Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain

Rainald Schmidt-Kastner*, Sinan Guloksuz, Thomas Kietzmann, Jim van Os, Bart P.F. Rutten

*Corresponding author for this work

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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.

Original languageEnglish
Article number393
Pages (from-to)1-9
JournalFrontiers in Psychiatry
Publication statusPublished - 12 May 2020


  • gene expression
  • gene-environment (G-E) interaction
  • HIF
  • hypoxia
  • ischemia
  • obstetric complications
  • schizophrenia
  • synapse


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