Mitochondrial DNA polymorphisms in bipolar disorder

Background: Previous studies suggested mitochondrial abnormality in bipolar disorder: (I) possible contribution of parent-of-origin effect in transmis sion of bipolar disorder; (2) abnormal brain phosphorus metabolism detected by phosphorus-31 magnetic resonance spectroscopy; (3) comorbidity of affec tive disorders in patients with mitochondrial encephalopathy; (4) increased levels of the 4977bp deletion of mitochondrial DNA (mtDNA) in the postmort em brains. We investigated mtDNA polymorphisms in association with bipolar disorder. Methods: Twelve PCR fragments including all tRNA genes were exami ned by the single-strand conformation polymorphism method in 43 bipolar pat ients. All observed polymorphisms were sequenced. Association of these poly morphisms 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 b een reported previously. The A10398G polymorphism was significantly associa ted with bipolar disorder (10398A genotype: 33.1% in bipolar, 22.2% in the control, P<0.05). Although this difference was not significant after Bonfer roni correction, the CA haplotype of the 5178 and 10398 polymorphisms was s till significantly associated with bipolar disorder (CA haplotype: 33.6% in bipolar, 16.8% in control, P < 0.001). Three rare mutations substituting e volutionary 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 s uspected. Discussion: The 5178C/10398A haplotype in mtDNA may be a risk fac tor of bipolar disorder (odds ratio, 2.4). Pathophysiological significance of rare mtDNA mutations needs to be verified in the future. This finding ma y imply the pathophysiological significance of mtDNA in bipolar disorder. ( C) 2001 Elsevier Science B.V. All rights reserved.