A major international study has uncovered several new genetic clues tied to hyperemesis gravidarum, a debilitating form of pregnancy sickness once widely misunderstood.
The USC team that recently identified the hormone-encoding gene GDF15 as a major driver of pregnancy sickness has now linked nine more genes to its most severe form, hyperemesis gravidarum (HG). Six of these genes had not been connected to the condition before.
HG affects about 2% of women and causes nausea and vomiting so intense that eating can become extremely difficult. For many years, the condition was poorly understood and often dismissed as psychological. Growing evidence now shows that HG has a strong biological and genetic foundation and can cause severe malnourishment, creating risks for both the mother and baby.
In the largest genetic study of HG so far, researchers from the Keck School of Medicine of USC and international collaborators examined data from 10,974 women with HG and 461,461 controls across European, Asian, African and Latino ancestries. The findings, published in Nature Genetics, provide new insight into the condition and may point toward better treatment options.
“Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” said Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, who led the present study and earlier research linking GDF15 to HG. “The fact that we’ve studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population.”
The researchers found 10 genes associated with HG, including four that were already known and six newly identified genes. The strongest association was with growth differentiation factor 15 (GDF15), a gene that produces a hormone with the same name and rises sharply during pregnancy. Earlier work by Fejzo and an international team showed that the connection involves women’s sensitivity to the hormone. Women exposed to lower levels of the hormone before pregnancy because of a mutation in the gene tend to have more severe symptoms, while women exposed to higher levels before pregnancy tend to experience less severe nausea and vomiting.
The other genes identified are connected to major pregnancy hormones, appetite and nausea, insulin and metabolism, the brain’s ability to learn and adapt, and certain pregnancy outcomes.
“Now that we’ve more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it,” Fejzo said.
The genetic basis of HG
The researchers carried out a genome-wide association study (GWAS), scanning the entire genome for genetic differences between women who developed HG during pregnancy and those who did not.
The four previously identified genes were GDF15; GFRAL, which produces the receptor for the GDF15 hormone; and IGFBP7 and PGR, both involved in placental development.
The six newly identified genes may offer additional clues about what causes HG or how it might be treated. They include FSHB, TCFL72, SLITRK1, SYN3, IGSF11, and CDH9.
TCF7L2 is especially notable because it is one of the strongest known genetic risk factors for type 2 diabetes and is also linked to gestational diabetes. It may affect glucagon-like peptide-1 (GLP-1), a gut hormone that helps regulate blood sugar and can also influence appetite and nausea.
“This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo said.
Several of the other identified genes are involved in appetite, nausea, and brain plasticity, which is the brain’s ability to learn and adapt to new information. Fejzo suggests that the brain may learn to connect certain foods with sickness, causing strong and lasting food aversions during pregnancy. More research is needed to investigate that possibility.
The researchers also found that some HG-linked genes were associated with other pregnancy outcomes, including shorter pregnancy length and preeclampsia, a serious blood pressure condition.
Treating pregnancy sickness
Several drugs are available to treat HG, but even Zofran, one of the most effective options, only partly relieves symptoms in about half of patients. The new findings reveal possible treatment targets and may eventually help doctors match existing medicines to patients based on their genetic profiles.
Fejzo and her team have just received approval to begin a clinical trial of metformin, a widely used diabetes drug that raises GDF15 levels. The study will test whether taking metformin before pregnancy can desensitize women to the hormone, potentially reducing nausea and vomiting or preventing HGObstetrics in women who have previously had the condition.
Reference: “Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting” by Marlena Fejzo, Xinran Wang, Qing Tan, Julia Zöllner, Natàlia Pujol-Gualdo, Triin Laisk, Estonian Biobank Research Team, Sarah Finer, David A. van Heel, Genes & Health Research Team, Ben Brumpton, Laxmi Bhatta, Kristian Hveem, Elizabeth A. Jasper, Digna R. Velez Edwards, Jacklyn N. Hellwege, Todd Edwards, Gail P. Jarvik, Yuan Luo, Atlas Khan, Kimber MacGibbon, Yuan Gao, Gaoxiang Ge, Inna Averbukh, Erin Soon, Michael Angelo, Per Magnus, Stefan Johansson, Pål R. Njølstad, Artem Kim, Steven Gazal, Marc Vaudel, Chang April Shu and Nicholas Mancuso, 14 April 2026, Nature Genetics.
DOI: 10.1038/s41588-026-02564-4
This work was supported by federal and private agencies across the world, including the National Institutes of Health, under grants R01HG012133, R01CA258808, R01GM140287 and U54HG013243.
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