(270) Genome-wide association study meta-analysis of hyperemesis gravidarum confirms GDF15 and identifies additional risk loci

Hyperemesis Gravidarum (HG), occurs in ~2% of pregnancies and is associated with adverse maternal and fetal outcomes. It is highly heritable, thus elucidating genetic risk factors may lead to more effective treatments. Herein we report results from the largest ever genome-wide association study (GWAS) of HG, comprised of 7,417 cases and 359,870 controls.

Study Design:

We performed a meta-analysis of 5 independent studies: a multi-ancestry whole-exome sequencing study from the US and 4 GWASs of European ancestry from 23andMe customers, FinnGen, Estonian and UK Biobanks.

Results: We identified genome-wide significant (P < 5E^-8) variants at GDF15 (rs1058587, P= 8.93E^-19), IGFBP7 (rs9312688, P= 8.45E^-11), and PGR_TRPC6 (rs4754754, P= 1.13E^-8), replicating our previous studies of HG. These genes are activated during placentation, consistent with a putative role in HG risk. Using a relaxed P-value threshold of 5 × 10⁻⁶, other potential associations include SDK1, linked to motion sickness, chemotherapy nausea, and mutated in a family with HG, PTPRD, an orexigenic receptor linked to postoperative nausea, as well as the GDF15 co-receptor gene RET unique to the Estonian GWAS, and the thyroid stimulating hormone receptor gene TSHR unique to the Finnish GWAS.  

Conclusion:

Genetic loci in hCG and its receptor, were not associated with HG in any of the analyses, providing no support for the historical hypothesis that the pregnancy hormone is the cause. Overall, this study contributes to our understanding of the biology of nausea and vomiting in pregnancy and may lead to future research evaluating new treatment avenues. Of note, drugs targeting the GDF15 pathway have shown great promise in mitigating weight loss, loss of appetite, and vomiting in animal models and are currently in clinical trials in cancer cachexia, a disease with similar symptoms to HG. The strong link to this pathway in HG suggests these drugs, if safe, may hold great promise for treating HG in the future.