Mitochondrial DNA polymorphisms in bipolar disorder.
BACKGROUND
Previous studies suggested mitochondrial abnormality in bipolar disorder: (1) possible contribution of parent-of-origin effect in transmission of bipolar disorder; (2) abnormal brain phosphorus metabolism detected by phosphorus-31 magnetic resonance spectroscopy; (3) comorbidity of affective disorders in patients with mitochondrial encephalopathy; (4) increased levels of the 4977bp deletion of mitochondrial DNA (mtDNA) in the postmortem brains. We investigated mtDNA polymorphisms in association with bipolar disorder.


METHODS
Twelve PCR fragments including all tRNA genes were examined by the single-strand conformation polymorphism method in 43 bipolar patients. All observed polymorphisms were sequenced. Association of these polymorphisms with bipolar disorder was examined by restriction fragment length polymorphism method in 135 bipolar patients and 187 controls.


RESULTS
In total, we found 28 polymorphisms including 14 polymorphisms that have not been reported previously. The A10398G polymorphism was significantly associated with bipolar disorder (10398A genotype: 33.1% in bipolar, 22.2% in the control, P<0.05). Although this difference was not significant after Bonferroni correction, the CA haplotype of the 5178 and 10398 polymorphisms was still significantly associated with bipolar disorder (CA haplotype: 33.6% in bipolar, 16.8% in control, P<0.001). Three rare mutations substituting evolutionary conserved bases; A5539G in tRNA(Trp) gene, A5747G in the origin of L-strand replication, and A8537G in ATPase subunit-6 and -8 genes, were found in patients with family history in which maternal transmission was suspected.


CONCLUSIONS
The 5178C/10398A haplotype in mtDNA may be a risk factor of bipolar disorder (odds ratio, 2.4). Pathophysiological significance of rare mtDNA mutations needs to be verified in the future. This finding may imply the pathophysiological significance of mtDNA in bipolar disorder.
Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-8655, Japan. tadafumi-tky@umin.ac.jp
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Kato
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Kunugi
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D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D012343:RNA, Transfer / Q000235:genetics
D004272:DNA, Mitochondrial; D012343:RNA, Transfer