A multi-ancestry genome-wide association study identifies novel candidate loci in theRARBgene associated with hypertensive disorders of pregnancy

Background Genetic factors related to pregnancy-related traits are understudied, especially among ancestrally diverse cohorts. This study assessed maternal contributions to hypertensive disorders of pregnancy (HDP) in multi-ancestry cohorts. Methods We performed a genome-wide association study of HDP using data from the Personalized Environment and Genes Study (PEGS) cohort (USA) with validation in the UK Biobank (UKBB). We performed gene-level and gene-set analyses and tested the association of polygenic scores (PGS) for systolic blood pressure (SBP), preeclampsia (PE), and gestational hypertension (GH). Results We identified two novel maternal genome-wide significant associations with HDP. The lead independent variants were rs114954125 on chromosome 2 (near LRP1B; OR (95% CI): 3.03 (2.05, 4.49); P =3.19 − 10 −8 ) and rs61176331 on chromosome 3 (near RARB; OR (95% CI): 3.09 (2.11, 4.53); P =7.97×10 −9 ). We validated rs61176331 in the UKBB ( P= 3.73 − 10 −2 ). When aggregating SNPs by genes, RARB ( P= 1.36 − 10 −3 ) and RN7SL283P ( P= 2.56 − 10 −2 ) were associated with HDP. Inflammatory and immunological biological pathways were most strongly related to HDP-associated genes. While all blood pressure and HDP-related PGS were significantly associated with HDP in PEGS, the SBP PGS was a stronger predictor of HDP (area under the curve (AUC): 0.57; R 2 =0.7%) compared to the PE PGS (AUC: 0.53; R 2 =0.2%). Conclusion Our study is the first to identify and validate maternal genetic variants near RARB associated with HDP. The findings demonstrate the power of multi-ancestry studies for genetic discovery and highlight the relationship between immune response and HDP and the utility of PGS for risk prediction. ClinicalTrials.gov Identifier for PEGS: NCT00341237