Homocysteine metabolism and risk of schizophrenia

The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine (tHcy) concentrations, and genetic determinants. We observed decreased plasma and elevated RBC folate levels as risk factors for schizophrenia, which appeared to be independent of tHcy concentrations (chapter 2). No deficiencies of vitamin B6 or vitamin B12 levels were found in our study. In a review we only found 7 case-control studies with data on folate levels in schizophrenia patients (chapter 3). These studies showed no substantial support for an aberrant folate metabolism in schizophrenia patients. However, all studies showed a variety of methodological flaws defying a more definite conclusion on the relationship between folate and schizophrenia. The results of a meta-analysis of the current literature (chapter 5) give support to the conclusion presented in our previous report (chapter 4) that elevated tHcy concentration is a risk factor for schizophrenia. We found that a 5 μmol/L higher tHcy concentration was associated with an increased risk of schizophrenia (OR=1.70 [95% CI: 1.27-2.29]). Next to the MTHFR 677TT genotype, we found elevated tHcy concentrations in schizophrenia patients with the heterozygous MTHFR 677C>T genotype compared to patients homozygous for the normal genotype (chapter 4). The MTHFR 677CT genotype itself may result in elevated tHcy concentrations. The results of our initial study showed no increased frequency of the 677TT genotype in schizophrenia patients (chapter 2). However, an enlargement of this initial study showed a nearly significant increased risk (OR=1.6 [95% CI: 0.96-2.8]) of schizophrenia associated with the 677TT genotype in the MTHFR gene (chapter 4). When these data were incorporated in a meta-analysis based on published studies the MTHFR 677C>T mutation in homozygous state appeared to be a significant genetic risk factor for schizophrenia with a pooled risk estimate of 1.36 (95% CI: 1.07-1.72) (chapter 5). We observed no transmission distortion of the 677T allele in 120 families with schizophrenia offspring, which is in accordance with the result of a meta-analysis using data from three family-based studies, including our data (chapter 6). When we applied a log-linear model to the case-parent data no evidence for a strong maternal genetic effect on schizophrenia risk was observed. In chapter 7 the effect of genetic variations of two interconnected enzymes of the methylation pathway, COMT and MTHFR, on schizophrenia risk were subject of study. Despite the low numbers of subjects carrying the combination of the COMT 324AA and MTHFR 677TT genotype an increased risk of schizophrenia was associated with this compound genotype in our study. Four polymorphisms of the COMT gene, and their effect on tHcy levels in population-based controls were examined (chapter 8). Only the COMT 324G>A variant was associated with homocysteine, although the effect of this polymorphism on tHcy concentration is lower than that of the MTHFR 677C>T polymorphism

Aberrant folate status in schizophrenic patients: what is the evidence?

Item does not contain fulltextA vast amount of case reports, open studies and, to a lesser extent, case-control studies have been published on the topic of psychopathology and folate deficiency. These studies reported a high incidence of serum folate deficiency in patients with various psychiatric disorders. Folate deficiency seems to be a particular consistent finding in depressive patients. The evidence for an association between aberrant folate status and schizophrenia seems less convincing. The lack of stringent methodology such as inclusion of age- and sex-matched controls was thought to be the main reason for the inconclusive results. The purpose of this article is to review the published case-control studies that provide data on folate levels in the population of patients with schizophrenia. Data extracted from these studies comprised methodological design, clinical characteristics and folate measurements. We found that none of the 7 case-control studies included in this review (in total 325 cases and 560 control subjects) explicitly reported on all critical factors in the assessment of folate. In addition, only three studies found lower plasma folate levels more frequently in patients with schizophrenia compared to controls. Further research on this topic is required to clarify the relationship between folate status and schizophrenia and should avoid the methodological pitfalls mentioned in this review. In addition, research should also focus on polymorphisms of genes related to folate metabolism

Differences of Symptom Distribution Across Adult Age in High Functioning Individuals on the Autism Spectrum Using Subscales of the Autism Spectrum Quotient

Contains fulltext : 197165.pdf (publisher's version ) (Open Access

Effects of season of birth and a common MTHFR gene variant on the risk of schizophrenia

Item does not contain fulltextSeason of birth - in particular winter birth - has been persistently related to increased schizophrenia risk. Variation in folate intake is among the explanations for this seasonal effect. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate mediated methylation transfer reactions. Interestingly, the MTHFR gene has been related to schizophrenia risk in various studies. We investigated a possible interaction between MTHFR 677C>T polymorphism and winter birth in the development of schizophrenia in a group of 742 schizophrenia patients and 884 control subjects. All subjects were of Dutch ancestry. Winter birth (December up to and including February) was associated with a 20% increase in schizophrenia risk (odds ratio (OR) of 1.20 and 95% confidence interval (CI), 0.96-1.5; P=0.113). The MTHFR 677TT genotype was associated with an overall schizophrenia risk of 1.13 (95% CI, 0.82-1.57; P=0.454) compared with the MTHFR 677CC genotype. In the winter period the MTHFR 677TT genotype associated schizophrenia risk was 0.90 (95% CI, 0.47-1.70; P=0.744). In conclusion, neither winter birth nor MTHFR genotype were significantly associated with increased schizophrenia risk. There was no evidence for interaction between MTHFR 677TT genotype and winter birth in the development of schizophrenia

Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study.

