Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

Nicodemus, Kristin K.; Marenco, Stefano; Batten, Adam; Vakkalanka, Radhakrishna; Egan, Michael; Straub, Richard E.; Weinberger, Daniel R.

doi:10.1038/sj.mp.4002153

Cited by 175 publications

(135 citation statements)

References 43 publications

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“…Using the McNeil-Sj€ ostr€ om Scale, 35 we assessed exposure to hOCs in 168 healthy humans demonstrating that the relationship between hOCs exposure and BDNF rs6265 methylation is affected by rs6265 genotype. In fact, we found an interaction Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, birth hypoxia has been associated with reduced BDNF levels in cord samples, taken at delivery, of individuals who developed schizophrenia later in life, 34 and other genetic variation of the BDNF signaling interact with early life hypoxia in affecting risk for the disorder. 35 Surprisingly, these studies failed to show a role of rs6265 in interacting with obstetric complications in affecting risk for schizophrenia. A possible explanation for these results is that epigenetic mechanisms related to these environmental factors modulate the effect of the most likely relevant functional SNP of BDNF.…”

Section: Introductionmentioning

confidence: 99%

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BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val 66 Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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“…To this end, a Pub Med search was carried out using the keywords "(NOS1AP OR CAPON) AND schizophrenia" as well as "NOS1 AND schizophrenia", to identify all genetic studies on NOS1AP (n=24 retrieved studies) or NOS1 (n=42 retrieved) and schizophrenic disorders. Titles and abstracts were scrutinized to exclude non-genetic studies, reducing the number of included studies to Costain et al, 2010;Fang et al, 2008;Greenwood et al, 2011;Husted et al, 2010;Kremeyer et al, 2009;Miranda et al, 2006;Nicodemus et al, 2008;Wratten et al, 2009) and one on NOS1 (Fallin et al, 2005), presented family-based, but not case-control data and were therefore not integrated in the meta-analysis for methodological reasons. The remaining studies on NOS1AP (n=6; (Aberg et al, 2010;Delorme et al, 2010;Nicodemus et al, 2010;Puri et al, 2007;Puri et al, 2006;Zheng et al, 2005)) and NOS1 (n=14; (Cui et al, 2010;Donohoe et al, 2009;Kawohl et al, 2008;Nicodemus et al, 2010;O'Donoghue et al, 2012;Okumura et al, 2009;Reif et al, 2006;Reif et al, 2011;Riley et al, 2010;Rose et al, 2012;Shinkai et al, 2002;Silberberg et al, 2010;Tang et al, 2008;Wang et al, 2012)) reported on case-control association data and were scrutinized in greater detailed.…”

Section: Meta-analysismentioning

confidence: 99%

“…Following up the studies of Brzustowicz and colleagues, both positive (Kremeyer et al, 2009;Miranda et al, 2006;Zheng et al, 2005) as well as negative Nicodemus et al, 2010;Nicodemus et al, 2008) family-based and case-control studies were published. In addition, a mutation analysis suggested that rare coding variants in NOS1AP underlie obsessive-compulsive disorder and autism (Delorme et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

Weber

Klamer

Freudenberg

et al. 2014

European Neuropsychopharmacology

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NO is a pleiotropic signaling molecule and has an important role for cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adaptor protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratios of 1.29 in the metaanalysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.

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“…[111][112][113][114] In particular, recent findings show that many of the susceptibility genes identified for schizophrenia are affected by hypoxia. [115][116][117] Nicodemus and colleagues 116 performed a gene-environment interaction analysis in a family study of schizophrenia probands, siblings, and controls. The authors examined whether a set of schizophrenia candidate genes affected by hypoxia or involved in vascular function in the brain interacted with serious OCs to influence risk for schizophrenia.…”

Section: Gene-environment Intreractionmentioning

confidence: 99%