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• W4387496650 abstract "Neurodevelopmental disorders (NDDs) are a spectrum of disorders associated to nervous system and its development. They are diagnosed in 11 – 22% of the general population. Pathogenic copy number variants (CNVs) are detected in 10-15% of patients referred for NDDs. Previous studies have shown that models stratifying genes based on their intolerance to loss of function scores (LOEUF) can accurately (78%) estimate the impact of CNVs on cognitive ability. Although these models assume that CNVs have a negative impact on cognitive abilities, they do not provide a comprehensive understanding of the underlying biological functions involved. Our hypothesis is partitioning the genome based on biological functions and constraint scores, will give new insights of biological mechanisms contributing to cognitive abilities. The purpose of this study is to characterize the diversity of effect sizes on cognitive abilities for various brain and non-brain gene-sets. From 258,292 individuals of 6 general populations, we identify all CNV >50Kb. The identification was performed with PennCNV and QuantiSNP from microarray. Cognitive ability of each individual was measured using different assessments. The genome was divided into multiples gene-sets following different biological features. These gene-sets are genes over expressed in particular brain cell types (7 adult and 16 fetal), preferentially expressed in 11 brain tissues and in 25 non-brain tissues. We use each gene-set to perform a linear regression to estimate the effect size of these genes on cognitive ability. LOEUF only reflects genetic fitness, so we designed a functional burden method to explore tissues and cells associated genes effects on cognitive ability. Deletions of genes preferentially expressed in brain tissues have stronger negative effects on cognitive ability than duplications. Furthermore, we observe that tissue with significant effect sizes (after FDR correction) for deletions and duplications are not overlapping, showing a gene dosage specificity for brain structures. At the cellular level, the largest effects for deletions and duplications were observed in gene-sets assigned to fetal cell types. Deletions showed larger effects in non-neuronal (endothelial, glia) cell types, while duplications of neuronal (excitatory) genes are the largest. Because of the growing interest in the brain-whole body health comorbidities, we asked if genes implicated in non-brain tissues were also associated with cognitive ability. Thus, many non-brain gene-sets showed similar or even larger effects sizes than brain tissues. This surprising result was not explained by the overlap between brain and non-brain gene-sets, or the existence of ubiquitous genes within gene-sets. These findings demonstrate that cognitive ability is not characterized by brain structures alone, but by numerous variables throughout the body. So future predictive models estimating genes effect sizes on cognitive ability should take gene fitness and biological expression in account to improve model accuracy. Finally, these observations open new perspectives on neurodevelopmental disorders studies to investigate rare CNVs effects on diagnoses." @default.
• W4387496650 created "2023-10-11" @default.
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• W4387496650 date "2023-10-01" @default.
• W4387496650 modified "2023-10-12" @default.
• W4387496650 title "T55. DESCRIBING THE BROAD SPECTRUM OF CNVS EFFECT SIZES ON COGNITIVE ABILITY ACROSS BRAIN AND NON-BRAIN TISSUE" @default.
• W4387496650 doi "https://doi.org/10.1016/j.euroneuro.2023.08.340" @default.
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