Researchers at the Keck School of Medicine of USC have identified nine additional genes associated with hyperemesis gravidarum (HG), the most severe form of pregnancy sickness, according to findings published in Nature Genetics. Six of the newly isolated genetic markers had never before been connected to the debilitating condition, marking a major leap forward in understanding the biological roots of extreme pregnancy nausea and vomiting that affects roughly 2% of expectant mothers.
Largest Genetic Study of HG Expands Biological Understanding
Led by Marlena Fejzo, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, the research team analyzed genomic data from 10,974 women with HG and 461,461 controls. According to the study, the cohort represented European, Asian, African, and Latino ancestries, making it the largest genetic investigation of the condition conducted to date.
“Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” Fejzo said, adding that studying women from multiple ancestry groups suggests the results are broadly generalizable.
GDF15 Remains the Strongest Genetic Link to Pregnancy Sickness
The investigation confirmed that the hormone-producing gene GDF15 remains the most powerful genetic association with hyperemesis gravidarum. Prior work by Fejzo and an international team established that the severity of pregnancy sickness depends partly on a woman’s pre-existing sensitivity to the GDF15 hormone. Women who encounter lower GDF15 exposure before pregnancy due to specific genetic mutations tend to experience more severe symptoms, whereas those with higher baseline exposure generally report less severe nausea and vomiting.
Did you know? GDF15 increases sharply during pregnancy, but a patient’s genetic baseline dictates how intensely their body reacts to the surge in hormone levels.
Aside from GDF15 and its receptor-producing partner GFRAL—alongside placental development regulators IGFBP7 and PGR—the study revealed six brand-new genetic associations: FSHB, TCF7L2, SLITRK1, SYN3, IGSF11, and CDH9.
TCF7L2 Gene and Potential Diabetes Drug Connections
Among the newly discovered markers, TCF7L2 stands out as one of the strongest known genetic risk factors for type 2 diabetes and has also been linked to gestational diabetes, according to the research team. The gene may influence glucagon-like peptide-1 (GLP-1), a gut hormone that regulates blood sugar while also modulating appetite and nausea.
“This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo noted regarding the TCF7L2 discovery.
Other newly mapped genes relate directly to pregnancy hormones, metabolism, brain adaptation, and insulin regulation. Researchers theorize that brain plasticity—the brain’s capacity to learn and adapt—may cause neural pathways to associate specific foods with sickness, potentially triggering the intense and persistent food aversions characteristic of severe HG.
Clinical Trials Look to Metformin for HG Prevention
Current pharmaceutical options like Zofran provide only partial symptom relief for about half of patients who take the medication. Armed with these expanded genetic insights, investigators hope to develop targeted treatments tailored to individual patient profiles.
Fejzo and her colleagues have already received approval to launch a clinical trial investigating metformin. Because the widely prescribed diabetes medication is known to raise GDF15 levels, researchers will test whether administering metformin before pregnancy can reduce patient sensitivity to the hormone, potentially preventing or lessening HG symptoms in women with a history of the condition.
Frequently Asked Questions
What is hyperemesis gravidarum (HG)?
HG is the most severe form of pregnancy sickness, characterized by extreme nausea and vomiting that makes eating and drinking extremely difficult. It affects approximately 2% of women and can lead to severe malnutrition.
How many genes are now linked to HG?
Researchers have identified 10 genes associated with the condition. Four were previously known, while six were newly discovered in the latest Keck School of Medicine of USC study.
What role does GDF15 play in pregnancy sickness?
GDF15 produces a hormone that spikes during pregnancy. A woman’s genetic sensitivity to this hormone—dictated by her exposure levels prior to pregnancy—directly influences the severity of her nausea and vomiting.
Are there new treatments being tested based on these findings?
Yes. Researchers have secured approval for a clinical trial testing metformin, a diabetes drug known to raise GDF15 levels, to see if pre-pregnancy administration can reduce symptom severity.
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