Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia

Abstract

Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate-homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (n = 820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high-risk families, with two or more affected siblings (n = 243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose-dependent manner (P = 0.0015), with lower age of onset with increasing numbers of the mutant T-allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high-risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild-type allele (P = 0.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and age of onset in schizophrenia: A combined analysis of independent samples

“…Age of onset in schizophrenia has been found to have genetic components [Cardno et al, 2001;Hare et al, 2010]. In a previous study, we reported association between the MTHFR C677T polymorphism and age at onset of schizophrenia in Scandinavian samples and a family sample from China [Vares et al, 2010]. In the present report the possible relationship between this MTHFR C677T polymorphism as well as the A1298C polymorphism and age at onset of schizophrenia was studied in a combined analysis of several independent samples of unrelated patients.…”

“…In addition, the association between MTHFR polymorphisms and the age at onset of schizophrenia were examined with survival analysis in order to replicate the results of the previous study [Vares et al, 2010], where the association between the 677TT genotype could be observed after the onset age of 24, and the effect of the 677 heterozygote genotype after the age of 38 years. For each study separately, the survival function for each MTHFR genotype was estimated with the Kaplan-Meier (product-limit) method in Proc Liftest (SAS/STAT Ò software), and the heterogeneity of survival functions were tested with the non-parametric trend test (genotype ordered by number of minor allele), using the log-rank weight function.…”

“…For each study separately, the survival function for each MTHFR genotype was estimated with the Kaplan-Meier (product-limit) method in Proc Liftest (SAS/STAT Ò software), and the heterogeneity of survival functions were tested with the non-parametric trend test (genotype ordered by number of minor allele), using the log-rank weight function. To test whether the association observed in the Scandinavian population [Vares et al, 2010] could be replicated, the Z-statistics from the individual studies were combined with the Rosenthal and Rubin method, and the probability for the combined outcome was calculated with a one-sided test [Rosenthal, 1991]. The Rosenthal and Rubin method is essentially a fixed-effect model and will inflate the estimate of the mean effect size and its significance if the effect size truly varies between studies [Field, 2001].…”

“…For the simulations we used the data structure of the included studies [excluding Vares et al, 2010] with respect to number of individuals, gender and C677T genotype. The age of onset was then TaqMan/combined multiplex PCR and invader DSM-III-R, diagnostic and statistical manual for mental disorders, third edition, revised; DSM-IV, diagnostic and statistical manual for mental disorders, fourth edition; ICD-9, international classification of diseases, ninth edition.…”

Associação entre polimorfismos em genes relacionados ao metabolismo de folato (RFC1, GCP2, MTHFR e MTHFD1) e alterações nas concentrações de folato, cobalamina e homocisteína em mulheres com história de abortos espontâneos recorrentes

“…Essa deficiência de função da MTHFR está associada com o aumento na concentração plasmática de tHcy Van Der Put, Steegers-Theunissen et al, 1995;Wilcken, 2012). De fato, alguns estudos mostraram que o genótipo 677TT foi associado ao maior risco para doença cardiovascular (Brattström e Wilcken, 2000;Ueland, Refsum et al, 2000), câncer (Chen, Giovannucci et al, 1999), demência (Nishiyama, Kato et al, 2000;Yoo, Choi et al, 2000), fetos com DFTN (Van Der Put, Steegers-Theunissen et al, 1995;Van Der Put, Eskes et al, 1997), esquizofrenia (Vares, Saetre et al, 2010) e sintomas de depressão durante a gravidez (Devlin, Brain et al, 2010).…”