What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn.

Psychiatric genetics has taught us a great deal about the nature of psychiatric disorders. Traditional family, twin and adoption studies have demonstrated the substantial role of genetic factors in their etiology, clarified the role of genetic factors in comorbidity, elucidated development pathways, and documented the importance of gene-environment correlation and interaction. We have also received some hard lessons when we were unable to detect replicable genes of large effect size and found that our much-valued candidate genes did not live up to their expected promise. With more mature molecular and statistical methods, we are entering now a different era. Statistical analyses of aggregate molecular signals are validating earlier heritability estimates. Replicated findings from genome-wide association studies are beginning to emerge, as are discoveries of large-effect size rare genomic variants. The number of such findings is likely to soon grow dramatically. The most pressing question facing the field is what biological picture these results will reveal. I articulate four possible scenarios that reflect (i) no, (ii) minimal, (iii) moderate and (iv) high biological coherence in the replicated molecular variant findings, which are soon likely to emerge. I discuss the factors that will likely influence these patterns, including the problems of etiological heterogeneity and multiple realizability. These findings could provide critical insights into the underlying biology of our psychiatric syndromes and potentially permit us to perceive, 'through a glass darkly,' the levels of the mind-brain system that are disordered.