Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p
Authors: Weiner Daniel J. , Ling Emi , Erdin Serkan , Tai Derek J. C. , Yadav Rachita , Grove Jakob , Fu Jack M. , Nadig Ajay , Carey Caitlin E. , Baya Nikolas , Bybjerg-Grauholm Jonas ,   iPSYCH Consortium, Mortensen Preben B. , Werge Thomas , Demontis Ditte , Mors Ole , Nordentoft Merete , Als Thomas D. , Baekvad-Hansen Marie , Rosengren Anders ,   ASD Working Group of the Psychiatric Genomics Consortium, Havdahl Alexandra , Hedemand Anne , Palotie Aarno , Chakravarti Aravinda , Arking Dan , Sulovari Arvis , Starnawska Anna , Thiruvahindrapuram Bhooma , de Leeuw Christiaan , Carey Caitlin , Ladd-Acosta Christine , van der Merwe Celia , Devlin Bernie , Cook Edwin H. , Eichler Evan , Corfield Elisabeth , Dieleman Gwen , Schellenberg Gerard , Hakonarson Hakon , Coon Hilary , Dziobek Isabel , Vorstman Jacob , Girault Jessica , Sutcliffe James S. , Duan Jinjie , Nurnberger John , Hallmayer Joachim , Buxbaum Joseph , Piven Joseph , Weiss Lauren , Davis Lea , Janecka Magdalena , Mattheisen Manuel , State Matthew W. , Gill Michael , Daly Mark , Uddin Mohammed , Andreassen Ole , Szatmari Peter , Lee Phil Hyoun , Anney Richard , Ripke Stephan , Satterstrom Kyle , Santangelo Susan , Kuo Susan , van Elst Ludger Tebartz , Rolland Thomas , Bougeron Thomas , Polderman Tinca , Turner Tychele , Underwood Jack , Manikandan Veera , Pillalamarri Vamsee , Warrier Varun ,   ADHD Working Group of the Psychiatric Genomics Consortium, Philipsen Alexandra , Reif Andreas , Hinney Anke , Cormand Bru , Bau Claiton H. D. , Rovaris Diego Luiz , Sonuga-Barke Edmund , Corfield Elizabeth , Grevet Eugenio Horacio , Salum Giovanni , Larsson Henrik , Buitelaar Jan , Haavik Jan , McGough James , Kuntsi Jonna , Elia Josephine , Lesch Klaus-Peter , Klein Marieke , Bellgrove Mark , Tesli Martin , Leung Patrick W. L. , Pan Pedro M. , Dalsgaard Soren , Loo Sandra , Medland Sarah , Faraone Stephen V. , Reichborn-Kjennerud Ted , Banaschewski Tobias , Hawi Ziarih , Berretta Sabina , Macosko Evan Z. , Sebat Jonathan , O’Connor Luke J. , Hougaard David M. , Børglum Anders D. , Talkowski Michael E. , McCarroll Steven A. , Robinson Elise B. 
Published: October 2022

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.