Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.
| Original language | English |
|---|---|
| Article number | e1002556 |
| Journal | PLoS Genetics |
| Volume | 8 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2012 |
Bibliographical note
Funding Information:We are grateful to Matthias Groszer (University Pierre and Marie Curie, France) and Daniel H. Geschwind (University of California Los Angeles, USA) for critical reading of the manuscript and for their very useful comments. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We gratefully acknowledge the families and researchers participating in the international Autism Genome Project (AGP) Consortium. We are grateful to all of the families at the participating SFARI Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to genotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study ( http://sfari.org/sfari-initiatives/simons-simplex-collection ) by applying at https://base.sfari.org .