Mapping neuropsychiatric mutation effects on functional brain connectivity to delineate dimensions contributing to autism and schizophrenia

Recording of Presentation

Event

Speaker: Clara Moreau

Bio: Clara Moreau is a PhD candidate in Neuroscience (2015-2020) co-directed by Sébastien Jacquemont (Geneticist, Sainte Justine Hospital) and Pierre Bellec (Associate professor in Psychology, CR-IUGM) at the University of Montreal. She obtained a master’s degree in Cognitive Science in 2014 from the Paris-Descartes University and the “Ecole Normale Supérieure”. She also worked as a research assistant at the Genetics Department of the CHUV (Lausanne, Switzerland, 2014-2015). She will pursue her postdoc at the Imaging Genetics Center of USC, supervised by Paul M. Thompson.

Talk Abstract: Copy number variants (CNVs) are among the most highly penetrant genetic risk factors for neuropsychiatric disorders. Because they confer risk for overlapping conditions, we hypothesized that they may converge on shared connectivity patterns. We performed connectome-wide analyses using resting-state fMRI data from 502 carriers of CNVs associated to different degrees with neuropsychiatric conditions, 756 individuals with idiopathic ASD, schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. We showed that the effect size of CNVs on connectivity was correlated with the known level of clinical risk conferred by mutations. We identified similarities between connectivity profiles of high-risk mutations and the connectivity architecture of individuals with schizophrenia and autism. Similarities were driven by the thalamus, and the posterior cingulate cortex, previously identified as major hubs altered across psychiatric conditions. Because these results raised questions about shared mechanisms across CNVs, we then posited that haploinsufficiency may reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. Using a continuous score to quantify the severity of deletions (pLI), we identified a connectivity profile that appears to be present in deletions irrespective of genomic location. This profile was correlated with lower general intelligence and higher autism severity scores in 3 unselected and disease cohorts. Such general brain signatures open new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for mental illnesses.

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