Three independent lines of evidence suggest retinoids as causal to schizophrenia.
Retinoid dysregulation may be an important factor in the etiology of schizophrenia. This hypothesis is supported by three independent lines of evidence that triangulate on retinoid involvement in schizophrenia: (i) congenital anomalies similar to those caused by retinoid dysfunction are found in schizophrenics and their relatives; (ii) those loci that have been suggestively linked to schizophrenia are also the loci of the genes of the retinoid cascade (convergent loci); and (iii) the transcriptional activation of the dopamine D2 receptor and numerous schizophrenia candidate genes is regulated by retinoic acid. These findings suggest a close causal relationship between retinoids and the underlying pathophysiological defects in schizophrenia. This leads to specific strategies for linkage analyses in schizophrenia. In view of the heterodimeric nature of the retinoid nuclear receptor transcription factors, e.g., retinoid X receptor beta at chromosome 6p21.3 and retinoic acid receptor beta at 3p24.3, two-locus linkage models incorporating genes of the retinoid cascade and their heterodimeric partners, e.g., peroxisome proliferator-activated receptor alpha at chromosome 22q12-q13 or nuclear-related receptor 1 at chromosome 2q22-q23, are proposed. New treatment modalities using retinoid analogs to alter the downstream expression of the dopamine receptors and other genes that are targets of retinoid regulation, and that are thought to be involved in schizophrenia, are suggested.
Goodman
A B
AB
Statistical Sciences and Epidemiology Division, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
D000818:Animals; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D010375:Pedigree; D012176:Retinoids / Q000494:pharmacology*; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics; D014212:Tretinoin / Q000502:physiology; D014801:Vitamin A / Q000235:genetics / Q000502:physiology
D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin