Asthma-susceptibility variants identified using probands in case-control and family-based analyses

Blanca E Himes, Jessica Lasky-Su, Ann C Wu, Jemma B Wilk, Gary M Hunninghake, Barbara Klanderman, Amy J Murphy, Ross Lazarus, Manuel E Soto-Quiros, Lydiana Avila, Juan C Celedón, Christoph Lange, George T O'Connor, Benjamin A Raby, Edwin K Silverman, Scott T Weiss, Blanca E Himes, Jessica Lasky-Su, Ann C Wu, Jemma B Wilk, Gary M Hunninghake, Barbara Klanderman, Amy J Murphy, Ross Lazarus, Manuel E Soto-Quiros, Lydiana Avila, Juan C Celedón, Christoph Lange, George T O'Connor, Benjamin A Raby, Edwin K Silverman, Scott T Weiss

Abstract

Background: Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.

Methods: We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.

Results: We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.

Conclusions: Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.

Figures

Figure 1
Figure 1
Study Design. (A) The initial study population consisted of CAMP probands used in (1) a case-control design composed of 359 CAMP cases and 846 Illumina controls and (2) a family-based design composed of 403 trios. Genome-wide association of individual SNPs to asthma status was assessed in each of these designs. SNPs with a case-control Cochran-Armitage trend test p-value < 0.01 and a family-based PBAT additive model p-value < 0.05 were selected for replication analysis. (B) The first replication stage, carried out in CR, measured the association of 1378 SNPs with asthma. Those SNPs with either (1) a CR PBAT additive model p-value < 0.05 or (2) a CR PBAT additive model p-value < 0.10 and a p-value < 1E-05 from the designs in (A) were selected for the next replication stage. (C) The second replication stage was carried out in two additional independent populations, FHS and iCAP. (D) Joint association analysis for 85 SNPs with data in the three independent populations was performed.
Figure 2
Figure 2
Association Results. (A) Plot of CAMP Trio vs. CAMP/Illumina GWA results. SNPs selected for replication analysis have family-based PBAT additive model p-values < 0.05 and case-control Cochran-Armitage trend test p-values < 0.01. The subset of these SNPs that was genotyped in CR is shown in blue. Points with a pink background are SNPs whose association in several populations was reported previously [15]. (B) Plot of CAMP Trio vs. CAMP/Illumina GWA results for the subset of SNPs that was successfully genotyped in CR. Shown in green are those SNPs with CR p-values < 0.05. Shown in red are those SNPs that have CR p-values < 0.05 and either a FHS or iCAP p-value < 0.05.

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