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Multicenter Study
. 2013;8(2):e56179.
doi: 10.1371/journal.pone.0056179. Epub 2013 Feb 14.

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

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Free PMC article
Multicenter Study

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

Blanca E Himes et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Study overview.
Mouse association study (in pink): (A) Baseline AHR slope measures were obtained for 31 mouse strains, and these were (B) used to perform an association study using EMMA software. (C) Mouse genes near or containing SNPs with p-values <0.001 were selected for follow-up study in human GWAS datasets. Integration of mouse results with human data (in blue): (D) HomoloGene maps were used to obtain human homologous genes corresponding to the top mouse genes. (E) Genes with SNPs having p-values <0.001 in the combined EVE meta-analysis or within race/ethnic specific GWAS were selected for (F) replication in other human GWAS.
Figure 2
Figure 2. Baseline AHR slope phenotype distribution among 31 mouse strains.
The AHR slope, displayed along the y-axis, was computed as the slope of the resistance measures vs. log-transformed methacholine concentrations for each mouse strain. Names for each mouse strain are displayed along the x-axis.
Figure 3
Figure 3. Manhattan plot of mouse AHR slope EMMA results.
The x-axis denotes position along each chromosome. The y-axis denotes –Log10(P) corresponding to EMMA P-values. None of the P-values are significant after corrections for multiple comparisons, but all those with nominal P-values <0.001 were selected for further study.
Figure 4
Figure 4. Top regions of association in mouse and human.
Mouse plots near (A) Kcnip4 and (B) Pdzd2/Golph3/Mtmr12/Zfr contain –Log10 of EMMA p-values vs. position along the corresponding mouse chromosome. Corresponding human homologous plots near (C) KCNIP4 and (D) PDZD2/GOLPH3/MTMR12/ZFR. The x-axis denotes position along corresponding human chromosome, while the y-axis denotes –Log10(P) corresponding to EVE p-values for the combined sample GWAS (C) or European American GWAS (D). LD between the SNPs with the lowest P-value to other SNPs in the human plots are denoted in colors and were computed according to HapMap Phase 2 CEU data using LocusZoom .
Figure 5
Figure 5. Mouse genotypes for SNPs with P-value <0.001 in the top two association regions.
A) Kcnip4 and B) Pdzd2/Golph3/Mtmr12/Zfr. Each column corresponds to a mouse strain, ordered as displayed in Figure 2, such that AHR slope increases from left to right.
Figure 6
Figure 6. Top regions of association in two independent human asthma GWAS.
KCNIP4 association in A) Sepracor/LOCCS/LODO/Illumina and C) GABRIEL. PDZD2/GOLPH3/MTMR12/ZFR association in B) Sepracor/LOCCS/LODO/Illumina and D) GABRIEL. The x-axis denotes position along corresponding human chromosome, while the y-axis denotes –Log10(P). LD between the SNPs with the lowest P-value to other SNPs in the plots are denoted in colors and were computed according to HapMap Phase 2 CEU data using LocusZoom .
Figure 7
Figure 7. Top regions of association in a human AHR GWAS.
(A) KCNIP4 and (B) PDZD2/GOLPH3/MTMR12/ZFR associations in SHARP. The x-axis denotes position along corresponding human chromosome, while the y-axis denotes –Log10(P). LD between the SNPs with the lowest P-value to other SNPs in the plots are denoted in colors and were computed according to HapMap Phase 2 CEU data using LocusZoom .

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