Second, in addition to achieving a more homogenous genetic background, larger estimated effect sizes may come from selecting more homogenous environmental backgrounds. The low heritability of liability for MDD implies an important role for environmental risk factors. Although genotype × environment interaction cannot explain the so-called ‘missing heritability',52 it can contribute to small effect sizes. Although genotype × environment studies are conceptually attractive, the lessons learned from the most studied genotype × environment hypothesis for MDD (5HTTLPR and stressful life event) are sobering.57 However, this broad conclusion has been challenged58, 59 with Uher and McGuffin58 arguing that replication has been achieved when stressful life event were recorded objectively, temporally and before the onset to MDD. More mileage might be gained by considering MDD in the context of more clearly defined exposures, such as pregnancy, in which women with perinatal and post-partum MDD have been exposed to a similar event.
