Frontiers in Psychiatry (May 2024)
Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability
- Zoe Schmilovich,
- Zoe Schmilovich,
- Zoe Schmilovich,
- Vincent-Raphaël Bourque,
- Vincent-Raphaël Bourque,
- Elise Douard,
- Elise Douard,
- Guillaume Huguet,
- Cécile Poulain,
- Cécile Poulain,
- Jay P. Ross,
- Jay P. Ross,
- Paria Alipour,
- Paria Alipour,
- Charles-Étienne Castonguay,
- Charles-Étienne Castonguay,
- Nadine Younis,
- Martineau Jean-Louis,
- Zohra Saci,
- Zdenka Pausova,
- Zdenka Pausova,
- Tomas Paus,
- Tomas Paus,
- Tomas Paus,
- Gunter Schuman,
- David Porteous,
- David Porteous,
- Gail Davies,
- Paul Redmond,
- Sarah E. Harris,
- Ian J. Deary,
- Heather Whalley,
- Caroline Hayward,
- Patrick A. Dion,
- Patrick A. Dion,
- Sébastien Jacquemont,
- Sébastien Jacquemont,
- Guy A. Rouleau,
- Guy A. Rouleau,
- Guy A. Rouleau
Affiliations
- Zoe Schmilovich
- Department of Human Genetics, McGill University, Montréal, QC, Canada
- Zoe Schmilovich
- Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada
- Zoe Schmilovich
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Vincent-Raphaël Bourque
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Vincent-Raphaël Bourque
- Département de Pédiatrie, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Elise Douard
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Elise Douard
- Département de Pédiatrie, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Guillaume Huguet
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Cécile Poulain
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Cécile Poulain
- Département de Pédiatrie, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Jay P. Ross
- Department of Human Genetics, McGill University, Montréal, QC, Canada
- Jay P. Ross
- Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada
- Paria Alipour
- Department of Human Genetics, McGill University, Montréal, QC, Canada
- Paria Alipour
- Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada
- Charles-Étienne Castonguay
- Department of Human Genetics, McGill University, Montréal, QC, Canada
- Charles-Étienne Castonguay
- Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada
- Nadine Younis
- Département de Pédiatrie, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Martineau Jean-Louis
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Zohra Saci
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Zdenka Pausova
- The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Zdenka Pausova
- Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada
- Tomas Paus
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Tomas Paus
- Departments of Psychiatry of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Tomas Paus
- Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada
- Gunter Schuman
- Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
- David Porteous
- 0Lothian Birth Cohorts Group, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- David Porteous
- 1Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, United Kingdom
- Gail Davies
- 0Lothian Birth Cohorts Group, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Paul Redmond
- 0Lothian Birth Cohorts Group, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Sarah E. Harris
- 0Lothian Birth Cohorts Group, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Ian J. Deary
- 0Lothian Birth Cohorts Group, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Heather Whalley
- 1Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, United Kingdom
- Caroline Hayward
- 1Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, United Kingdom
- Patrick A. Dion
- Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada
- Patrick A. Dion
- 2Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
- Sébastien Jacquemont
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Sébastien Jacquemont
- Département de Pédiatrie, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Guy A. Rouleau
- Department of Human Genetics, McGill University, Montréal, QC, Canada
- Guy A. Rouleau
- Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada
- Guy A. Rouleau
- 2Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
- DOI
- https://doi.org/10.3389/fpsyt.2024.1369767
- Journal volume & issue
-
Vol. 15
Abstract
IntroductionRare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability.MethodsIn a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability.ResultsBottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD.DiscussionOur findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.
Keywords
- CNV (copy number variant)
- polygenic risk score (PRS)
- ASD autism spectrum disorders
- cognitive abilities
- intelligence quotient (IQ)
