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The road to precision psychiatry: translating genetics into disease mechanisms

Abstract

Hundreds of genetic loci increasing risk for neuropsychiatric disorders have recently been identified. This success, perhaps paradoxically, has posed challenges for therapeutic development, which are amplified by the highly polygenic and pleiotropic nature of these genetic contributions. Success requires understanding the biological impact of single genetic variants and predicting their effects within an individual. Comprehensive functional genomic annotation of risk loci provides a framework for interpretation of neurobiological impact, requiring experimental validation with in vivo or in vitro model systems. Systems-level, integrative pathway analyses are beginning to elucidate the additive, polygenic contributions of risk variants on specific cellular, molecular, developmental, or circuit-level processes. Although most neuropsychiatric disease modeling has focused on genes disrupted by rare, large-effect-size mutations, common smaller-effect-size variants may also provide solid therapeutic targets to inform precision medicine approaches. Here we enumerate the promise and challenges of a genomics-driven approach to uncovering neuropsychiatric disease mechanisms and facilitating therapeutic development.

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Figure 1: Genetic and environmental contribution to liability for neuropsychiatric disease.
Figure 2: Neurobiological framework for interpretation of individual disease-associated variants.

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Acknowledgements

The authors thank A. Gordon, L. Perez-Cano, G. Ramaswami, E. Ruzzo, J. Rexach, G. Morris, and members of the Geschwind laboratory for discussions. This work was supported by US National Institute of Health (NIH) grants 5R01MH094714 (D.H.G.), 5P50MH106438 (D.H.G.), 1R01MH109912 (D.H.G.), and F30MH099886 (N.N.P.). This work was also supported by the Glenn/AFAR Postdoctoral Fellowship (20145357, H.W.), Basic Science Research Program through the National Research Foundation of Korea (2013024227, H.W.), and the UCLA Medical Scientist Training Program (N.N.P.). D.H.G. is a scientific advisor to Ovid Pharmaceuticals.

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Correspondence to Daniel H Geschwind.

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Gandal, M., Leppa, V., Won, H. et al. The road to precision psychiatry: translating genetics into disease mechanisms. Nat Neurosci 19, 1397–1407 (2016). https://doi.org/10.1038/nn.4409

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