Researchers at the University of Southern California have identified nine additional genes linked to hyperemesis gravidarum, the most severe form of pregnancy sickness, more than doubling the known genetic drivers of a condition that affects approximately 2% of pregnant women. The findings, published in Nature Genetics, stem from the largest genetic study of the condition to date, analyzing data from 10,974 women with hyperemesis gravidarum and 461,461 controls across European, Asian, African, and Latino ancestries.
Gene Discovery Doubles Known Risk Factors for Pregnancy Sickness
Hyperemesis gravidarum causes nausea and vomiting so extreme that eating becomes difficult, frequently leading to severe malnourishment and health risks for both mother and child. Historically, the condition was often dismissed as psychological. However, the new genome-wide association study led by the Keck School of Medicine of USC confirms a distinct biological basis by isolating 10 associated genes—four previously identified and six entirely new.
The previously identified genes include GDF15, GFRAL, IGFBP7, and PGR. The six newly uncovered genes are FSHB, TCFL72, SLITRK1, SYN3, IGSF11, and CDH9. Among the new findings, TCF7L2 stands out as a major genetic risk factor for type 2 diabetes and gestational diabetes, potentially influencing glucagon-like peptide-1, a gut hormone that regulates blood sugar, appetite, and nausea.
Low Hormone Exposure Increases Symptom Severity
The strongest genetic association remains with GDF15, a gene that encodes a hormone of the same name which spikes during pregnancy. According to Marlena Fejzo, 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 research, the severity of symptoms depends heavily on pre-pregnancy hormone exposure. Women exposed to lower levels of GDF15 prior to pregnancy due to gene mutations experience more severe symptoms, whereas those exposed to higher baseline levels suffer less intense nausea and vomiting.
Additional genes identified in the study govern key pregnancy hormones, insulin, metabolism, and brain plasticity. Researchers suggest that brain plasticity—how the brain learns and adapts—may explain why patients develop strong, lasting aversions by associating specific foods with feeling sick. Certain genes linked to the condition also correlated with shortened pregnancy length and preeclampsia.
Clinical Trials Target Genetic Pathways
Current treatments, such as the medication Zofran, only partially relieve symptoms for about half of patients. The newly mapped genetic pathways open pathways for potential targeted therapies and personalized medicine based on individual genetic profiles.
Fejzo and her team have received approval to launch a clinical trial testing metformin, a diabetes medication known to increase GDF15 levels. The trial will evaluate whether administering metformin prior to pregnancy can desensitize women to the hormone, potentially preventing or reducing hyperemesis gravidarum in patients with a history of the condition.
Frequently Asked Questions About Hyperemesis Gravidarum Genetics
What ancestry groups were included in the USC genetic study?
Researchers analyzed data from 10,974 women with hyperemesis gravidarum and 461,461 controls across European, Asian, African, and Latino ancestries, ensuring the results are generalizable across a broad population.
Which gene has the strongest association with severe pregnancy sickness?
Growth differentiation factor 15, or GDF15, displays the strongest genetic link to hyperemesis gravidarum by producing a hormone that surges sharply during pregnancy.
How many total genes are now linked to the condition?
The study identified 10 genes associated with hyperemesis gravidarum, consisting of four previously known genes and six newly discovered ones.