Genetic association studies in stroke: methodological issues and proposed standard criteria.

Abstract

A large number of candidate gene association studies have attempted to identify genes implicated in stroke, but there have been few replicable and robust associations reported. The skantness of replicable associations partly relates to poor study design. Important methodological considerations include adequate sample size, the selection of appropriate controls, careful clinical phenotyping using standardized classification systems, and determining associations with stroke subtypes as well as stroke as a whole. The use of intermediate phenotypes, particularly carotid intima-media thickness and MRI white matter hyperintensities, appears promising. It is essential that positive associations are replicated in independent populations, and appropriate methodology is used in such studies. To be of use for others, association studies should meet certain standards. In particular, genetic association studies should enable replication studies and meta-analyses. This article discusses key methodological aspects and suggests standard criteria for candidate gene studies in stroke.