Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

Abstract

The present study aims at investigating the association between common and rare variants of mitochondrial DNA (mtDNA), and increased risk of schizophrenia (SZ) and bipolar disorder (BPD) in a cohort of patients originating from the same Italian population. The distribution of the major European mtDNA haplogroups was determined in 89 patients and their frequencies did not significantly differ from those observed in the Italian population. Moreover, 27 patients with high probability of having inherited the disease from the maternal side were selected for whole mitochondrial genome sequencing to investigate the possible presence of causative point mutations. Overall, 213 known variants and 2 novel changes were identified, but none of them was predicted to have functional effects. Hence, none of the sequence changes we found in our sample could explain the maternal component of SZ and BPD predisposition. Keywords: bipolar disorder; mtDNA variants; schizophrenia INTRODUCTION Schizophrenia (SZ) and bipolar disorder (BPD) are among the top ten causes of disability worldwide. 1 Despite extensive genetic and pharmacological studies, the etiology and pathophysiology of these mental disorders are still unknown, and the nuclear susceptibility loci identified so far can explain only a small fraction of the genetic component of these diseases. 2 The growing body of observations published in the last decade points to the involvement of mitochondria in the pathophysiology of psychiatric disorders, including SZ and BPD. 3 Several genetic studies reported association between these diseases and common mitochondrial DNA (mtDNA) polymorphisms defining ethnic-specific mitochondrial haplogroups. [4][5] Other analyses found new rare variants with a putative functional effect 6 and a global excess of synonymous substitutions in the dorsolateral prefrontal cortex of SZ patients. 7 Despite the great interest of these findings, the role of mtDNA in the pathogenesis of SZ/BDP remains unclear.The present study aims at investigating the association between common and rare variants of mtDNA and the increased risk of SZ/ BPD in a sample of patients originating from the same Italian population.

Paradox of schizophrenia genetics: is a paradigm shift occurring?

“…Although a recent study failed to detect any pathogenic mitochondrial genome in the blood cells [158], it cannot necessarily deny the possibility of the MGM because of the heteroplasmy of the mitochondrial genome. It has been well known that pathogenic mitochondrial genome cannot necessarily be detected in the blood cells in known mitochondrial diseases [159].…”

The mutations m.5628T>C and m.8348A>G in single muscle fibers of a patient with chronic progressive external ophthalmoplegia

“…In another report, only 34% of m.8348A>G mutation was found but other mtDNA mutations were not excluded as only tRNA genes were sequenced and SF-PCR was not performed [22]. It was also proposed that m.8348A>G could be a diagnostic marker for a sub-clade of the H1b, typical of Italian population [24], however confirmation is still needed. According to the Human Mitochondrial Genome Database [25] m.8348A>G was observed in 3 out of 2704 human mitochondrial genomes, giving an estimated frequency of 0.11%.…”

Mitochondrial Mutations and Polymorphisms in Psychiatric Disorders

“…For neuropsychiatric disorders, higher rates of disease are observed in offspring of maternal probands compared to offspring of paternal probands in SZ (Goldstein et al, 1992; Wolyniec et al, 1992; Verge et al, 2011) and bipolar disorder (BD; McMahon et al, 1995). Additionally, previous studies have also shown that mtDNA mutations and variations can play a role of susceptibility to both BD and SZ (Rollins et al, 2009; Bertolin et al, 2011; Kato et al, 2011; Verge et al, 2011), suggesting a direct role for the mitochondrial genome in neuropsychiatric disorders (Shao et al, 2008). Imaging studies also support the hypothesis that mtDNA alterations lead to neurotransmitter and metabolic changers in BD and SZ (Dager et al, 2004; Stork and Renshaw, 2005).…”

“…In our previous study we used a re-sequencing array to study mtDNA in the dorsolateral prefrontal cortex (DLPFC) of SZ, BD, and major depressive disorder (MDD) patients and observed an increase of synonymous substitutions in SZ (Rollins et al, 2009). Recently, another group also used a re-sequencing array to study mtDNA in blood samples from patients with SZ and BD but did not find additional evidence that mtDNA contributes significantly to the maternal component of SZ and BD predisposition (Bertolin et al, 2011). To date, few studies have examined somatic mutations in multiple regions, and most studies have concentrated on DLPFC only (Shao et al, 2008).…”