Mitochondrial Variants in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Vawter, MP et al
International Congress on Schizophrenia Research. 2009:93.


An increasing number of brain studies implicate mitochondrial dysfunction in psychiatric disorders. The present study evaluated mtDNA variants in brain tissue including substitutions, synonymous and non-synonymous, and rare variants, which could predispose to bipolar disorder (BD), schizophrenia (SZ) and major depressive disorder (MDD). Genomic DNA from dorsolateral prefrontal cortex (DLPFC) from a total of 77 subjects (12 withBD,14 with SZ, 15 withMDD,and36 controls)wasstudied formtDNA sequence variations using Affymetrix GeneChip Mitochondrial Resequencing Arrays 2.0. The microarray resequencing of mtDNA was 100% concordant with conventional capillary electrophoresis sequencing results for 103 mtDNA variants. There was 99.997% concordance for 3 individuals that were completely resequenced using both methods. In 45 000 sequences there was 1 discordant base call. The mitochondrial microarray however showed alargeNcall rate,whichmaybeimprovedbyusingsimilarPCRconditions as the National Institute of Standards and Technology. DLPFC from subjects with schizophrenia had an increased rate (22% higher compared to the control rate (P = .0017)) of synonymous base substitutions in mtDNA. A novel risk factor for BD and MDD was found in the ND4L gene at T10652C. In addition, there was a significant increase of themtDNAcommon deletion in brainDLPFCin theND4LT10652Ccarriers. Postmortem brain pH, used as a quantitative trait, showed significant association (P = .004) with three mtDNASNPs (tRNA Leu, ND4, and ND5). These 3mtDNASNPs are ethnic-specific haplotype-defining polymorphisms for the super haplogroup cluster (U, K, UK). This super-haplogroup showed a significantly increased postmortem pH (mean 7.0 6 0.18 SD) compared to the other haplogroups combined. Focusing on haplogroup susceptibility factors in psychiatric disorders and considering mtDNA variants in brain may lead to innovative treatments that improve mitochondrial health and brain function.