Identification of Genes for a Complex Trait: Examples from Hypertension

Abstract

Essential hypertension (EH) affects approximately 20% of the adult population, and has a multifactorial origin arising from an interaction between susceptibility genes and environmental factors. Several strategies and methods have been used to identify hypertension susceptibility genes. This review is thought to highlight current strategies for a better understanding of their limitations and strengths in a complex trait like EH. Linkage analysis is less effective at identifying common variants with modest effects typical for complex traits, and has therefore proved to be largely unsuccessful in EH. No candidate gene was assessed by a human linkage study so far. Possible redesigns of the linkage approach for complex diseases may include larger sample sizes and dense marker maps. Genetic association studies may be an effective approach to the problems posed by complex traits. With the explosion of genotyping technologies, genome-wide association studies have become feasible, and small-scale association studies have become plentiful. The different types of association studies are reviewed and issues that are important to consider when interpreting association studies of complex traits are discussed. Properly defined phenotypes, large enough sample cohorts to achieve sufficient statistical power, carefully matched samples to avoid population stratification are all integral parts of a high-quality association study. Multiple testing often results in false-positive results by chance, and inconclusive results may arise from ignoring linkage disequilibrium of the tested polymorphism, an effect avoidable by haplotype analysis. A new evolutionary development of the candidate gene approach is introduced which will extent traditional association study settings gaining better understanding of complex diseases like hypertension and might give better chances to evaluate association studies for their functional relevance.

A review of the genetics of essential hypertension

“…This analysis showed linkage of a new locus at chromosome 5q13 with essential hypertension, but was no longer able to support the originally found genome-wide linkage on chromosome 6q. Furthermore, finding the significance level to declare linkage is problematic [59 ]. In two-point linkage studies, a Lod score of 3.0 is classically accepted as statistically significant.…”

“…Linkage scans of SNPs [65] will likely provide more information about coinheritance of alleles, and therefore greater power than traditional 10 cM microsatellite scans [66]. Nevertheless, this will not change the principal drawback that linkage is less effective at identifying common variants with modest effects typical of complex traits [59 ].…”

“…Ethnicity is particularly important, as the representation of different genetic polymorphisms is quite different between ethnic groups. This may lead to spurious findings in the analysis of common diseases like essential hypertension (for a review, see [59 ]). …”

Protein C promoter polymorphisms associate with sepsis in children with systemic meningococcemia

“…We were examining haplotypes whereas Walley and Russell conWned their analysis to one SNP only. It is a known problem that divergent results may arise from unrecognized haplotype eVects in genetic studies limited to the investigation of single SNPs (Binder 2006). Actually, Walley and Russell did note that the presented association of the ¡1641A SNP was completely conWned to the ¡1641A ¡1654C haplotype.…”

Exploring the perioptome: the role of genomics in thoracic surgery and anaesthesia

“…The incidence is still unacceptably high, and is not due to surgeon, institution or procedure-related risk factors alone. It is likely that there is a genetic tendency for an individual to respond to a given stimulus in a certain way, and it is also likely that this response is not Mendelian in nature, rather -as is the case for hypertension -it represents a complex trait [7 ]. In thinking about the ways in which complex traits originate, it is important to understand that the end product (the phenotype) is likely determined by small effects arising from variants in many genes, rather than by a large effect arising from a single gene.…”