Variants on chromosome 6p22.3 associated with blood pressure in the HyperGEN study: follow-up of FBPP quantitative trait loci.

BACKGROUND A recent meta-analysis of genome-wide linkage scans of blood pressure (BP) in the large (N = 13,044) Family Blood Pressure Program (FBPP) identified five quantitative trait loci (QTLs) on chromosomes 6, 8, 20, and 21. We conducted follow-up fine mapping studies in 1,251 African (AA) and 1,254 European American (EA) participants of the Hypertension Genetic Epidemiology Network (HyperGEN). METHODS Ethnic-specific linear mixed effects models were used to test associations of BP with genotyped and imputed single nucleotide polymorphisms (SNPs) contained in the logarithm of odds (LOD) score ≥2 interval under each of the QTL peaks. We used multipoint variance components models to perform linkage analysis conditional on each significant SNP in the QTL region to see if the SNP explained the QTL. RESULTS Three intergenic SNPs (rs898164, rs2876587, rs6935795) on chromosome 6p22.3 were significantly associated with pulse pressure (using appropriate Bonferroni correction). Conditioning on the significant SNPs reduced the chromosome 6 QTL linkage evidence by 14-30%. Both AAs and EAs exhibited suggestive associations between BP and intronic SNPs on chromosomes 8q24.12 (genes: OPG in AAs, SAMD12 in EAs), 20q13.12 (genes: SLC13A3 in AAs, SLC12A5 in EAs), and 21q21.1 (genes: C21orf34 in AAs, BC039377 in EAs). CONCLUSIONS Significant associations with common SNPs explained less than 1/3 of the QTL evidence. Our results cannot refute the hypothesis that rare variants account for most of the statistical evidence for the FBPP linkage peaks. Whole genome resequencing can identify the variants driving the linkage peaks and genome-wide association study (GWAS) hits thereby spurring investigations to deepen our understanding of hypertension pathophysiology.