Genome-Wide Association Studies of Hypertension: Light at the End of the Tunnel

Claire E Hastie,Anna F Dominiczak,Sandosh Padmanabhan

doi:10.4061/2010/509581

Abstract

Despite its significant genetic component, the study of hypertension by genome-wide association presents more challenges than other common complex diseases. Its high prevalence, heterogeneity, and somewhat unclear definition are the challenges that need to be overcome on one hand. On the other hand, there are issues of small effect sizes and pleiotropism that are not specific to hypertension alone but nonetheless magnify the problems of genetic dissection when coupled with phenotypic misclassification. We discuss issues of study design and summarise published genome-wide association studies (GWASs) of hypertension and blood pressure. With careful study design and analysis success is possible, as demonstrated by the recent large-scale studies. Following these, there is still further scope to advance the field through high fidelity phenotyping and deep sequencing.

Highlights

Hypertension is the major factor responsible for the most deaths worldwide and this is 46% more than tobacco usage, the major risk factor [1]
Clinical risk assessment is based on a predefined threshold at which the quantitative blood pressure phenotype in converted into a binary trait and management strategies are directed towards blood pressure reduction below this threshold at which the risk of excess cardiovascular events is abolished
While the causation of hypertension is multifactorial with both genetic and environmental components, the purpose of this paper is to discuss the genetic determinants of high blood pressure and genome-wide association studies (GWASs) study design

Summary

Introduction

Hypertension is the major factor responsible for the most deaths worldwide (around 7 million or 12.8% per year) and this is 46% more than tobacco usage, the major risk factor [1]. From an epidemiological and clinical perspective, blood pressure at the higher end of the normal population distribution is associated with an increased risk of cardiovascular mortality and morbidity. The observed normal unimodal distribution of blood pressure and its complex multifactorial aetiology support studies of blood pressure as a quantitative phenotype. According to the latter argument, if hypertension is a dichotomous risk trait, one would expect a bimodal distribution and this is not observed. Both approaches are useful and complementary in the genetic dissection of this trait which has so far been extremely resistant to the GWAS approach

Evidence for a Genetic Component in Hypertension

Strategies for Gene Mapping of Complex Diseases

The GWAS Strategy

Study Design Issues in GWAS

Findings

Future Directions