Abstract
Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity – as measured by fractional anisotropy (FA) – is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA.
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Acknowledgements
This study was funded by the Netherlands Scientific Organization Grants NWO 400-08-206 and NWO/ZONW 40-00812-98-07-032 (to Posthuma). The MIND Research Network consortium is supported by the National Institute of Mental Health Grant Numbers K08 MH068540 (to White) and MH060662; the National Institute on Drug Abuse Grant Number P2ODA024196; and the National Association for Research in Schizophrenia and Affective Disorders (NARSAD) (to White). The funding agencies had no role in the design and conduct of the study. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is hosted by SURFsara and supported by the Netherlands Scientific Organization along with the Dutch Brain Foundation and the VU University Amsterdam.
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Chavarria-Siles, I., White, T., de Leeuw, C. et al. Myelination-related genes are associated with decreased white matter integrity in schizophrenia. Eur J Hum Genet 24, 381–386 (2016). https://doi.org/10.1038/ejhg.2015.120
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DOI: https://doi.org/10.1038/ejhg.2015.120
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