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Nat Neurosci. 2016 Oct 26;19(11):1397-1407. doi: 10.1038/nn.4409.

The road to precision psychiatry: translating genetics into disease mechanisms.

Gandal MJ1,2,3,4, Leppa V2,3,4, Won H2,3,4, Parikshak NN2,3,4, Geschwind DH2,3,4.

Author information

1
Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
2
Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
3
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
4
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

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.

PMID:
27786179
DOI:
10.1038/nn.4409
[Indexed for MEDLINE]
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