The most debilitating form of pregnancy sickness can threaten the lives of expectant mothers through relentless nausea, dehydration and weight loss. A new genetic investigation now offers clearer insight into why some women endure this condition while others do not.
Researchers from the Keck School of Medicine of USC and their international collaborators have completed the largest study of hyperemesis gravidarum to date. Their multi-ancestry genome-wide association analysis, published in Nature Genetics, examined DNA from 10,974 affected women and 461,461 controls spanning European, Asian, African and Latino backgrounds.
The work identified ten genetic associations in total. Four had been known before: GDF15, IGFBP7, PGR and GFRAL. Six new loci emerged from the data: SLITRK1, SYN3, IGSF11, FSHB, TCF7L2 and CDH9.
Biological pathways come into focus
Further examination revealed where and how these genes operate. Expression of GDF15 and TCF7L2 occurs mainly in extravillous trophoblasts, the cells that anchor the placenta. Their effects differ depending on whether the variant comes from the mother or the fetus. In contrast, IGFBP7 and PGR act primarily in the mother's spiral arteries, with influence limited to her own genome.
Selected loci also correlated with practical pregnancy outcomes such as abnormal weight gain, duration of pregnancy, birth weight and pre-eclampsia. Additional functional work pointed to antisense IGFBP7-AS1 and the protein ACP1.
The candidate genes cluster around pathways that regulate appetite, insulin signalling and brain plasticity. These connections ground the condition in verifiable biological processes rather than earlier assumptions about psychological origins.
