Cortical differences across psychiatric disorders and associated common and rare genetic variants

Abstract Genetic studies have identified common and rare variants increasing the risk for neurodevelopmental and psychiatric disorders (NPDs). These risk variants have also been shown to influence the structure of the cerebral cortex. However, it is unknown whether cortical differences associated with genetic variants are linked to the risk they confer for NPDs. To answer this question, we analyzed cortical thickness (CT) and surface area (SA) for common and rare variants associated with NPDs, in ∼33000 individuals from the general population and clinical cohorts, as well as ENIGMA summary statistics for 8 NPDs. Rare and common genetic variants increasing risk for NPDs were preferentially associated with total SA, while NPDs were preferentially associated with mean CT. Larger effects on mean CT, but not total SA, were observed in NPD medicated subgroups. At the regional level, genetic variants were preferentially associated with effects in sensorimotor areas, while NPDs showed higher effects in association areas. We show that schizophrenia- and bipolar-disorder- associated SNPs show positive and negative effect sizes on SA suggesting that their aggregated effects cancel out in additive polygenic models. Overall, CT and SA differences associated with NPDs do not relate to those observed across individual genetic variants and may be linked with critical non-genetic factors, such as medication and the lived experience of the disorder. Competing Interest Statement The authors have declared no competing 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. G.D. is supported by the Institute for Data Valorization, Montreal (IVADO; CF00137433), the Fonds de recherche du Quebec (FRQ; 285289), the Natural Sciences and Engineering Research Council of Canada (NSERC; DGECR-2023-00089), and the Azrieli Global Scholars Fellowship from the Canadian Institute for Advanced Research (CIFAR) in the Brain, Mind, & Consciousness program. 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: This study, using an aggregate dataset, obtained ethics approval from the CHU Sainte-Justine Hospital. 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. 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