Elevated plasma homocysteine concentration has been suggested as a risk factor for schizophrenia, but the results of epidemiological studies have been inconsistent. The most extensively studied genetic variant in the homocysteine metabolism is the 677C4T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, resulting in reduced enzyme activity and, subsequently, in elevated homocysteine. A meta-analysis of eight retrospective studies (812 cases and 2113 control subjects) was carried out to examine the association between homocysteine and schizophrenia. In addition, a meta-analysis of 10 studies (2265 cases and 2721 control subjects) on the homozygous (TT) genotype of the MTHFR 677C4T polymorphism was carried out to assess if this association is causal. A 5 lmol/l higher homocysteine level was associated with a 70% (95% confidence interval, CI: 27-129) higher risk of schizophrenia. The TT genotype was associated with a 36% (95% CI: 7-72) higher risk of schizophrenia compared to the CC genotype. The performed meta-analyses showed no evidence of publication bias or excessive influence attributable to any given study. In conclusion, our study provides evidence for an association of homocysteine with schizophrenia. The elevated risk of schizophrenia associated with the homozygous genotype of the MTHFR 677C4T polymorphism provides support for causality between a disturbed homocysteine metabolism and risk of schizophrenia.

No abstract

SummaryAdisturbed methylation has been proposedasamechanism via which homocysteine is associated with diseaseslikevascular disease,n eural tube defects and mental disorders. Catechol-O-methyltransferase (COMT) is involved in the S-adenosylmethionine-dependent methylation of catecholamines and catecholestrogens and in this waycontributes to homocysteine synthesis.C OMT dysfunctionh as been related to schizophrenia and breast cancer. We hypothesized that COMT dysfunction by virtue of functional genetic polymorphisms maya ffectp lasma total homocysteine (tHcy).Our primaryobjectivewas to study thea ssociationb etween common COMT polymorphisms and tHcy.Secondly, we evaluatedthese polymorphisms as ariskfactor forr ecurrent venous thrombosis.Weo btained genotype datafromfour polymorphisms in theCOMT gene (rs2097603, KeywordsHomocysteine, haplotype,c atechol-O-methyltransferase,v enous thrombosis rs4633, rs4680 [324G>A] and rs174699) from 401population-basedcontrols.Weperformedhaplotype analysis to investigate theassociationbetween common haplotypesand tHcy.Inaddition, we assessedthe rs4680 variant as agenetic riskfactor in a case-controls tudy on recurrent venous thrombosis (n= 169). We identified acommon haplotypethat wassignificantly associatedw ith tHcy levels.This effect was largelye xplained by the rs4680 variant, resulting in an increase in tHcy of 10.4% (95%CI 0.01 to 0.21, p=0.03) for3 24AA compared with 324GG subjects.Interestingly, we found thatthe 324AA genotype wasmore common in venous thrombosis patients (OR1.61 [95% CI 0.97 to 2.65], p = 0.06) compared to control subjects.We show that the COMT rs4680 variant modulatestHcy, and mightbeassociated with venous thrombosis risk as well.