A genome-wide association study identifies a new genetic susceptibility factor for Kawasaki Disease

Abstract

We performed a case-control GWAS on KD, initially analyzing 494,236 genetic markers in a total of 405 KD cases of European descent matched to 6,252 controls. The independent replication sample set included an additional 1,768 KD cases of European- Caucasian and Asian descent and 3,131 family and population controls in aggregate. The total sample size of 2,173 KD cases and 9,383 controls was assembled by team members from different nations and research networks. Single-SNP analysis for association with KD susceptibility was performed using logistic regression fi tted for genotype trend effects (1 degree of freedom), with adjustment for the top four principal components of population ancestry. We attempted replication of the 62 most signifi cantly associated SNPs in a family-based sample collection of 760 complete parent-offspring trios and 139 discordant sibling pairs using the Sequenom Mass-Array genotyping platform. A total of 5 SNPs showed a consistent direction of effect with the GWAS (1.96 × 10−3 < P < 0.068) in the family-based analysis. Combined analysis of both the GWAS and family-based tests for these 5 SNPs resulted in four exceeding P < 1.0 × 10−5 and representing four distinct genetic loci. We then followed up these SNPs in three Asian collections comprising 438 KD cases vs. 446 controls from Taiwan, 460 KD cases vs. 498 controls from Korea, and 130 KD cases vs. 568 controls from Hong Kong and Shanghai. The specifi c loci and possible functional implications for understanding the immune activation of KD pathogenesis will be discussed.