Whole‐exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum

Objective A genome‐wide association study (GWAS) linked the placenta and appetite hormone gene GDF15 to hyperemesis gravidarum (HG). This paradigm‐changing finding has shifted the field away from the prevailing hypotheses, but more evidence is needed. This study was performed to identify coding variants in addition to the non‐coding variants implicated by GWAS. Setting Case–control research study performed in a university setting. Design Case–control study. Population Hyperemesis gravidarum cases requiring intravenous fluid treatment for disease ( n  = 926) and controls with normal or no nausea and vomiting of pregnancy ( n  = 660), from the USA. Methods Whole exome‐wide sequencing and genome informatics were performed using the standard Regeneron pipeline. All variants were compared between cases and controls using dominant, recessive, and allelic models to identify variants with exome‐wide significant p values ( p  < 10 −6 ). Odds ratios and associated p values were calculated for exome‐wide significant allele(s) in subgroups of genetically predicted ancestries. Variants were filtered to identify rare pathogenic variants occurring in ≥10 cases and in no controls. Main outcome measures Identification of exome‐wide significant and rare genetic variant(s) associated with HG. Results A common coding variant in GDF15 was the only exome‐wide significant association, and a rare coding variant in GDF15 was the only predicted disease‐causing variant occurring in 10 or more cases. Conclusions This study confirms the GWAS finding that GDF15 is the greatest genetic risk factor for HG. The new variants identified may have implications for prediction and diagnosis. The findings provide insight into the cause, and molecular mechanisms for developing therapeutics for HG. Tweetable abstract Whole‐exome sequencing reveals placenta and vomiting hormone GDF15 most likely cause of Hyperemesis Gravidarum.