and Mayumi Tamari and Yusuke Nakamura and Litonjua, {Augusto A.} and Tantisira, {Kelan G.} and Raby, {Benjamin A.} and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and London, {Stephanie J.} and Barnes, {Kathleen C.} and Gilliland, {Frank D.} and Williams, {L. Keoki} and Burchard, {Esteban G.} and Nicolae, {Dan L.} and Carole Ober and DeMeo, {Dawn L.} and Silverman, {Edwin K.} and Beverly Paigen and Gary Churchill and Shapiro, {Steve D.} and Weiss, {Scott T.}",
year = "2013",
month = "2",
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Himes, BE, Sheppard, K, Berndt, A, Leme, AS, Myers, RA, Gignoux, CR, Levin, AM, Gauderman, WJ, Yang, JJ, Mathias, RA, Romieu, I, Torgerson, DG, Roth, LA, Huntsman, S, Eng, C, Klanderman, B, Ziniti, J, Senter-Sylvia, J, Szefler, SJ, Lemanske, RF, Zeiger, RS, Strunk, RC, Martinez, FD, Boushey, H, Chinchilli, VM, Israel, E, Mauger, D, Koppelman, GH, Postma, DS, Nieuwenhuis, MAE, Vonk, JM, Lima, JJ, Irvin, CG, Peters, SP, Kubo, M, Tamari, M, Nakamura, Y, Litonjua, AA, Tantisira, KG, Raby, BA, Bleecker, ER, Meyers, DA, London, SJ, Barnes, KC, Gilliland, FD, Williams, LK, Burchard, EG, Nicolae, DL, Ober, C, DeMeo, DL, Silverman, EK, Paigen, B, Churchill, G, Shapiro, SD & Weiss, ST 2013, 'Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene', PloS one, vol. 8, no. 2, e56179. https://doi.org/10.1371/journal.pone.0056179

Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene. / Himes, Blanca E.; Sheppard, Keith; Berndt, Annerose; Leme, Adriana S.; Myers, Rachel A.; Gignoux, Christopher R.; Levin, Albert M.; Gauderman, W. James; Yang, James J.; Mathias, Rasika A.; Romieu, Isabelle; Torgerson, Dara G.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Boushey, Homer; Chinchilli, Vernon M.; Israel, Elliot; Mauger, David; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A.E.; Vonk, Judith M.; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Litonjua, Augusto A.; Tantisira, Kelan G.; Raby, Benjamin A.; Bleecker, Eugene R.; Meyers, Deborah A.; London, Stephanie J.; Barnes, Kathleen C.; Gilliland, Frank D.; Williams, L. Keoki; Burchard, Esteban G.; Nicolae, Dan L.; Ober, Carole; DeMeo, Dawn L.; Silverman, Edwin K.; Paigen, Beverly; Churchill, Gary; Shapiro, Steve D.; Weiss, Scott T.

In: PloS one, Vol. 8, No. 2, e56179, 14.02.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

AU - Himes, Blanca E.

AU - Sheppard, Keith

AU - Berndt, Annerose

AU - Leme, Adriana S.

AU - Myers, Rachel A.

AU - Gignoux, Christopher R.

AU - Levin, Albert M.

AU - Gauderman, W. James

AU - Yang, James J.

AU - Mathias, Rasika A.

AU - Romieu, Isabelle

AU - Torgerson, Dara G.

AU - Roth, Lindsey A.

AU - Huntsman, Scott

AU - Eng, Celeste

AU - Klanderman, Barbara

AU - Ziniti, John

AU - Senter-Sylvia, Jody

AU - Szefler, Stanley J.

AU - Lemanske, Robert F.

AU - Zeiger, Robert S.

AU - Strunk, Robert C.

AU - Martinez, Fernando D.

AU - Boushey, Homer

AU - Chinchilli, Vernon M.

AU - Israel, Elliot

AU - Mauger, David

AU - Koppelman, Gerard H.

AU - Postma, Dirkje S.

AU - Nieuwenhuis, Maartje A.E.

AU - Vonk, Judith M.

AU - Lima, John J.

AU - Irvin, Charles G.

AU - Peters, Stephen P.

AU - Kubo, Michiaki

AU - Tamari, Mayumi

AU - Nakamura, Yusuke

AU - Litonjua, Augusto A.

AU - Tantisira, Kelan G.

AU - Raby, Benjamin A.

AU - Bleecker, Eugene R.

AU - Meyers, Deborah A.

AU - London, Stephanie J.

AU - Barnes, Kathleen C.

AU - Gilliland, Frank D.

AU - Williams, L. Keoki

AU - Burchard, Esteban G.

AU - Nicolae, Dan L.

AU - Ober, Carole

AU - DeMeo, Dawn L.

AU - Silverman, Edwin K.

AU - Paigen, Beverly

AU - Churchill, Gary

AU - Shapiro, Steve D.

AU - Weiss, Scott T.

PY - 2013/2/14

Y1 - 2013/2/14

N2 - Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.

AB - Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.

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Himes BE, Sheppard K, Berndt A, Leme AS, Myers RA, Gignoux CR et al. Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene. PloS one. 2013 Feb 14;8(2). e56179. https://doi.org/10.1371/journal.pone.0056179