Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain
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 test...
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doaj-c19ac1717071414f93e2b5eb6bbb7a5f2020-11-25T03:10:42ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402020-05-011110.3389/fpsyt.2020.00393504884Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the BrainRainald Schmidt-Kastner0Sinan Guloksuz1Sinan Guloksuz2Thomas Kietzmann3Jim van Os4Jim van Os5Jim van Os6Bart P. F. Rutten7Integrated Medical Science Department, C.E. Schmidt College of Medicine, Florida Atlantic University (FAU), Boca Raton, FL, United StatesDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, NetherlandsDepartment of Psychiatry, Yale School of Medicine, New Haven, CT, United StatesFaculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, FinlandDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, NetherlandsDepartment of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Psychosis Studies, Institute of Psychiatry, King’s College London, King’s Health Partners, London, United KingdomDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, NetherlandsObstetric 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.https://www.frontiersin.org/article/10.3389/fpsyt.2020.00393/fullschizophreniagene-environment (G-E) interactionobstetric complicationsischemiahypoxiaHIF |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rainald Schmidt-Kastner Sinan Guloksuz Sinan Guloksuz Thomas Kietzmann Jim van Os Jim van Os Jim van Os Bart P. F. Rutten |
spellingShingle |
Rainald Schmidt-Kastner Sinan Guloksuz Sinan Guloksuz Thomas Kietzmann Jim van Os Jim van Os Jim van Os Bart P. F. Rutten Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain Frontiers in Psychiatry schizophrenia gene-environment (G-E) interaction obstetric complications ischemia hypoxia HIF |
author_facet |
Rainald Schmidt-Kastner Sinan Guloksuz Sinan Guloksuz Thomas Kietzmann Jim van Os Jim van Os Jim van Os Bart P. F. Rutten |
author_sort |
Rainald Schmidt-Kastner |
title |
Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain |
title_short |
Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain |
title_full |
Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain |
title_fullStr |
Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain |
title_full_unstemmed |
Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain |
title_sort |
analysis of gwas-derived schizophrenia genes for links to ischemia-hypoxia response of the brain |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Psychiatry |
issn |
1664-0640 |
publishDate |
2020-05-01 |
description |
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. |
topic |
schizophrenia gene-environment (G-E) interaction obstetric complications ischemia hypoxia HIF |
url |
https://www.frontiersin.org/article/10.3389/fpsyt.2020.00393/full |
work_keys_str_mv |
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