Interleukin‐1β (IL‐1β) gene and increased risk for the depressive symptom‐dimension in schizophrenia spectrum disorders

Interleukin‐1β (IL‐1β), as well as other cytokines, has been classically implicated in the pathophysiology of major psychiatric disorders such as schizophrenia and major depression, and recent studies have implicated the IL‐1β gene and schizophrenia. Nevertheless, new approaches to this complex phenotype are necessary to clarify the risk conferred by this gene, either to the disorder or to its clinical manifestations. The aim of the present study was to explore the effect of a genetic polymorphism of the promoter region of the IL‐1β gene, in schizophrenia defined with: (i) a categorical diagnosis and (ii) a multidimensional symptom approach. We studied 356 individuals from 89 nuclear families consisting of one affected individual and the unaffected father, mother, and sib, in a family‐based association study design. We find a trend for biased transmission of allele 2 from heterozygous parents to affected offspring, categorically defined (P = 0.07). This tendency was not observed in the healthy offspring. Using a multidimensional symptom approach to the diagnosis, the association was confirmed in psychotic patients showing the depressive symptom‐dimension (P = 0.02). © 2003 Wiley‐Liss, Inc.

[1]  M. Owen,et al.  No Major Schizophrenia Locus Detected on Chromosome 1q in a Large Multicenter Sample , 2002, Science.

[2]  S. Faraone,et al.  Heterogeneity of Schizophrenia , 1990, British Journal of Psychiatry.

[3]  CR Plata-Salamán,et al.  Cytokine action in the brain , 1999, Molecular Psychiatry.

[4]  J. Krebs,et al.  Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  A. Dunn,et al.  The role of interleukin-6 in the activation of the hypothalamo-pituitary-adrenocortical axis and brain indoleamines by endotoxin and interleukin-1β , 1999, Brain Research.

[6]  N. Andreasen,et al.  COMPREHENSIVE ASSESSMENT OF SYMPTOMS AND HISTORY (CASH) , 2000 .

[7]  N C Andreasen,et al.  The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. , 1992, Archives of general psychiatry.

[8]  M. Hurme,et al.  Polymorphisms of the interleukin-1 gene complex in schizophrenia , 1999, Molecular Psychiatry.

[9]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[10]  C. Plata-salamán,et al.  Cytokine interactions and cytokine balance in the brain: relevance to neurology and psychiatry , 1999, Molecular Psychiatry.

[11]  R. Suddath,et al.  Interleukin-1 alpha and interleukin-2 in cerebrospinal fluid of schizophrenic subjects. , 1993, Progress in Neuro-psychopharmacology and Biological Psychiatry.

[12]  M. Tsuang.  Defining alternative phenotypes for genetic studies: what can we learn from studies of schizophrenia? , 2001, American journal of medical genetics.

[13]  M. Baron,et al.  Genetics of schizophrenia and the new millennium: progress and pitfalls. , 2001, American journal of human genetics.

[14]  M. Wong,et al.  The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection , 1999, Molecular Psychiatry.

[15]  M. Carrington,et al.  Interleukin-1 polymorphisms associated with increased risk of gastric cancer , 2000, Nature.

[16]  D. Curtis,et al.  An extended transmission/disequilibrium test (TDT) for multi‐allele marker loci , 1995, Annals of human genetics.

[17]  R. Rimón,et al.  Plasma levels of interleukin-1β and interleukin-6 in schizophrenia, other psychoses, and affective disorders , 1994, Schizophrenia Research.

[18]  V. Peralta,et al.  How many and which are the psychopathological dimensions in schizophrenia? Issues influencing their ascertainment , 2001, Schizophrenia Research.

[19]  P. Sham,et al.  1q21-q22 locus is associated with susceptibility to the reality-distortion syndrome of schizophrenia spectrum disorders. , 2002, American journal of medical genetics.

[20]  W. Honer,et al.  Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. , 2000, Science.

[21]  C. Mcallister,et al.  Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. , 1995, The American journal of psychiatry.

[22]  Kari Stefansson,et al.  Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. , 2003, American journal of human genetics.

[23]  Ming T Tsuang,et al.  Genome scan of three quantitative traits in schizophrenia pedigrees , 2002, Biological Psychiatry.

[24]  H. Meltzer,et al.  Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? , 1993, The American journal of psychiatry.

[25]  R. Suddath,et al.  Interleukin-1α and interleukin-2 in cerebrospinal fluid of schizophrenic subjects , 1993, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[26]  J. Mallet,et al.  Detection of two new polymorphic sites in the human interleukin‐1β gene: lack of association with schizophrenia in a French population , 1997, Psychiatric genetics.

[27]  R. Wyatt,et al.  Serum cytokine concentrations in patients with schizophrenia , 1996, Schizophrenia Research.

[28]  H. Praag.  Faulty cortisol/serotonin interplay. Psychopathological and biological characterisation of a new, hypothetical depression subtype (SeCA depression) , 1996, Psychiatry Research.

[29]  N. Rothwell,et al.  Cytokines and acute neurodegeneration , 1997, Molecular Psychiatry.

[30]  M. Tsuang.  Heterogeneity of schizophrenia. , 1975, Biological psychiatry.

[31]  P. Sham,et al.  Psychopathological syndromes in the functional psychoses: associations with course and outcome , 1996, Psychological Medicine.

[32]  Peter McGuffin,et al.  A twin study of genetic relationships between psychotic symptoms. , 2002, The American journal of psychiatry.

[33]  Faulty cortisol/serotonin interplay. Psychopathological and biological characterisation of a new, hypothetical depression subtype (SeCA depression) , 1996, Psychiatry research.

[34]  A. Rigaud.  [Depression in schizophrenia]. , 1991, La Revue du praticien.

[35]  H. Stefánsson,et al.  Neuregulin 1 and susceptibility to schizophrenia. , 2002, American journal of human genetics.

[36]  U Hegerl,et al.  Association of an interleukin-1beta genetic polymorphism with altered brain structure in patients with schizophrenia. , 2001, The American journal of psychiatry.

[37]  P. Sham,et al.  Familiality of symptom dimensions in schizophrenia , 2001, Schizophrenia Research.

[38]  T. Perneger.  What's wrong with Bonferroni adjustments , 1998, BMJ.