Maternal and offspring genome-wide association study of C-reactive protein reveals limited polygenic association with gestational diabetes mellitus

Abstract

BackgroundC-reactive protein (CRP) is a well-established biomarker of systemic inflammation. In pregnancy, several studies show association of elevated CRP with gestational diabetes mellitus (GDM). However, the genetic contributions of CRP levels during early pregnancy and their potential association with GDM remain largely understudied. MethodsWe conducted maternal and offspring genome-wide association studies (GWAS) of first-trimester CRP levels in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) cohort. Genetic correlation between CRP and GDM was assessed using linkage disequilibrium score regression (LDSC), and polygenic risk scores (PRS) of CRP were further evaluated for associations with GDM. ResultsIn the European maternal sub-cohort of nuMoM2b, three genome-wide significant loci (CRP, LEPR, and HNF1A) were associated with early pregnancy CRP, consistent with previous GWAS. Multi-ancestry maternal GWAS revealed two additional associated loci (ENSG00000257703 and APOC1). Offspring GWAS did not identify any genome-wide significant associations. LDSC using the nuMoM2b European maternal CRP GWAS showed no significant genetic correlation with GDM. In contrast, a significant correlation was observed using the large population-based CRP GWAS, suggesting context-specific genetic architecture. However, PRS of CRP, based on GWAS summary statistics from either study, was not significantly associated with GDM risk in the nuMoM2b cohort. ConclusionsOur findings validate known genetic loci regulating systematic inflammation in a cohort of pregnant individuals, correlating with serum CRP levels, and highlight the value of pregnancy-specific GWAS in uncovering unique biological pathways relevant to maternal-fetal health. Author summaryInflammation plays an important role in pregnancy and has been linked to conditions like gestational diabetes. C-reactive protein (CRP) is a widely used marker of inflammation, but how the genetic makeup of pregnant individuals and their offspring influence maternal CRP levels during early pregnancy is not well understood. We studied the genetic factors affecting CRP levels in over 4,000 pregnant women and 2,000 babies from a large, multi-ancestry U.S. pregnancy study. We found that genes linked to inflammation in the general population, such as CRP, LEPR, HNF1A, APOE, and APOC1 previously, also influence maternal CRP levels during early pregnancy. While CRP levels have been linked to gestational diabetes, we found no strong genetic connection between CRP and GDM. Our study provides important new insight into how genes influence inflammation during pregnancy and offers a foundation for future research in maternal and child health.