The road to precision psychiatry: Translating genetics into disease mechanisms

Michael J. Gandal, Virpi Leppa, Hyejung Won, Neelroop N. Parikshak, Daniel H. Geschwind

Research output: Contribution to journalReview articlepeer-review

154 Scopus citations

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.

Original languageEnglish
Pages (from-to)1397-1407
Number of pages11
JournalNature Neuroscience
Volume19
Issue number11
DOIs
StatePublished - 26 Oct 2016
Externally publishedYes

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