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. Author manuscript; available in PMC: 2014 May 15.
Published in final edited form as: Biol Psychiatry. 2013 Feb 12;73(10):951–966. doi: 10.1016/j.biopsych.2013.01.001

Table 2.

Immune-related Genetic Polymorphisms Associated with Schizophrenia

Author Year Journal Technique Population Major Finding Strength of Association
Jia et al. 2010 Schizophrenia Research Genome-wide association study (GWAS) (369,808 SNPs mapped to 19,896 protein-coding genes, which were involved in 511 biological pathways) using two statistical methods, Gene Set Enrichment Analysis (GSEA) and hypergeometric test 1158 schizophrenia cases and 1378 controls from unrelated European ancestry samples Three pathways related to apoptosis, inflammation, and the immune system showed a significant association with schizophrenia using both GSEA and hypergeometric methods: the transforming growth factor beta (TGF-beta) signaling pathway, the tumor necrosis factor receptor 1 (TNFR1) pathway, and the TOB1 pathway Normalized enrichments scores (NES):

  • TGF-beta signaling pathway: 1.845;

  • TNFR1 pathway: 1.649;

  • TOB1 pathway: 1.497


(TOB1 was not significant by GSEA: p =.070)
Purcell et al. 2009 Nature GWAS of case-control sample for approximately 1 million SNPs, augmented by imputed common HapMap SNPs 3,322 European individuals with schizophrenia and 3,587 controls; combined sample (after exchanging GWAS summary results with the Molecular Genetics of Schizophrenia (MGS) and SGENE consortia for genotyped SNPs) included 8,008 schizophrenia cases and 19,077 controls of European decent Significant association of schizophrenia with more than 450 SNPs on chromosome 6 spanning the major histocompatibility complex (MHC) Odds ratios for classical human leukocyte antigen (HLA) alleles associated with schizophrenia:

  • HLA-A0101: .785;

  • HLA-C0701: .778;

  • HLA-B0801: .757;

  • HLA-DRB0301: .768;

  • HLA-DQB0201: .857;

  • HLA-DQA0501: .798


(the six HLA alleles were significant at P < 10−3, though the association could not ascribed to any specific HLA allele, haplotype, or region)
(Confidence intervals not reported)
Shi et al. 2009 Nature GWAS of common SNPs (671,424 SNPs passed quality control (QC) filters in European ancestry samples; 811,340 SNPs passed QC filters in African-American samples) in the MGS case-control sample; meta-analysis of European-ancestry data from MGS, ISC and SGENE datasets MGS case-control samples of European ancestry (2,681 cases, 2,653 controls) and African-American (1,286 cases, 973 controls); cases were included with diagnoses of schizophrenia or (in 10% of cases) schizoaffective disorder; meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls) Schizophrenia was significantly associated with SNPs in the extended MHC region on chromosome 6. No MGS finding achieved genome-wide statistical significance. In meta-analysis of European-ancestry subjects, significant association with schizophrenia observed in region of linkage disequilibrium on chromosome 6p22.1, a region that includes a histone gene cluster and several immunity-related genes No MGS findings reached genome-wide significance.
From meta-analysis of European ancestry subjects, odds ratios for seven SNPs on chromosome 6p22.1 showed genome-wide significant associations with schizophrenia — odds ratios listed as follows (MGS-OR, ISC-OR, SGENE-OR):

  • rs6904071 (.879, .819, .799); rs926300 (.879, .819, .791); rs6913660 (.884, .819, .798); rs13219181 (.881, .819, .791); rs13194053 (.880, .819, .783); rs3800307 (.886, .880, .787); rs3800316 (.856, .886, .834)


