TY - JOUR T1 - Systematic Reconstruction of Autism Biology with Multi-Level Whole Exome Analysis JF - bioRxiv DO - 10.1101/052878 SP - 052878 AU - Weijun Luo AU - Chaolin Zhang AU - Cory R. Brouwer Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/11/052878.abstract N2 - 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. ER -