Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2)

•Whole-exome sequencing in Hyperemesis Gravidarum (HG) identifies link to RYR2.•Novel variant L3277R segregates with disease in large HG family.•US genotyping, and Norwegian and Australian GWAS support link to G1886S in RYR2.•RYR2 deletion identified in severe case treated with total parenteral nutrition.•Common variants rs790899 and rs1891246 significantly associated with weight loss.

Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.