S1772 Genetic Insights into Gastroparesis: A Comprehensive GWAS Reveals Distinct and Shared Risk Factors in Diabetic and Idiopathic Subtypes

Introduction: Gastroparesis is a severe medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. The genetic risk factors for nausea in gastroparesis remain largely unknown. Hereby, we investigated the association between genetic variants and gastroparesis risk using whole-genome sequencing (WGS) data from a large set of patients all over United States. Methods: Blood samples were obtained from both controls and gastroparesis adults with a diagnosis of diabetic or idiopathic, having evidence of delayed gastric emptying, and moderate to severe nausea, daily average nausea score of >2.5, at least one episode of vomiting, PAGI-SYM nausea score of ≥2 at screening, and controlled blood glucose levels. WGS was conducted with 30× read depth. Genotypes were then called, filtered, and QCed using stringent conditions. GWAS using logistic regression was conducted on variants with minor allele frequency (MAF) ≥0.01, adjusting for age, sex, and the first 3 principal components. Results: After quality control, 2202 gastroparesis cases and 1511 controls were included in the analyses. Logistic regression identified significant variant clusters in genes including SORD, FA230C, SUZ12, PRKRA, SNTG2, TUBGCP5, and TJP1, among others. Especially, a cluster of intergenic variants between FRG1DP and FRG2EP showed strong association (P = 2.86e-37, OR = 5.35). Stratified analyses revealed that this cluster was more significant in idiopathic than diabetic gastroparesis compared to controls. Further comparisons with previously reported differentially expressed genes showed overlap. In the diabetic vs control group, SCUBE1 was identified in both GWAS and differential expression analyses. While for idiopathic vs control, shared genes included ALOX5, C5AR2, EMB, METRNL, PRKG2, PTHLH, and SAMSN1. Conclusion: This study provided a comprehensive GWAS analysis of gastroparesis, identifying risk loci clusters in several genes and some were shared across diabetic and idiopathic gastroparesis. Both known and novel associated were delineated in this large set of patients. The strongest association was from an intergenic cluster between FRG1DP and FRG2EP which reside in a centromere region. However, with the stringent variant filtering criteria applied, and replication we believe these variants are of high quality and this association is potentially worth further investigation.