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

Abstract Background C-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. The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) provides a unique opportunity to investigate these questions due to its rich design, including early pregnancy biospecimens, genome-wide genotype data, and detailed clinical outcomes across multiple ancestry groups. Results We performed genome-wide association studies (GWAS) of first-trimester CRP levels using maternal ( n = 4,326) and offspring ( n = 2,140) genotypes from the nuMoM2b cohort. In the European-ancestry maternal sub-cohort of nuMoM2b, three genome-wide significant loci ( CRP , LEPR , and HNF1A ) were associated with early pregnancy CRP levels, consistent with findings from previous GWAS in non-pregnant populations. Analysis of the full multi-ancestry maternal cohort identified two additional loci ( ENSG00000257703 and APOC1 ) associated with CRP levels. No genome-wide significant associations were detected in the offspring GWAS of CRP levels. Linkage disequilibrium score regression did not detect a significant genetic correlation between CRP and GDM using the nuMoM2b CRP GWAS. In contrast, a significant correlation was observed when using an external large population-based CRP GWAS, suggesting that genetic overlap between CRP and GDM may vary across study contexts. However, Polygenic risk scores for CRP derived from either GWAS source were not significantly associated with GDM risk in the nuMoM2b cohort. Conclusions These findings provide insights into the genetic architecture of CRP levels during early pregnancy and illustrate the potential value of pregnancy-specific genomic studies for improving understanding of inflammatory processes relevant to maternal-fetal health. They also highlight the need for larger pregnancy cohorts to better understand the relationship between inflammation and metabolic complications during pregnancy.