Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia.
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.
Vares
Maria
M
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.
Saetre
Peter
P
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.
Deng
Hong
H
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Cai
Guiqing
G
Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, New York.
Liu
Xiehe
X
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Hansen
Thomas
T
Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Rasmussen
Henrik B
HB
Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Werge
Thomas
T
Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Melle
Ingrid
I
Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department Psychiatry, Oslo University Hospital, Ullevål, Oslo, Norway.
Djurovic
Srdjan
S
Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department of Medical Genetics, Oslo University Hospital, Ullevål, Oslo, Norway.
Andreassen
Ole A
OA
Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department Psychiatry, Oslo University Hospital, Ullevål, Oslo, Norway.
Agartz
Ingrid
I
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.|Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department of Psychiatry, Section Vinderen, University of Oslo, Oslo, Norway.
Hall
Håkan
H
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.|Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Terenius
Lars
L
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.
Jönsson
Erik G
EG
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D016022:Case-Control Studies; D002681:China; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012537:Scandinavian and Nordic Countries; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*
D042965:Methylenetetrahydrofolate Reductase (NADPH2)