Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia.
Many studies suggest that mitochondrial dysfunction is involved in the pathophysiology of schizophrenia. We performed a case-control study using tag SNPs in the mitochondrial uncoupling protein genes, UCP2, UCP4, and BMCP1/UCP5, to investigate their association with schizophrenia. These neuronal UCPs are expressed in various brain tissues and may exert a neuroprotective effect against increased oxidative stress. We found modest associations between schizophrenia and the four tag SNPs, rs660339 (odds ratio (OR) = 1.330; P = 0.0043) and rs649446 (OR = 0.739; P = 0.0069) in UCP2, and rs10807344 (OR = 0.622; P = 0.0029) and rs2270450 (OR = 0.704; P = 0.0043) in UCP4, all of which were statistically significant even after correcting for multiple comparisons. Moreover, we found a statistically significant synergistic interaction between UCP2 and UCP4 by using the multifactor dimensionality reduction (MDR) method. The synergistic interaction was also confirmed by the logistic regression analysis, where the maximal OR was obtained when the risk alleles at rs660339 and rs10807344 were simultaneously homozygous. Individuals possessing homozygous risk alleles at these two loci have a 7.6-fold risk of developing schizophrenia compared with those of minimal OR. Our findings suggest that UCP2 and UCP4 have a modest but important involvement in the genetic etiology of schizophrenia. This is the first report of the association between schizophrenia and neuronal UCPs.
Yasuno
Katsuhito
K
Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa, Japan.
Ando
Satoshi
S
Misumi
Shinnosuke
S
Makino
Satoshi
S
Kulski
Jerzy K
JK
Muratake
Tatsuyuki
T
Kaneko
Naoshi
N
Amagane
Hideki
H
Someya
Toshiyuki
T
Inoko
Hidetoshi
H
Suga
Hidemichi
H
Kanemoto
Kousuke
K
Tamiya
Gen
G
D000483:Alleles; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D000071245:Mitochondrial Uncoupling Proteins; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D012984:Software; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D009419:Nerve Tissue Proteins; C116584:SLC25A14 protein, human; C117577:SLC25A27 protein, human; C000604389:UCP2 protein, human; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2