Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting

Most pregnancies are affected by nausea and vomiting, but the most severe form-hyperemesis gravidarum-can be life threatening. Here we performed a multi-ancestry genome-wide association study of hyperemesis gravidarum in 10,974 cases and 461,461 controls across European, Asian, African and Latino ancestries. We identified ten associations: four identified previously (GDF15, IGFBP7, PGR and GFRAL) and six additional loci (SLITRK1, SYN3, IGSF11, FSHB, TCF7L2 and CDH9). Downstream analyses revealed GDF15 and TCF7L2 expression primarily in extravillous trophoblasts, with opposing effects for GDF15 between maternal and fetal genotype. Conversely, IGFBP7 and PGR were expressed primarily in maternal spiral arteries, with effects limited to the maternal genome. Selected loci were associated with abnormal pregnancy weight gain, duration, birth weight and pre-eclampsia. Functional studies identified additional associations including antisense IGFBP7-AS1 and protein ACP1. Potential roles for candidate genes in appetite, insulin signaling and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.