Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders

Pac Symp Biocomput. 2018;23:68-79.

Abstract

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 wild-type 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Computational Biology
  • Epilepsy / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Glycoproteins / genetics
  • Humans
  • Lipocalin-2 / genetics
  • Loss of Function Mutation*
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Knockout
  • Neurodevelopmental Disorders / etiology
  • Neurodevelopmental Disorders / genetics*
  • Neuronal Plasticity / genetics*
  • Neuropeptides / deficiency
  • Neuropeptides / genetics
  • Phenotype
  • Risk Factors
  • Schizophrenia / genetics
  • Visual Cortex / metabolism

Substances

  • Glycoproteins
  • LCN2 protein, human
  • LRG1 protein, human
  • Lipocalin-2
  • Lynx1 protein, mouse
  • Membrane Glycoproteins
  • Neuropeptides