(Confidence intervals not reported)
Stefansson et al. 2009 Nature GWAS of 314,868 SNPs to search for sequence variants associated with schizophrenia; 2,663 schizophrenia cases and 13,498 controls from 8 European locations (SGENE-plus GWAS dataset); the top 1500 markers were combined with results from the non-overlapping 2602 cases and 2885 controls in the ISC and the 2681 cases and 2653 controls from the European-American portion of the MGS study; 25 of the top 1500 markers were followed up in four additional samples from Europe for an additional 4,999 cases and 15,555 controls Significant association of several markers spanning the MHC region on chromosome 6p21.3–22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2; findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition Odds ratios and 95% confidence intervals for the 7 markers associated with schizophrenia:

  • rs6913660[C]: 1.15 (1.10, 1.21)

  • rs13219354[T]: 1.20 (1.14, 1.27)

  • rs6932590[T]: 1.16 (1.11, 1.21)

  • rs13211507[T]: 1.24 (1.16, 1.32)

  • rs3131296[G]: 1.19 (1.13, 1.25)

  • rs12807809[T]: 1.15 (1.10, 1.20)

  • rs9960767[C]: 1.23 (1.15, 1.32)
Sun et al. 2009 Brain Research Family-based association study genotyping 2 SNPs (rs6603272 and rs6645249) at the interleukin 3 receptor alpha (IL3RA) gene using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) 101 Chinese parent-offspring trios (parent, affected offspring, and unaffected offspring) of Han descent Single marker analysis showed a significant association for rs6603272 with schizophrenia but not for rs6645249. There was significant genotypic association of both SNPs with schizophrenia. Haplotype transmission disequilibrium test (TDT) was statistically significant, with the rs6603272(T)-rs6645249(G) haplotype significantly associated with schizophrenia Single marker analysis of rs6603272 (X2=5.15, df=1, p = 0.023)**
Genotypic associations: rs6603272 (X2=6.15, df=2, p=0.046)**
rs6645249 (X2=21.79, df=2, p=1.85e−005)**
Odds ratio and 95% CI for association of rs6603272(T)-rs6645249(G) haplotype with schizophrenia: 1.66 (1.08, 2.55)
Chen et al. 2007 Molecular Psychiatry 12 SNPs on chromosome 5q21-33, in and around the interleukin 3 (IL-3) gene, were genotyped in two family samples and one case-control sample using either TaqMan assay or the FP-TDI protocol Study included 3 samples:
1. Irish Study of High Density Schizophrenia Families (ISHDSF) sample collected in Northern Ireland, the United Kingdom and the Republic of Ireland. Cases were split into three overlapping diagnostic classes: narrow (n=515), intermediate, (n=634), and broad (n=686) definitions of schizophrenia ranging from schizophrenia and poor-outcome schizoaffective disorder (narrow) to the entire schizophrenia spectrum (broad). Sample included 273 unaffected relatives with significant family history.
2. A subset of the Irish Case-Control Study of Schizophrenia (ICCSS) sample comprising 657 affected subjects with diagnosis of schizophrenia or poor-outcome schizoaffective disorder and 411 controls.
3. Irish Trio Study of Schizophrenia (ITRIO) comprising 187 families, including 87 probands with positive family history		 5 SNPs in the promoter and enhancer of the IL-3 gene (rs3914025, rs3846726, rs3916441, rs31400, and rs2069803) were associated with schizophrenia in the ISHDSF; two- and three-marker haplotypes involving rs31400, rs31480 (single marker not significant), and rs2069803 were significant in all diagnostic classes. The associations were largely driven by females. Results showed similar female-specific patterns in the ICCSS and ITRIO, but only in those subjects with a family history of schizophrenia (all subjects in ISHSF had a family history of schizophrenia). Risk haplotypes identified in the family studies were found to be protective in the case-control study. Significant odds ratios and p-values disequilibrium tests for two- and three-marker haplotypes (statistics are for females only unless otherwise specified; ISHDSF refers to narrow definition only; ICCSS and ITRIO refer to probands with family history of schizophrenia only):

  • rs3914025-rs3846726-rs3916441

    haplotype 1-1-1: ISHDSF, OR=.63, p=.0087 (in males, OR=1.25, p=.0066); ICCSS, OR=1.27, p=.0142

