As a final limitation, ENIGMA analyses have been cross-sectional to date, rather than longitudinal. Genetic predictors of brain changes over time have substantial importance for clinical trial enrichment (e.g., TREM2, which harbors variants that predict rates of brain atrophy over time; Rajagopalan et al. 2013; see Kohannim et al. 2013, for an approach to boost power in drug trials by multi-locus genetic profiling; see Andreasen et al. 2012, for an approach examining epistatic relationships between multiple genes and progressive brain tissue loss in schizophrenia).
