Meta-analyses to investigate gene-environment interactions in neuroepidemiology

Most chronic neurological diseases are caused by a combination of multiple genetic and environmental factors. Increasingly, gene-environment interactions (GxE) are being examined, providing opportunities to combine studies systematically using meta-analysis.

Systematic review of the literature on how to examine GxE using observational study designs, and how to conduct a meta-analysis of studies on GxE.

Most methods and challenges related to a standard meta-analysis apply to a GxE meta-analysis. There are, however, some substantive differences. With GxE, there is the capability of using a case-only design. Research on GxE interactions may be more prone to publication bias, since interactions are usually not the primary hypothesis and only 'exciting' significant GxE findings are reported out of a range of secondary analyses. In disease aetiology research, there has been debate whether to measure interaction on a multiplicative or additive scale. There are some significant challenges associated with measuring interaction on an additive scale, and thus the uptake of the measures of additive interaction has been limited. As a result, the methods of analysing interaction have been less consistent and reporting has been highly variable. We suggest using the STROBE/STREGA reporting guidelines to allow evaluation of interaction on both scales.

We identified a number of differences of a GxE meta-analysis over a standard meta-analysis. Awareness of these issues is important. Using established reporting guidelines for GxE studies is recommended. The development of consortia for neurological disorders that include both genetic and environmental data might offer benefits for GxE meta-analyses in the future.