Abstract
Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74–96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.
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Code availability
The present study applied previously published approaches, of which codes are shared on public repositories: MiXeR v1.3 (https://github.com/precimed/mixer), conjFDR analysis (https://github.com/precimed/pleiofdr), PrediXcan (https://github.com/hakyimlab/PrediXcan), and S-PrediXcan (https://github.com/hakyimlab/MetaXcan).
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Acknowledgements
The authors thank the Psychiatric Genetics Consortium (PGC, https://www.med.unc.edu/pgc/), the UK biobank (https://www.ukbiobank.ac.uk/), the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA, http://enigma.ini.usc.edu/) consortium for access to GWAS data, as well as Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org) for access to genotype and brain imaging data. We thank all participants and employees of PGC, UK biobank (Application ID 27412), and ENIGMA, ABCD for their contribution to this study. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers: U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners/. The authors were funded by the National Institutes of Health (grants NS057198 and EB00790), the Research Council of Norway (grants 229129, 276082, 213837, 223273, and 248980), the South-East Regional Health Authority (grant 2017–112), Stiftelsen Kristian Gerhard Jebsen (grants SKGJ-MED-008 and SKGJ-MED-021), the Psychiatric Genomics Consortium US Norway Collaboration (RCN 248980), part of convergence environment (MultiModal Mental Models [4MENT]) funded by the University of Oslo Life Science and Scientia Fellows, European Union’s Horizon 2020 Research and Innovation Active Grant (847776 CoMorMent), and European Union’s Horizon 2020 research and innovation programme (801133 Marie Skłodowska-Curie grant agreement), and have received internationalization support from UiO:Life Science. This work was performed on resources provided by Sigma2 (the National Infrastructure for High Performance Computing and Data Storage in Norway) and the TSD (Tjeneste for Sensitive Data) facilities.
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WQ and OA designed the study; WQ and DvdM pre-processed the data. WQ performed all analyses, with conceptual input from OA, DvdM, YW, NP, GH, and OS. All authors helped shape the research, and contributed to interpretation of results. WQ drafted the manuscript with input from OA, OS, NP, GH, and DvdM. All authors contributed to and approved the final manuscript.
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Dr. Andreassen reported grants from Stiftelsen Kristian Gerhard Jebsen, South-East Regional Health Authority, Research Council of Norway, and European Union’s Horizon 2020 during the conduct of the study; personal fees from HealthLytix (stock options), Lundbeck (speaker’s honorarium), and Sunovion (speaker’s honorarium) outside the submitted work; and had a pending patent for systems and methods for identifying polymorphisms. Dr. Dale reported grants from the National Institutes of Health outside the submitted work; had a patent for US7324842 licensed to Siemens Healthineers; is a founder of and holds equity in Cortechs Labs and serves on its scientific advisory board; is a member of the scientific advisory board of Human Longevity; a member of the scientific advisory board of Healthlytix; and receives funding through a research agreement with GE Healthcare. No other disclosures were reported.
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Cheng, W., van der Meer, D., Parker, N. et al. Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood. Mol Psychiatry 27, 5167–5176 (2022). https://doi.org/10.1038/s41380-022-01751-z
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DOI: https://doi.org/10.1038/s41380-022-01751-z
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