Genetic correlates of phenotypic heterogeneity in autism

Varun Warrier*, Xinhe Zhang, Patrick Reed, Alexandra Havdahl, Tyler M Moore, Freddy Cliquet, Claire S Leblond, Thomas Rolland, Anders Rosengren, David H Rowitch, Matthew E Hurles, Daniel H Geschwind, Anders D Børglum, Elise B Robinson, Jakob Grove, Hilary C Martin, Thomas Bourgeron, Simon Baron-Cohen, EU-AIMS LEAP, iPSYCH-Autism Working GroupSpectrum 10K and APEX Consortia

*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 substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.

Original languageEnglish
JournalNature Genetics
Volume54
Issue9
Pages (from-to)1293-1304
Number of pages12
ISSN1061-4036
DOIs
Publication statusPublished - Sept 2022

Keywords

  • AGE
  • ARCHITECTURE
  • CHILDREN
  • COMMON
  • DE-NOVO MUTATIONS
  • GENOME-WIDE ASSOCIATION
  • IDENTIFICATION
  • RISK
  • SIMONS SIMPLEX COLLECTION
  • SPECTRUM DISORDER

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