Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: A dutch population based case‐control study

Abstract

Evidence 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.

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

“…The minor allele of both these polymorphisms is associated with lower enzyme activity, with a more prominent effect for the C677T polymorphism [Lievers et al, 2001]. One or both of these polymorphisms have been reported to be associated with schizophrenia in several [Arinami et al, 1997;Joober et al, 2000;Sazci et al, 2003Sazci et al, , 2005Muntjewerff et al, 2005;Kempisty et al, 2006Kempisty et al, , 2007Feng et al, 2009], but not all studies [Kunugi et al, 1998;Virgos et al, 1999;Tan et al, 2004;Yu et al, 2004;Vilella et al, 2005;Philibert et al, 2006;J€ onsson et al, 2008;Mavros et al, 2008;Betcheva et al, 2009]. All meta-analyses hitherto performed have advocated an association between the C677T polymorphism and the disorder, although the support for association with the A1298C variant have been somewhat less convincing [Lewis et al, 2005;Muntjewerff et al, 2006;Zintzaras, 2006;Gilbody et al, 2007;Allen et al, 2008;J€ onsson et al, 2008;Shi et al, 2008].…”

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis

“…Data for the meta-analysis were obtained from eight published case-control studies 22,[29][30][31][32][33][34][35] with a total number of 812 cases and 2113 control subjects. Figure 1 shows the ORs and 95% CIs of schizophrenia associated with a 5 mmol/l increase in measured plasma total homocysteine, separately for individual studies and for all studies when taken together.…”

“…A total of nine published articles 22,31,33,[36][37][38][39][40][41] reported on the relationship between schizophrenia and the MTHFR 677C4T polymorphism. One article provided data on two separate studies.…”

“…Susser et al 30 Regland et al 29 Muntjewerff et al 33 Muntjewerff et al 22 Goff et al 35 Virgos et al 31 Applebaum et al 34 Levine Figure 1 Odds ratios (ORs) and 95% confidence intervals (CIs) of schizophrenia for a 5 mmol/l increase in plasma total homocysteine concentration for each study separately and combined (Studies are ordered by the inverse of the s.e. of each estimate.…”

“…Muntjewerff et al 33 Muntjewerff et al 22 Yu et al, Chinese series 40 Yu et al, Scottish series 40 Tan et al 41 Joober et al 38 Sazci et al 39 Virgos et al 31 Kunugi et al 37 Arinami Figure 2 Odds ratios (ORs) and 95% confidence intervals (Cls) of schizophrenia for TT versus CC genotype of the MTHFR 677C4T polymorphism of each study seperately and combined (Studies are ordered by the inverse of the s.e. of each estimate.…”