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; EU-AIMS LEAP; iPSYCH-Autism Working Group; Spectrum 10K and APEX Consortia; 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

doi:10.1038/s41588-022-01072-5

Genetic correlates of phenotypic heterogeneity in autism

Nat Genet. 2022 Sep;54(9):1293-1304. doi: 10.1038/s41588-022-01072-5. Epub 2022 Jun 2.

Authors

Varun Warrier¹, Xinhe Zhang², Patrick Reed², Alexandra Havdahl^{3

4

5}, Tyler M Moore^{6

7}, Freddy Cliquet⁸, Claire S Leblond⁸, Thomas Rolland⁸, Anders Rosengren^{9

10}; EU-AIMS LEAP; iPSYCH-Autism Working Group; Spectrum 10K and APEX Consortia; David H Rowitch¹¹, Matthew E Hurles¹², Daniel H Geschwind^{13

14

15

16}, Anders D Børglum^{9

17

18}, Elise B Robinson^{19

20

21}, Jakob Grove^{9

17

18

22}, Hilary C Martin¹², Thomas Bourgeron⁸, Simon Baron-Cohen²³

Collaborators

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, Elodie Cauvet, Kristiina Tammimies, Rouslan Sitnikow, Guillaume Dumas, Yang-Min Kim, Thomas Bourgeron, David M Hougaard, Jonas Bybjerg-Grauholm, Thomas Werge, Preben Bo Mortensen, Ole Mors, Merete Nordentoft, Dwaipayan Adhya, Armandina Alamanza, Carrie Allison, Isabelle Garvey, Tracey Parsons, Paula Smith, Alex Tsompanidis, Graham J Burton, Alexander E P Heazell, Lidia V Gabis, Tal Biron-Shental, Madeline A Lancaster, Deepak P Srivastava, Jonathan Mill

Affiliations

¹ Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK. vw260@medschl.cam.ac.uk.
² Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK.
³ Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁴ Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
⁵ PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
⁶ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Lifespan Brain Institute of the Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA.
⁸ Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris Cité, Paris, France.
⁹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
¹⁰ Institute of Biological Psychiatry, MHC Sct Hans, Copenhagen University Hospital, Copenhagen, Denmark.
¹¹ Department of Paediatrics, Cambridge University Clinical School, Cambridge, UK.
¹² Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹³ Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁶ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁷ Center for Genomics and Personalized Medicine (CGPM), Aarhus University, Aarhus, Denmark.
¹⁸ Department of Biomedicine (Human Genetics) and iSEQ Center, Aarhus University, Aarhus, Denmark.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²² Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
²³ Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK. sb205@cam.ac.uk.

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 (n_max = 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
Cognition
Female
Humans
Intellectual Disability* / genetics
Male

Abstract

Publication types

MeSH terms

Grants and funding