Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability

Zoe Schmilovich; Vincent-Raphaël Bourque; Elise Douard; Guillaume Huguet; Cécile Poulain; Jay P Ross; Paria Alipour; Charles-Étienne Castonguay; Nadine Younis; Martineau Jean-Louis; Zohra Saci; Zdenka Pausova; Tomas Paus; Gunter Schuman; David Porteous; Gail Davies; Paul Redmond; Sarah E Harris; Ian J Deary; Heather Whalley; Caroline Hayward; Patrick A Dion; Sébastien Jacquemont; Guy A Rouleau

doi:10.3389/fpsyt.2024.1369767

Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability

Front Psychiatry. 2024 May 1:15:1369767. doi: 10.3389/fpsyt.2024.1369767. eCollection 2024.

Authors

Zoe Schmilovich^{1

2

3}, Vincent-Raphaël Bourque^{3

4}, Elise Douard^{3

4}, Guillaume Huguet³, Cécile Poulain^{3

4}, Jay P Ross^{1

2}, Paria Alipour^{1

2}, Charles-Étienne Castonguay^{1

2}, Nadine Younis⁴, Martineau Jean-Louis³, Zohra Saci³, Zdenka Pausova^{5

6}, Tomas Paus^{3

7

8}, Gunter Schuman⁹, David Porteous^{10

11}, Gail Davies¹⁰, Paul Redmond¹⁰, Sarah E Harris¹⁰, Ian J Deary¹⁰, Heather Whalley¹¹, Caroline Hayward¹¹, Patrick A Dion^{2

12}, Sébastien Jacquemont^{3

4}, Guy A Rouleau^{1

2

12}

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, Canada.
² Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada.
³ Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada.
⁴ Département de Pédiatrie, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
⁵ The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁶ Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
⁷ Departments of Psychiatry of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
⁸ Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada.
⁹ Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
¹⁰ Lothian Birth Cohorts Group, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
¹¹ Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, United Kingdom.
¹² Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.

Abstract

Introduction: Rare 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.

Methods: In 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.

Results: Bottom 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.

Discussion: Our 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: ASD autism spectrum disorders; CNV (copy number variant); cognitive abilities; intelligence quotient (IQ); polygenic risk score (PRS).

Copyright © 2024 Schmilovich, Bourque, Douard, Huguet, Poulain, Ross, Alipour, Castonguay, Younis, Jean-Louis, Saci, Pausova, Paus, Schuman, Porteous, Davies, Redmond, Harris, Deary, Whalley, Hayward, Dion, Jacquemont and Rouleau.

Abstract

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