A pilot genome-wide association study meta-analysis of gastroparesis

Authors: TAVARES, LETICIA - Monash University; ZHENG, TENGHAO - Monash University; KWICKLIS, MADELINE - University Of Michigan; MITCHELL, EMILY - Johns Hopkins School Of Public Health; PANDIT, ANITA - University Of Michigan; PULLAPANTULA, SURAJ - Mayo Clinic; BERNARD, CHERYL - Mayo Clinic; TEDER-LAVING, MARIS - University Of Tartu; MARQUES, FRANCINE - Monash University; ESKO, TONU - University Of Tartu; KUO, BRADEN - Massachusetts General Hospital; SHULMAN, ROBERT - Children'S Nutrition Research Center (CNRC); CHUMPITAZI, BRUNO - Children'S Nutrition Research Center (CNRC); KOCH, KENNETH - Wake Forest University; SAROSIEK, IRENE - Texas Tech University Health Science Center; ABELL, THOMAS - University Of Louisville; MCCALLUM, RICHARD - Texas Tech University Health Science Center; PARKMAN, HENRY - Temple University; PASRICHA, PANKAJ - Mayo Clinic College Of Medicine; HAMILTON, FRANK - National Institute Of Diabetes And Digestive And Kidney Diseases; TONASCIA, JAMES - Johns Hopkins School Of Public Health; ZAWISTOWSKI, MATTHEW - University Of Michigan; FARRUGIA, GIANRICO - Mayo Clinic; GROVER, MADHUSUDAN - Mayo Clinic; D'AMATO, MAURO - Monash University

Submitted to: United European Gastroenterology Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2023
Publication Date: 10/11/2023
Citation: Tavares, L.C., Zheng, T., Kwicklis, M., Mitchell, E., Pandit, A., Pullapantula, S., Bernard, C., Teder-Laving, M., Marques, F.Z., Esko, T., Kuo, B., Shulman, R.J., Chumpitazi, B.P., Koch, K.L., Sarosiek, I., Abell, T.L., McCallum, R.W., Parkman, H.P., Pasricha, P.J., Hamilton, F.A., Tonascia, J., Zawistowski, M., Farrugia, G., Grover, M., D'Amato, M. 2023. A pilot genome-wide association study meta-analysis of gastroparesis. United European Gastroenterology Journal. 11(8):784-796. https://doi.org/10.1002/ueg2.12453.
DOI: https://doi.org/10.1002/ueg2.12453

Interpretive Summary: Slow stomach emptying (gastroparesis) often causes multiple severe symptoms including belly pain, vomiting, loss of appetite, and weight loss that affects children and adults and lasts for years. In the vast majority of cases, the cause of slow stomach emptying is unknown. We investigated whether we could identify a genetic cause of slow stomach emptying by evaluating the genes in a large group of individuals. We identified nine possible genes that might contribute to the development of slow stomach emptying. By carrying out a study in a larger group of individuals we will ultimately determine how important gene changes may be to the development of slow stomach emptying.

Technical Abstract: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction. Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed. We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene-set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls. While no SNP associations were detected at strict significance (p<= 5 x 10^-8), nine independent genomic loci were associated at suggestive significance (p<= 1 x 10^-5), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 x 10^-7) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein-coding candidate genes. Gene-set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR<= 0.05). The GP risk allele rs6984536A (Peroxidasin-Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls). We report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory-motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.