University of Oulu

Schmidt-Kastner R, Guloksuz S, Kietzmann T, van Os J and Rutten BPF (2020) Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain. Front. Psychiatry 11:393. doi: 10.3389/fpsyt.2020.00393

Analysis of GWAS-derived schizophrenia genes for links to ischemia-hypoxia response of the brain

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Author: Schmidt-Kastner, Rainald1; Guloksuz, Sinan2,3; Kietzmann, Thomas4;
Organizations: 1Integrated Medical Science Department, C.E. Schmidt College of Medicine, Florida Atlantic University (FAU), Boca Raton, FL, United States
2Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, Netherlands
3Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
4Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
5Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
6Department of Psychosis Studies, Institute of Psychiatry, King’s College London, King’s Health Partners, London, United Kingdom
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: Frontiers Media, 2020
Publish Date: 2020-07-10


Obstetric complications (OCs) can induce major adverse conditions for early brain development and predispose to mental disorders, including schizophrenia (SCZ). We previously hypothesized that SCZ candidate genes respond to ischemia-hypoxia as part of OCs which impacts neurodevelopment. We here tested for an overlap between SCZ genes from genome-wide association study (GWAS) (n=458 genes from 145 loci of the most recent GWAS dataset in SCZ) and gene sets for ischemia-hypoxia response. Subsets of SCZ genes were related to (a) mutation-intolerant genes (LoF database), (b) role in monogenic disorders of the nervous system (OMIM, manual annotations), and (c) synaptic function (SynGO). Ischemia-hypoxia response genes of the brain (IHR genes, n=1,629), a gene set from RNAseq in focal brain ischemia (BH, n=2,449) and genes from HypoxiaDB (HDB, n=2,289) were overlapped with the subset of SCZ genes and tested for enrichment with Chi-square tests (p < 0.017). The SCZ GWAS dataset was enriched for LoF (n=112; p=0.0001), and the LoF subset was enriched for IHR genes (n=25; p=0.0002), BH genes (n=35; p=0.0001), and HDB genes (n=23; p=0.0005). N=96 genes of the SCZ GWAS dataset (21%) could be linked to a monogenic disorder of the nervous system whereby IHR genes (n=19, p=0.008) and BH genes (n=23; p=0.002) were found enriched. N=46 synaptic genes were found in the SCZ GWAS gene set (p=0.0095) whereby enrichments for IHR genes (n=20; p=0.0001) and BH genes (n=13; p=0.0064) were found. In parallel, detailed annotations of SCZ genes for a role of the hypoxia-inducible factors (HIFs) identified n=33 genes of high interest. Genes from SCZ GWAS were enriched for mutation-intolerant genes which in turn were strongly enriched for three sets of genes for the ischemia-hypoxia response that may be invoked by OCs. A subset of one fifth of SCZ genes has established roles in monogenic disorders of the nervous system which was enriched for two gene sets related to ischemia-hypoxia. SCZ genes related to synaptic functions were also related to ischemia-hypoxia. Variants of SCZ genes interacting with ischemia-hypoxia provide a specific starting point for functional and genomic studies related to OCs.

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Series: Frontiers in psychiatry
ISSN: 1664-0640
ISSN-E: 1664-0640
ISSN-L: 1664-0640
Volume: 11
Article number: 393
DOI: 10.3389/fpsyt.2020.00393
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3111 Biomedicine
Funding: RS-K was supported by IMSD, COM. BR was funded by a VIDI award (no. 91718336) from the Netherlands Scientific Organization. BR, JO, and SG were funded by the grant agreement HEALTH‐F2‐2010‐241909 from the European Community’s Seventh Framework Programme (project EU-GEI). TK was supported by grants from the Finnish Center of International Mobility, Finnish Academy of Sciences (SA296027), Jane and Aatos Erkko Foundation, Finnish Cancer Foundation, Sigrid Juselius Foundation, Biocenter Oulu, and University of Oulu.
Academy of Finland Grant Number: 296027
Detailed Information: 296027 (Academy of Finland Funding decision)
Copyright information: © 2020 Schmidt-Kastner, Guloksuz, Kietzmann, van Os and Rutten. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.