TY - JOUR
T1 - Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability
AU - Schmilovich, Zoe
AU - Bourque, Vincent Raphaël
AU - Douard, Elise
AU - Huguet, Guillaume
AU - Poulain, Cécile
AU - Ross, Jay P.
AU - Alipour, Paria
AU - Castonguay, Charles Étienne
AU - Younis, Nadine
AU - Jean-Louis, Martineau
AU - Saci, Zohra
AU - Pausova, Zdenka
AU - Paus, Tomas
AU - Schuman, Gunter
AU - Porteous, David
AU - Davies, Gail
AU - Redmond, Paul
AU - Harris, Sarah E.
AU - Deary, Ian J.
AU - Whalley, Heather
AU - Hayward, Caroline
AU - Dion, Patrick A.
AU - Jacquemont, Sébastien
AU - Rouleau, Guy A.
N1 - ZSc: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing. VB: Writing – original draft, Writing – review & editing. ED: Conceptualization, Data curation, Investigation, Visualization, Writing – original draft, Writing – review & editing. GH: Conceptualization, Data curation, Investigation, Supervision, Writing – original draft, Writing – review & editing. CP: Data curation, Methodology, Software, Writing – original draft, Writing – review & editing. JR: Data curation, Visualization, Writing – original draft, Writing – review & editing. PA: Formal analysis, Writing – original draft, Writing – review & editing. CC: Formal analysis, Writing – original draft, Writing – review & editing. NY: Data curation, Writing – original draft, Writing – review & editing. MJ: Data curation, Writing – original draft, Writing – review & editing. ZSa: Data curation, Writing – original draft, Writing – review & editing. ZP: Data curation, Resources, Writing – original draft, Writing – review & editing. TP: Data curation, Resources, Writing – original draft, Writing – review & editing. GS: Data curation, Resources, Writing – original draft, Writing – review & editing. DP: Data curation, Resources, Writing – original draft, Writing – review & editing. GD: Data curation, Resources, Writing – original draft, Writing – review & editing. PR: Data curation, Resources, Writing – original draft, Writing – review & editing. SH: Data curation, Resources, Writing – original draft, Writing – review & editing. ID: Data curation, Resources, Writing – original draft, Writing – review & editing. HW: Data curation, Resources, Writing – original draft, Writing – review & editing. CH: Data curation, Resources, Writing – original draft, Writing – review & editing. PD: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing. SJ: Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing. GR: Writing – original draft, Writing – review & editing.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - ASD autism spectrum disorders
KW - CNV (copy number variant)
KW - cognitive abilities
KW - intelligence quotient (IQ)
KW - polygenic risk score (PRS)
UR - https://www.sfari.org/resource/simons-simplex-collection/
U2 - 10.3389/fpsyt.2024.1369767
DO - 10.3389/fpsyt.2024.1369767
M3 - Article
AN - SCOPUS:85193512852
SN - 1664-0640
VL - 15
JO - Frontiers in Psychiatry
JF - Frontiers in Psychiatry
M1 - 1369767
ER -