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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

(A) In cohort 2, the main effect of sex was significant (F = 5.5, p = 0.02) on common deletion percentage in DLPFC, with females exhibiting significantly higher percentages of the mitochondrial common deletion compared to males. The age-adjusted means and standard error bars are displayed.(B) In cohort 2, the BD group showed a significant increase in the common deletion compared to controls (p = 0.022) and MDD showed a trend compared to controls (p = 0.058) while schizophrenia compared to controls was not different (p = 0.59).
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Figure 3: (A) In cohort 2, the main effect of sex was significant (F = 5.5, p = 0.02) on common deletion percentage in DLPFC, with females exhibiting significantly higher percentages of the mitochondrial common deletion compared to males. The age-adjusted means and standard error bars are displayed.(B) In cohort 2, the BD group showed a significant increase in the common deletion compared to controls (p = 0.022) and MDD showed a trend compared to controls (p = 0.058) while schizophrenia compared to controls was not different (p = 0.59).

Mentions: Results of the common deletion study in DLPFC only (cohort 2) showed also a significant relationship between age and common deletion levels (F = 6.7, p = 0.01), (Figure S3 in Supplementary Material) as well as sex and common deletion (F = 5.5, p = 0.02; Figure 3A). Our hypothesis that psychiatric disorders (BD, MDD, and SZ) have increased common deletion was tested in a planned comparison of the age-adjusted data in DLPFC (cohort 2). The BD group showed a significant increase in the common deletion compared to controls (p = 0.022, Figure 3B) by a fold change of 2.4 using age-adjusted least square means, MDD showed a 2.0 fold increase compared to controls (p = 0.058), while SZ was not significantly different compared to controls (p = 0.59). These findings validated previous data for BD and MDD for the same subjects in cohort 2 (Shao et al., 2008), however in the present study we used a more accurate method using a standard curve. Thus, we show increased mtDNA common deletion in BD, no change in SZ or MDD, compared to controls in DLPFC.


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)

(A) In cohort 2, the main effect of sex was significant (F = 5.5, p = 0.02) on common deletion percentage in DLPFC, with females exhibiting significantly higher percentages of the mitochondrial common deletion compared to males. The age-adjusted means and standard error bars are displayed.(B) In cohort 2, the BD group showed a significant increase in the common deletion compared to controls (p = 0.022) and MDD showed a trend compared to controls (p = 0.058) while schizophrenia compared to controls was not different (p = 0.59).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: (A) In cohort 2, the main effect of sex was significant (F = 5.5, p = 0.02) on common deletion percentage in DLPFC, with females exhibiting significantly higher percentages of the mitochondrial common deletion compared to males. The age-adjusted means and standard error bars are displayed.(B) In cohort 2, the BD group showed a significant increase in the common deletion compared to controls (p = 0.022) and MDD showed a trend compared to controls (p = 0.058) while schizophrenia compared to controls was not different (p = 0.59).
Mentions: Results of the common deletion study in DLPFC only (cohort 2) showed also a significant relationship between age and common deletion levels (F = 6.7, p = 0.01), (Figure S3 in Supplementary Material) as well as sex and common deletion (F = 5.5, p = 0.02; Figure 3A). Our hypothesis that psychiatric disorders (BD, MDD, and SZ) have increased common deletion was tested in a planned comparison of the age-adjusted data in DLPFC (cohort 2). The BD group showed a significant increase in the common deletion compared to controls (p = 0.022, Figure 3B) by a fold change of 2.4 using age-adjusted least square means, MDD showed a 2.0 fold increase compared to controls (p = 0.058), while SZ was not significantly different compared to controls (p = 0.59). These findings validated previous data for BD and MDD for the same subjects in cohort 2 (Shao et al., 2008), however in the present study we used a more accurate method using a standard curve. Thus, we show increased mtDNA common deletion in BD, no change in SZ or MDD, compared to controls in DLPFC.

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