  • haplotype: 2-2-2: ISHDSF, OR=2.00, p=.0087 (in males, OR=.74, p=.0073); ICCSS, OR=.75, p=.0445

  • rs31400-rs31480

    haplotype 1-1: ISHDSF, OR=.43, p=.0002; ITRIO, OR=.54, p=.0134

  • haplotype 2-1:

    ISHDSF, OR=1.91, p=.0064

  • rs31400-rs31480-rs2069803

    haplotype 1-1-2: ISHDSF, OR=.43, p=.0005; ITRIO, OR=.56, p=.0216

  • haplotype 2-1-1: ISHDSF, OR=2.00, p=.0060; ITRIO, OR=2.28, p=.0344
Hanninen et al. 2007 European Archives of Psychiatry and Clinical Neuroscience Genomic DNA isolated for genotyping from blood samples by salting-out method; screening of IL-1β −511 gene polymorphisms and neuregulin-1 (NRG-1) SNP8NRG221533 113 Finnish schizophrenia patients and 393 healthy controls Allele and genotype frequencies of IL-1β and NRG-1 did not differ between schizophrenia patients and controls, but the risk of schizophrenia was more than 10 times higher among subjects with the IL-1β 2.2, NRG-1 CC genotypes compared to subjects with the IL-1β 2.2, NRG-1 T-allele carriage Odds ratio and 95% CI: 10.20 (2.53, 41.09)
Lencz et al. 2007 Molecular Psychiatry Case-control whole-genome association (WGA) study examining approximately 500,000 markers 178 patients with schizophrenia-spectrum disorders (schizophrenia, n = 158; schizoaffective, n = 13, schizophreniform, n = 7) and 144 healthy controls rs4129148 locus near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region (PAR1) was significantly associated with schizophrenia; sequencing of CSF2RA and its neighbor, interleukin 3 receptor alpha (IL3RA) revealed common intronic haplotypes and several rare exonic missense variants – CSF2RA (exon 3 C/G, exon 7 G/A, exon 7 C/T, exon 8 C/T) and IL3RA (exon 5 G/A, exon 7 G/A, exon 7 C/G) – associated with schizophrenia (rare missense variants were collectively associated with schizophrenia) Homozygosity for the C allele of SNP rs4129148 was significantly associated with schizophrenia, with 59% of cases but only 31% of controls being CC homozygotes (OR = 3.23; 95% CI = 2.04 – 5.15; population attributable risk = 23.5%)
* Odds ratio for rare exonic missense variants within the CSF2RA and IL3RA genes collectively associated with schizophrenia: OR = 6.703
Schwarz et al. 2006 European Archives of Psychiatry and Clinical Neuroscience Genotyping of interleukin 2 (IL-2) (IL-2 − 330 T/G SNP) and interleukin 4 (IL-4) (IL-4 − 590 C/T SNP) gene polymorphisms performed by fluorescence resonance energy transfer method (FRET) using the Light Cycler System in a study comparing schizophrenia patients and controls 230 schizophrenia patients and 251 healthy controls Identified a significant association of the IL-2 − 330 TT genotype and of the IL-4 − 590 CC genotype with schizophrenia * IL-2 polymorphism: ϕ = .124 (small effect);
IL-4 polymorphism: ϕ = .123 (small effect)
Yu et al. 2004 Schizophrenia Research Analyzed the −1082G/A, −819T/C, and −592A/C polymorphisms of the IL-10 gene promoter; polymorphisms amplified using PCR 341 schizophrenia patients and 334 controls of Han Chinese descent Statistically significant differences observed in allelic and genotypic frequencies of the −592A/C polymorphism in the promoter region of the IL-10 gene between schizophrenia patients and controls Odds ratios and 95% CI for:

  • Allelic frequencies of −592A allele: 1.26 (1.02 – 1.5)

