Multi-ancestry GWAS of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity.

While most pregnancies are affected by nausea and vomiting, hyperemesis gravidarum (HG) is at the severe end of the clinical spectrum and is associated with dehydration, undernutrition, and adverse maternal, fetal, and child outcomes. Herein we performed a multi-ancestry genome-wide association study (GWAS) of severe nausea and vomiting of pregnancy of 10,974 cases and 461,461 controls across European, Asian, African, and Latino ancestries. We identified ten significantly associated loci, of which six were novel (, , , , , and , and confirmed previous genome-wide significant associations with risk genes , , , and . In a spatiotemporal analysis of placental development, and were expressed primarily in extra villous trophoblast, and using a weighted linear model of maternal, paternal, and fetal effects, we confirmed opposing effects for between maternal and fetal genotype. Conversely, and were primarily expressed in developing maternal spiral arteries during placentation, with effects limited to the maternal genome. Risk loci were found to be under significant evolutionary selection, with the strongest effects on nausea and vomiting mid-pregnancy. Selected loci were associated with abnormal pregnancy weight gain, pregnancy duration, birth weight, head circumference, and pre-eclampsia. Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide new pathways to explore etiological mechanisms and novel therapeutic avenues.