Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia

Abstract

It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be 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 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) 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 MT-RNR2 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 p.Ile195Thr 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. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia.

Association between mitochondrial DNA variations and schizophrenia in the northern Chinese Han population

“…In this study, there was no evidence of an association between haplogroups and schizophrenia in the northern Chinese Han population. In Europe, similar results were found [ 35 , 36 ]. Ueno et al [ 37 ] did not observe an association between haplogroups and schizophrenia among the Japanese population.…”

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

“…Another study also identified mitochondrial variants within the hypervariable region that were associated with risk or protection in multiple late-onset diseases including SZ [50]. In addition to mitochondrial allele associations with SZ, several studies have reported nominal associations with specific mitochondrial haplogroups and SZ, although other studies have additionally suggested such nominal associations are not pathogenic [44, 45, 48, 49, 51]. As such, these associations and haplogroup assignments may also be better warranted for population stratification, analysis of additional variables like disease onset and symptom severity, and enhancement of statistical power to discover variants enriched within SZ subgroups or populations with differences in mitochondrial ancestry.…”

Mitochondrial Dysfunction in Schizophrenia

“…[ 72–75 ] Thus, further studies with a larger sample size will be needed to identify associated variants with genome‐wide significance. [ 76 ]…”