Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia.
BACKGROUND
Folate deficiency may contribute to negative symptoms in schizophrenia, but the underlying mechanism remains uncertain. We examined whether the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C functional polymorphisms contribute to negative symptoms.


METHODS
Outpatients with schizophrenia (n = 200) were evaluated with the Positive and Negative Syndrome Scale (PANSS). Subjects also provided a blood sample for MTHFR genotype and serum chemistries. Comparisons of PANSS symptoms, folate, and homocysteine status were conducted based on genotype.


RESULTS
The 677T allele load was associated with negative symptom severity. Contrary to our expectations, the T allele was also found to be protective against positive symptoms. The A1298C polymorphism did not contribute to negative symptoms, and only weakly to positive symptoms. The specific effects of the C677T polymorphism were confirmed with haplotype analysis. Among patients homozygous for the 667T allele, serum folate levels correlated with negative symptom severity.


CONCLUSIONS
Increased MTHFR 677T allele load confers risk for negative symptoms in schizophrenia, while reducing severity of positive symptoms. Further, the biochemical interaction of low serum folate with 677T-variant MTHFR may induce downstream effects salient to the expression of negative symptoms.
Roffman
Joshua L
JL
Schizophrenia Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. jroffman@partners.org
Weiss
Anthony P
AP
Purcell
Shaun
S
Caffalette
Christopher A
CA
Freudenreich
Oliver
O
Henderson
David C
DC
Bottiglieri
Teodoro
T
Wong
Donna H
DH
Halsted
Charles H
CH
Goff
Donald C
DC
D000328:Adult; D000704:Analysis of Variance; D001526:Behavioral Symptoms / Q000209:etiology / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011624:Pteroylpolyglutamic Acids / Q000097:blood; D012306:Risk; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*; D012565:Schizophrenic Psychology
D011624:Pteroylpolyglutamic Acids; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)