Abstract
Several GWAS reported Myocyte Enhancer Factor 2 C (MEF2C) gene associations with white matter microstructure and psychiatric disorders, and MEF2C involvement in pathways related to neuronal development suggests a common biological factor underlying these phenotypes. We aim to refine the MEF2C effects in the brain relying on an integrated analysis of white matter and psychiatric phenotypes in an extensively characterized sample. This study included 870 Brazilian adults (47% from an attention-deficit/hyperactivity disorder outpatient clinic) assessed through standardized psychiatric interviews, 139 of which underwent a magnetic resonance imaging scan. We evaluated variants in the MEF2C region using two approaches: 1) a gene-wide analysis, which uses the sum of polymorphism effects, and 2) SNP analyses, restricted to the independent variants within the gene. The outcomes included psychiatric phenotypes and fractional anisotropy for brain images. Results: The gene-wide analyses pointed to a nominal association between MEF2C and the Temporal Portion of the Superior Longitudinal Fasciculus (SLFTEMP). The SNP analysis identified four independent variants significantly associated with SLFTEMP and one (rs4218438) with Substance Use Disorder. Our findings showing specific associations of MEF2C variants with temporal−frontal circuitry components may help to elucidate how the MEF2C gene underlies a broad range of psychiatric phenotypes since these regions are relevant to executive and cognitive functions.
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Acknowledgements
We would like to acknowledge the patients assessed in ProDAH-A and all its members. This study was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES, Finance Code 001) and FIPE-HCPA 160600, GPPG-HCPA 01-321. In addition to the financial support received from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Grants 466722/2014-1, 424041/2016-2, 426905/2016-2, 140853/2019-7), grant #2020/05652-0 São Paulo Research Foundation (FAPESP), and the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Grants PqG-19/2551-0001731-6; PqG-19/2551-0001668-9). The funding agencies mentioned were not involved in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.
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MEAT and RBC designed the study, performed the data analysis, and prepared the first drafts of the manuscript. CEB, MEAT, and RBC collected and processed the neuroimaging data, providing essential contributions to these analyses. ESV, BSS, FAP, and DLR provided substantial contributions to data acquisition, analyses, and interpretation of the results. CAIS and ESV were responsible for the clinical assessment of the patients and helped with the evaluation of the clinical outcomes. RSS contributed to the manuscript preparation and editing. DLR, LAR, and EHG provided critical discussion and insights into the intellectual content of the manuscript. CHDB contributed to the conception and design of the study and participated in all its stages of its preparation. All authors carefully revised and approved the final version of this manuscript.
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The authors declare the following potential conflict of interest: Dr. Grevet was on the speaker’s bureau for Novartis and Shire for three years and received travel awards (air tickets and hotel accommodations) for participating in two psychiatric meetings from Shire and Novartis. Luis Augusto Rohde has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Aché, Bial, Medice, Novartis/Sandoz, Pfizer/Upjohn, and Shire/Takeda in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Dr Rohde have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Novartis/Sandoz and Shire/Takeda. Dr. Rohde has received authorship royalties from Oxford Press and ArtMedAll other authors declare that they have no conflict of interest.
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de Araujo Tavares, M.E., Cupertino, R.B., Bandeira, C.E. et al. Refining patterns of MEF2C effects in white matter microstructure and psychiatric features. J Neural Transm 130, 697–706 (2023). https://doi.org/10.1007/s00702-023-02626-5
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DOI: https://doi.org/10.1007/s00702-023-02626-5