Genomic Exploration of Essential Hypertension in African-Brazilian Quilombo Populations: A Comprehensive Approach With Pedigree Analysis and Family-Based Association Studies.

Abstract

Background: Essential hypertension (EH) is a global health issue. Despite extensive research, much of EH heritability remains unexplained. We investigated the genetic basis of EH in African-derived individuals from partially isolated quilombo populations in Vale do Ribeira (São Paulo, Brazil).

Methods and results: Samples from 431 individuals (167 affected, 261 unaffected, 3 unknown) were genotyped using a 650 000 single-nucleotide polymorphism array. Estimated global ancestry proportions were 47% African, 36% European, and 16% Native American. We constructed 6 pedigrees using additional data from 673 individuals and created 3 nonoverlapping single-nucleotide polymorphism subpanels. We phased haplotypes and performed local ancestry analysis to account for admixture. Genome-wide linkage analysis and fine-mapping via family-based association studies were conducted, prioritizing EH-associated genes through a systematic approach involving databases like PubMed, ClinVar, and GWAS (Genome-Wide Association Studies) Catalog. Linkage analysis identified 22 regions of interest with logarithm of the odds scores ranging from 1.45 to 3.03, encompassing 2363 genes. Fine-mapping (family-based association studies) identified 60 EH-related candidate genes and 117 suggestive/significant variants. Among these, 14 genes, including PHGDH, S100A10, MFN2, and RYR2, were strongly related to hypertension harboring 29 suggestive/significant single-nucleotide polymorphisms.

Conclusions: Through a complementary approach combining admixture-adjusted Genome-wide linkage analysis based on Markov chain Monte Carlo methods, family-based association studies on known and imputed data, and gene prioritizing, new loci, variants, and candidate genes were identified. These findings provide targets for future research, replication in other populations, facilitate personalized treatments, and improve public health toward African-derived underrepresented populations. Limitations include restricted single-nucleotide polymorphism coverage, self-reported pedigree data, and lack of available EH genomic studies on admixed populations for independent validation, despite the performed genetic correlation analyses using summary statistics.