Limits...
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

There was no overall region × diagnosis (schizophrenia compared to control) interaction effect on age-adjusted mtDNA common deletion percentages but regional differences were observed. This figure shows the least squares mean and standard errors of non-age-adjusted common deletion percentages per region, plotted by diagnosis in cohort 1 (schizophrenia compared to controls).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3379031&req=5

Figure 2: There was no overall region × diagnosis (schizophrenia compared to control) interaction effect on age-adjusted mtDNA common deletion percentages but regional differences were observed. This figure shows the least squares mean and standard errors of non-age-adjusted common deletion percentages per region, plotted by diagnosis in cohort 1 (schizophrenia compared to controls).

Mentions: A repeated measures ANCOVA was also performed for the common deletion with age as a covariate, region as a repeated measure factor, and sex and diagnosis as between-subjects factors for cohort 1. There was a significant overall effect of region [F(9, 63) = 6.49; p = 1.7 × 10−06], while sex [F(1, 6) = 0.39; p = 0.55], and diagnosis [F(1, 6) = 3.73; p = 0.10] factors were not significant, and interaction terms were not statistically significant (Figure 2). The significant region effect was further examined by post hoc comparisons of the mean percentage of common deletion per brain region and p-values were corrected for multiple comparisons using Tukey’s Honest Significant Difference test for each regional-comparison (AMY, ACC, CAUN, CB, DLPFC, HIPP, NACC, OFC, PUT, SN, and THAL). The two regions with the highest levels of common deletion were the CAUN and SN, with a 39- to 40-fold increase compared to the CB, which had the lowest common deletion level (Figure S2 in Supplementary Material) which is consistent with earlier reports (Corral-Debrinski et al., 1992; Soong et al., 1992; Meissner et al., 2008). These three regional differences account for most of the significant post hoc differences observed, while the remaining regions were not significantly different when corrected for multiple comparisons (Table S4 in Supplementary Material). The mtDNA common deletion percentage was 0.5 ± 0.4 SEM for blood (n = 3), but was greatly increased in the brain for the same subjects, consistent with prior observation of low common deletion levels in blood and higher levels in post mitotic tissue.


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)

There was no overall region × diagnosis (schizophrenia compared to control) interaction effect on age-adjusted mtDNA common deletion percentages but regional differences were observed. This figure shows the least squares mean and standard errors of non-age-adjusted common deletion percentages per region, plotted by diagnosis in cohort 1 (schizophrenia compared to controls).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: There was no overall region × diagnosis (schizophrenia compared to control) interaction effect on age-adjusted mtDNA common deletion percentages but regional differences were observed. This figure shows the least squares mean and standard errors of non-age-adjusted common deletion percentages per region, plotted by diagnosis in cohort 1 (schizophrenia compared to controls).
Mentions: A repeated measures ANCOVA was also performed for the common deletion with age as a covariate, region as a repeated measure factor, and sex and diagnosis as between-subjects factors for cohort 1. There was a significant overall effect of region [F(9, 63) = 6.49; p = 1.7 × 10−06], while sex [F(1, 6) = 0.39; p = 0.55], and diagnosis [F(1, 6) = 3.73; p = 0.10] factors were not significant, and interaction terms were not statistically significant (Figure 2). The significant region effect was further examined by post hoc comparisons of the mean percentage of common deletion per brain region and p-values were corrected for multiple comparisons using Tukey’s Honest Significant Difference test for each regional-comparison (AMY, ACC, CAUN, CB, DLPFC, HIPP, NACC, OFC, PUT, SN, and THAL). The two regions with the highest levels of common deletion were the CAUN and SN, with a 39- to 40-fold increase compared to the CB, which had the lowest common deletion level (Figure S2 in Supplementary Material) which is consistent with earlier reports (Corral-Debrinski et al., 1992; Soong et al., 1992; Meissner et al., 2008). These three regional differences account for most of the significant post hoc differences observed, while the remaining regions were not significantly different when corrected for multiple comparisons (Table S4 in Supplementary Material). The mtDNA common deletion percentage was 0.5 ± 0.4 SEM for blood (n = 3), but was greatly increased in the brain for the same subjects, consistent with prior observation of low common deletion levels in blood and higher levels in post mitotic tissue.

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