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.