A multi-ancestry genome-wide association study identifies novel candidate loci in the RARB gene 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; R2=0.7%) compared to the PE PGS (AUC: 0.53; R2=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][1] Identifier for PEGS: [NCT00341237][2] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The Clinical Trials Identifier for the Personalized Environment and Genes Study (PEGS is [NCT00341237][2]. ### Funding Statement This study was supported by the National Institutes of Health Intramural Research Program and the NIH-Oxford-Cambridge Scholars program. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Internal Review Board of the National Institute for Environmental Health Sciences. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in this study are available to researchers through application to dbGAP 152 the UK Biobank (). Reference panel data 153 from the 1000 Genomes Project and polygenic scores from the PGS Catalog are 154 publicly available. The summary statistics that support the study findings are available from the corresponding author upon reasonable request. * AFR : African ancestry AMR : Admixed American ancestry EAF : Effect allele frequency EAS : East Asian ancestry EUR : European ancestry GH : Gestational hypertension GWAS : Genome-wide association study HDP : Hypertensive disorders of pregnancy KEGG : Kyoto Encyclopedia of Genes and Genomes MAC : Minor allele count MIM : Mendelian Inheritance in Man PCA : Principal components analysis PE : Preeclampsia PEGS : Personalized Environment and Genes Study PGS : Polygenic score SAS : South Asian ancestry SNP : Single nucleotide polymorphism SNV : Single nucleotide variant UKBB : UK Biobank [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00341237&atom=%2Fmedrxiv%2Fearly%2F2023%2F11%2F01%2F2023.10.30.23297806.atom