Identifier: TDX:1375
Authors: Torrell Galceran, Helena
Abstract:
Schizophrenia, bipolar disorder and major depressive disorder are mental illnesses with unknown ethology. However, genetic epidemiological studies have identified a major genetic contribution that interacts with environmental factors. Several genetic studies support this genetic contribution but large nuclear genome-wide association studies have thus far not yielded a clear disease-associated genetic marker for any psychiatric disorder. Most genetic studies are based on the nuclear genome but almost all cells contain another genome: the mitochondrial genome (mtDNA) which plays an essential role in energy production and cell maintenance. The present work analyses the implication of mtDNA in three major mental disorders: schizophrenia, bipolar disorder and major depressive disorder. The paper Torrell H, et al, Am J Med Genet 2013 analyzed the mtDNA expression, content and presence of the common deletion in a myelinated region of the brain in schizophrenia (SCH), bipolar disorder (BD) and major depressive disorder (MDD) patients because the mtDNA is vital to the proper function of the respiratory chain. The method used for obtaining these results was reverse transcription quantitative real-time PCR (RT-qPCR) due to its high specificity, large dynamic range, and high accuracy. However, a lack of consensus exists on how best to perform and interpret RT-qPCR data and for that reason we first identified and evaluated suitable reference genes and variables related to clinical, demographic, and specimen characteristics of each sample that could affect the interpretation of RT-qPCR data. We identified five potential reference genes and the RNA quality index as highly correlated with gene expression and these results were published in a previous paper Abasolo N, Torrell H, et al, J Psychiatr Res. The paper Torrell H, et al, Am J Med Genet 2013 reported that 1) MT-ND1 gene expression was significantly increased in the BD group compared with the C group and 2) MDD and SCH patients showed a similar pattern of mtDNA expression, which was different from that in BD patients. The paper Torrell H Am J Med Genet (under review) tested whether mtDNA mutations and/or variants are present in schizophrenia patients and related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: 1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; 2) case‐control association study of 23 mtDNA variants identified in step 1 in 495 patients and 615 controls; and 3) analyses of the associated variants according to the clinical, psychopathological and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MTRNR2 1811A>G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological or neuropsychological variables, and the MT‐ATP6 9110T>C variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. Future work should focus on next generation sequencing and genome-wide association studies with large samples in order to identify low risk variants associated with schizophrenia and/or other major mental disorders.
Repositori URV