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 M Fu, Ajay Nadig, Caitlin E Carey, Nikolas Baya, Jonas Bybjerg-Grauholm, iPSYCH Consortium, ASD Working Group of the Psychiatric Genomics Consortium, ADHD Working Group of the Psychiatric Genomics Consortium, Sabina Berretta, Evan Z Macosko, Jonathan Sebat, Luke J O'Connor, David M Hougaard, Anders D BørglumMichael E Talkowski, Steven A McCarroll, Elise B Robinson

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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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.

Original languageEnglish
JournalNature Genetics
Volume54
Issue11
Pages (from-to)1630-1639
Number of pages10
ISSN1061-4036
DOIs
Publication statusPublished - Nov 2022

Keywords

  • Autistic Disorder/genetics
  • Chromosome Deletion
  • Chromosomes
  • Chromosomes, Human, Pair 16/genetics
  • DNA Copy Number Variations
  • Humans

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