Aggregation of Genome-Wide Association Data from FinnGen and UK Biobank Replicates Multiple Risk Loci for Pregnancy Complications

Abstract

Complications endangering mother or fetus affect around one in seven pregnant women. Investigation of the genetic susceptibility to such diseases is of high importance for better understanding of the disease biology as well as for prediction of individual risk. In this study, we collected and analyzed GWAS summary statistics from the FinnGen cohort and UK Biobank for 24 pregnancy complications. In FinnGen, we identified 11 loci associated with pregnancy hypertension, excessive vomiting, and gestational diabetes. When UK Biobank and FinnGen data were combined, we discovered six loci reaching genome-wide significance in the meta-analysis. These include rs35954793 in FGF5 (p=6.1×10−9), rs10882398 in PLCE1 (p=8.9×10−9), and rs167479 in RGL3 (p=5.2×10−9) for pregnancy hypertension, rs10830963 in MTNR1B (p=4.5×10−41) and rs36090025 in TCF7L2 (p=3.4×10−15) for gestational diabetes, and rs2963457 in the EBF1 locus (p=6.5×10−9) for preterm birth. In addition to the identified genome-wide associations, we also replicated 14 out of 40 previously reported GWAS markers for pregnancy complications, including four more preeclampsia-related variants. Finally, annotation of the GWAS results identified a causal relationship between gene expression in the cervix and gestational hypertension, as well as both known and previously uncharacterized genetic correlations between pregnancy complications and other traits. These results suggest new prospects for research into the etiology and pathogenesis of pregnancy complications, as well as early risk prediction for these disorders.

2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association

“…MTHRF , FGF5 , and ZNF831 were previously linked to pregnancy complications, whereas PLCE1 , RGL3 , and PREX1 were novel. 48…”

“…All maternal loci are known to affect type 2 diabetes. 48 Similarly, in a multiethnic GWAS of n=5485 females with gestational diabetes and n=347 856 females without gestational diabetes that also included UK Biobank participants, 5 gestational diabetes loci were identified: MTNR11-1B , TCF7L2 , CDKAL1 , CDKN2A/2B , and HKDC1 . HKDC1 was the only locus without evidence pointing to a shared pathophysiology between gestational diabetes and type 2 diabetes.…”

Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study

“…Fejzo et al identified the association between loci related to GDF15 and IGFBP7 (placentation, appetite, and cachexia genes) and HG in European ancestry populations [ 5 ]. Changalidis et al also identified the association between GDF15 -related loci and excessive vomiting in pregnancy in European ancestry populations [ 6 ]. Furthermore, the GWAS meta-analysis of European and Asian ancestry populations, including British Bangladeshis and Pakistanis, revealed the association between the GDF15 -related locus and HG [ 7 ].…”

Genetic studies of gestational diabetes mellitus in 21,813 Chinese women

“…The first one was published in 2012, which recruited 1,710 Korean pregnant women and identified two genome-wide significant loci ( MTNR1B and CDKAL1 ) 12 . The other studies were issued in recent years, including one Chinses study 13 , two European studies 14,15 , a mixed of multiple populations 16 , and European population with FinnGen and UK Biobank participants 17 . Neither the Chinese study or the two European studies uncovered genome-wide significant variants.…”