PhD Defense: Mapping Genome-wide Neuropsychiatric Mutation Effects On Functional Brain Connectivity
Channel: Clara Moreau
Date: 2020-09-03

Clara Moreau, Département de Neurosciences, Faculté de Médecine, Université de Montréal, CA
Supervised by Sébastien Jacquemont & Pierre Bellec

Mapping Genome-wide Neuropsychiatric Mutation Effects On Functional Brain Connectivity: Copy Number Variants Delineate Dimensions Contributing To Autism And Schizophrenia

Summary
Research on Autism Spectrum Disorder (ASD) and schizophrenia (SZ) has mainly adopted a ‘top-down’ approach, starting from psychiatric diagnosis, and moving to intermediate brain phenotypes and underlying genetic factors. Recent cross-disorder studies have raised questions about diagnostic boundaries and pleiotropic mechanisms. By contrast, the recruitment of groups based on the presence of a genetic risk factor allows for the investigation of molecular pathways related to a particular risk for neuropsychiatric conditions (NPs). Copy number variants (CNVs, loss or gain of a DNA segment), which confer high risk for NPs are natural candidates to conduct such bottom-up approaches. 
Because CNVs have a similar range of adverse effects on NPs, we hypothesized that entire classes of CNVs may converge upon shared connectivity dimensions contributing to mental illness.
Resting-state functional MRI (rs-fMRI) studies have provided critical insight into the architecture of brain networks involved in NPs, but so far only a few studies have investigated networks modulated by CNVs. 
We aimed at 1) Delineating the effects of neuropsychiatric variants on functional connectivity (FC), 2) Investigating whether the alterations associated with CNVs are also found among idiopathic psychiatric populations, 3) Testing whether deletions reorganize FC along general dimensions, irrespective of their localization in the genome. 
We gathered rsfMRI data on 502 carriers of eight NP-CNVs (high-risk), four CNVs without prior association to NPs as well as carriers of eight scarcer NP-CNVs. We also analyzed 756 subjects with idiopathic ASD, SZ, and attention deficit hyperactivity disorder (ADHD), and 5,377 controls.
Connectome-wide analyses showed a positive gene dosage effect for the 22q11.2 and 1q21.1 CNVs, and a negative association for the 16p11.2 CNV. The effect size of CNVs on relative FC (mean-connectivity adjusted) was correlated with the known level of NP-risk conferred by CNVs. Consistent with results on cognition, we also reported that deletions had a larger effect size on FC than duplications. 
We identified similarities between high-risk CNV profiles and the connectivity architecture of individuals with NPs. The level of similarity was associated with mutation severity and was strongest in SZ, followed by ASD, and ADHD. The similarity was driven by the thalamus, and the posterior cingulate cortex, previously identified as hubs in transdiagnostic psychiatric studies. These results raised questions about shared mechanisms across CNVs. By comparing deletions at the 16p11.2 and 22q11.2 loci, we identified similarities at the connectivity, and at the gene expression level. We extended this work by pooling all deletions available for analysis. We asked if connectivity alterations were associated with the severity of deletions scored using pLI, a measure of intolerance to haploinsufficiency. The haploinsufficiency profile involved the thalamus, anterior cingulate cortex, and somatomotor network and was correlated with lower general intelligence and higher autism severity scores in 3 unselected and disease cohorts. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and NPs.
Our results open new avenues for understanding polygenicity in psychiatric conditions, and the pleiotropic effect of CNVs on cognition and on risk for neuropsychiatric disorders. 

Keywords
Autism spectrum disorder, Schizophrenia, Copy number variant, Connectome-wide association study, Resting-state functional MRI, Pleiotropy, Thalamus, Bottom-up approach, Neuropsychiatric conditions