Biology subjects

Douard, E.

Publications and source records attributed to Douard, E..

3 recordsLinked to original sources

bioRxiv2020

Effects-sizes of deletions and duplications on autism risk across the genome

ObjectiveDeleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains. MethodsWe identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains. ResultsAmong 9 scores of genes, the "probability-of-being loss-of-function intolerant" (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller. The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ. Once CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behaviour, and phonological memory, whereas both equally affect motor skills. ConclusionsAutism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.

genetics↗

bioRxiv2019

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibited worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.

neuroscience↗

bioRxiv2019

Superior temporal sulcus hypoperfusion in children with autism spectrum disorder: an arterial spin-labeling magnetic resonance study

Advances in neuroimaging techniques have significantly improved our understanding of the neural basis of autism spectrum disorder (ASD). Several attempts have been made to label the main neuroimaging phenotype of ASD, mostly by anatomical and functional activation studies, but none of the frameworks have been without controversy. Over the past decade, a renewed interest for rest brain functioning has emerged in the scientific community, reflected on a large number of resting state fMRI (rs-fMRI) studies, but results remain heterogeneous. It is possible today to investigate rest brain functioning by measuring rest cerebral blood flow (CBF) with MRI using arterial spin labeling (ASL). Here, we investigated rest CBF abnormalities using non-invasive ASL-MRI in 18 children with ASD without cognitive delay (10.4 {+/-} 2.8 y) and 30 typically developing children (10.6 {+/-} 3.0 y). Following quality control, images from a final sample of 12 children with ASD (11.2 {+/-} 2.9 y) and 28 typically developing children (10.1 {+/-} 2.5 y) were analyzed. Whole brain voxel-by-voxel analysis showed significant rest CBF decrease in temporal regions, mainly in the superior temporal sulcus (STS), in children with ASD. This hypoperfusion was individually detected in 83% of children with ASD. Finally, negative correlation was observed between ASD severity scores and rest CBF in the right posterior STS. Strikingly, despite the small sample studied here, our results are extremely similar to previous PET and SPECT findings describing decreased rest CBF in the same superior temporal regions at group and individual levels, as well as correlation with symptoms severity. The congruence between these results, with different methods and in different ASD profiles, reinforce the strength of rest functional abnormalities within these superior temporal regions in ASD and strongly indicates it might be a core characteristic of the disorder. Identifying a core dysfunctional region in ASD bears direct implications to the development of novel therapeutic interventions, such as transcranial magnetic stimulation. In addition, if confirmed in a larger sample, rest temporal hypoperfusion could become a reliable brain imaging biomarker in ASD.

neuroscience↗