title: Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.
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.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: A G
authors.initials: AG
authors.lastname: Chiocchetti
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Haslinger
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: de la Torre-Ubieta
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cocchi
authors.affiliation: Institute of Legal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Rothämel
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lindlar
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Waltes
authors.affiliation: Institute of Experimental Cancer Research in Pediatrics, Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, JW Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Freitag
mesh_terms: D000465:Algorithms; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001921:Brain / Q000254:growth & development; D045744:Cell Line, Tumor; D005600:Fragile X Syndrome / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D000069550:Machine Learning; D055495:Neurogenesis / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012044:Regression Analysis; D012559:Schizophrenia / Q000235:genetics*; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger