TY - JOUR
T1 - Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders
AU - Smith, Milo R.
AU - Glicksberg, Benjamin S.
AU - Li, Li
AU - Chen, Rong
AU - Morishita, Hirofumi
AU - Dudley, Joel T.
N1 - Funding Information:
This work was funded by a Traineeship, National Institute of Child Health and Human Development - Interdisciplinary Training in Systems and Developmental Biology and Birth Defects Grant T32H-D0-75735 (to M.R.S.); the Mindich Child Health and Development Institute Pilot Fund (to J.T.D. and H.M.); the Knights Templar Eye Foundation (to H.M.); the March of Dimes (to H.M.); the Whitehall Foundation (to H.M.); the Harris Center for Precision Wellness (to J.T.D); and National Institutes of Health Grants P30-ES-023515 (to J.T.D. and H.M.), R01-DK-098242 (to J.T.D.), and R01-EY-024918, R01-EY-026053, and R21 MH106919 (to H.M.).
Publisher Copyright:
© 2017 The Authors.
PY - 2018
Y1 - 2018
N2 - High and increasing prevalence of neurodevelopmental disorders place enormous personal and economic burdens on society. Given the growing realization that the roots of neurodevelopmental disorders often lie in early childhood, there is an urgent need to identify childhood risk factors. Neurodevelopment is marked by periods of heightened experience-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are disrupted, development of normal brain function can be permanently altered, leading to neurodevelopmental disorders. Here, we aim to systematically identify human variants in neuroplasticity-related genes that confer risk for neurodevelopmental disorders. Historically, this knowledge has been limited by a lack of techniques to identify genes related to neurodevelopmental plasticity in a high-throughput manner and a lack of methods to systematically identify mutations in these genes that confer risk for neurodevelopmental disorders. Using an integrative genomics approach, we determined loss-of-function (LOF) variants in putative plasticity genes, identified from transcriptional profiles of brain from mice with elevated plasticity, that were associated with neurodevelopmental disorders. From five shared differentially expressed genes found in two mouse models of juvenile-like elevated plasticity (juvenile wildtype or adult Lynx1-/- relative to adult wild-type) that were also genotyped in the Mount Sinai BioMe Biobank we identified multiple associations between LOF genes and increased risk for neurodevelopmental disorders across 10,510 patients linked to the Mount Sinai Electronic Medical Records (EMR), including epilepsy and schizophrenia. This work demonstrates a novel approach to identify neurodevelopmental risk genes and points toward a promising avenue to discover new drug targets to address the unmet therapeutic needs of neurodevelopmental disease.
AB - High and increasing prevalence of neurodevelopmental disorders place enormous personal and economic burdens on society. Given the growing realization that the roots of neurodevelopmental disorders often lie in early childhood, there is an urgent need to identify childhood risk factors. Neurodevelopment is marked by periods of heightened experience-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are disrupted, development of normal brain function can be permanently altered, leading to neurodevelopmental disorders. Here, we aim to systematically identify human variants in neuroplasticity-related genes that confer risk for neurodevelopmental disorders. Historically, this knowledge has been limited by a lack of techniques to identify genes related to neurodevelopmental plasticity in a high-throughput manner and a lack of methods to systematically identify mutations in these genes that confer risk for neurodevelopmental disorders. Using an integrative genomics approach, we determined loss-of-function (LOF) variants in putative plasticity genes, identified from transcriptional profiles of brain from mice with elevated plasticity, that were associated with neurodevelopmental disorders. From five shared differentially expressed genes found in two mouse models of juvenile-like elevated plasticity (juvenile wildtype or adult Lynx1-/- relative to adult wild-type) that were also genotyped in the Mount Sinai BioMe Biobank we identified multiple associations between LOF genes and increased risk for neurodevelopmental disorders across 10,510 patients linked to the Mount Sinai Electronic Medical Records (EMR), including epilepsy and schizophrenia. This work demonstrates a novel approach to identify neurodevelopmental risk genes and points toward a promising avenue to discover new drug targets to address the unmet therapeutic needs of neurodevelopmental disease.
KW - Drug targets
KW - Inflammation
KW - Integrative genomics
KW - Neurodevelopment
KW - Neuroplasticity
KW - Risk genes
UR - http://www.scopus.com/inward/record.url?scp=85048468975&partnerID=8YFLogxK
U2 - 10.1142/9789813235533_0007
DO - 10.1142/9789813235533_0007
M3 - Conference article
C2 - 29218870
AN - SCOPUS:85048468975
SN - 2335-6936
VL - 0
SP - 68
EP - 79
JO - Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
JF - Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
T2 - 23rd Pacific Symposium on Biocomputing, PSB 2018
Y2 - 3 January 2018 through 7 January 2018
ER -