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Nat Genet DOI:10.1038/s41588-022-01203-y

Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p.

Publication TypeJournal Article
Year of Publication2022
AuthorsWeiner, DJ, Ling, E, Erdin, S, Tai, DJC, Yadav, R, Grove, J, Fu, JM, Nadig, A, Carey, CE, Baya, N, Bybjerg-Grauholm, J, Berretta, S, Macosko, EZ, Sebat, J, O'Connor, LJ, Hougaard, DM, Børglum, AD, Talkowski, ME, McCarroll, SA, Robinson, EB
Corporate AuthorsiPSYCH Consortium, ASD Working Group of the Psychiatric Genomics Consortium, ADHD Working Group of the Psychiatric Genomics Consortium
JournalNat Genet
Date Published2022 Oct 24
ISSN1546-1718
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.

DOI10.1038/s41588-022-01203-y
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36280734?dopt=Abstract

Alternate JournalNat Genet
PubMed ID36280734
Grant ListF30MH129009 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01MH115957 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
T15LM007092 / / U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM) /
T32GM007753 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
R01HD096326 / / U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) /
R01NS093200 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /