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Schizophr Bull. 2014 Jul;40(4):925-35. doi: 10.1093/schbul/sbt109. Epub 2013 Aug 16.

Specific glial functions contribute to schizophrenia susceptibility.

Author information

1
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands; danielle.posthuma@vu.nl.
2
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands; Institute for Computing and Information Sciences, Radboud University, Nijmegen, the Netherlands;
3
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
4
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;
5
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY;
6
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center for Psychiatric Genomics, Department of Genetics, University of North Carolina, Chapel Hill, NC;
7
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands;
8
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands; danielle.posthuma@vu.nl.

Abstract

Schizophrenia is a highly polygenic brain disorder. The main hypothesis for disease etiology in schizophrenia primarily focuses on the role of dysfunctional synaptic transmission. Previous studies have therefore directed their investigations toward the role of neuronal dysfunction. However, recent studies have shown that apart from neurons, glial cells also play a major role in synaptic transmission. Therefore, we investigated the potential causal involvement of the 3 principle glial cell lineages in risk to schizophrenia. We performed a functional gene set analysis to test for the combined effects of genetic variants in glial type-specific genes for association with schizophrenia. We used genome-wide association data from the largest schizophrenia sample to date, including 13 689 cases and 18 226 healthy controls. Our results show that astrocyte and oligodendrocyte gene sets, but not microglia gene sets, are associated with an increased risk for schizophrenia. The astrocyte and oligodendrocyte findings are related to astrocyte signaling at the synapse, myelin membrane integrity, glial development, and epigenetic control. Together, these results show that genetic alterations underlying specific glial cell type functions increase susceptibility to schizophrenia and provide evidence that the neuronal hypothesis of schizophrenia should be extended to include the role of glia.

KEYWORDS:

GWAS; PGC; gene set analysis; genome-wide association; glia; psychiatric disease

PMID:
23956119
PMCID:
PMC4059439
DOI:
10.1093/schbul/sbt109
[Indexed for MEDLINE]
Free PMC Article

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