Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Genetics |
| Vol/bind | 54 |
| Sider (fra-til) | 1630-1639 |
| ISSN | 1061-4036 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank the following for their generous support of this work: the SFARI (grant no. 704413 to E.B.R. and L.J.O.), the NIMH (grant nos. F30MH129009 to D.J.W., R01MH111813 to E.B.R., R01MH115957 to M.E.T. and 1R01MH124851-01 to A.D.B.), the National Institute of General Medical Sciences (grant nos. T32GM007753 and T32GM144273 to A.N. and D.J.W.), the National Institute of Child Health and Development (grant no. R01HD096326 to M.E.T.), the National Institute of Neurological Disorders and Stroke (grant no. R01NS093200 to M.E.T.), the National Library of Medicine (grant no. T15LM007092 to D.J.W.), the Lundbeck Foundation (grant nos. R102-A9118, R155-2014-1724, and R248-2017-2003 to iPSYCH), the Novo Nordisk Foundation (to the Danish National Biobank) and the universities and university hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark through a grant to A.D.B. Human tissue was obtained from the NIH NeuroBioBank. We thank all the families who participated in the cohorts included in this analysis, without whom this work would not have been possible. We also thank R. Collins and R. Walters for their assistance with these analyses. Finally, we thank the following members of the ADHD Working Group of the PGC: A. R. Hammerschlag, A. Corsico, A. Havdahl, A. Todorov, A. Charach, A. Ashley-Koch, A. Doyle, A. Hervas, A. Miranda, A. Borglum, A. Scherag, A. Thapar, A. Rommel, A. Starnawska, A. Wheeler, A. Rothenberger, A. Arnatkeviciute, B. Franke, B. Neale, C. Liao, C. Hartman, C. Burton, C. Cornforth, C. Bandeira, C. Bau, C. Sanchez, D. Posthuma, F. Cerrato, F. Mulas, F. Degenhardt, G. C. A. Martins, G. P. Stromstad Knudsen, H. C. Steinhausen, H. Hakonarson, H.-C. Steinhausen, H. Roeyers, H.-W. Kim, I. Gizer, I. Waldman, I. Brikell, J. Crosbie, J. Agnew-Blais, J. Martin, J. Gelernter, J. Hebebrand, J. A. Ramos-Quiroga, J. Biederman, J. Sergeant, J. Gamble, J. Pinsonneault, J. Deckert, K. Langley, L. Yang, L. Kent, L. Rohde, M. Mattheisen, M. J. Arranz Calderun, M. Soler Artigas, M. Ribases, M. Mariano, M. Gill, M. O’Donovan, M. Casas, M. Bayes, N. Martin, N. P. Ole Mors, N. Williams, N. Roth Mota, O. A. Andreassen, P. Sham, P. Sullivan, P. Arnold, P. Lichtenstein, P. Rovira, P. Holmans, P. Asherson, P. B. Mortensen, R. Guerra, R. Walters, R. Anney, R. Ebstein, R. Karlsson Linnér, R. Joober, R. Oades, R. Schachar, S. M. Sengupta, S. Johansson, S. H. Witt, S. Nelson, S. Smalley, S. Scherag, T. Zayats, T. Werge, T. Silk, T. Polderman, T. Banaschewski, T. Altar, V. Manikandan, Y. Zhang, Y. Athanasiadis and Y. Wang. Support for the title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute.
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© 2022, The Author(s).
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