Shared gene co-expression networks in autism from induced pluripotent stem cell (iPSC) neurons

TitleShared gene co-expression networks in autism from induced pluripotent stem cell (iPSC) neurons
Publication TypeConference Paper
Year of Publication2018
AuthorsAdhya, D, Swarup, V, Nowosaid, P, Shum, C, Jozwik, K, McAlonan, G, Mendez, MA, Horder, J, Murphy, D, Geschwind, DH, Price, J, Carroll, J, Srivastava, DP, Baron-Cohen, S
Conference NameBioRxiv
Date Published6/19/2018
Abstract

Autism Spectrum Conditions (henceforth, autism) are a diverse set of neurodevelopmental phenotypes with a complex genetic basis. Idiopathic autism, characterized by a diagnosis of autism not caused by a known genetic variant, is associated with hundreds of rare and common genetic variants each of small effect. Functional genomics analyses of post mortem brain tissue have identified convergent atypical gene correlation networks in idiopathic autism. However, post mortem tissue is difficult to obtain and is susceptible to unknown confounding factors related to the cause of death and to storage conditions. To circumvent these limitations, we created induced pluripotent stem cells (iPSCs) from hair follicles of idiopathic autistic individuals and made iPSC-derived neurons, to investigate its usefulness as a substitute for post mortem brain tissue. Plucking hair follicles is a relatively painless and ethical procedure, and hair samples can be obtained from anyone. Functional genomics analyses were used as a replicable analysis pipeline to assess efficacy of iPSC-derived neurons. Gene expression networks, previously identified in adult autism brains, were atypical in the iPSC autism neural cultures in this study. These included those associated with neuronal maturation, synaptic maturation, immune response and inflammation, and gene regulatory mechanisms. In addition, GABRA4, HTR7, ROBO1 and SLITRK5 were atypically expressed among genes previously associated with autism. A drawback of this study was its small sample size, reflecting practical challenges in generating iPSCs from patient cohorts. We conclude that, using rigorous functional genomics analyses, atypical molecular processes seen in the adult autistic postmortem brain can be modelled in hair follicle iPSC-derived neurons. There is thus potential for scaling up of autism transcriptome studies using an iPSC-based model system.

DOI10.1101/349415

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