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Nat Commun. 2019 Sep 2;10(1):3933. doi: 10.1038/s41467-019-11797-3.

Sex-specific transcriptional and proteomic signatures in schizophrenia.

Author information

1
Department of Clinical Neuroscience, Karolinska Institutet, Byggnad R5, SE-171 76, Stockholm, Sweden. jari.tiihonen@ki.se.
2
Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Niuvankuja 65, FI-70240, Kuopio, Finland. jari.tiihonen@ki.se.
3
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland.
4
Neuroscience Center, University of Helsinki, PO Box 63, FI-00271, Helsinki, Finland.
5
Department of Pharmacology, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland.
6
Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Niuvankuja 65, FI-70240, Kuopio, Finland.
7
Department of Psychology and Psychiatry, Yale University, 1 Prospect Street, New Haven, Connecticut, 06511, USA.
8
Mental Health Unit, Department of Public Health Solutions, National Institute for Health and Welfare, PO Box 30, FI-00271, Helsinki, Finland.
9
Department of Psychiatry, University of Helsinki, PO Box 22, FI-00014, Helsinki, Finland.
10
Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, PO Box 30, FI-00271, Helsinki, Finland.
11
Department of Public Health, University of Helsinki, PO Box 20, FI-00014, Helsinki, Finland.
12
Institute for Molecular Medicine FIMM, University of Helsinki, PO Box 20, FI-00014, Helsinki, Finland.
13
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Science Drive, Bundoora, VIC, 3083, Australia.
14
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland. sarka.lehtonen@uef.fi.
15
Neuroscience Center, University of Helsinki, PO Box 63, FI-00271, Helsinki, Finland. sarka.lehtonen@uef.fi.
16
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland. jari.koistinaho@helsinki.fi.
17
Neuroscience Center, University of Helsinki, PO Box 63, FI-00271, Helsinki, Finland. jari.koistinaho@helsinki.fi.

Abstract

It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.

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