title: Transcriptomic analysis of autistic brain reveals convergent molecular pathology.
abstract: Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.
authors: Program in Neurogenetics and Neurobehavioral Genetics, Department of Neurology and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1769, USA.
authors: Irina
authors: I
authors: Voineagu
authors: Xinchen
authors: X
authors: Wang
authors: Patrick
authors: P
authors: Johnston
authors: Jennifer K
authors: JK
authors: Lowe
authors: Yuan
authors: Y
authors: Tian
authors: Steve
authors: S
authors: Horvath
authors: Jonathan
authors: J
authors: Mill
authors: Rita M
authors: RM
authors: Cantor
authors: Benjamin J
authors: BJ
authors: Blencowe
authors: Daniel H
authors: DH
authors: Geschwind
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