Candidate gene studies in the 21st century: meta-analysis, mediation, moderation.

The results of a large body of candidate gene studies of behavioural and psychiatric phenotypes have been largely inconclusive, with most findings failing to replicate reliably. A variety of approaches that augment the 'traditional' candidate gene approach are discussed, including the use of meta-analysis to combine findings from existing published reports, the investigation of mediating variables (including the use of intermediate phenotypes or endophenotypes) and the awareness of possible moderating influences (such as sex or ethnicity) and gene-environment interactions on genetic associations, possibly via epigenetic mechanisms. Advances in genotyping technology will also allow the routine use of haplotype analysis and linkage disequilibrium mapping. Examples of how these approaches may improve our understanding of how genetic associations with behavioural and psychiatric phenotypes obtain are given.