Nat Genet
Largest genetic study yet reveals biological drivers of severe pregnancy nausea
Clinical takeaway: Hyperemesis gravidarum is a biologically driven disease with a strong genetic basis. These findings support early diagnosis, validate patient symptoms, and point toward future mechanism‑based therapies beyond symptomatic treatment.
Nausea and vomiting affect most pregnancies, but hyperemesis gravidarum (HG) is a distinct and potentially life‑threatening condition marked by intractable vomiting, dehydration, and weight loss. Affecting about 2% of pregnancies, HG has historically been underrecognized and sometimes misattributed to psychological causes.
In the largest genetic study of HG to date, researchers analyzed genome‑wide data from 10,974 women with HG and 461,461 controls, spanning European, Asian, African, and Latino ancestries. The study identified 10 genome‑wide significant loci, including four previously known genes (GDF15, IGFBP7, PGR, GFRAL) and six novel associations involving appetite regulation, insulin signaling, and brain plasticity.
The strongest signal was linked to GDF15, a placental hormone that rises sharply during pregnancy and influences nausea and appetite. Prior work suggests symptom severity may depend on maternal sensitivity to GDF15 rather than hormone levels alone—helping explain why some women develop severe disease.
TCF7L2, one of the newly identified genes, drew particular interest because of its established role in type 2 and gestational diabetes. In this study, TCF7L2 was expressed in placental extravillous trophoblasts and is involved in incretin and insulin signaling, including GLP‑1 pathways that influence appetite and nausea—pointing to shared metabolic mechanisms in HG.
“Because this is the largest study of hyperemesis gravidarum ever conducted, we’ve been able to tease out important new details that were previously unknown,” said lead author Marlena Fejzo, PhD of the Center for Genetic Epidemiology at the USC Keck School of Medicine.
Current HG therapies—such as vitamin B6/doxylamine, antihistamines, dopamine antagonists, and ondansetron—often provide incomplete relief. By identifying biological drivers of disease, this study highlights new targets for drug development and repurposing, including hormonal desensitization, metabolic modulation, and neuro‑appetite signaling. These insights may ultimately shift HG care toward targeted, mechanism‑based prevention and treatment strategies.
Building on these findings, the research team has received approval to launch a clinical trial testing whether metformin, a widely used diabetes medication known to increase GDF15 levels, could reduce the risk or severity of HG when taken before pregnancy. The study will explore whether gradual hormonal exposure may desensitize patients at high risk.
Source: Fejzo M, et al. (2026, April 14). Nat Genet. Multi‑ancestry genome‑wide association study of severe pregnancy nausea and vomiting