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Genetic factors related to pregnancy-related traits are understudied, especially in ancestrally diverse cohorts. To assess maternal contributions to hypertensive disorders of pregnancy (HDP), we performed a multi-ancestry genome-wide association study (GWAS) of HDP in data from the North Carolina-based Personalized Environment and Genes Study (PEGS) cohort with validation in the UK Biobank (UKBB). The GWAS revealed two maternal loci associated with HDP at the genome-wide significance level. The lead independent variants were rs114954125 on chromosome 2 (near LRP1B; odds ratio [OR] [95% confidence interval {CI}]): 2.96 [2.02-4.34]; p = 2.82 × 10 -8 ) and rs61176331 on chromosome 3 (on RARB; OR (95% CI): 3.08 (2.12-4.48); p = 3.52 × 10 -9 ). We validated the associations near RARB with a meta-analysis of PEGS and the UKBB. We also identified cis-expression quantitative trait loci in the candidate region associated with decreased RARB expression in macrophage cells exposed to Salmonella. Chromatin mapping in FUMA identified a significant interaction within chromosome 3's enhancer and open chromatin regions, with strong effects observed for RARB and H3P10 gene regulation in mesendoderm cells, mesenchymal stem cells, and trophoblast-like stem cells. We applied existing polygenic scores (PGS) for preeclampsia and gestational hypertension and found that the scores were significantly associated with HDP in PEGS. The findings demonstrate the power of multi-ancestry studies for genetic discovery and highlight the relationship between immune response, regulation, and HDP and the utility of PGS for risk prediction. (PEGS is registered at ClinicalTrials.gov: NCT00341237.)., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Introduction: We investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications., Methods: We conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial ( N = 7,913) using linear regression and additive genotype encoding on variants with minor allele frequency greater than 3%. We conducted replication analyses of top findings in the Atherosclerosis Risk in Communities (ARIC) study with inverse variance-weighted meta-analysis. We followed up with stratified GWAS analyses by sex and self-reported race., Results: In ACCORD, we identified single nucleotide polymorphisms (SNPs) associated with HGI, including a peak with the strongest association at the intergenic SNP rs73407935 (7q11.22) ( P = 5.8e-10) with a local replication in ARIC. In black individuals, the variant rs10739419 on chromosome 9 in the Whirlin ( WHRN ) gene formally replicated (meta- P = 2.2e-9). The SNP-based heritability of HGI was 0.39 ( P < 1e-10). HGI had significant sex-specific associations with SNPs in or near GALNT11 in women and HECW2 in men. Finally, in Hispanic participants, we observed genome-wide significant associations with variants near USF1 and NXNL2/SPIN1 ., Discussion: Many HGI-associated SNPs were distinct from those associated with fasting plasma glucose or HbA1c, lending further support for HGI as a distinct biomarker of diabetes complications. The results of this first evaluation of the genetic etiology of HGI indicate that it is highly heritable and point to heterogeneity by sex and race., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 House, Breeyear, Akhtari, Evans, Buse, Hempe, Doria, Mychaleckyi, Fonseca, Shi, Li, Liu, Kelly, Rotroff and Motsinger-Reif.)