Genome-wide case/control studies in hypertension: only the 'tip of the iceberg'

Abstract

Recent advances in genome technology have enabled genome-wide searching for disease predisposition loci, using dense SNP and haplotype maps. Over the past year, such approaches have yielded positive results in human hypertension. Here we outline factors underlying the rationale for the approach and consider reasons for false positive and negative results. Although the approach has yielded positive results, typically the trait-associated loci explain only a small fraction of the heritable fraction of trait variance. Finally, we consider alternative approaches and emerging strategies to probe the role of heredity in control of blood pressure.

Figure 1

Re-estimation of statistical power for hypertension in the Wellcome Trust Case Control Consortium (WTCCC). Computation of power used variance components tools, implemented at <http://pngu.mgh.harvard.edu/~purcell/gpc>, considering a spectrum of reasonable assumptions (disease allele relative risk; marker and disease allele frequencies; D’ [linkage disequilibrium]), as well as the effects of the likely ~25% trait misclassification in the “control” group.

Figure 2. Common Disease/Rare Variant (CD/RV) hypothesis. Human CHGA/Catestatin Gly364Ser (~3% minor allele frequency)

Profound effects on autonomic function and BP in vivo. Left: Effects of Gly/Ser heterozygosity on catecholamine secretion. Center: Effects of Gly/Ser heterozygosity on autonomic function (baroreceptor sensitivity as measured in either the time or frequency domains). Right: Effect of Gly/Ser heterozygosity on resting DBP in the population, with replication in an independent sample. CHGA Gly364Ser is rs9658667. Reproduced from F Rao et al.