Getting Serious about Variation: Lessons for Clinical Neuroscience (A Commentary on ‘The Myth of Optimality in Clinical Neuroscience’)

Psychiatric illness poses a significant burden on global public health and the economy. Recent decades have witnessed the development of powerful new tools for quantifying variation in the genome and brain, leading to initial optimism that psychopathology might soon be defined and diagnosed on the basis of objective biological assays. [70_TD$DIFF]Yet, major breakthroughs have proven elusive. In psychiatric genetics, the first wave of small-scale studies proved difficult to replicate, leading some to question whether gene hunting should be abandoned altogether [1]. The resulting period of crisis and reflection ultimately motivated the widespread adoption of more rigorous analytic approaches and the development of mega-cohorts and consortia with the tens of thousands of subjects needed to reliably detect subtle gene–disease associations [1]. This second-wave research demonstrates that the amount of disease-relevant information captured by the vast majority of individual genetic variants (loci) is vanishingly small [71_TD$DIFF]<1% [1]. In short, while genomic approaches have proven valuable for discovering new molecular targets and validating existing therapeutics, they are not useful for routine screening or diagnosis.