Genes behind severe pregnancy nausea

Pregnancy nausea is common, but the most severe form now looks increasingly tied to inherited biology, not just chance or stress. (nature.com) In a paper published April 14 in *Nature Genetics*, researchers analyzed genetic data from 10,974 women with hyperemesis gravidarum and 461,461 controls across European, Asian, African and Latino ancestries. They found 10 genome-wide significant signals, including six not previously linked to the condition. (nature.com) Hyperemesis gravidarum is the severe end of pregnancy nausea and vomiting: it can cause dehydration, weight loss and hospital treatment, and it affects roughly 1% to 3% of pregnancies. Clinical guidance distinguishes it from more typical “morning sickness,” which often improves earlier and does not usually lead to the same level of nutritional or fluid loss. (nhs.uk; guysandstthomas.nhs.uk) The strongest genetic signal in the new study again pointed to GDF15, a hormone made during pregnancy that acts on a nausea-sensing pathway in the brainstem through the receptor GFRAL. Four previously reported loci — GDF15, IGFBP7, PGR and GFRAL — were confirmed in the larger analysis. (nature.com; pmc.ncbi.nlm.nih.gov) The six newly reported loci were near SLITRK1, SYN3, IGSF11, FSHB, TCF7L2 and CDH9. The authors linked those signals to appetite, insulin signaling, metabolism, brain plasticity and pregnancy hormones rather than to a single isolated cause. (nature.com) A genome-wide association study works like a large comparison of DNA spelling differences between people with and without a condition. In this case, the comparison suggests that susceptibility to severe pregnancy nausea is spread across several biological systems that become especially relevant during pregnancy. (nature.com) The paper also looked at where some of these genes are active in the placenta. It found that GDF15 and TCF7L2 were expressed mainly in extravillous trophoblasts — placental cells that help anchor the placenta and remodel blood vessels early in pregnancy — while IGFBP7 and PGR were concentrated in maternal spiral arteries. (nature.com) One of the more unusual findings involved whose genes were acting. The authors reported opposing effects for GDF15 from maternal and fetal genotype, adding to 2023 evidence that much of the GDF15 in a pregnant woman’s blood comes from the feto-placental unit and that prepregnancy exposure may shape later sensitivity to the hormone. (nature.com; pmc.ncbi.nlm.nih.gov) The broader shift started before this paper. A 2023 *Nature* study tied higher circulating GDF15 in pregnancy to vomiting and hyperemesis gravidarum, and found that women with chronically higher GDF15 exposure before pregnancy reported less nausea and vomiting, pointing to a sensitivity model rather than a purely hormone-level model. (pmc.ncbi.nlm.nih.gov) Researchers said the larger gene map could help sort patients by mechanism and guide treatment studies. The University of Southern California team said this week it has approval to launch a clinical trial testing metformin before pregnancy, based on prior work suggesting the drug raises GDF15 levels and might reduce later sensitivity in women with a history of hyperemesis gravidarum. (keck.usc.edu) For patients who have been told severe pregnancy sickness is just part of pregnancy, the evidence base now points somewhere more specific: a condition with measurable genetic signals, a defined hormone pathway and several new targets for follow-up. (nature.com; pmc.ncbi.nlm.nih.gov)