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      Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia


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          Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase ( MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort ( N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender ( N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia ( N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects ( N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.

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          Most cited references 77

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          Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.

          Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.
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            Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2.

             Yue Wang,  Yan Ruan,  Jun Yan (2011)
            To identify susceptibility loci for schizophrenia, we performed a two-stage genome-wide association study (GWAS) of schizophrenia in the Han Chinese population (GWAS: 746 individuals with schizophrenia and 1,599 healthy controls; validation: 4,027 individuals with schizophrenia and 5,603 healthy controls). We identified two susceptibility loci for schizophrenia at 6p21-p22.1 (rs1233710 in an intron of ZKSCAN4, P(combined) = 4.76 × 10(-11), odds ratio (OR) = 0.79; rs1635 in an exon of NKAPL, P(combined) = 6.91 × 10(-12), OR = 0.78; rs2142731 in an intron of PGBD1, P(combined) = 5.14 × 10(-10), OR = 0.79) and 11p11.2 (rs11038167 near the 5' UTR of TSPAN18, P(combined) = 1.09 × 10(-11), OR = 1.29; rs11038172, P(combined) = 7.21 × 10(-10), OR = 1.25; rs835784, P(combined) = 2.73 × 10(-11), OR = 1.27). These results add to previous evidence of susceptibility loci for schizophrenia at 6p21-p22.1 in the Han Chinese population. We found that NKAPL and ZKSCAN4 were expressed in postnatal day 0 (P0) mouse brain. These findings may lead to new insights into the pathogenesis of schizophrenia.
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              Re: Estimation of bias in nongenetic observational studies using "Mendelian triangulation" by Bautista et al.


                Author and article information

                Schizophr Bull
                Schizophr Bull
                Schizophrenia Bulletin
                Oxford University Press (US )
                September 2014
                17 February 2014
                17 February 2014
                : 40
                : 5
                : 1154-1163
                1Department of Psychiatry , Course of Integrated Brain Sciences , Medical Informatics , Institute of Health Biosciences , The University of Tokushima Graduate School , Tokushima, Japan;
                2Department of Human Genetics , Institute of Health Biosciences , The University of Tokushima Graduate School , Tokushima, Japan;
                3Department of Neuropsychiatry , Kochi Medical School , Kochi University , Kochi, Japan;
                4Department of Mental Health , Institute of Health Biosciences , The University of Tokushima Graduate School , Tokushima, Japan;
                5Department of Psychiatry , Osaka University Graduate school of Medicine , Osaka, Japan;
                6Molecular Research Center for Children’s Mental Development , United Graduate School of Child Development , Osaka University , Osaka, Japan
                Author notes
                *To whom correspondence should be addressed; Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-8-15 Kuramoto-cho, Tokushima 770–8503, Japan; tel: 81-886-33-7130, fax: 81-886-33-7131, e-mail: shu-numata@ 123456umin.ac.jp
                © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Page count
                Pages: 10
                Regular Article


                mendelian randomization, snp, japanese, plasma homocysteine


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