Patterns of genetic variation in the hypertension candidate gene GRK4:: Ethnic variation and haplotype structure

Association studies using single nucleotide polymorphisms (SNPs) have the potential to help unravel the genetic basis of hypertension. Nevertheless, to date, association studies of hypertension have yielded ambiguous results. It is becoming clear that such association studies must be interpreted within the context of the genetic structure of the populations being studied, and patterns of variation within specific genomic regions. With this in mind we analyzed genetic variation in the G protein-coupled receptor kinase 4 (GRK4) gene, a gene whose product has recently been shown to inhibit the dopamine receptor D1 (DRD1) from increasing sodium excretion. We genotyped three previously identified GRK4 SNPs, as well as ten additional SNPs, over 71.6 kb of the GRK4 locus in four populations: African Americans, Asians, Hispanics and Caucasians. Haplotype structure varied among populations, with Hispanics and Caucasians having the most linkage disequilibrium (LD) among SNPs. African Americans had three shorter haplotype blocks, while patterns of markers in the Asian populations demonstrated less LD among markers, a pattern inconsistent with block structure. We observed limited haplotype diversity in each of the four populations, with differing haplotype frequencies among the ethnic groups. We also found substantial evidence for population differentiation, with the largest differences between the African-American and Asian samples with F-ST values in the upper 90(th) percentile when compared to a genome-wide distribution. However, for all population comparisons, F-ST values decreased sharply in the 3' region of the gene. This pattern of differentiation among populations is consistent with selection in this part of the gene maintaining similar patterns of variation among otherwise divergent populations. Our results document not only different allele frequencies between populations, but differences in haplotype structure that may be important in evaluating association studies between hypertension and GRK4.