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

Abstract

Objective: A genome-wide association study (GWAS) linked the placenta and appetite hormone gene GDF15 to hyperemesis gravidarum (HG). This paradigmchanging 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 diseasecausing 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.

Demographic, Clinical, and Obstetrical Characterization of Women with Hyperemesis Gravidarum Using a More Restrictive Diagnosis

“…On the other hand, there does not appear to be any plausible evidence for hCG being associ-ated with HG [1,2,5]. We look forward to new evidence of a genetic involvement in HG [37]. Perhaps the most severe cases are related to alterations in gene sequences and the milder cases are not.…”

Whole‐exome sequencing and hyperemesis gravidarum: Is there a role of hCG?

“…Dear Dr. Papageorghiou, Thank you for your letter highlighting our study that implicates growth differentiation factor 15 (GDF15), and does not support a direct causal role for human chorionic gonadotropin (hCG), in hyperemesis gravidarum (HG). 1,2 Both GDF15 and hCG are expressed in blastocysts and increase in the first trimester, 2 so any association between the two hormones in early pregnancy is not surprising and does not imply that one controls the expression of the other. Although it is possible that hCG plays a secondary role contributing to GDF15 levels, it is unlikely to be important for HG for the following reasons.…”

Author’s reply

“…Dear Dr. Papageorghiou, Thank you for your letter highlighting our study that implicates growth differentiation factor 15 (GDF15), and does not support a direct causal role for human chorionic gonadotropin (hCG), in hyperemesis gravidarum (HG). 1,2 Both GDF15 and hCG are expressed in blastocysts and increase in the first trimester, 2 so any association between the two hormones in early pregnancy is not surprising and does not imply that one controls the expression of the other. Although it is possible that hCG plays a secondary role contributing to GDF15 levels, it is unlikely to be important for HG for the following reasons.…”