Largest Genetic Study Reveals New Biological Clues for Severe Pregnancy Sickness

The USC research team that recently identified the hormone-encoding gene GDF15 as a key driver of pregnancy sickness has identified 9 additional genes linked to its most severe form, hyperemesis gravidarum (HG). Six of these genes had not been previously linked to the condition. 

HG, which affects about 2% of women, causes nausea and vomiting so severe that eating can become extremely difficult. The condition was long misunderstood and often dismissed as psychological. But growing evidence shows it has a strong biological and genetic basis and can lead to severe malnourishment, putting both mother and baby at risk.

In the largest genetic study of HG to date, researchers from the Keck School of Medicine of USC and their international collaborators analyzed data from 10,974 women with the condition and 461,461 controls across European, Asian, African and Latino ancestries. The findings, just published in Nature Genetics, offer new clues about the condition and new hope for those affected.

"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 identified 10 genes linked to HG-four previously identified and six new. The strongest link by far was to growth differentiation factor 15 (GDF15), a gene that produces a hormone of the same name, which rises sharply during pregnancy. Earlier research by Fejzo and an international team showed that the link lies in women's sensitivity to the hormone: Women exposed to lower levels of the hormone before pregnancy because of a mutation in the gene experience more severe symptoms, while women exposed to higher levels of the hormone before pregnancy have less severe nausea and vomiting symptoms.

The other genes identified relate to key pregnancy hormones, appetite and nausea, insulin and metabolism, how the brain learns and adapts, 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." 

Marlena Fejzo, PhD, clinical assistant professor of population and public health sciences, Center for Genetic Epidemiology, Keck School of Medicine

The Genetic Basis of HG

The researchers conducted a genome-wide association study (GWAS), scanning the entire genome for differences between women who developed HG during pregnancy and those who did not.

The four genes previously identified were GDF15; GFRAL, which produces the receptor for the GDF15 hormone; and IGFBP7 and PGR, both of which are involved in development of the placenta.

The six newly identified genes offer further clues that might help explain the basis of HG or point to new ways of treating it. They include FSHB, TCFL72 SLITRK1, SYN3, IGSF11 and CDH9.

TCF7L2 stands out because it is one of the strongest genetic risk factors for type 2 diabetes and is also associated with gestational diabetes. It may influence glucagon-like peptide-1 (GLP-1), a gut hormone that controls blood sugar and can 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 genes identified are involved in appetite and nausea, as well as brain plasticity, or how the brain learns and adapts to new information. Fejzo suggests the brain may learn to associate certain foods with feeling sick, leading to strong, lasting aversions during pregnancy. More research is needed to explore this possibility.

The researchers also found that some genes linked to HG were associated with other pregnancy outcomes, including shorter pregnancy length and preeclampsia, a serious blood pressure condition. 

Treating Pregnancy Sickness

Several medications are available for treating HG, but even the most effective, Zofran, only partly relieves symptoms for about half of patients. The findings reveal new potential treatment targets and could possibly also help match existing medications to patients based on their genetic profiles.

Fejzo and her team just received approval to launch a clinical trial of metformin, a widely used diabetes medicine that increases GDF15 levels. The study will test whether taking metformin before pregnancy can desensitize women to the hormone, potentially reducing nausea and vomiting or preventing HG in women who have had it before.