Genetic breakthrough reveals hidden causes of severe morning sickness in pregnancy

A large-scale genetic study has identified nine additional genes linked to hyperemesis gravidarum (HG), a severe form of morning sickness affecting 2% of women. The research, which analyzed data from over 470,000 women, confirms the hormone GDF15 as the main contributor and reveals new biological pathways. These findings could lead to new treatments, with a clinical trial planned for the drug metformin to prevent HG.

Hyperemesis gravidarum characteristics

• ▪HG causes extreme nausea and vomiting that can lead to severe malnutrition, threatening the health of both the mother and baby.
• ▪Hyperemesis gravidarum (HG) is a severe form of pregnancy sickness that affects about 2% of women.
• ▪For years, hyperemesis gravidarum was poorly understood and sometimes dismissed as a psychological problem, but evidence now shows it has strong biological roots.
• ▪Some genes related to HG have also been linked to other pregnancy outcomes, including shorter pregnancy length and preeclampsia.

Genetic study methodology

• ▪The study, led by Marlena Fejzo of USC's Keck School of Medicine, included participants of European, Asian, African, and Latino ancestries.
• ▪Researchers conducted a genome-wide association study analyzing data from 10,974 women with hyperemesis gravidarum and 461,461 controls.

GDF15 hormone connection

• ▪Women with a genetic mutation causing lower GDF15 exposure before pregnancy tend to experience more severe symptoms of hyperemesis gravidarum.
• ▪The gene GDF15, which produces a hormone that increases sharply during pregnancy, has the strongest genetic association with hyperemesis gravidarum.
• ▪The severity of pregnancy sickness is partly dependent on a woman's sensitivity to the GDF15 hormone.

Newly identified genes

• ▪A recent study uncovered nine additional genes associated with hyperemesis gravidarum (HG), six of which were newly discovered.
• ▪Previously identified genes associated with HG include GDF15, GFRAL, IGFBP7, and PGR.
• ▪The six newly identified genes linked to HG are FSHB, TCF7L2, SLITRK1, SYN3, IGSF11 and CDH9.
• ▪The newly identified gene TCF7L2 is a known strong genetic risk factor for type 2 diabetes and has also been linked to gestational diabetes.

Treatment implications

• ▪Researchers have received approval for a clinical trial to test if taking the diabetes drug metformin before pregnancy can prevent or reduce HG symptoms.
• ▪The new genetic findings may reveal additional drug targets and help doctors select treatments based on a patient's genetic profile.
• ▪The metformin trial will investigate whether the drug can reduce sensitivity to the GDF15 hormone by raising its levels before pregnancy.
• ▪Current HG medications, such as Zofran, provide only partial symptom relief for about half of the patients who take them.

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