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

被引：24

作者：

Chiocchetti, A. G. ^{[1
]}

Haslinger, D. ^{[1
]}

Stein, J. L. ^{[2
]}

de la Torre-Ubieta, L. ^{[2
]}

Cocchi, E. ^{[3
]}

Rothaemel, T. ^{[4
]}

Lindlar, S. ^{[1
]}

Waltes, R. ^{[1
]}

Fulda, S. ^{[5
]}

Geschwind, D. H. ^{[2
]}

Freitag, C. M. ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Univ Hosp Frankfurt, Dept Child & Adolescent Psychiat Psychosomat & Ps, Goethe Univ Deutschordenstr 50, D-60528 Frankfurt, Germany

[2] Univ Calif Los Angeles, Dept Neurol, Ctr Autism Res & Treatment, Neurogenet Program,Semel Inst,David Geffen Sch Me, Los Angeles, CA 90024 USA

[3] Univ Bologna, Dept Biomed & NeuroMotor Sci, Bologna, Italy

[4] Hannover Med Sch, Inst Legal Med, Hannover, Germany

[5] Inst Expt Canc Res Pediat, Frankfurt, Germany

来源：

TRANSLATIONAL PSYCHIATRY | 2016年 / 6卷

关键词：

PLURIPOTENT STEM-CELLS; DE-NOVO MUTATIONS; NEUROTROPHIC FACTOR; RETINOIC ACID; HUMAN BRAIN; IMPLICATE; VARIANTS; SCHIZOPHRENIA; EXPRESSION; NETWORKS;

D O I：

10.1038/tp.2016.119

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

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.

引用

页码：e864 / e864

页数：12

共 64 条

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