Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study

Abstract

Essential hypertension is a major cardiovascular risk factor and a large proportion of this risk is genetic. Identification of genomic regions consistently associated with hypertension has been difficult in association studies to date as this requires large sample sizes.We previously published a large genome-wide linkage scan in Americans of African (AA) and European (EA) descent in the GenNet Network of the Family Blood Pressure Program (FBPP). A highly significant linkage peak was identified on chr1q spanning a region of 100 cM. In this study, we genotyped 1569 SNPs under this linkage peak in 2379 individuals to identify whether common genetic variants were associated with blood pressure (BP) at this locus.Our analysis, using two different family-based association tests, provides suggestive evidence (P< or =2 x 10(-5)) for a collection of single nucleotide polymorphisms (SNPs) associated with BP. In EAs, using diastolic BP as a quantitative phenotype, three variants located in or near the GPA33, CD247, and F5 genes, emerge as our top hits; for systolic BP, variants in GPA33, CD247, and REN are our best findings. No variant in AAs came close to suggestive evidence after multiple-test corrections (P> or =8 x 10(-5)). In summary, we show that systematic follow-up of a linkage signal can help discover candidate variants for essential hypertension that require a follow-up in yet larger samples. The failure to identify common variants is either because of low statistical power or the existence of rare coding variants in specific families or both, which require additional studies to clarify.

Figure 1

P-value Manhattan plot for age and sex adjusted phenotypes in European-Americans: SBP phenotypes (a) and DBP (b). Nominal P-values for association with SBP and DBP are plotted by genomic position on chromosome 1 for each SNP tested. Phenotypes adjusted for age and sex were used for this analysis. The three regions assayed are depicted with different background colors (region 1: light green; region 2: light blue; region 3: light violet). The top panel shows P-values obtained with two family-based association tests (MERLIN in orange and FBAT in blue) and the bottom panel depicts the local recombination rate (cM/Mb).

Figure 2

P-value Manhattan plot for phenotypes without adjustment in European-Americans, same as in Figure 1, except that phenotypes used for this analysis were not adjusted for age and sex: SBP phenotypes (a) and DBP phenotypes (b).