Towards a gene-level map of resilience to genetic variants associated with autism

Thomas Rolland (1) , Freddy Cliquet (1) , Richard J. L. Anney (2) , Nicolas Traut (1, 3) , Alexandre Mathieu (1) , Guillaume Huguet (4, 5) , Claire S. Leblond (1) , Elise Douard (4, 5) , Frédérique Amsellem (1, 6) , Simon Malesys (1) , Anna Maruani (1, 6) , Roberto Toro (1, 3) , Alan Packer (7) , Wendy K. Chung (7, 8) , Sébastien Jacquemont (4, 5) , Richard Delorme (1, 6) , Thomas Bourgeron (1)

1 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
2 Cardiff University
3 CRI - Centre de Recherches Interdisciplinaires
4 UdeM - Université de Montréal
5 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
6 Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré]
7 Simons Foundation
8 CUMC - Columbia University Medical Center

While over 100 genes are now significantly associated with autism spectrum disorders (ASD), the penetrance of the variants affecting these genes remains poorly understood. Here, we quantified the prevalence of rare loss-of-function (LoF) mutations affecting 156 genes robustly associated with ASD (SPARK genes) using genetic data from more than 10,000 individuals with ASD and 100,000 undiagnosed individuals. We then investigated the clinical, brain imaging and genetic profiles of individuals heterozygous for these rare deleterious variants who were not diagnosed with ASD. These “resilient” individuals, observed in less than 1% of the general population, were equally distributed among males and females, but displayed low polygenic scores for ASD compared to LoF heterozygotes diagnosed with ASD. The interplay between rare and common variants may therefore contribute to the clinical profiles of the individuals carrying LoF in genes associated with ASD.

Domaines: Génétique humaine; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Bio-informatique [q-bio.QM]

Thomas Rolland, Freddy Cliquet, Richard J. L. Anney, Nicolas Traut, Alexandre Mathieu, et al.. Towards a gene-level map of resilience to genetic variants associated with autism. 2021. ⟨pasteur-03261138v1⟩