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From SNPedia

Geno Mag Summary
(C;C) 0 normal
(C;T) 2 some association with bipolar disorder
(T;T) 2 some association with bipolar disorder
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs10937823
1000 genomesrs10937823
GWAS Ctlgrs10937823
Max Magnitude2
? (C;C) (C;T) (T;T) 28

rs10937823 is a SNP associated with the gene SORCS2, variants of which may play a role in bipolar disorder. The allele most frequently occurring is C, and the variant is T. In the HapMap-CEU population, CC, CT, and TT genotype frequencies were 0.894, 0.097, and 0.009, respectively. However, in the HapMap-CHB population, CT was the most frequently expressed genotype; CC, CT, and TT genotype frequencies were 0.366, 0.439, and 0.195, respectively. In some sample populations, the TT genotype did not exist (TSI, MKK, LWK, ASW). [dbSNP]

The SORCS2 (sortillin-related VPS10 domain containing receptor 2) gene on chromosome 4p16.1 is found to be highly expressed in the mature human brain and kidney. High levels of expression are also seen in the brain during mouse development. [PMID 11165493] [GeneCards] This gene family is responsible for trafficking lysosomal enzymes that are modified within the Golgi to their packaging vacuole. [PMID 8187177] Sortillins have been found to facilitate neurotrophin binding to its receptor, which is necessary for mediating neuronal apoptosis, growth and survival. Given these roles, it has been proposed that alterations to the SORCS2 gene can lead to neuronal dysfunction. [PMID 14985763][PMID 19002190][PMID 20351716]

In 2008, a genome-wide association study indicated the SORCS2 gene in bipolar disorder. The study conducted by Baum et al. analyzed 461 affected individuals and 563 matched controls (from the National Institutes of Mental Health Genetics Initiative, all of European ancestry), and a replication sample of 772 affected individuals and 876 matched controls (affected individuals recruited from German hospital admissions, and controls recruited from a German census). The C allele of rs10937823 was found at a frequency of 0.949 in cases and 0.912 in controls in NIMH cohort (p=0.001); 0.954 in cases and 0.931 in controls in the German cohort (p=0.004). The resulting combined odds ratio was 1.67 between the German and NIMH cohorts. [PMID 17486107OA-icon.png]Table 3 Furthermore, with multi-locus analysis, the authors found that the highest risk of bipolar disorder was associated with presence of both rs10937823 and rs1170191, a SNP in diacylglycerol kinase eta (DGKH Rs1170191), suggesting that these SNPs have a combinatorial effect in conferring risk (p=1.2x10-8). [PMID 17486107OA-icon.png]

A Finnish bipolar family study in 2009 replicated the association between rs10937823 and bipolar disorder. The researchers genotyped the 26 SNPs most strongly associated SNPs as found by the Wellcome Trust Case Control Consortium, and the aforementioned study by Baum et al. in 723 individuals from 180 families. The study classified individuals as falling into diagnostic classes of bipolar type I disorder (cases = 214; controls = 509) or a broad mood spectrum disorder encompassing all types of bipolar disorder (cases = 298; controls = 495). In an opposite finding to that of Baum et al., the minor allele (T) frequency in the unaffected individuals was 0.999; in cases, the frequency was 0.112. The lower frequency of the T allele of rs10937823 in cases versus controls was statistically significant (p=0.004187 using broad mood spectrum disorder; p=0.004703 using broad mood spectrum disorder). [PMID 19308021OA-icon.png]

In 2011, In a Japanese cohort of 736 individuals, rs10937823 was again found to be significantly associated with bipolar disorder by Takata et al. (363 cases, 370 controls; p=0.0175). However, the results showed that the risk allele (more commonly associated allele in cases) was T, not C. The minor allele frequency in the bipolar disorder sample was 0.275, versus 0.253 in the control sample. An odds ratio for this SNP was not reported. [PMID 21507135]

In 2011, Cristoforou et al. identified an association between rs10937823 and bipolar disorder in a Scottish population (506 cases, 607 controls; p=0.031; OR not reported). Like the Japanese study by Takata et al., the minor allele (T) was found to be associated with bipolar disease. [PMID 20351716] Similar observations of this “flip-flop” phenomenon where opposite alleles appear to confer risk have been reported in other genes, such as COMT gene and schizophrenia, and GSTO1 gene and age of onset in Alzheimer’s Disease. The authors suggest that such different results could be due to allelic heterogeneity, the effects of multiple loci, or varying linkage disequilibrium amongst the subjects, if the findings across the studies and populations are indeed correct. [PMID 17273975OA-icon.png]

[PMID 21483023OA-icon.png] Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.