Subcortical brain alterations in carriers of genomic copy number variants

Objectives Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs) including autism (ASD) and schizophrenia (SZ). Overall, little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, we investigated gross volume, and vertex level thickness and surface maps of subcortical structures in 11 different CNVs and 6 different NPDs. Methods Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (at the following loci: 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2) and 782 controls (Male/Female: 727/730; age-range: 6-80 years) as well as ENIGMA summary-statistics for ASD, SZ, ADHD, Obsessive-Compulsive-Disorder, Bipolar-Disorder, and Major-Depression. Results Nine of the 11 CNVs affected volume of at least one subcortical structure. The hippocampus and amygdala were affected by five CNVs. Effect sizes of CNVs on subcortical volume, thickness and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and SZ. Shape analyses were able to identify subregional alterations that were averaged out in volume analyses. We identified a common latent dimension - characterized by opposing effects on basal ganglia and limbic structures - across CNVs and across NPDs. Conclusion Our findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions. We also observed distinct effects with some CNVs clustering with adult conditions while others clustered with ASD. This large cross-CNV and NPDs analysis provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD, as well as why a single CNV increases the risk for a diverse set of NPDs. ### Competing Interest Statement MvdB reports grants from Takeda Pharmaceuticals, outside the submitted work. P.M.T. and CRKC received a research grant from Biogen Inc. for work unrelated to this manuscript. P.T. received a grant from the Canadian Institute of health research (CIHR) that financed her master's degree. All other authors reported no biomedical financial interests or potential conflicts of interest. ### Funding Statement This research was supported by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca), the Brain Canada Multi-Investigator initiative, NIH U01 grant for CAMP (1U01MH119690-01), the Canadian Institutes of Health Research, CIHR\_400528, The Institute of Data Valorization (IVADO) through the Canada First Research Excellence Fund, Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund. Dr Jacquemont is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. The Cardiff CNV cohort was supported by the Wellcome Trust Strategic Award "DEFINE" and the National Centre for Mental Health with funds from Health and Care Research Wales (code 100202/Z/12/Z). The CHUV cohort was supported by the SNF (Maillard Anne, Project, PMPDP3 171331). Data from the UCLA cohort provided by Dr. Bearden (participants with 22q11.2 deletions or duplications and controls) was supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, R03MH105808), and the Simons Foundation (SFARI Explorer Award). Claudia Modenato was supported by the doc. mobility grant provided by the Swiss National Science Foundation (SNSF). Kuldeep Kumar was supported by The Institute of Data Valorization (IVADO) Postdoctoral Fellowship program, through the Canada First Research Excellence Fund. CRKC and PMT are supported in part by NIMH grants R01MH116147, R01MH123163, and R01MH121246, and by the Milken Institute and the Baszucki Brain Research Fund. Dr. Sonderby is supported by the Research Council of Norway (#223273), South-Eastern Norway Regional Health Authority (#2020060), European Union's Horizon2020 Research and Innovation Programme (CoMorMent project; Grant #847776), and Kristian Gerhard Jebsen Stiftelsen (SKGJ-MED-021). BD is supported by the Swiss National Science Foundation (NCCR Synapsy, project grant numbers 32003B\_135679, 32003B\_159780, 324730\_192755 and CRSK-3_190185), the Roger De Spoelberch and the Leenaards Foundations. We thank all of the families participating at the Simons Searchlight sites, as well as the Simons Searchlight Consortium. We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons Searchlight population dataset described in this study by applying at https://base.sfari.org. We are grateful to all families who participated in the 16p11.2 European Consortium. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of CHU Ste Justine research center gave ethical approval for this work. In addition, each cohort and the corresponding study received approval from their local institutional review board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes UK Biobank data was downloaded under the application 40980, and may be accessed via their standard data access procedure (see http://www.ukbiobank.ac.uk/register-apply). UK Biobank CNVs were called using the pipeline developed in the Jacquemont Lab, as described at https://github.com/labjacquemont/MIND-GENESPARALLELCNV. The final CNV calls are available for download from the UK Biobank returned datasets (Return ID: 3104, https://biobank.ndph.ox.ac.uk/ukb/dset.cgi?id=3104). References to the processing pipeline and R package versions used for analysis are listed in methods.