University of Groningen Integration of mouse and human genome-wide association data identifies KCNIP 4 as an asthma gene

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 geneand SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e04), 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 2.1e03 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. PLOS ONE | www.plosone.org 1 February 2013 | Volume 8 | Issue 2 | e56179 Citation: Himes BE, Sheppard K, Berndt A, Leme AS, Myers RA, et al. (2013) Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene. PLoS ONE 8(2): e56179. doi:10.1371/journal.pone.0056179 Editor: Huiping Zhang, Yale University, United States of America Received October 2, 2012; Accepted January 7, 2013; Published February 14, 2013 Copyright: 2013 Himes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and T32 HL07427 from the NHLBI, National Institutes of Health (NIH). Additional support was provided by NIH U10 HL064287, U10 HL064288, U10 HL064295, U10 HL064305, U10 HL064307, U01 HL064313, RC2 HL101487, R01 HL087699 and U01 HL65899, an NIH Pharmacogenomics Research Network (PGRN) – RIKEN Center for Genomic Medicine (CGM) Global Alliance and by funding from the BioBank Japan project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. We thank the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) for use of LOCCS and LODO study samples. B.E.H. was supported by NIH K99 HL105663. L.K.W. is funded by the American Asthma Foundation, the Fund for Henry Ford Hospital, and by NIH R01AI079139 and R01AI061774 from the National Institute of Allergy and Infectious Diseases (NIAID). K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. S.J.L. is supported by the Division of Intramural Research, National Institute of Environmental Health Sciences. D.A.G. was supported by the Netherlands Asthma Foundation grant AF (AF 95.09, AF 98.48, AF 3.2.02.51 and AF 3.2.07.015) and a grant from the University Medical Center Groningen. GHK was supported by a Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences. D.S.P. was supported by a Royal Netherlands Academy of Arts and Sciences Honorary Professorship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: blanca.himes@channing.harvard.edu