Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for hyperemesis gravidarum.

Abstract

Background: Hyperemesis gravidarum (HG), excessive vomiting in pregnancy, occurs in 0.3-10.8% of pregnancies and is associated with maternal and fetal morbidity. Despite the existence of several off-label treatment options that have shown clinical effectiveness in managing HG symptoms, the variability in treatment response highlights the need for more effective therapies. Our study aims to identify novel therapeutic targets that could lead to the development of additional, more effective treatment options.

Methods: A two-sample Mendelian randomization (MR) analysis was performed to estimate the causal effects of blood-druggable genes on HG. Summary statistics for HG were obtained from the FinnGen study and UK Biobank. Cis-expression quantitative trait loci (cis-eQTL) for blood druggable genes were obtained from the eQTLGen Consortium and used as genetic instrumental variables. Another MR method, summary level mendelian randomization (SMR), was used to further confirm our results. We also used eQTL data of other vomiting-related tissues, brain regions, and esophagus, to validate our MR results. Finally, the potential side effects of the druggable genes for HG treatment were assessed using a phenome-wide MR.

Results: Overall, 2499 unique druggable genes were gathered. Two blood drug targets (OVGP1 and LGALS1) showed significant MR results in two independent datasets. No significant heterogeneity of instrumental variables or pleiotropy was detected. In addition, SMR analysis further confirmed the significance of these two prior druggable genes in the brain and esophagus tissues. Further phenome-wide MR analysis revealed no association between genetic proxies of OVGP1, and LGALS1 has been detected in increasing the risk of adverse pregnancy outcomes and other common diseases.

Conclusions: This study provides genetic evidence that targeting two druggable genes for HG has potential therapeutic advantages. This information is of considerable value in guiding and prioritizing the development of more effective therapies for HG.