Microarray results suggest altered transport and lowered synthesis of retinoic acid in schizophrenia

Goodman, Ann B.

doi:10.1038/sj.mp.4001668

Cited by 23 publications

(10 citation statements)

References 18 publications

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“…Of all associated GOs a total of 9/38 GOs were related to the metabolism of retinol (Table S1). These findings were supported by several independent lines of evidence, such as schizophrenia mouse models with impaired retinoic acid signaling (Lamantia 1999), microarray studies on human brains showing alterations in the whole retinoid cascade (Goodman 2005), and finally that low maternal vitamin A intake was associated with a threefold increase in the risk of schizophrenia in the offspring (Bao et al 2012). Immunological changes have also been associated with the risk of developing schizophrenia (Maino et al 2007), which supported our findings of a significant immunological signature (Table 1).…”

Section: Biological Insights From Set Testssupporting

confidence: 78%

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

et al. 2016

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Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies.

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Section: Biological Insights From Set Testssupporting

confidence: 78%

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

et al. 2016

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“…Early work using gene expression microarrays to quantify transcriptomic alterations identified several retinoid genes differentially expressed in postmortem neural tissue. For instance, in a 2005 study albumin (ALB) and the RALDH gene ALDH1A1, which oxidises retinaldehyde to at-RA, were significantly downregulated in schizophrenia [101]. Next generation sequencing of RNA (RNAseq) has now been applied to much larger cohorts, with better power to detect dysregulated transcripts in the disorder.…”

Section: Differential Expression Of Retinoid Related Transcripts In Smentioning

confidence: 99%

The role of the retinoids in schizophrenia: genomic and clinical perspectives

Cairns

2019

Mol Psychiatry

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Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, however, is required to expand on the largely observational data collected thus far and confirm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia.

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“…New findings add direct and independent molecular support to the hypothesis that retinoids and thyroid hormones may increase vulnerability to schizophrenia: (1) the recent discovery of the specific differential upregulation of RARA in granule cells of the dentate gyrus in schizophrenia (Rioux and Arnold, 2005); (2) the report that RBP4 is highly expressed in association and limbic cortex of adult primate brains (Komatsu et al, 2005), regions specifically implicated in schizophrenia (Heinz et al, 2003); (3) a recent microarray study showing the retinoic acid receptor as a top functional gene group altered in schizophrenia (Middleton et al, 2005); (4) the observation that albumin and ALDH1A1, proteins involved in the transport and synthesis of thyroid hormone and RA, respectively, are highly significantly differentially expressed in a microarray study of schizophrenia brains (Goodman, 2005;Prabakaran et al, 2004); (5) the independent immunohistochemical confirmation that ALDH1A1 is decreased in the ventral tegmental area in schizophrenia (Galter et al, 2003); (6) evidence showing that the drug, Accutane, which is a retinoic acid analogue, causes altered brain function and decreased metabolism in the orbitofrontal cortex of Accutane-treated acne patients compared to acne patients not so treated (Bremner et al, 2005); and (7) the demonstration that Accutane causes decrease in hippocampal size and learning ability in exposed mice (Crandall et al, 2004).…”

Section: Altered Gene Expression In Schizophreniamentioning

confidence: 99%

Thyroid hormones and retinoids: A possible link between genes and environment in schizophrenia

Palha

Goodman

2006

Brain Research Reviews

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Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia.

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Microarray results suggest altered transport and lowered synthesis of retinoic acid in schizophrenia

Cited by 23 publications

References 18 publications

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

The role of the retinoids in schizophrenia: genomic and clinical perspectives

Thyroid hormones and retinoids: A possible link between genes and environment in schizophrenia

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