Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.

A G Chiocchetti,D H Geschwind,D Haslinger,R Waltes,L De La Torre-Ubieta,S Lindlar,J L Stein,C M Freitag,E Cocchi,T Rothämel,S Fulda

doi:10.1038/tp.2016.119

Abstract

Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder-specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders.

Highlights

Autism spectrum disorders (ASD) share some of their genetic architecture with other neuropsychiatric disorders such as fragile X syndrome (FXS), schizophrenia (SCZ) and intellectual disabilities (ID)
It is known that the fragile X mental retardation protein (FMRP), a translational repressor causal for FXS, binds ASD risk genes,[1] and common variants of genes involved in the regulation of FMRP pathways are associated with ASD.[2]
Several genes affected by copy number variations (CNVs) and mutations detected in ASD patients were associated with SCZ3,4 or ID.[5,6]

Summary

Introduction

Autism spectrum disorders (ASD) share some of their genetic architecture with other neuropsychiatric disorders such as fragile X syndrome (FXS), schizophrenia (SCZ) and intellectual disabilities (ID). It is known that the fragile X mental retardation protein (FMRP), a translational repressor causal for FXS, binds ASD risk genes,[1] and common variants of genes involved in the regulation of FMRP pathways are associated with ASD.[2] In addition, several genes affected by copy number variations (CNVs) and mutations detected in ASD patients were associated with SCZ3,4 or ID.[5,6] integrative analyses investigating the functional overlap between ID and ASD showed that only ASD genes, but not ID-implicated genes, are enriched in neocortical developmental networks.[7,8] it is unclear to which extent the genetic overlap reflects shared or differential pathomechanisms. It should be acknowledged that embryonic stem cell, iPSC and human NPC models are expensive, and culturing and differentiating of these cells in a reproducible manner is far more difficult

Results

Discussion

Conclusion