Su1031 – Prevalence of Germline Mutations and Variable of Uncertain Significance (VUS) among Hispanics with Suspected Hereditary Colorectal Cancer Syndromes

Despite directionally consistent effects at many of the known IBD loci (73%, P = 2.5 x 10 - 11 , sign test), we noted genetic heterogeneity pertaining to allele frequency distribution between African American vs European individuals.SKAT-O analyses identified aggregates of rare variants in ATP1A4 for the first time to be associated with both CD (63 variants; P = 1.4 x 10 -6 ) and IBD (66 variants; P = 3.2 x 10 -8 ) at genome-wide significance (FDR<0.05;adjusted for 22,521 gene sets).However, these strengths of association seem consistent with a locus of weak to moderate effects.ATP1A4 encodes an ATPase involved in the maintenance of Na + and K + electrochemical gradients, and these electrolyte imbalance has previously been implicated in IBD.Similarly, aggregates of rare variants in CALB2 (20 variants; P = 1.6 x 10 -6 ) encoding a neuroimmunomodulator, calretinin, were found to be associated with UC at FDR<0.05.Conclusion:Our first African American whole-genome sequencing study adds to the complexity of the genetic architecture of IBD across diverse populations.We detected aggregates of rare variants in genes not previously implicated in IBD.While our results support an overlap of common variant risk for IBD susceptibility between African American and European ancestries, they highlight the possibility of population specificity in rare variant contributions to IBD.