Aetiological stratification as a conceptual framework for gene-by-environment interaction research in psychiatry

It has been argued that gene-by-environment interactions (GxE) research is unlikely to progress knowledge about psychiatric disorders, in contrast to genome-wide association (GWA) studies. However, GxE approaches are not alternatives for gene-hunting but a way to identify genetic and biological mechanisms within subgroups of patients exposed to a similar aetiological (environmental) factor via a process of aetiological stratification'. This is important as diagnostic categories targeted by GWA studies are inherently heterogeneous and lack biological validity. Aetiological stratification builds on examining possible phenotypic and/or molecular specificity associated with exposure to the environmental factor across multiple potentially relevant disorders, combined with efforts to identify an underlying biological substrate. GxE hypotheses within this framework investigate (1) which genes influence the degree to which individuals develop identified biological alterations that link environmental exposure to specific phenotypic and/or molecular characteristics within or across psychiatric disorders and (2) which genes are implicated in determining the development of psychopathology once this biological alteration has been brought about. As gene-hunting is not a goal in itself, the examination of pathway and/or polygenic risk scores may be more informative than the examination of individual markers, at the same time reducing multiple testing and the associated risk of spurious findings.