Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p
Daniel J. Weiner, Emi Ling, Serkan Erdin, Derek J.C. Tai, Rachita Yadav, Jakob Grove, Jack Fu, Ajay Nadig, Caitlin E. Carey, Nikolas Baya, Jonas Bybjerg‐Grauholm, Preben Bo Mortensen, Thomas Werge, Ditte Demontis, Ole Mors, Merete Nordentoft, Thomas D. Als, Marie Bækvad‐Hansen, Anders Rosengren, Alexandra Havdahl, Anne Hedemand, Aarno Palotie, Aravinda Chakravarti, Dan E. Arking, Arvis Sulovari, Anna Starnawska, Bhooma Thiruvahindrapuram, Christiaan de Leeuw, Caitlin E. Carey, Christine Ladd‐Acosta, Celia van der Merwe, Bernie Devlin, Edwin H. Cook, Evan E. Eichler, Elisabeth Corfield, Gwen Dieleman, Gerard D. Schellenberg, Håkon Håkonarson, Hilary Coon, Isabel Dziobek, Jacob Vorstman, Jessica B. Girault, James S. Sutcliffe, Jinjie Duan, John I. Nürnberger, Joachim Hallmayer, Joseph D. Buxbaum, Joseph Piven, Lauren A. Weiss, Lea K. Davis, Magdalena Janecka, Manuel Mattheisen, Matthew W. State, Michael Gill, Mark J. Daly, Mohammed Uddin, Ole A. Andreassen, Péter Szatmári, Phil Hyoun Lee, Richard Anney, Stephan Ripke, Kyle Satterstrom, Susan L. Santangelo, Susan S. Kuo, Ludger Tebartz van Elst, Thomas Rolland, Thomas Bougeron, Tinca J. C. Polderman, Tychele N. Turner, Jack F. G. Underwood, Veera Manikandan, Vamsee Pillalamarri, Varun Warrier, Alexandra Philipsen, Andreas Reif, Anke Hinney, Bru Cormand, Claiton H.D. Bau, Diego Luiz Rovaris, Edmund Sonuga‐Barke, Elizabeth C. Corfield, Eugênio H. Grevet, Giovanni Abrahão Salum, Henrik Larsson, Jan Buitelaar, Jan Haavik, James J. McGough, Jonna Kuntsi, Josephine Elia, Klaus‐Peter Lesch, Marieke Klein, Mark A. Bellgrove, Martin Tesli, Patrick W. L. Leung, Pedro Mário Pan, Søren Dalsgaard, Sandra K. Loo, Sarah E. Medland, Stephen V. Faraone, Ted Reichborn‐Kjennerud
Abstract
The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism's common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.