SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

Abstract

Chromosome 22q11-13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case-control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP-Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. We also validated 9 out of 14 dbSNPs in our population. Case-control analysis revealed allelic (P=0.028-0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.

The role of lithium in modulation of brain genes: relevance for aetiology and treatment of bipolar disorder

“…S100 proteins are involved in multiple intracellular functions, including maintenance of calcium homoeostasis, cytoskeletal rearrangement, transcription and enzyme regulation [32]. S100A8/A9, S100B and S100A11 and other S100 proteins can be secreted and extracellularly exhibit cytokine-like functions related to inflammation [33,34]. S100A11 has been observed to be overexpressed in colorectal, gastric, prostrate and pancreatic cancers [35].…”

Association study and mutational screening of SYNGR1 as a candidate susceptibility gene for schizophrenia

“…A nominally significant difference between patients and controls was observed for rs715505 (P = 0.028), with an increased frequency of the minor C allele in the patient group in comparison with the control group (0.24 vs. 0.19). Interestingly, the C allele of rs715505 was the same which gave the strong evidence of association in the previous study (Verma et al, 2005).…”

“…For the marker that showed strong association in the previous study (i.e. rs715505), the power reached 99.9% assuming an OR equal to that reported (2.01) (Verma et al, 2005). Differences in the frequency of rare variants between patients and controls were evaluated by the Fisher's exact test.…”

“…They were rs137698, rs909685, rs715505, rs715503, rs739363, rs4821888, c.606_607ins/delAAC, and rs1010169. Five of these markers (rs909685, rs715505, rs739363, rs4821888, and c.606_607ins/delAAC) have already been analyzed in other studies (Verma et al, 2005). The SNPs rs137698, rs909685, rs4821888, and rs1010169 were genotyped by restriction digestion using the Bsh1236I, Hsp92II, PstI, and RsaI enzymes, respectively.…”

“…This mutation, reported as Trp27Ter, should affect the minor SYNGR1 c isoform. In a subsequent Indian case-control study, the same group reported an association of two SYNGR1 single nucleotide polymorphisms (SNPs) located in intron 1 either with schizophrenia or with bipolar disorder (Verma et al, 2005). In the same study, a possible damaging Lys99Glu mutation was identified in a patient with bipolar disease.…”