{{Rsnum
|rsid=6932590
|Gene=TRNAV27
|Chromosome=6
|position=27281152
|Orientation=plus
|GMAF=0.2048
|Assembly=GRCh38
|GenomeBuild=38.1
|dbSNPBuild=141
|geno1=(C;C)
|geno2=(C;T)
|geno3=(T;T)
}}{{ population diversity
| geno1=(C;C)
| geno2=(C;T)
| geno3=(T;T)
| CEU | 5.3 | 29.2 | 65.5
| HCB | 0.0 | 5.2 | 94.8
| JPT | 0.0 | 0.9 | 99.1
| YRI | 11.8 | 50.0 | 38.2
| ASW | 15.8 | 35.1 | 49.1
| CHB | 0.0 | 5.2 | 94.8
| CHD | 0.0 | 5.5 | 94.5
| GIH | 3.0 | 27.7 | 69.3
| LWK | 14.7 | 41.3 | 44.0
| MEX | 3.4 | 31.0 | 65.5
| MKK | 12.2 | 51.3 | 36.5
| TSI | 4.0 | 37.6 | 58.4
| HapMapRevision=28
}}
{{PMID Auto GWAS
|PMID=19571808
|Trait=Schizophrenia
|Title=Common variants conferring risk of schizophrenia
|RiskAllele=T
|Pval=1E-12
|OR=1.16
|ORtxt=[NR]
|OA=1
}}

[[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|OA=1
}}.

The T allele at [[rs6932590]] purportedly confers an increased risk for schizophrenia, with reported odds ratios of 1.16  {{PMID|19571808|OA=1
}} and 1.31 {{PMID|20673877}}.

=== Evidence ===
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|OA=1
}} {{PMID|19571811|OA=1
}} [http://blog.23andme.com/2009/07/03/snpwatch-researchers-show-importance-of-common-dna-variants-in-schizophrenia/ 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|OA=1
}}, 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.

=== Biological Explanation ===
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|OA=1
}}.

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.

=== Competing/Complementary Theories ===
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|OA=1
}}.
  		
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|OA=1
}} {{PMID|18668039|OA=1
}} 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}}.

=== References ===
{{PMID|19571808|OA=1
}} 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|OA=1
}} 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|OA=1
}} Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders

{{PMID|18668039|OA=1
}} 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|OA=1
}} 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

{{omim
|id=181500
|rsnum=6932590
}}

{{PMID Auto
|PMID=19571809
|Title=Common variants on chromosome 6p22.1 are associated with schizophrenia.
|OA=1
}}

{{GET Evidence
|impact=pathogenic
|qualified_impact=Insufficiently evaluated pathogenic
|inheritance=unknown
|quality_scores=Array
|dbsnp_id=rs6932590
|overall_frequency_n=9
|overall_frequency_d=72
|overall_frequency=0.125
|n_genomes=8
|n_genomes_annotated=0
|n_haplomes=11
|n_articles=0
|n_articles_annotated=0
|in_gwas=Y
|autoscore=1
|webscore=N
}}

{{PMID Auto
|PMID=22005930
|Title=Genome-wide association study of Alzheimer's disease with psychotic symptoms.
|OA=1
}}

{{PMID Auto
|PMID=25124521
|Title=Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain
}}
{{on chip | 23andMe v1}}
{{on chip | 23andMe v2}}
{{on chip | 23andMe v3}}
{{on chip | 23andMe v4}}
{{on chip | HumanOmni1Quad}}
{{on chip | Illumina Human 1M}}