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Systematic Reconstruction of Autism Biology with Multi-Level Whole Exome Analysis

Weijun Luo, Chaolin Zhang, Cory R. Brouwer
doi: https://doi.org/10.1101/052878
Weijun Luo
1Department of Bioinformatics and Genomics, UNC Charlotte, Charlotte, NC 28223
2UNC Charlotte Bioinformatics Service Division, North Carolina Research Campus, Kannapolis, NC 28081
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  • For correspondence: Weijun.Luo@uncc.edu
Chaolin Zhang
3Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA
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Cory R. Brouwer
1Department of Bioinformatics and Genomics, UNC Charlotte, Charlotte, NC 28223
2UNC Charlotte Bioinformatics Service Division, North Carolina Research Campus, Kannapolis, NC 28081
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Abstract

Whole exome/genome studies on autism spectrum disorder (ASD) identified thousands of variants, yet not a coherent and systematic disease mechanism. We conduct novel integrated analyses across multiple levels on ASD exomes. These mutations do not recur or replicate at variant level, but significantly and increasingly so at gene and pathway level. Genetic association reveals a novel gene+pathway dual-hit model, better explaining ASD risk than the well-accepted mutation burden model.

In multiple analyses with independent datasets, hundreds of variants or genes consistently converge to several canonical pathways. Unlike the reported gene groups or networks, these pathways define novel, relevant, recurrent and systematic ASD biology. At sub-pathway level, most variants disrupt the pathway-related gene functions, and multiple interacting variants spotlight key modules, e.g. cAMP second-messenger system and mGluR signaling regulation by GRK in synapses. At super-pathway level, these distinct pathways are highly interconnected, and further converge to a few biology themes, i.e. synaptic function, morphology and plasticity. Therefore, ASD is a not just multi-genic but a multi-pathway disease.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted May 11, 2016.
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Systematic Reconstruction of Autism Biology with Multi-Level Whole Exome Analysis
Weijun Luo, Chaolin Zhang, Cory R. Brouwer
bioRxiv 052878; doi: https://doi.org/10.1101/052878
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Systematic Reconstruction of Autism Biology with Multi-Level Whole Exome Analysis
Weijun Luo, Chaolin Zhang, Cory R. Brouwer
bioRxiv 052878; doi: https://doi.org/10.1101/052878

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