Interleukin-1 cluster is associated with genetic risk for schizophrenia and bipolar disorder.

S chizophrenia and affective psychoses are severe and prevalent psychiatric disorders described in all cultures and populations. Whether these functional psychoses are two distinct disorders, or are closely related in aetiology, has been debated in the literature during the last century. Several studies have suggested that schizophrenia and bipolar disorder are on a continuum of liability. Psychopathological dimensions and psychiatric symptoms shared by both groups of patients would be compatible with this overlap. Likewise, other risk factors, such as cerebral ventricle enlargement, markers of prenatal suffering, or life events, have been described in both mental disorders. Recent molecular linkage studies have suggested the possible existence of shared disease loci for both disorders. Of special interest are the family studies showing that first degree relatives of bipolar patients have a three times increased risk for schizophrenia compared with first degree relatives of controls. 11 These data suggest the presence of a common genetic risk background in both disorders. However, it should be noted that other family studies have not been able to replicate these latter results. 13 Over the last decade, several studies have reported an imbalance in pro-inflammatory/anti-inflammatory cytokines or their soluble receptors level in plasma or cerebrospinal fluid of schizophrenic and bipolar disorder patients. 15 These results have been replicated by recent studies in both diagnostic groups. 17 Genes coding for some of these cytokines are located on the IL-1 cluster within chromosome 2q13. This cluster contains nine genes of the IL-1 family of cytokines (IL-1A, IL-1B, IL1RN, and IL-1F5–F10). Several polymorphic variants of these genes have been associated with human diseases. The IL-1b gene (IL-1B) consists of seven exons with an extension of 7 kb and codes for a precursor form (proIL-1b) which is cleaved by a protease (ICE) to give the active IL-1b form. This pro-inflammatory cytokine is involved in acute and chronic neurodegeneration and in embryonic development of the CNS. During CNS neurodevelopment, IL-1b promotes proliferation and production of cytokines and trophic factors, such as nerve growth factor (NGF), in astrocytes and inhibits normal expression of brain-derived neurotrophic factor (BDNF). In addition, IL-1 (a and b) participates in differentiation of mesencephalic progenitor cells into dopaminergic neurons in cell culture. On the other hand, the IL-1Ra gene (IL-1RN) consists of seven exons in a region of 16 kb, and several splice variants can be obtained from the coding sequence. Its product, IL-1 receptor antagonist (IL-1Ra), is an endogenous antagonist at IL-1 receptors and modulates the action of IL-1 agonists. Altered levels of IL-1Ra have been described in the pathogenesis of several diseases where inflammatory or autoimmune processes are involved. Recent studies have shown that drug-naive schizophrenic patients exhibit a significant increase in both IL-1b and IL1Ra plasma levels when compared with healthy controls. 16 : it is generally agreed that regulatory processes affecting IL-1 function are, at least in part, determined by genetic variation. Thus, production of IL-1b and IL-1Ra may be modulated by the effect of polymorphisms in the IL-1 cluster. Unfortunately, data regarding the functional effect of these polymorphisms on cytokine production are unclear and even contradictory. Taken together, all functional data suggest that allelic status in both IL-1B and IL-1RN genes determines, acting coordinately, the levels of these proteins. Over the last few years, genetic studies have shown an association of polymorphisms in the IL-1 cluster with either schizophrenia or clinical subgroups of this disorder. 30 31