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Mitochondrial mutations and polymorphisms in psychiatric disorders.

Sequeira A, Martin MV, Rollins B, Moon EA, Bunney WE, Macciardi F, Lupoli S, Smith EN, Kelsoe J, Magnan CN, van Oven M, Baldi P, Wallace DC, Vawter MP - Front Genet (2012)

Bottom Line: By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction.However, nominal association of mtSNPs (p < 0.05) to SZ and BD were found in the hypervariable region of mtDNA to T195C and T16519C.The results confirm prior reports that certain brain regions accumulate somatic mutations at higher levels than blood.

View Article: PubMed Central - PubMed

Affiliation: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, CA, USA.

ABSTRACT
Mitochondrial deficiencies with unknown causes have been observed in schizophrenia (SZ) and bipolar disorder (BD) in imaging and postmortem studies. Polymorphisms and somatic mutations in mitochondrial DNA (mtDNA) were investigated as potential causes with next generation sequencing of mtDNA (mtDNA-Seq) and genotyping arrays in subjects with SZ, BD, major depressive disorder (MDD), and controls. The common deletion of 4,977 bp in mtDNA was compared between SZ and controls in 11 different vulnerable brain regions and in blood samples, and in dorsolateral prefrontal cortex (DLPFC) of BD, SZ, and controls. In a separate analysis, association of mitochondria SNPs (mtSNPs) with SZ and BD in European ancestry individuals (n = 6,040) was tested using Genetic Association Information Network (GAIN) and Wellcome Trust Case Control Consortium 2 (WTCCC2) datasets. The common deletion levels were highly variable across brain regions, with a 40-fold increase in some regions (nucleus accumbens, caudate nucleus and amygdala), increased with age, and showed little change in blood samples from the same subjects. The common deletion levels were increased in the DLPFC for BD compared to controls, but not in SZ. Full mtDNA genome resequencing of 23 subjects, showed seven novel homoplasmic mutations, five were novel synonymous coding mutations. By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction. However, nominal association of mtSNPs (p < 0.05) to SZ and BD were found in the hypervariable region of mtDNA to T195C and T16519C. The results confirm prior reports that certain brain regions accumulate somatic mutations at higher levels than blood. The study in mtDNA of common polymorphisms, somatic mutations, and rare mutations in larger populations may lead to a better understanding of the pathophysiology of psychiatric disorders.

No MeSH data available.


Related in: MedlinePlus

The highest correlations between the common deletion and age are shown for cohort 1 subjects. (A) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing the nucleus accumbens (NACC), r = 0.97. (B) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing caudate nucleus (CAUN), r = 0.98. (C) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing amygdala (AMY), r = 0.96.
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Figure 1: The highest correlations between the common deletion and age are shown for cohort 1 subjects. (A) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing the nucleus accumbens (NACC), r = 0.97. (B) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing caudate nucleus (CAUN), r = 0.98. (C) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing amygdala (AMY), r = 0.96.

Mentions: We measured the levels of the common 4977 bp deletion across all brain regions in cohort 1. We observed, in a multivariate analysis, that age was significantly correlated with common deletions levels, R2 for age and common deletion calculated for 11 brain regions can be seen in Table S2 in Supplementary Material (p = 0.024). The most significant individual brain regional correlations with age were observed in the NACC, CAUN, and AMY (Figures 1A–C) for cohort 1; the additional figures for the other brain regions can be seen in Figure S1 in Supplementary Material. Common deletion percentages for individual regions were significantly correlated with age in seven regions, while four regions did not show significant Pearson correlations (Table S3 in Supplementary Material). The regional correlation matrix of the common deletion shows nominally significant (p < 0.05) relationships of the common deletion between brain regions for 31 pair wise correlations of 55 pairs. Thus, slightly over half of these paired brain regions show significant correlations for accumulation of the common deletion with age.


Mitochondrial mutations and polymorphisms in psychiatric disorders.

