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

Abstract

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.

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

“…Furthermore, dysfunction of retinoid signaling pathway has been hypothesized to be involved in human neurodevelopmental pathologies such as schizophrenia or late-onset Alzheimer's disease (for review, Goodman, 1998Goodman, , 2006Goodman and Pardee, 2003;Palha and Goodman, 2006).…”

Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls

“…Although it is important to stress that a larger and independent group, which includes women with schizophrenia, must be tested, we have chosen the male gender due to the possible confounding of female hormonal states at the time of blood sampling and the effect of contraceptives, which influence on the gene expression profiles (Nakamura et al, 2008). Besides, we used a customised microarray platform, with enrichment for neurodevelopment genes, due to their involvement with the disease (Palha and Goodman, 2006;Ruano et al, 2008) and the current accepted view that schizophrenia is a neurodevelopment disorder in which genes and environment interplay for disease onset and progression.…”

“…A substantial body of evidence from family, twin and adoption studies indicated that a genetic component underlies increased risk for schizophrenia, although replications of these results have been elusive (Tsuang et al, 2001;Ng et al, 2009;Purcell et al, 2009;Shi et al, 2009;Stefansson et al, 2009;Sun et al, 2010). These data support the idea that schizophrenia involves many genes interacting with one another and with environmental risk factors (Palha and Goodman, 2006;Ruano et al, 2008;Sun et al, 2010).…”

Candidate genes for schizophrenia: A survey of association studies and gene ranking

“…The GO term ''amino acid and derivative metabolic process'' is related to metabolic pathways. Alterations of expression of genes in some metabolic pathways have been thought to serve as bridges or modulators between genes and environment in schizophrenia [Palha and Goodman, 2006]. For example, evidence has been found to support the role of the retinoid and thyroid hormone metabolism in schizophrenia [Palha and Goodman, 2006].…”