Genetic Polymorphisms Associated with Adverse Pregnancy Outcomes in Nulliparas
Authors: Guerrero Rafael F. , Khan Raiyan R. , Wapner Ronald J. , Hahn Matthew W. , Raja Anita , Salleb-Aouissi Ansaf , Grobman William A. , Simhan Hyagriv , Silver Robert , Chung Judith H. , Reddy Uma M. , Radivojac Predrag , Pe’er Itsik , Haas David M. 
Published: March 2022

Background

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet, the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions.

Objective

To search for genetic risk markers for four APOs, we performed genome-wide association studies (GWAS) for preterm birth, preeclampsia, gestational diabetes, and pregnancy loss.

Study Design

A total of 9,757 nulliparas from the nuMoM2b study were genotyped. We clustered participants by their genetic ancestry and focused our analyses on the three sub-cohorts with the largest sample sizes: European (EUR, n=6,082), African (AFR, n=1,425), and American (AMR, n=846). Association tests were carried out separately for each sub-cohort and brought together via meta-analysis. Four APOs were tested by GWAS: preeclampsia (n=7,909), gestational length (n=4,781), gestational diabetes (n=7,617), and pregnancy loss (n=7,809). Using the results of the genome-wide associations for each APO, SNP-based heritability of these traits was inferred using LDscore. Putative regulatory effects were inferred by transcriptome-wide association analysis.

Results

Two variants were significantly associated with pregnancy loss (rs62021480: OR = 3.29, P = 7.83×10−11, and rs142795512: OR = 4.72, P = 9.64×10−9), implicating genes TRMU and RGMA in this APO. An intronic variant was significantly associated with gestational length (rs73842644: beta = -0.667, P = 4.9×10−8). Three loci were significantly associated with gestational diabetes (rs72956265: OR = 3.09, P = 2.98×10−8, rs10890563: OR = 1.88, P = 3.53×10−8, rs117689036: OR = 3.15, P = 1.46×10−8), located on or near ZBTB20, GUCY1A2, and MDGA2, respectively. Several loci previously correlated with preterm birth (in genes WNT4, EBF1, PER3, IL10, and ADCY5), gestational diabetes (in TCF7L2), and preeclampsia (in MTHFR) were found to be associated with these outcomes in our cohort as well.

Conclusion

Our study identified genetic associations with gestational diabetes, pregnancy loss, and gestational length. We also confirm correlations of several previously identified variants with these APOs.

Disclosure Statement

The authors declare no conflict of interest

Source of financial support

Precision Health Initiative of Indiana University, National Institutes of Health award R01HD101246 to DMH and PR. Cooperative agreement funding from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development: grant U10-HL119991 to RTI International; grant U10-HL119989 to Case Western Reserve University; grants U10-HL120034 and R01LM013327 to Columbia University; grant U10-HL119990 to Indiana University; grant U10-HL120006 to the University of Pittsburgh; grant U10-HL119992 to Northwestern University; grant U10-HL120019 to the University of California, Irvine; grant U10-HL119993 to University of Pennsylvania; and grant U10-HL120018 to the University of Utah. National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health to Clinical and Translational Science Institutes at Indiana University (grant UL1TR001108) and University of California, Irvine (grant UL1TR000153).