TY - JOUR
T1 - The road to precision psychiatry
T2 - Translating genetics into disease mechanisms
AU - Gandal, Michael J.
AU - Leppa, Virpi
AU - Won, Hyejung
AU - Parikshak, Neelroop N.
AU - Geschwind, Daniel H.
N1 - Publisher Copyright:
© Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2016/10/26
Y1 - 2016/10/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84994130171&partnerID=8YFLogxK
U2 - 10.1038/nn.4409
DO - 10.1038/nn.4409
M3 - Review article
C2 - 27786179
AN - SCOPUS:84994130171
SN - 1097-6256
VL - 19
SP - 1397
EP - 1407
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 11
ER -