“Phenotypic Effects of Genetic Variants Associated With Autism”, Thomas Rolland, Freddy Cliquet, Richard J. L. Anney, Clara Moreau, Nicolas Traut, Alexandre Mathieu, Guillaume Huguet, Jinjie Duan, Varun Warrier, Swan Portalier, Louise Dry, Claire S. Leblond, Elise Douard, Frédérique Amsellem, Simon Malesys, Anna Maruani, Roberto Toro, Anders Børglum, Jakob Grove, Simon Baron-Cohen, Alan Packer, Wendy K. Chung, Sébastien Jacquemont, Richard Delorme, Thomas Bourgeron2023-06-26 (genetic correlation, rare mutations, IQ, autism)⁠:

While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis.

Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism.

We show that these variants are associated with a small but statistically-significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes.

[In addition] Using brain imaging data from 21,040 individuals from the UK Biobank, we:

could not detect statistically-significant differences in the overall brain anatomy between LoF carriers and non-carriers.

Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.

…We further investigated the effect of S-LoFs within more homogeneous subgroups based on their cognitive and socioeconomic scores and observed that the highest effect sizes of S-LoFs were found for the subgroups of individuals with lower scores of fluid intelligence, income, qualification and higher scores of the Townsend deprivation index (Extended Data Figure 8). Notably, in contrast to the impact of S-LoFs, the autism PGS was positively associated with fluid intelligence and qualification level; however, as for S-LoFs, the autism PGS was also associated with increased level of the Townsend deprivation index (Figure 5b). Altogether our results on a large sample of individuals with autism and undiagnosed individuals indicate that S-LoFs mostly affect the cognitive skills of individuals rather than their socio-communication abilities, as previously reported for large copy-number variants or de novo single-nucleotide variants^{7,28,29,30,31}.