  • Genotypic frequencies for the distribution of −592A/C genotypes: 1.55 (1.09 – 2.19)
Tan et al. 2003 Biological Psychiatry Investigation of 4 biallelic polymorphisms (−1031T/C, −863C/A, −857C/T, and −308G/A) in the TNFα gene promoter using PCR 302 schizophrenia patients and 152 controls subjects Statistically significant differences in genotype distribution and allele frequencies for the −308G/A polymorphism in TNFα gene promoter between schizophrenia patients and controls Odds ratios and 95% CIs for:

  • −308 G/A allele frequencies between control and patients: 2.16 (1.49, 3.12)

  • G allele (when G allele was considered as recessive) between cases and controls: 2.48 (1.61, 3.76) (difference in distribution of G allele was not significant when it was considered as dominant)

  • TNFα gene promoter haplotypes −1031T, −863C, −857C, −308A: .51 (.34, .77)

  • TNFα gene promoter haplotypes −1031C, −863T, −857C, −308A: .33 (.13, .81)
Chiavetto et al. 2002 Biological Psychiatry Analyzed allele, genotype, and haplotype distributions of interleukin-10 (IL-10) in a case-control study using PCR-Single Strand Conformation Polymorphism (PCR-SSCP) and PCR RFLP methods 106 schizophrenia patients (schizophrenia: n = 91; schizoaffective disorders: n = 15) and 143 unrelated healthy volunteers Significant increase of GCC homozygotes (the high IL-10-producing haplotype) in schizophrenia patients compared to control subjects Odds ratio and 95% CI: 3.30 (1.274, 7.355)
Boin et al. 2001 Molecular Psychiatry Analyzed allelic and genotype distributions of TNF-α −308 gene polymorphism in schizophrenia patients and controls 84 schizophrenia patients recruited from an inpatient facility and 138 unrelated healthy controls Significant increase in frequency of TNF − 308A (TNF2) allele in schizophrenia patients as compared to healthy controls; genotype distribution was also significantly different, with TNF2 homozygotes represented only in the patient group * For allele frequency: ϕ = .192 (small effect); for genotype: ϕ = .233 (small effect)
Katila et al. 1999 Molecular Psychiatry DNA isolation and screening of polymorphisms of the interleukin 1 (IL-1) gene complex (IL-1α (−889), IL-1β (−511), IL-1RA variable number tandem repeat (VNTR), located on chromosome 2q13–q21 50 schizophrenia patients and 400 controls Frequencies of IL-1α (−889) allele 2, IL1-β (−511) allele 1 and IL-1RA allele 1 were higher in schizophrenia patients. Number of carriers of this IL-1 complex haplotype was significantly higher in the schizophrenia patients than in controls, and the number of homozygotes of this haplotype was significantly high in schizophrenia patients Odds ratios for association with schizophrenia:

  • Number of carriers of the IL-1α (−889) allele 2 positive/IL1-β

    (−511) allele 2 negative/IL1RA allele 2 negative: OR = 2.0

  • Number of IL-1α (−889) allele 2/IL-1β (−511) allele 1/IL-2RA allele 1 homozygotes: OR = 4.3

    (Confidence intervals not reported)
Laurent et al. 1997 Psychiatric Genetics Association study of TaqI and IB-175/IB-173 polymorphisms (within the 3′UTR) of the IL-1β gene using PCR-SSCP 75 schizophrenia patients and 75 controls There was no significant difference in allelic or genotypic distribution of the IL-1β gene polymorphisms (TaqI and 1B-175/1B-173) between schizophrenia patients and healthy controls Allelic and genotypic distributions of TaqI polymorphism in patients and controls were not significantly different (χ2= .073, df = 1, NS; χ2 = .128, df = 2, NS)**
Similarly, no differences in allelic/genotypic distribution of IB-175/IB-173 (χ2= .444, df = 1, NS; χ2 = .447, df = 2, NS)**
*

Effect size or odds ratio not reported in paper. Calculated by authors based on available data reported in manuscripts.

**

No effect size or odds ratio reported