Genetic Study Identifies New Genes Linked to Severe Pregnancy Sickness

Researchers have identified nine new genes connected to hyperemesis gravidarum (HG), a severe pregnancy sickness characterized by intense nausea and vomiting that affects about 2% of pregnant women. This discovery builds on previous work linking the hormone-encoding gene GDF15 to the condition.

Expanded Genetic Links to Pregnancy Sickness

A team from the Keck School of Medicine of USC, collaborating internationally, analyzed genetic data from 10,974 women diagnosed with HG and 461,461 controls from diverse ancestries, including European, Asian, African, and Latino backgrounds. Their findings, published in Nature Genetics, reveal a total of 10 genes associated with HG—four previously known and six newly identified.

The strongest association remains with the gene GDF15, which produces a hormone that increases significantly during pregnancy. Earlier studies demonstrated that women’s sensitivity to this hormone influences the severity of their symptoms. Women with mutations causing lower hormone exposure before pregnancy tend to experience more severe nausea and vomiting, while those with higher pre-pregnancy levels have milder symptoms.

New Genetic Insights and Their Implications

The newly discovered genes include FSHB, TCF7L2, SLITRK1, SYN3, IGSF11, and CDH9. Notably, TCF7L2 is recognized as a major genetic risk factor for type 2 diabetes and is linked to gestational diabetes. It may influence glucagon-like peptide-1 (GLP-1), a gut hormone involved in blood sugar regulation, appetite, and nausea, although its role in pregnancy remains unclear.

Other identified genes relate to appetite regulation, nausea, and brain plasticity—the brain’s capacity to adapt and learn. Researchers propose that brain plasticity might contribute to persistent food aversions during pregnancy by associating certain foods with sickness, but further study is required to confirm this hypothesis.

Additionally, some HG-associated genes correlate with other pregnancy outcomes such as shorter gestation periods and preeclampsia, a serious hypertensive disorder.

Advancing Treatment Options for Hyperemesis Gravidarum

Current treatments for HG, including the drug Zofran, provide only partial symptom relief for approximately half of patients. The identification of new genetic targets offers potential pathways for improved therapies and personalized medicine approaches based on genetic profiles.

The research team recently received approval to initiate a clinical trial testing metformin, a diabetes medication known to increase GDF15 levels. The trial will evaluate whether administering metformin before pregnancy can reduce sensitivity to the hormone and thereby lessen nausea and vomiting or prevent HG in women with a history of the condition.

Study Details and Support

This genome-wide association study (GWAS) represents the largest genetic investigation of HG to date. The four genes previously linked to HG include GDF15; GFRAL, which encodes the receptor for the GDF15 hormone; and IGFBP7 and PGR, both involved in placental development.