Introduction: The genetic architecture underlying susceptibility to Kawasaki disease (KD) remains incompletely understood, particularly in underrepresented populations. Large-scale whole-genome sequencing (WGS) studies of KD are limited, and Hispanic ancestry has been systematically underrepresented in prior genetic investigations. To address these gaps, we performed WGS on 218 complete Hispanic KD trios recruited in San Diego.
Methods: Focusing on a previously reported susceptibility region on chromosome 19, we applied KnockoffTrio (KOT), an analytical framework that leverages family-based transmission while modeling genome-wide correlation structure to achieve exact false discovery rate (FDR) control in WGS data. This approach enables robust and powerful variant prioritization beyond traditional trio-based methods. Discovery analyses were conducted in 218 Hispanic KD trios, with validation performed in an independent case–control cohort consisting of 219 Hispanic KD cases and 350 Hispanic-ancestry KD-free reference samples from the 1000 Genomes Project. Functional relevance was assessed through integrative expression quantitative trait locus (eQTL) analyses using linked whole-blood RNA-seq data and external immune eQTL resources.
Results: At an FDR of 0.2, KOT identified 22 significant genomic windows between SHKBP1 and CYP2A7 on Chr19q13.2. The top window (chr19:40585175-40585967), located within SHKBP1, showed the strongest signal (W = 6.18), exceeding the data-driven cutoff (W = 3.38). At SNP level, KOT identified 16 significant variants within this region, including 12 SNPs in SHKBP1 gene and one SNP each in PRX, BLVRB, LTBP4, and CYP2T3P. All top signals were supported in the independent validation cohort. The most significant variant, rs7171 in SHKBP1 (W = 5.15), showed consistent association across analyses. In contrast, rs28493229 in ITPKC, a KD susceptibility variant previously replicated in Asian and Western populations, was not significantly associated with KD, likely reflecting population-specific linkage disequilibrium structure and reduced heterozygosity in this ancestry. eQTL analysis revealed that rs7171 acts as a cis-eQTL for both SHKBP1 and LTBP4 both SHKBP1 and LTBP4 (P=0.003), genes implicated in TGF-beta signaling, with concordant evidence across GTEx and multiple immune eQTL datasets.
Discussion: These findings reveal ancestry-specific genetic risk architecture for KD and demonstrate the power of family-based WGS combined with linked transcriptomic data to identify regulatory mechanisms contributing to disease susceptibility.