Item does not contain fulltextEvidence for an involvement of aberrant homocysteine metabolism in the aetiology of schizophrenia is limited and controversial. A case-control study was performed to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations or homozygosity for the 677C --> T polymorphism (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene in subjects of Dutch ancestry. We determined the 677C --> T MTHFR genotype distribution in 254 well-defined patients and 414 healthy controls. Plasma homocysteine concentrations were measured in 62 patients with schizophrenia and 432 control subjects. When homocysteine concentrations were stratified into quartiles of the control distribution, we calculated an increased risk for schizophrenia in the fourth and third quartile versus the lowest quartile [odds ratio (OR) = 3.3; 95% confidence interval (CI): 1.2-9.2, and OR = 3.1; 95% CI: 1.2-8.0, respectively]. A significant dose-response relation of increasing homocysteine levels and increasing risk for schizophrenia was observed (P = 0.036). The 677TT genotype was associated with an OR of 1.6 [95% CI: 0.96-2.8] of having schizophrenia. Heterozygosity for the T allele compared to 677CC subjects accounted for an OR of 1.3 [95% CI: 0.91-1.8]. Elevated homocysteine levels and the MTHFR 677TT genotype are associated with an increased risk for schizophrenia. These observations support a causal relation between disturbed homocysteine metabolism and schizophrenia

Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia.

Contains fulltext : 71436.pdf (publisher's version ) (Closed access)BACKGROUND: Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia. METHODS: We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry. RESULTS: The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR)=1.38 [95% CI: 0.88-2.16], P=0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR=1.65 [95% CI: 0.97-2.82], P=0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08-8.76) (P=0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P=0.017). CONCLUSIONS: Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility

No evidence for a preferential transmission of the methylenetetrahydrofolate reductase 677T allele in families with schizophrenia offspring.

Contains fulltext : 52961.pdf (publisher's version ) (Closed access)The methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism has been associated with an increased risk of schizophrenia in various case-control studies. However, case-control studies are sensitive to population stratification, which is not an issue in family-based studies. We conducted a family-based study comprising 120 families with a schizophrenic family member to explore the association between the parental MTHFR 677C > T polymorphism and schizophrenia risk in offspring. In addition, a meta-analysis was performed using the available studies with data on this subject. Transmission Disequilibrium Test (TDT) analysis showed no preferential transmission of the 677T allele from parents heterozygous for the MTHFR 677C > T polymorphism to schizophrenia offspring (P = 0.27). The genotype relative risks were 1.43 (95% CI: 0.83-2.47) for the 677TT and 1.42 (95% CI: 0.54-3.78) for the 677CT genotype, relative to the 677CC genotype. A meta-analysis using data from family-based studies comprising a total of 416 parent-child triads yielded no evidence implicating the 677T allele in schizophrenia risk (P = 0.58). By applying a log-linear model, we found no asymmetry within parental mating type. Our data provided no evidence that transmission of the MTHFR 677T allele is associated with schizophrenia risk. In addition, we found no evidence that the maternal genotype influences the risk of having schizophrenia offspring substantially

Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia.

Item does not contain fulltextTwo apparently unrelated disorders, neural tube defects (NTD) and schizophrenia showed increased risks in birth cohorts exposed to famine during early gestation. NTD is associated with impaired folate metabolism. We investigated whether schizophrenia is also linked with a dysfunctional folate metabolism. In addition to the prevalence of the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, we compared plasma and red blood cell (RBC) folate, vitamin B6, vitamin B12, and homocysteine (Hcy) concentrations of 35 schizophrenic patients with those of 104 unrelated controls. Schizophrenic patients had significantly lower plasma folate concentrations after adjustment for Hcy levels, and elevated RBC folate levels compared to controls. Vitamin B6, vitamin B12, and Hcy levels did not differ from control values. Plasma folate levels below the 10th percentile of controls were associated with an approximate 4-7-fold (before and after adjustment of folate levels for Hcy, respectively) risk of having schizophrenia. In addition, a significant dose-response relation between plasma folate concentrations and risk for schizophrenia suggested a protective effect by high plasma folate concentrations. Elevated Hcy levels and, in line with this finding, homozygosity for the 677C-->T mutation in the MTHFR gene were not associated with an increased risk for schizophrenia. Evidence is presented suggesting that folate metabolism is disturbed in schizophrenic patients, independently of Hcy

Autism spectrum disorders and autistic traits share genetics and biology

Contains fulltext : 191416.pdf (publisher's version ) (Open Access)8 p