Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum

Olga V Sazonova,J Fah Sathirapongsasuti,Nicholas Mancuso,Frederic P Schoenberg,Dennis J Slamon,Marlena S Fejzo,Vladimir Vacic,Kimber W Macgibbon,Ingileif B Hallgrímsdóttir,Patrick M Mullin

doi:10.1038/s41467-018-03258-0

Abstract

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10−8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.

Highlights

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity
A total of 1306 research participants reporting that they received intravenous fluid (IV) therapy for Nausea and vomiting of pregnancy (NVP) were classified as HG cases, and 15,756 participants who reported no NVP served as controls
Manhattan and quantile–quantile plots are shown in Fig. 1a and Supplementary Fig. 1a, respectively, and single-nucleotide polymorphisms (SNPs)-level QC information is shown in Supplementary Table 1b

Summary

Introduction

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. We conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease. The severity of the disease has been well documented, for instance with the death of author Charlotte Brontë[5] To this day, HG remains the second leading cause of hospitalization during pregnancy[6]. We report a genome-wide association study (GWAS) aimed at identifying variants that influence the risk of HG. The key findings were replicated in two independent populations of women with clinically defined HG

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