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.

Introduction

While there is strong evidence supporting genetic causation in schizophrenia, epigenetic and environmental factors are also believed to play a major role in the disease onset (Goodman, 1998, Mackay-Sim et al., 2004, Owen et al., 2004, Ozer et al., 2004, Sharma, 2005, Suzuki et al., 2004, Tsuang et al., 2001). Recently, some success has been achieved in identifying significant involvement of single genes across several different ethnic or population groups but in no instance has there been total replication of such involvement across all groups studied. The disease is thought to be initially characterized by diverse neurodevelopmental insults occurring in the later half of gestation, with the subsequent combination of both genetic vulnerabilities and environmental stressors resulting in the usual age of onset in mid-to-late adolescence. Based on response to treatment, various neurotransmitter cascades have been implicated in the etiology of schizophrenia, with special emphasis on the dopaminergic hypothesis in which schizophrenia results from increased dopaminergic stimulation in the limbic system.

In view of the lack of wide replicability of genome-wide scans and inconclusive results from association studies of missense and nonsense mutations such as those responsible for simple genetic disorders, the approach to study this complex disease has broadened to include investigations and functional analyses of human promoter polymorphisms. There are hopes that such approaches will prove productive for recent studies have shown a large proportion of genes with polymorphic promoters (Buckland et al., 2004, Hoogendoorn et al., 2003, Perkins et al., 2005) responsible for altered gene expression. It is possible that, rather than being caused by mutated genes alone, schizophrenia results from the altered expression of normal genes (Goodman, 1996a). In addition to discrete mutations in coding regions, altered expression of candidate genes could result either from polymorphisms in the promoter and regulatory regions of the genes or from inadequate supply of modulators of transcription factors activity (Nobel et al., 2001).

Transcriptional factors and their ligands (such as hormones and vitamins) are promising candidates in the link between the genetic and environmental components of complex diseases such as schizophrenia. The genetic cascades which make ligands available to activate nuclear transcription factors at specific times in development and at specific cellular locations are complex. Normal allelic variants in any of the metabolic enzymes of the cascade or of the ligand transporters could combine to alter ligand availability.