The genetic architecture underlying susceptibility to Kawasaki disease (KD) remains incompletely understood, particularly in underrepresented populations. To date, large-scale whole-genome sequencing (WGS) studies of KD have been 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, California. Focusing on a previously reported susceptibility region on Chr 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. At an FDR of 0.2, KOT identified 22 significant 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 the 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. Validation analyses demonstrated that all top signals identified in the discovery cohort were supported in an independent case–control cohort comprising 219 independent Hispanic KD cases and 350 Hispanic-ancestry samples from the 1000 Genomes Project. 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. Integrative expression quantitative trait locus (eQTL) analysis using linked whole-blood RNA-seq data revealed that rs7171 acts as a cis-eQTL for both SHKBP1 and LTBP4, genes implicated in TGF-beta signaling, with concordant evidence across GTEx and multiple immune eQTL datasets. Collectively, these findings highlight the ancestry-specific genetic architecture underlying KD susceptibility and demonstrate the power of trio analysis combined with linked whole blood RNA for eQTL analysis to uncover regulatory mechanisms contributing to disease risk.