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.