|(C;C)||0||rare but normal|
|(C;T)||1||1.1x increased risk for schizophrenia|
|(T;T)||1||1.1x increased risk for schizophrenia|
|Title||Common variants conferring risk of schizophrenia|
|Odds Ratio||1.16 [NR]|
rs6932590 is a SNP that is postulated to have a role in conferring increased susceptibility for schizophrenia. rs6932590 lies in the major histocompatibility complex (MHC) region on chromosome 6, a region that codes for several genes with significant roles in autoimmunity, such as human leukocyte antigens. Specifically, rs6932590 lies in an intergenic region between PRSS16 (a serine protease expressed in the thymus that plays a role in positive T cell selection) and POM121L2 (a membrane glycoprotein) [PMID 20673877] [PMID 12045153].
One large-scale case-controlled genome-wide association study (GWAS) that examined differential genotypes in individuals with schizophrenia, found five significant schizophrenia-associated SNP markers in the MHC region: rs6913660, rs13219354, rs6932590, rs13211507, and rs3131296, with significant linkage disequilibrium between them. This GWAS was performed by the International Schizophrenia Consortium (ISC), Molecular Genetics of Schizophrenia (MGS), and SGENE and included, in all, 12,945 cases and 34,591 controls. Samples were taken from Caucasian populations across Europe (eight separate geographical locations) [PMID 19571808] [PMID 19571811] 23andMe blog. rs6932590 was found to be the most significant SNP between cases and controls, with a p-value of 1.4x10e-12. The T allele was found to confer increased risk for schizophrenia with an odds ratio of 1.16.
In a separate GWAS that was designed to examine only the top eight significant SNPs (i.e., candidates) reported by the previous ISC/SGENE/MGS study [PMID 19571808], 2,496 cases and 5,184 control subjects from the Shanghai, China, population were genotyped. rs6932590 was again found to be significant (corrected p-value of 0.00096), as well as other SNPs in the MHC region (rs3131296, rs3130375) [PMID 20673877]. The 0.00096 p-value is much higher than the one reported by the aforementioned ISC/SGENE/MGS study, however, the investigators deemed it significant. This study also found the T allele at rs6932590 to confer an increased risk for schizophrenia, but with an odds ratio of 1.31. Overall, this study found only four of the eight candidate SNPs from the ISC/SGENE/MGS study to be significant (i.e., validated) in the genotyped Shanghai, China sample.
Importantly, in both of the above studies, rs2958182, a SNP that lies in the TCF4 gene (outside of the MHC region), was also found to be significant. TCF4 codes for a transcription factor that is primarily expressed in pre-B cells and potentially plays a role in cognitive development [PMID 20434134].
A recent expression quantitative trait locus (eQTL) study investigated whether the SNPs reported by ISC/MGS/SGENE affect gene expression in normal human cortical brain tissue. The study did not find that rs6932590 was associated with any significant differential expression [PMID 21339752]. However, the investigators noted that MHC region SNPs such as rs6932590 may affect gene expression earlier in development, which is difficult to observe temporally, particularly in the elderly, post-mortem brain samples that were used in the eQTL study.
It is still unclear what role immune system genes may have on schizophrenia etiology, or whether the significant genes in the MHC region are even immune genes (there are other, non-immunity genes in the MHC region). One interesting finding is that a single allele variant in a schizophrenia SNP marker in the MHC region, rs3131296 (which has an r^2 of .86 with the HLA-DRB1*03 gene), while conferring risk for schizophrenia, confers increased protection for type-1 diabetes, celiac disease, and systemic lupus erythematosus [PMID 19571808].
There have been hypotheses that a winter or spring season of birth (i.e., an implicit increased risk of maternal influenza infection during pregnancy; which could lead to inflammation and aberrant neuronal development/growth) or early childhood infections (e.g., measles) may catalyze the development of schizophrenia. However, these hypotheses remain unproven and there was no evidence for them in the ISC/SGENE/MGS patient history data.
The polygenic inheritance model of schizophrenia is predicated on the idea that dozens of common variants combine to increase an individual's risk of schizophrenia. However, there has been limited success in finding significant common SNPs that are associated with schizophrenia. For example, in a study consisting of 1,870 schizophrenia cases and 2,002 controls that were genotyped for 789 SNPs that were hand-picked for their purported significance in schizophrenia susceptibility, no statistically significant associations were found [PMID 18198266]. At present, the most optimistic estimates of the magnitude of the effect of the polygenic model on disease susceptibility variance is approximately 20% [PMID 19571811].
The most promising explanation of schizophrenia heritability may come from the significantly increased presence of rare structural variants such as deletions and duplications in individuals with schizophrenia [PMID 18369103]. Certainly, it is possible that certain SNPs, say in brain development or the immune system, may operate in concert with the effects of rare structural variants.
Other theories to explain the missing heritability include effects from certain copy number variations (CNV) [PMID 19883952] [PMID 18668039] and effects from a few of many highly impactful, independent, rare alleles [PMID 17329737].
As of May 2011, the Psychiatric GWAS Consortium is working on the largest GWAS for schizophrenia ever performed, with 59,000 cases and 7,700 family trios [PMID 19002139].
[PMID 19571808] Common variants conferring risk of schizophrenia.
[PMID 20673877] Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese
[PMID 19571811] Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
[PMID 21339752] Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain
[PMID 18198266] No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics
[PMID 18369103] Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia
[PMID 19883952] Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders
[PMID 18668039] Large recurrent microdeletions associated with schizophrenia
[PMID 17329737] Schizophrenia: a common disease caused by multiple rare alleles
[PMID 19002139] A framework for interpreting genome-wide association studies of psychiatric disorders
[PMID 12045153] The human genome browser at UCSC
[PMID 20434134] Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain[PMID 19571809] Common variants on chromosome 6p22.1 are associated with schizophrenia.
[PMID 22005930] Genome-wide association study of Alzheimer's disease with psychotic symptoms.
[PMID 25124521] Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain
[PMID 28855605] Attempts to replicate genetic associations with schizophrenia in a cohort from north India.