No evidence that major mtDNA European haplogroups confer risk to schizophrenia

Abstract

Previous studies suggest that genetic factors could be involved in mitochondrial dysfunction observed in schizophrenia (SZ), some of them claiming a role of mtDNA common variants (mtSNPs) and/or haplogroups (hgs) in developing this disorder. These studies, however, have mainly been undertaken on relatively small cohorts of patients and control individuals and most have not yet been replicated. To further analyze the role of mtSNPs in SZ risk, we have carried out the largest genotyping effort to date using two Spanish case-control samples comprising a total of 942 schizophrenic patients and 1,231 unrelated controls: 454 patients and 616 controls from Santiago de Compostela (Galicia) and 488 patients and 615 controls from Reus (Catalonia). A set of 25 mtSNPs representing main branches of the European mtDNA phylogeny were genotyped in the Galician cohort and a subset of 16 out of these 25 mtSNPs was genotyped in the Catalan cohort. These 16 common variants characterize the most common European branches of the mtDNA phylogeny. We did not observe any positive association of mtSNPs and hgs with SZ. We discuss several deficiencies of previous studies that might explain the false positive nature of previous findings, including the confounding effect of population sub-structure and deficient statistical methodologies. It is unlikely that mtSNPs defining the most common European mtDNA haplogroups are related to SZ.

mtDNA Heteroplasmy in Monozygotic Twins Discordant for Schizophrenia

“…However, we found no clear evidence for an mtDNA contribution to the phenotypic difference in these MZ twins, indicating that heteroplasmy of common mtDNA variants might have very limited effects on the risk of schizophrenia. Indeed, most of the positive results in the literature concerning common mtDNA variants/haplogroups and schizophrenia are probably false positives [42]. Our result is in agreement with previous studies concerning the role of mtDNA heteroplasmy in discordant MZ twins with other human diseases [36,43], indicating that factors, such as epigenetic changes and environmental factors, may play a more important role in shaping the discordance between MZ twins with disease [1,41,44].…”

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

“…Recently, we have shown that relatives who shared mtDNA with a schizophrenic patient had a higher risk of presenting with schizophrenia than relatives who did not share mtDNA, thus supporting the hypothesis that mtDNA may be involved in schizophrenia [Verge et al, 2012]. However, we did not observe any positive association between the common variants of the most common European branches of mtDNA and the risk of developing schizophrenia [Mosquera-Miguel et al, 2012]. Therefore, we hypothesized that variants or mutations present in the mtDNA could be associated with the disease.…”

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

“…These specific SNP associations were specific to SZ, and were not significant for bipolar disorder (BD) or psychiatric illness in general (SZ + BD) [42]. Allelic association at position 16519 was not observed as significant in a published Santiago cohort of SZ patients; however, allele frequencies were reported in this study, so we utilized these data for a meta-analysis across three separate cohorts [49]. Specifically, analysis was performed on pooled data from (1) the GAIN-WTCCC2 cohort set, (2) the Santiago cohort, and (3) a dataset of 632 Bulgarian father-offspring pairs, resulting in a meta-analysis of 7,375 subjects (2,209 SZ vs. 5,166 controls) [19, 42, 49].…”