Advisors: Thomas Bourgeron
Advisors: Pierre Bellec
Mapping genome-wide neuropsychiatric mutation effects on functional brain connectivity: Copy number variants delineate dimensions contributing to autism and schizophrenia.
Co-supervised by: Sébastien Jacquemont (Geneticist, Sainte Justine Hospital) and Pierre L. Bellec (Computer Science Department, SIMEXP lab, CR-IUGM, University of Montreal)
Advisors: P.M. Thompson, University of South California
Skills: DTI analyses (ENIGMA) - Cross-CNVs data
Skills: MRI Protocol development and Scanning, Analyses (R, Matlab), Website development for family recruitment, neuropsychological assessment. S. Jacquemont’s laboratory
Ecole Normale Supérieure and Descartes University, Paris
Advisors: Marion Noulhiane and Lucie Hertz-Pannier UNIACT
Skills: fMRI analysis (SPM, Matlab), Neurodevelopmental cohort, memory tasks.
Advisor: Pr. P. Jolicoeur, Neuroscience department
Skills: MEG/EEG analyses for an auditory task.
Advisors: Pr. M. Noulhiane and Dr C. Chiron, Necker Children Hospital
Descartes University, Paris-V
Advisor: Pr. N. Ravel and Pr. Rémi Gervais
Skills: Recording olfactory cells in mice (electrophysiology) and signal processing
Victor Duruy High School, Paris 75007 France
Symposium “Large Scale Imaging Studies of Rare Copy Number variants: Brain Imaging from Enigma and Other Large-Scale International Studies”
Symposium “Human and Animal Models: Impact of High-Risk Copy Number Variants on Brain Structure, Functional Connectivity, and Sexual Development.”
Lecture "From the first human genome to recent application in genome edition: ethical issues.”(45 min)
Symposium Conciliate Research, Innovation and Open Science
Genomic information (C. Pernet).
Co-organizer with Pierre Bellec, Lausanne, Switzerland
Brain and Development research section at the Ste Justine Hospital, Montreal
For PhD students, n=6 editions
Lausanne (EPFL), and Paris (ENS, CogInnov, and ESPCI).
National political committee
French organization of researchers
“Conciliate Open Science, Patents, and Intellectual property issues”
Citizen lab in Paris
Consciousness process of intelligence across the animal, the human, and the computer
To promote Open Access of scientific publications
Open Knowledge Conference, Geneva, Switzerland
French Federation of Cognitive Science students)
Martin-Brevet, S., Rodríguez-Herreros, B., Nielsen, J. A., Moreau, C., Modenato, C., Maillard, A. M., Pain, A., Richetin, S., Jønch, A. E., Qureshi, A. Y., Zürcher, N. R., Conus, P., 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, Chung, W. K., Sherr, E. H., Spiro, J. E., Kherif, F., Beckmann, J. S., … Jacquemont, S.
16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.
Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.
Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen’s d > 1), the superior and middle temporal gyri (deletion > control; Cohen’s d inf −1), and the caudate and hippocampus (control > duplication; −0.5 > Cohen’s d > −1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder.
These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.
Sønderby, I. E., Gústafsson, Ó., Doan, N. T., Hibar, D. P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D. I., Bralten, J., Brattbak, H.-R., Brodaty, H., Brouwer, R. M., Bülow, R., … Moreau, C., … 16p11.2 European Consortium, for the ENIGMA-CNV working group.
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia.
We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV.
After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P inf 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers.
This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
van der Meer, D., Sønderby, I. E., Kaufmann, T., Walters, G. B., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Cahn, W., Calhoun, V. D., Caspers, S., ..., Moreau C., … Andreassen, O. A.
Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.
In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.
The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.
These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
Cárdenas-de-la-Parra, A., Martin-Brevet, S., Moreau, C., Rodriguez-Herreros, B., Fonov, V. S., Maillard, A. M., Zürcher, N. R., 16p11.2 European Consortium, Hadjikhani, N., Beckmann, J. S., Reymond, A., Draganski, B., Jacquemont, S., and Collins, D. L.
Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4-5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age.
In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry.
Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23.
Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.
Jønch, A. E., Douard, E., Moreau, C., Van Dijck, A., Passeggeri, M., Kooy, F., Puechberty, J., Campbell, C., Sanlaville, D., Lefroy, H., Richetin, S., Pain, A., Geneviève, D., Kini, U., Le Caignec, C., Lespinasse, J., Skytte, A.-B., Isidor, B., Zweier, C., ..., Ousager LB., Jacquemont, S., on behalf of 15q11.2 Working Group
The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case–control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.
