1Psychiatry Res 2008 Jan 157: 241-5
TitleGenetic polymorphism in the DNA repair gene XRCC1 and susceptibility to schizophrenia.
AbstractThe X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. A high level of XRCC1 mRNA and/or protein has been found in rat and baboon brains. An exon 10 variant at codon 399 of XRCC1 leads to an Arg to Gln amino acid change. The 399Gln allele is associated with an increased risk of several types of cancers, increased DNA adducts and chromosomal changes; therefore, it appears that the 399Gln allele may alter the role of the XRCC1 protein in DNA repair. The present case-control study was performed on 303 (223 males, 80 females) in-patients with chronic schizophrenia and 303 healthy blood donors matched to the patients by age (+/-5 years) and gender. The XRCC1 genotypes were determined using a PCR-based method. Heterozygosity (OR=1.48, 95% CI: 1.05-2.09) and homozygosity (OR=2.00, 95% CI: 1.17-3.42) for the Gln399 allele increased the risk of schizophrenia. There was a significant linear trend in risk associated with zero, one, and two 399Gln alleles. The present finding indicates that XRCC1 is a candidate gene for susceptibility to schizophrenia.
SCZ Keywordsschizophrenia
2Psychiatry Res 2009 Sep 169: 186
TitleAssociation between genetic polymorphism of XRCC1 Arg194Trp and risk of schizophrenia.
SCZ Keywordsschizophrenia
3Neuropharmacology 2013 Dec 75: 233-45
TitleActive DNA demethylation in post-mitotic neurons: a reason for optimism.
AbstractOver the last several years proteins involved in base excision repair (BER) have been implicated in active DNA demethylation. We review the literature supporting BER as a means of active DNA demethylation, and explain how the various components function and cooperate to remove the potentially most enduring means of epigenetic gene regulation. Recent evidence indicates that the same pathways implicated during periods of widespread DNA demethylation, such as the erasure of methyl marks in the paternal pronucleus soon after fertilization, are operational in post-mitotic neurons. Neuronal functional identities, defined here as the result of a combination of neuronal subtype, location, and synaptic connections are largely maintained through DNA methylation. Chronic mental illnesses, such as schizophrenia, may be the result of both altered neurotransmitter levels and neurons that have assumed dysfunctional neuronal identities. A limitation of most current psychopharmacological agents is their focus on the former, while not addressing the more profound latter pathophysiological process. Previously, it was believed that active DNA demethylation in post-mitotic neurons was rare if not impossible. If this were the case, then reversing the factors that maintain neuronal identity, would be highly unlikely. The emergence of an active DNA demethylation pathway in the brain is a reason for great optimism in psychiatry as it provides a means by which previously pathological neurons may be reprogrammed to serve a more favorable role. Agents targeting epigenetic processes have shown much promise in this regard, and may lead to substantial gains over traditional pharmacological approaches.
SCZ Keywordsschizophrenia
4Genet Test Mol Biomarkers 2016 Jan 20: 11-7
TitleAssociation Between Polymorphisms of DNA Repair Genes and Risk of Schizophrenia.
AbstractDNA repair gene polymorphisms have recently been implicated as potential pathogenic contributors of mental disorders. The aims of our study were to investigate the participation of nucleotide and base excision repair mechanisms in schizophrenia and to identify novel candidate DNA repair susceptibility genes.
For these purposes, we genotyped apurinic/apyrimidinic endonuclease 1 (APE1), human 8-oxoguanine DNA N-glycosylase 1 (hOGG1), X-ray repair cross-complementation group 1 (XRCC1), XRCC3, xeroderma pigmentosum group D (XPD), and xeroderma pigmentosum group G (XPG) genes in schizophrenia subjects, their healthy relatives, and unrelated healthy controls.
Carriers of XRCC1 glutamine (Gln), XRCC3 threonine (Thr), hOGG1 cysteine (Cys), and XPD lysine (Lys) alleles were significantly more frequent among the cohort of schizophrenia patients than in controls. In contrast, the frequencies of XRCC3 methionine (Met) and XPD Gln allele carriers and hOGG1 serine (Ser)/Ser genotype carriers were higher among controls than in patients, suggesting a possible protective role for these gene variants against schizophrenia. Moreover, healthy relatives had significantly higher frequencies of XRCC3 Thr+ and XPD Lys+ genotypes than unrelated healthy controls. Minor allele frequencies, haplotypes, and overtransmitted alleles of DNA repair genes were also identified.
Our findings support XRCC1, XRCC3, hOGG1, and XPD as risk genes for schizophrenia and suggest that altered DNA repair functions may be involved in schizophrenia pathophysiology.
SCZ Keywordsschizophrenia
5PLoS ONE 2016 -1 11: e0147348
TitleDNA Repair Gene (XRCC1) Polymorphism (Arg399Gln) Associated with Schizophrenia in South Indian Population: A Genotypic and Molecular Dynamics Study.
AbstractThis paper depicts the first report from an Indian population on the association between the variant Arg399Gln of XRCC1 locus in the DNA repair system and schizophrenia, the debilitating disease that affects 1% of the world population. Genotypic analysis of a total of 523 subjects (260 patients and 263 controls) revealed an overwhelming presence of Gln399Gln in the case subjects against the controls (P < 0.0068), indicating significant level of association of this nsSNP with schizophrenia; the Gln399 allele frequency was also perceptibly more in cases than in controls (p < 0.003; OR = 1.448). The results of the genotypic studies were further validated using pathogenicity and stability prediction analysis employing computational tools [I-Mutant Suite, iStable, PolyPhen2, SNAP, and PROVEAN], with a view toassess the magnitude of deleteriousness of the mutation. The pathogenicity analysis reveals that the nsSNP could be deleterious inasmuch as it could affect the functionality of the gene, and interfere with protein function. Molecular dynamics simulation of 60ns was performed using GROMACS to analyse structural change due to a mutation (Arg399Gln) that was never examined before. RMSD, RMSF, hydrogen bonds, radius of gyration and SASA analysis showedthe existence of asignificant difference between the native and the mutant protein. The present study gives astrong indication that the XRCC1 locus deserves serious attention, as it could be a potential candidatecontributing to the etio-pathogenesis of the disease.
SCZ Keywordsschizophrenia