Original Research ARTICLE

Front. Genet., 20 June 2012 |

Mitochondrial mutations and polymorphisms in psychiatric disorders

Adolfo Sequeira1, Maureen V. Martin1, Brandi Rollins1, Emily A. Moon1, William E. Bunney2, Fabio Macciardi2,3, Sara Lupoli3, Erin N. Smith4, John Kelsoe5,6, Christophe N. Magnan7, Mannis van Oven8, Pierre Baldi7, Douglas C. Wallace9 and Marquis P. Vawter1*
  • 1 Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA
  • 2 Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA
  • 3 Department of Medicine, Surgery and Dentistry, University of Milan, Milan, Italy
  • 4 Department of Pediatrics, School of Medicine, Rady’s Children’s Hospital, University of California, San Diego, CA, USA
  • 5 Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
  • 6 Department of Psychiatry, University of California, San Diego, CA, USA
  • 7 School of Information and Computer Sciences, Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA, USA
  • 8 Department of Forensic Molecular Biology, Erasmus MC University Medical Center, Rotterdam, Netherlands
  • 9 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

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.

Keywords: mitochondria, homoplasmy, common deletion, novel mutations, schizophrenia, bipolar disorder

Citation: 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 and Vawter MP (2012) Mitochondrial mutations and polymorphisms in psychiatric disorders. Front. Gene. 3:103. doi: 10.3389/fgene.2012.00103

Received: 18 January 2012; Paper pending published: 31 March 2012;
Accepted: 20 May 2012; Published online: 20 June 2012.

Edited by:

Berit Kerner, University of California Los Angeles, USA

Reviewed by:

Dawn Thiselton, Virginia Commonwealth University, USA
Maria R. Dauvermann, University of Edinburgh, UK

Copyright: © 2012 Sequeira, Martin, Rollins, Moon, Bunney, Macciardi, Lupoli, Smith, Kelsoe, Magnan, van Oven, Baldi, Wallace and Vawter. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

*Correspondence: Marquis P. Vawter, Functional Genomics Laboratory, GNRF Room 2119, Department of Psychiatry and Human Behavior, School of Medicine, Irvine, CA 92697-4260, USA. e-mail:

Adolfo Sequeira, Maureen V. Martin and Brandi Rollins have contributed equally to this work