Sequeira A, Martin MV, Rollins B, Moon EA, Bunney WE, Macciardi F, Lupoli S, Smith EN, Kelsoe J, Magnan CN, van Oven M, Baldi P, Wallace DC, Vawter MP - Front Genet (2012)

The highest correlations between the common deletion and age are shown for cohort 1 subjects. (A) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing the nucleus accumbens (NACC), r = 0.97. (B) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing caudate nucleus (CAUN), r = 0.98. (C) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing amygdala (AMY), r = 0.96.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3379031&req=5

Figure 1: The highest correlations between the common deletion and age are shown for cohort 1 subjects. (A) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing the nucleus accumbens (NACC), r = 0.97. (B) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing caudate nucleus (CAUN), r = 0.98. (C) The correlation between age (x-axis) and mtDNA common deletion (y-axis) showing amygdala (AMY), r = 0.96.
Mentions: We measured the levels of the common 4977 bp deletion across all brain regions in cohort 1. We observed, in a multivariate analysis, that age was significantly correlated with common deletions levels, R2 for age and common deletion calculated for 11 brain regions can be seen in Table S2 in Supplementary Material (p = 0.024). The most significant individual brain regional correlations with age were observed in the NACC, CAUN, and AMY (Figures 1A–C) for cohort 1; the additional figures for the other brain regions can be seen in Figure S1 in Supplementary Material. Common deletion percentages for individual regions were significantly correlated with age in seven regions, while four regions did not show significant Pearson correlations (Table S3 in Supplementary Material). The regional correlation matrix of the common deletion shows nominally significant (p < 0.05) relationships of the common deletion between brain regions for 31 pair wise correlations of 55 pairs. Thus, slightly over half of these paired brain regions show significant correlations for accumulation of the common deletion with age.

Bottom Line: By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction.However, nominal association of mtSNPs (p < 0.05) to SZ and BD were found in the hypervariable region of mtDNA to T195C and T16519C.The results confirm prior reports that certain brain regions accumulate somatic mutations at higher levels than blood.

View Article: PubMed Central - PubMed

Affiliation: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, CA, USA.

ABSTRACT
Mitochondrial deficiencies with unknown causes have been observed in schizophrenia (SZ) and bipolar disorder (BD) in imaging and postmortem studies. Polymorphisms and somatic mutations in mitochondrial DNA (mtDNA) were investigated as potential causes with next generation sequencing of mtDNA (mtDNA-Seq) and genotyping arrays in subjects with SZ, BD, major depressive disorder (MDD), and controls. The common deletion of 4,977 bp in mtDNA was compared between SZ and controls in 11 different vulnerable brain regions and in blood samples, and in dorsolateral prefrontal cortex (DLPFC) of BD, SZ, and controls. In a separate analysis, association of mitochondria SNPs (mtSNPs) with SZ and BD in European ancestry individuals (n = 6,040) was tested using Genetic Association Information Network (GAIN) and Wellcome Trust Case Control Consortium 2 (WTCCC2) datasets. The common deletion levels were highly variable across brain regions, with a 40-fold increase in some regions (nucleus accumbens, caudate nucleus and amygdala), increased with age, and showed little change in blood samples from the same subjects. The common deletion levels were increased in the DLPFC for BD compared to controls, but not in SZ. Full mtDNA genome resequencing of 23 subjects, showed seven novel homoplasmic mutations, five were novel synonymous coding mutations. By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction. However, nominal association of mtSNPs (p < 0.05) to SZ and BD were found in the hypervariable region of mtDNA to T195C and T16519C. The results confirm prior reports that certain brain regions accumulate somatic mutations at higher levels than blood. The study in mtDNA of common polymorphisms, somatic mutations, and rare mutations in larger populations may lead to a better understanding of the pathophysiology of psychiatric disorders.

No MeSH data available.


Related in: MedlinePlus