The meta-analysis of genome-wide association studies

The pressure to publish novel genetic associations has meant that meta-analysis has been applied to genome-wide association studies without the time for a careful consideration of the methods that are used. This review distinguishes between the use of meta-analysis to validate previously reported genetic associations and its use for gene discovery, and advocates viewing gene discovery as an exploratory screen that requires independent replication instead of treating it as the application of hundreds of thousands of statistical tests. The review considers the use of fixed and random effects meta-analyses, the investigation of between-study heterogeneity, adjustment for confounding, assessing the combined evidence and genomic control, and comments on alternative approaches that have been used in the literature.