An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model

Abstract

Investigating and understanding gene-environment interaction (G Â E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia-hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n = 42 genes) met the criteria for a link to ischemia-hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia-hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G Â E interactions in clinical genetic and translational neuroscience studies.

O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development

“…Further, functional annotation clustering of these affected genes revealed a significant enrichment for pathways involved in energy utilization, protein regulation, and synapse formation, processes important in neurodevelopment (Fig. 3A) (19,20). Similar to the extensive gene expression changes we detected in the hypothalamus, we also found robust differences in the brain microRNA environment, where hemizygous placental OGT expression shifted the pattern of 250 of the most abundant brain microRNAs to be distinct from that of wild-type females by hierarchical clustering analyses (Fig.…”

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…Since we found that rs6265 methylation is related with hOCs which are a risk factor for schizophrenia, 25,35 we assessed the relationship between hOCs exposure, BDNF rs6265 genotype and methylation in PBMCs, and WM performance and related prefrontal activity, 2 well established intermediate phenotypes for this neurodevelopmental disorder. 15 Fig.…”

“…18 BDNF expression is sensitive to early-life environment [19][20][21] and specifically hypoxic-stressors, 22,23 which, in turn, are critical factors involved in the pathophysiology of schizophrenia. [24][25][26][27] The failure to find association between BDNF and schizophrenia in large-scale case control studies may conceivably reflect a complex interaction of genotype and environmental experience that alters methylation status.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…There is evidence that prenatal maternal immune activation (MIA) (Brown and Derkits, 2010), perinatal hypoxia (Cannon et al, 2002;Schmidt-Kastner et al, 2012), adolescent cannabis use (Arseneault et al, 2004;Henquet et al, 2008), stress (Norman and Malla, 1993), obstetric complications (Dalman et al, 1999), urbanicity (Vassos et al, 2012), migrant status (Cantor-Graae and Selten, 2005), advanced paternal age (Malaspina, 2001), and others (Brown, 2011;Tandon et al, 2008) interact with predisposing genetics to increase risk for illness.…”