Interleukin 3 and schizophrenia: the impact of sex and family history

Chen, X; Wang, X; Hossain, Shaon; O'Neill, F. Anthony; Walsh, Dermot; Oord, Edwin van den; Fanous, Ayman H.; Kendler, Kenneth S.

doi:10.1038/sj.mp.4001932

Cited by 49 publications

(39 citation statements)

References 72 publications

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“…Intriguingly, a very recent study has identified several schizophrenia-related SNPs and haplotypes both in and near the gene for interleukin 3 (the ligand for IL3RA), which is located within a commonly identified linkage peak on chromosome 5q. 21 Results of the present study are also notable in that associations to illness were found for common variants in non-coding regions as well as rare missense mutations. Whereas hereditary patterns and linkage data in schizophrenia are consistent with a polygenic, common disease/common variant model, 22 it has also been suggested that heterogeneous rare mutations may play an important role.…”

Section: Discussionsupporting

confidence: 54%

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia

et al. 2007

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Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets demonstrating several promising candidate genes of modest effect. The recent introduction of technological platforms for whole-genome association (WGA) studies can provide an opportunity to rapidly identify novel targets, although no WGA studies have been reported in the psychiatric literature to date. We report results of a case-control WGA study in schizophrenia, examining B500 000 markers, which revealed a strong effect (P = 3.7 Â 10 À7 ) of a novel locus (rs4129148) near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region. Sequencing of CSF2RA and its neighbor, IL3RA (interleukin 3 receptor alpha) in an independent case-control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. The presence of cytokine receptor abnormalities in schizophrenia may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia.

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Section: Discussionsupporting

confidence: 54%

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia

et al. 2007

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“…Besides, there is evidence that certain genes are associated with a risk of schizophrenia only in females (Shifman et al 2008). Such gender-specific associations were earlier found by Chen et al (2007).…”

Section: Discussionmentioning

confidence: 93%

Functional Polymorphism in the Interleukin-6 and Interleukin-10 Genes in Patients with Paranoid Schizophrenia —A Case-Control Study

et al. 2010

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Schizophrenia is a multifactorial disease with changes in immunological system. Such changes are the result of cytokine-level disturbances connected with cytokine gene polymorphisms. However, research about cytokine gene polymorphisms in schizophrenia has been surprisingly limited and ambiguous. The aim of the study was to identify whether polymorphisms of interleukin (IL)-6 and IL-10 are risk factors for the development of paranoid schizophrenia in case-control study. IL-6 (-174G/C; rs 1800795) and IL-10 (-1082G/A; rs 1800896) promoter polymorphisms in patients with paranoid schizophrenia and healthy individuals were genotyped using polymerase chain reaction-restriction fragment length polymorphism method. Differences in IL-6 and IL-10 promoter haplotypes may play an important role in determining the transcription level for IL-6 and IL-10 genes in schizophrenic patients. The presence of allele C at position -174 of IL-6 promoter sequence may correlate with increasing risk of paranoid schizophrenia in the Polish population, but research on a broadened group of people is needed. The presence of allele G at position -1082 of IL-10 promoter sequence correlates with increasing risk of paranoid schizophrenia in the Polish population. The coexistence of genotype GG at position -1082 of IL-10 promoter sequence and genotype GC at position -174 of IL-6 promoter sequence correlates with increasing risk of paranoid schizophrenia in the Polish population.

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“…47 We have reported that IL3 is associated with schizophrenia and the associations observed are sex-specific and FHdependent. 3 Others report the association of IL3RA. 24 Since CSF2RB is required to achieve the biological functions of IL3, if IL3 is involved in schizophrenia via change of expression or activities, then changes in the CSF2RB gene, in either expression or activities, could lead to similar consequences.…”

Section: Discussionmentioning

confidence: 99%

“…We found that IL3 is associated with the disease in three independent samples including family and case -control samples, and the associations of IL3 are sex-specific and dependent on family history (FH). 3 Immunological abnormalities have been found to be associated with schizophrenia for decades and there are hypotheses proposing that the immune system is involved in the etiology of schizophrenia. [4][5][6] Changes in activities of cytokines, cytokine receptors and cytokine activity modifiers have been reported in the serum and cerebrospinal fluid of schizophrenic patients.…”

Section: Introductionmentioning

confidence: 99%

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

et al. 2007

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Colony stimulating factor 2 receptor, beta (CSF2RB) is the shared subunit of receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2) and IL5, and is responsible for the initiation of signal transduction triggered by ligand binding. In our previous study, we showed the evidence that the IL3 gene is associated with schizophrenia and the associations observed are sex-specific and dependent on family history (FH). In this article, we studied 10 singlenucleotide polymorphisms in the CSF2RB gene in the Irish Study of High-Density Schizophrenia Families (ISHDSF) and the Irish Case -Control Study of Schizophrenia (ICCSS), and tested allele and haplotype associations with schizophrenia. Using the pedigree disequilibrium test, we found that two markers (rs11705394 and rs7285064) reached nominal significance. In sex-stratified analyses, for both the markers the association signals were mainly derived from male subjects. In the ICCSS sample, we found that several markers (rs2072707, rs2284031 and rs909486) showed sex-specific and FH-dependent associations with schizophrenia. In multimarker haplotype analyses, both ISHDSF and ICCSS samples showed globally significant associations in multiple linkage disequilibrium (LD) blocks sharing minimal LD. Since CSF2RB is essential for IL3 signaling, the findings that both IL3 and CSF2RB showed sex-specific and FH-dependent associations suggest that the IL3 pathway is involved in schizophrenia.

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Interleukin 3 and schizophrenia: the impact of sex and family history

Cited by 49 publications

References 72 publications

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia

Functional Polymorphism in the Interleukin-6 and Interleukin-10 Genes in Patients with Paranoid Schizophrenia —A Case-Control Study

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

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