A second implication of our results is that the use of longitudinal phenotypes may be essential for advancing etiological research. Concerns have been expressed about the replicability of G×E studies (Risch et al., 2009), but apparent inconsistencies may reflect methodological heterogeneity such as differences in the assessment of environmental exposures (Karg et al., 2011; Uher and McGuffin, 2008, 2010). The present findings suggest that differences between cross-sectional and longitudinal studies also contribute to the heterogeneity of results. We found that detection of a statistically significant G×E from a single assessment may be unreliable (significant G×E was detected two out of four times in each cohort), but becomes more reliable when data from multiple assessments are considered. Focus on first-episode depression is another approach that capitalizes on homogenous course characteristics within a sample and has also brought very promising results (Bukh et al., 2009). These findings suggest that tests of hypotheses about the developmental origins of adult disease (Ben-Shlomo and Kuh, 2002) and about the biological embedding of childhood adversity (Hertzman, 1999) may benefit from adopting a life-course approach to measuring phenotypes. A central challenge for future research is whether reliable assessment of clinical course can be achieved in non-longitudinal studies.
