Mitochondrial DNA haplogroups and age at onset of schizophrenia

Magri, Chiara; Gardella, Rita; Barlati, Stefano; Valsecchi, Paolo; Sacchetti, Emilio; Barlati, Sergio

doi:10.1002/ajmg.b.30496

Cited by 21 publications

(15 citation statements)

References 25 publications

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“…11 However, these negative results could be due to the small size of our sample, which would allow to detect only large changes in haplogroup frequency distribution.…”

Section: Resultsmentioning

confidence: 88%

“…Haplogroup distribution analysis did not reveal a disease susceptibility to mt-hgs; all major European mt-hgs were represented in the sample and no significant differences in their overall distribution were observed when compared with those reported for three Italian control samples (Table 1). [11][12][13] The frequencies of each mt-hg in patients and controls were then analyzed by applying the Bonferroni's adjustment for multiple comparisons and no statistically significant differences were observed.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2011

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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.

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“…11 However, these negative results could be due to the small size of our sample, which would allow to detect only large changes in haplogroup frequency distribution.…”

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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

et al. 2011

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“…One reported an over-representation of the HV lineage in Israeli-Arab patients with schizophrenia (OR 1.8) [Amar et al, 2007]. The other did not find any alterations in haplogroup frequency distribution, but did report that patients with the J-T haplogroup and schizophrenia showed an earlier onset of the disorder [Magri et al, 2007]. Ueno et al [2009] did not find any haplogroup association with schizophrenia [Ueno et al, 2009].…”

Section: Mitochondria-related Genetic Variations and Psychiatric Illnessmentioning

confidence: 93%

The mitochondrial genome and psychiatric illness

Anglin

Mazurek

Tarnopolsky

et al. 2012

American J of Med Genetics Pt B

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Psychiatric disorders are a leading cause of morbidity and mortality, yet their underlying pathophysiology remains unclear. Searches for a genetic cause of bipolar disorder, schizophrenia, and major depressive disorder have yielded inconclusive results. There is increasing interest in the possibility that defects in the mitochondrial genome may play an important role in psychiatric illness. We undertook a review of the literature investigating mitochondria and adult psychiatric disorders. MEDLINE, PsycINFO, and EMBASE were searched from their inception through September 2011, and the reference lists of identified articles were reviewed for additional studies. While multiple lines of evidence, including clinical, genetic, ultrastructural, and biochemical studies, support the involvement of mitochondria in the pathophysiology of psychiatric illness, many studies have methodological limitations and their findings have not been replicated. Clinical studies suggest that psychiatric features can be prominent, and the presenting features of mitochondrial disorders. There is limited but inconsistent evidence for the involvement of mitochondrial DNA haplogroups and mitochondria-related nuclear gene polymorphisms, and for mitochondrial ultrastructural and biochemical abnormalities in psychiatric illness. The current literature suggests that mitochondrial dysfunction and mitochondrial genetic variations may play an important role in psychiatric disorders, but additional methodologically rigorous and adequately powered studies are needed before definitive conclusions can be drawn.

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“…Being essential for electron transport chain, the mutations in CytB rs3088309 and ND4 rs3915952 might leave neurons more vulnerable to genetic and environmental risk factors. In addition, mitochondrial haplogroup JT (the top mtSNPs rs3088309 and rs3915952 are part of the haplogroup-defining SNP) has been implicated in early-onset schizophrenia, though the mechanism underlying this association is still unknown [47]. …”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

et al. 2017

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Mitochondrial DNA mutations have been reported to be associated with bipolar disorder (BD). In this study, we performed genome-wide analyses to assess mitochondrial single-nucleotide polymorphism (mtSNP) effects on BD risk and early-onset BD (EOBD) among BD patients, focusing on interaction effects between nuclear SNPs (nSNPs) and mtSNPs. Common nSNP and mtSNP data from European American BD cases (n = 1,001) and controls (n = 1,034) from the Genetic Association Information Network BD study were analyzed to assess the joint effect of nSNP and nSNP-mtSNP interaction on the risk of BD and EOBD. The effect of nSNP-mtSNP interactions was also assessed. For BD risk, the strongest evidence of an association was obtained for nSNP rs1880924 in MGAM and mtSNP rs3088309 in CytB (p_joint = 8.2 × 10^-8, p_int = 1.4 × 10^-4). Our results also suggest that the minor allele of the nSNP rs583990 in CTNNA2 increases the risk of EOBD among carriers of the mtSNP rs3088309 minor allele, while the nSNP has no effect among those carrying the mtSNP major allele (OR = 4.53 vs. 1.05, p_joint = 2.1 × 10^-7, p_int = 1.16 × 10^-6). While our results are not statistically significant after multiple testing correction and a large-sample replication is required, our exploratory study demonstrates the potential importance of considering the mitochondrial genome for identifying genetic factors associated with BD.

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Mitochondrial DNA haplogroups and age at onset of schizophrenia

Cited by 21 publications

References 25 publications

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

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

The mitochondrial genome and psychiatric illness

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

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