We performed meta-analyses on new and previously published case–control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers.
15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant. The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.
We recommend that the deletion should be classified as ‘pathogenic of mild effect size’. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.
Urchs, S., Armoza, J., Moreau, C., Benhajali, Y., St-Aubin, J., Orban, P., Bellec, P.
The functional architecture of the brain is organized across multiple levelsof spatial resolutions, from distributed networks to the localized areas theyare made of. A brain parcellation that defines functional nodes at multipleresolutions is required to investigate the functional connectome acrossthese scales.
Here we present the Multiresolution Intrinsic SegmentationTemplate (MIST), a multi-resolution group level parcellation of the cortical,subcortical and cerebellar gray matter. The individual MIST parcellationsmatch other published group parcellations in internal homogeneity andreproducibility and perform very well in real-world application benchmarks.In addition, the MIST parcellations are fully annotated and provide ahierarchical decomposition of functional brain networks across nineresolutions (7 to 444 functional parcels). We hope that the MISTparcellation will accelerate research in brain connectivity acrossresolutions. Because visualizing multiresolution parcellations is challenging,we provide to explore the MIST. The MIST isan interactive web interfacealso available through the popular toolbox.
Douard, E., Zeribi, A., Schramm, C., Tamer, P., Loum, M. A., Nowak, S., Saci, Z., Lord, M.-P., Rodriguez-Herreros, B., Jean-Louis, M., Moreau, C., Loth, E., Schumann, G., Pausova, Z., Elsabbagh, M., Almasy, L., Glahn, D. C., Bourgeron, T., Labbe, A., … Jacquemont, S.
Objective Deleterious 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.
Methods We 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.
Results Among 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.
Conclusions Autism 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.
Moreau, C., Martineau J.L., Blair, R., Markiewicz C, Turner J., Calhoun V., Nichols T, Pernet C.
Metadata are key in our ability to search databases. Without them, researchers would spend hours examining datasets in the hope to find data with features they are interested in. Brain imaging genetics is at the intersection of two disciplines each one with dedicated dictionaries and ontologies facilitating data search and analysis.
Here we present the genetics brain imaging data structure extension: it consists of metadata files for human brain imaging data to which they are linked to and describe succinctly the genomic and transcriptomic data associated to them, possibly in different databases. This extension will facilitate identifying micro-scale molecular features that are linked to macro-scale imaging repositories facilitating data aggregation across studies.
Moreau, C., Raznahan, A., Bellec P.,, Chakravarty M., Thompson, P.M., Jacquemont, S.
Top-down neuroimaging and genomic studies of autism spectrum disorder and schizophrenia have revealed intriguingly small neuroimaging effect-sizes and an extreme polygenic architecture. It is also evident that both genomic variants and neuroimaging patterns are shared across psychiatric diagnoses - suggesting pleiotropic mechanisms. However, it remains unknown if variants and patterns are related to core cognitive dimensions or to comorbidities.
Bottom-up studies start at the level of molecular factors to study mechanisms related to biological risk irrespective of clinical manifestations. Such approaches reveal that the effect-sizes of high-risk psychiatric mutations are equally large for neuroimaging, cognitive and behavioural traits in stark contrast to top-down studies. Low specificity has been perplexing with studies showing that broad classes of genomic variants affect a similar range of psychiatric and cognitive dimensions.
We propose a roadmap based on multivariate strategies to integrate genomics, transcriptomics, neuroimaging and phenotypic data to deconvolve mechanisms involved in psychiatric conditions. New profiling based on specific biological processes and expression scores has considerable potential for parsing the contribution of genes and mechanisms to dimensions underlying psychiatric conditions. Such approaches will improve mechanistically informed predictive modelling for diagnosis and treatment outcomes.
Moreau, C., Huguet, G., Urchs, S., Douard, E. A., Sharmarke, H., Orban, P., Labbe, A., Modenato, C., Martin-Brevet, S., Kuldeep, K., Martin, C.-O., Jizi, K., Younis, N., Tamer, P., Martineau, J.-L., Silva, A. I., Jonch, A. E., Lin, A., Simons VIP Foundation, ..., Thompson, P.M., Bellec, P., Jacquemont, S.
