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; 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

doi:10.1371/journal.pone.0056179

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. LemanskeRobert 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

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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.

Original language	English
Article number	e56179
Journal	PloS one
Volume	8
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0056179
Publication status	Published - 14-02-2013
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Himes, B. E., Sheppard, K., Berndt, A., Leme, A. S., Myers, R. A., Gignoux, C. R., Levin, A. M., Gauderman, W. J., Yang, J. J., Mathias, R. A., Romieu, I., Torgerson, D. G., Roth, L. A., Huntsman, S., Eng, C., Klanderman, B., Ziniti, J., Senter-Sylvia, J., Szefler, S. J., ... Weiss, S. T. (2013). Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene. PloS one, 8(2), Article e56179. https://doi.org/10.1371/journal.pone.0056179

@article{c15b2f3069ab4a90bf01577eac998a20,

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

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.}",

note = "Funding Information: We thank all CAMP subjects for their ongoing participation in this study. We acknowledge the CAMP investigators and research team, supported by the National Heart, Lung and Blood Institute (NHLBI), for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women{\textquoteright}s Hospital under appropriate CAMP policies and human subject{\textquoteright}s protections. We acknowledge the following GALA 1 investigators: Michael A. LeNoir, MD (Bay Area Pediatrics, Oakland, CA, USA), Harold J. Farber, MD (Section of Pulmonology, Baylor College of Medicine, Houston, TX, USA), Rajesh Kumar, MD, MPH (Division of Allergy and Immunology, Children's Memorial Hospital, Chicago, IL, USA), Pedro C. Avila, MD (Department of Medicine, Northwestern University, Chicago, IL, USA), Kelley Meade, MD (Children's Hospital of Oakland, Oakland, CA, USA), Denise Serebrisky, MD (Jacobi Medical Center and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA), Shannon Thyne, MD (Department of Medicine, University of California, San Francisco, San Francisco, CA, USA), William Rodriguez-Cintron, MD (Veterans Affairs Medical Center, San Juan, Puerto Rico), Jose R. Rodriguez-Santana, MD (Centro de Neumologia Pediatrica, San Juan, Puerto Rico), Luisa N. Borrell, DDS, PhD (Department of Health Sciences, Lehman College, City University of New York, New York, NY, USA).",

year = "2013",

month = feb,

day = "14",

doi = "10.1371/journal.pone.0056179",

language = "English",

volume = "8",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

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

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.

N1 - Funding Information: We thank all CAMP subjects for their ongoing participation in this study. We acknowledge the CAMP investigators and research team, supported by the National Heart, Lung and Blood Institute (NHLBI), for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women’s Hospital under appropriate CAMP policies and human subject’s protections. We acknowledge the following GALA 1 investigators: Michael A. LeNoir, MD (Bay Area Pediatrics, Oakland, CA, USA), Harold J. Farber, MD (Section of Pulmonology, Baylor College of Medicine, Houston, TX, USA), Rajesh Kumar, MD, MPH (Division of Allergy and Immunology, Children's Memorial Hospital, Chicago, IL, USA), Pedro C. Avila, MD (Department of Medicine, Northwestern University, Chicago, IL, USA), Kelley Meade, MD (Children's Hospital of Oakland, Oakland, CA, USA), Denise Serebrisky, MD (Jacobi Medical Center and Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA), Shannon Thyne, MD (Department of Medicine, University of California, San Francisco, San Francisco, CA, USA), William Rodriguez-Cintron, MD (Veterans Affairs Medical Center, San Juan, Puerto Rico), Jose R. Rodriguez-Santana, MD (Centro de Neumologia Pediatrica, San Juan, Puerto Rico), Luisa N. Borrell, DDS, PhD (Department of Health Sciences, Lehman College, City University of New York, New York, NY, USA).

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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DO - 10.1371/journal.pone.0056179

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SN - 1932-6203

VL - 8

JO - PloS one

JF - PloS one

IS - 2

M1 - e56179

ER -

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

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