Genetic correlates of phenotypic heterogeneity in autism

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  • Varun Warrier
  • Xinhe Zhang
  • Patrick Reed
  • Alexandra Havdahl
  • Tyler M. Moore
  • Freddy Cliquet
  • Claire S. Leblond
  • Thomas Rolland
  • Anders Rosengren
  • Antonia San Jose Caceres
  • Hannah Hayward
  • Daisy Crawley
  • Jessica Faulkner
  • Jessica Sabet
  • Claire Ellis
  • Bethany Oakley
  • Eva Loth
  • Tony Charman
  • Declan Murphy
  • Rosemary Holt
  • Jack Waldman
  • Jessica Upadhyay
  • Nicola Gunby
  • Meng Chuan Lai
  • Gwilym Renouf
  • Amber Ruigrok
  • Emily Taylor
  • Hisham Ziauddeen
  • Julia Deakin
  • Sara Ambrosino di Bruttopilo
  • Sarai van Dijk
  • Yvonne Rijks
  • Tabitha Koops
  • Miriam Douma
  • Alyssia Spaan
  • Iris Selten
  • Maarten Steffers
  • Anna Ver Loren van Themaat
  • Nico Bast
  • Sarah Baumeister
  • Larry O’Dwyer
  • Carsten Bours
  • Annika Rausch
  • Daniel von Rhein
  • Ineke Cornelissen
  • Yvette de Bruin
  • Maartje Graauwmans
  • Elzbieta Kostrzewa
  • Werge, Thomas
  • Nordentoft, Merete
  • EU-AIMS LEAP
  • iPSYCH-Autism Working Group
  • Spectrum 10K and APEX Consortia

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
Issue number9
Pages (from-to)1293-1304
Number of pages12
ISSN1061-4036
DOIs
Publication statusPublished - 2022

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