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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

Phylogenetic tree of the 23 complete mtDNA sequences generated in this study. Haplogroups are labeled in boxes and follow PhyloTree Build 12 nomenclature (van Oven and Kayser, 2009). Mutations are denoted as nucleotide position numbers corresponding to the rCRS. Mutations are transitions unless an exact base change is specified. Deletions and insertions are indicated by “d” and “0.1,” respectively, followed by the base(s) involved. Back mutations (from the perspective of the ancestral root) are preceded by “@.” Variants 309.1C, 315.1C, 16182C, 16183C, and 16519 were not considered for tree construction and are therefore not shown. The samples that have appeared in the study are given numerical labels followed by brain region abbreviations. As an example, in the first column individual 58, belonging to haplogroup L1c3b2, was sequenced in 11 brain regions which all showed the same phylogenetic relationship, indicating a lack of novel mutations between brain regions from the same individual.
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Figure 4: Phylogenetic tree of the 23 complete mtDNA sequences generated in this study. Haplogroups are labeled in boxes and follow PhyloTree Build 12 nomenclature (van Oven and Kayser, 2009). Mutations are denoted as nucleotide position numbers corresponding to the rCRS. Mutations are transitions unless an exact base change is specified. Deletions and insertions are indicated by “d” and “0.1,” respectively, followed by the base(s) involved. Back mutations (from the perspective of the ancestral root) are preceded by “@.” Variants 309.1C, 315.1C, 16182C, 16183C, and 16519 were not considered for tree construction and are therefore not shown. The samples that have appeared in the study are given numerical labels followed by brain region abbreviations. As an example, in the first column individual 58, belonging to haplogroup L1c3b2, was sequenced in 11 brain regions which all showed the same phylogenetic relationship, indicating a lack of novel mutations between brain regions from the same individual.

Mentions: Only one homoplasmic deletion was detected, an AC deletion at mt523-524, present in 11 brain regions sampled from two control subjects that have distant haplogroups (L1cb2 and H5, Figure 4). This mt523-524 AC deletion was previously reported (Han et al., 2003; Wanrooij et al., 2004). Two homoplasmic insertions were detected. One control subject had a T insertion at mt455. A second common insertion was also observed in the mononucleotide repeat (poly-C) region known as D310 for Displacement Loop (D-Loop), which consists of a series of C nucleotides (between 7 and 9) intercalated with a single T at position 310 followed by another series of C nucleotides (Sanchez-Cespedes et al., 2001), a hot spot for mutations possibly involved in Alzheimer’s (Wang et al., 2009), and cancer (Tang et al., 2004). Six subjects (three controls, two BP, and one SZ) had 309.1C or 309.1CC insertions in this poly-C tract. Due to the small number of subjects in this re-sequencing arm of the study, the rates of de novo mutations were not compared among groups. In summary, there were seven novel mutations in Cohort 3: four novel mutations in the 10 control subjects, one novel mutation in the four SZ subjects, one novel mutation in the five MDD subjects, and one novel mutation in the four BD subjects.


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)

Phylogenetic tree of the 23 complete mtDNA sequences generated in this study. Haplogroups are labeled in boxes and follow PhyloTree Build 12 nomenclature (van Oven and Kayser, 2009). Mutations are denoted as nucleotide position numbers corresponding to the rCRS. Mutations are transitions unless an exact base change is specified. Deletions and insertions are indicated by “d” and “0.1,” respectively, followed by the base(s) involved. Back mutations (from the perspective of the ancestral root) are preceded by “@.” Variants 309.1C, 315.1C, 16182C, 16183C, and 16519 were not considered for tree construction and are therefore not shown. The samples that have appeared in the study are given numerical labels followed by brain region abbreviations. As an example, in the first column individual 58, belonging to haplogroup L1c3b2, was sequenced in 11 brain regions which all showed the same phylogenetic relationship, indicating a lack of novel mutations between brain regions from the same individual.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Phylogenetic tree of the 23 complete mtDNA sequences generated in this study. Haplogroups are labeled in boxes and follow PhyloTree Build 12 nomenclature (van Oven and Kayser, 2009). Mutations are denoted as nucleotide position numbers corresponding to the rCRS. Mutations are transitions unless an exact base change is specified. Deletions and insertions are indicated by “d” and “0.1,” respectively, followed by the base(s) involved. Back mutations (from the perspective of the ancestral root) are preceded by “@.” Variants 309.1C, 315.1C, 16182C, 16183C, and 16519 were not considered for tree construction and are therefore not shown. The samples that have appeared in the study are given numerical labels followed by brain region abbreviations. As an example, in the first column individual 58, belonging to haplogroup L1c3b2, was sequenced in 11 brain regions which all showed the same phylogenetic relationship, indicating a lack of novel mutations between brain regions from the same individual.
Mentions: Only one homoplasmic deletion was detected, an AC deletion at mt523-524, present in 11 brain regions sampled from two control subjects that have distant haplogroups (L1cb2 and H5, Figure 4). This mt523-524 AC deletion was previously reported (Han et al., 2003; Wanrooij et al., 2004). Two homoplasmic insertions were detected. One control subject had a T insertion at mt455. A second common insertion was also observed in the mononucleotide repeat (poly-C) region known as D310 for Displacement Loop (D-Loop), which consists of a series of C nucleotides (between 7 and 9) intercalated with a single T at position 310 followed by another series of C nucleotides (Sanchez-Cespedes et al., 2001), a hot spot for mutations possibly involved in Alzheimer’s (Wang et al., 2009), and cancer (Tang et al., 2004). Six subjects (three controls, two BP, and one SZ) had 309.1C or 309.1CC insertions in this poly-C tract. Due to the small number of subjects in this re-sequencing arm of the study, the rates of de novo mutations were not compared among groups. In summary, there were seven novel mutations in Cohort 3: four novel mutations in the 10 control subjects, one novel mutation in the four SZ subjects, one novel mutation in the five MDD subjects, and one novel mutation in the four BD subjects.

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