Large effect-size mutations such as copy number variants (CNVs) have the potential to provide key insights into the underlying biological mechanisms linking deleterious genetic variants to brain architecture and neuropsychiatric disorders. To date, the effect of CNVs on functional brain connectivity remains mostly unstudied, and findings are derived from analyses conducted one mutation at a time. The lack of systematic cross-CNV comparisons hinders our understanding of any potential general mechanisms linking CNVs to effects on brain organization.
We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, and 4 neutral-effect CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity.
The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. We reported architecture similarities between individuals with idiopathic psychiatric conditions and high-risk neuropsychiatric-CNVs, predominantly in the thalamus, the posterior cingulate cortex, and the anterior insula. We identified a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders.
We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.
Modenato, C., Kumar, K., Moreau, C., Martin-Brevet, S., Huguet, G., Schramm, C., Martineau, J.-L., Martin, C.-O., Younis, N., Tamer, P., Douard, E. A., Thebault-Dagher, F., Cote, V., Charlebois, A.-R., Deguire, F., Maillard, A. M., Rodriguez-Herreros, B., Pain, A., Richetin, S., … Jacquemont.
Background: Copy Number Variants (CNVs) associated with autism and schizophrenia have large effects on brain anatomy. Yet, neuroimaging studies have been conducted one mutation at a time. We hypothesize that neuropsychiatric CNVs may exert general effects on brain morphometry because they confer risk for overlapping psychiatric conditions.
Methods: We analyzed T1-weighted MRIs and characterized shared patterns on brain anatomy across 8 neuropsychiatric CNVs. Clinically ascertained samples included 1q21.1 (n=48), 16p11.2 (n=156), or 22q11.2 (n=96) and 331 non-carriers. Non-clinically ascertained samples from the UK Biobank included 1q21.1 (n=19), 16p11.2 (n=8), 22q11.2 (n=9), 15q11.2 (n=148) and 965 non-carriers. Canonical correlation analysis (CCA) and univariate models were used to interrogate brain morphometry changes across 8 CNVs.
Results: Eight CNVs affect regional brain volumes along two main gene-morphometry dimensions identified by CCA. While fronto-temporal regions contributed to dimension 1, dimension 2 was driven by subcortical, parietal and occipital regions. Consistently, voxel-wise whole-brain analyses identified the same regions involved in patterns of alteration present across the 4 deletions and duplications. These neuroanatomical patterns are similar to those observed in cross-psychiatric disorder meta-analyses. Deletions and duplications at all 4 loci show mirror effects at either the global and/or the regional level.
Conclusion: Neuropsychiatric CNVs share neuroanatomical signatures characterized by a parsimonious set of brain dimensions. The latter may underlie the risk conferred by CNVs for a similar spectrum of neuropsychiatric conditions.
Sønderby, I.E., Van der Meer, D., Kaufmann, T., Moreau, C., …, Jacquemont, S., Thompson, P., Andreassen.
Urchs, S. G. W., Tam, A., Orban, P., Moreau, C., Benhajali, Y., Nguyen, H. D., Evans, A. C., Bellec, P.
Our understanding of the changes in functional brain organization in autism is hampered by the extensive heterogeneity that characterizes this neurodevelopmental disorder. Data driven clustering offers a straightforward way to decompose this heterogeneity into subtypes of distinguishable connectivity types and promises an unbiased framework to investigate behavioural symptoms and causative genetic factors. Yet the robustness and generalizability of these imaging subtypes is unknown.
Here, we show that unsupervised functional connectivity subtypes are moderately associated with the clinical diagnosis of autism, and that these associations generalize to independent replication data. We found that subtypes identified robust patterns of functional connectivity, but that a discrete assignment of individuals to these subtypes was not supported by the data.
Our results support the use of data driven subtyping as a data dimensionality reduction technique, rather than to establish clinical categories.
Moreau, C., Urchs, S., Orban, P., Schramm, C., Dumas, G., Labbe, A., Huguet, G., Douard, E., Quirion, P.-O., Lin, A., Kushan, L., Grot, S., Luck, D., Mendrek, A., Potvin, S., Stip, E., Bourgeron, T., Evans, A. C., SimonsVIP Consortium, Bearden, CE., Bellec, P., Jacquemont, S.
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) networks 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 major dimensions contributing to complex idiopathic conditions.
CNVs had large mirror effects on FC at the global and regional level, and their effect-sizes were twice as large as those of idiopathic conditions. 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 behavioral and cognitive symptoms. These seemingly distinct neuropsychiatric mutations showed similar gene co-expression patterns and converged on FC dimensions, that may represent mechanistic building blocks shared across idiopathic conditions.