Matthew State

Abstract

• A genome-wide search for autism genes in the Simons Simplex Collection

  The central aim of this study is to pursue a multi-site genome-wide scan of the Simons Simplex Collection (SSC) to identify and confirm sequence and structural variations contributing to Autism. The research plan involves four stages: Stage 1 involves the detection of rare de novo structural variation to identify regions likely to harbor autism genes and then prioritizes 100 of the highest priority transcripts within these intervals using both traditional and novel approaches; Stage 2 leverages deep re-sequencing association methodology and segregation analysis to identify putative ASD-related transcripts; Stage 3 proposes replication studies of the top loci emerging from Stage 2 in an independent sample; evaluation of possible association with ASD of CNVs that cluster in regions of the genome and those that have been identified as promising in other Autism CNV investigations. Stage 4 will focus on the study of transmitted and common CNVs and genome-wide studies of association of sequence variation.

  The State Lab will oversee the administrative aspects of the project, genotype the SSCGC samples, lead the effort to predict CNVs and coordinate the sequencing of genes selected by the SSCGC as being the highest priority candidates. The Geschwind Lab will have primary responsibility for expression studies and take the lead in conducting pathway analysis. The Sutcliffe and Cook Labs will contribute to development of gene network analysis by leveraging genome-wide expression QTL and CNV data from unaffected families to identify variation in the genome that predicts expression variation in genes and regions of interest. The Beaudet Lab will have primary responsibility for conducting exon specific array analysis using the Agilent platform. The Cook, Walsh, Sutcliffe, State and Beaudet Labs will participate in the confirmation of CNVs, the analysis of CNV data and the resequencing effort. The Devlin Lab will have primary responsibility for the statistical analyses of CNVs and rare variants. The Cantor Lab will take the lead on the common variant statistical analyses along with the Devlin lab and will collaborate with the Devlin Lab on the rare variant studies.

Institution

• Yale University School of Medicine