title: Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia.
abstract: Genetic evidence has supported the hypothesis that schizophrenia (SZ) is a polygenic disorder caused by the disruption in function of several or many genes. The most common and reproducible cellular phenotype associated with SZ is a reduction in dendritic spines within the neocortex, suggesting alterations in dendritic architecture may cause aberrant cortical circuitry and SZ symptoms. Here, we review evidence supporting a multifactorial model of mitochondrial dysfunction in SZ etiology and discuss how these multiple paths to mitochondrial dysfunction may contribute to dendritic spine loss and/or underdevelopment in some SZ subjects. The pathophysiological role of mitochondrial dysfunction in SZ is based upon genomic analyses of both the mitochondrial genome and nuclear genes involved in mitochondrial function. Previous studies and preliminary data suggest SZ is associated with specific alleles and haplogroups of the mitochondrial genome, and also correlates with a reduction in mitochondrial copy number and an increase in synonymous and nonsynonymous substitutions of mitochondrial DNA. Mitochondrial dysfunction has also been widely implicated in SZ by genome-wide association, exome sequencing, altered gene expression, proteomics, microscopy analyses, and induced pluripotent stem cell studies. Together, these data support the hypothesis that SZ is a polygenic disorder with an enrichment of mitochondrial targets.
authors.affiliation: Departments of Psychiatry & Human Behavior, University of California, Irvine, Calif., USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Hjelm
authors.affiliation: Departments of Psychiatry & Human Behavior, University of California, Irvine, Calif., USA.
authors.forename: Brandi
authors.initials: B
authors.lastname: Rollins
authors.affiliation: Departments of Psychiatry & Human Behavior, University of California, Irvine, Calif., USA.
authors.forename: Firoza
authors.initials: F
authors.lastname: Mamdani
authors.affiliation: Departments of Anatomy & Neurobiology, University of California, Irvine, Calif., USA.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Lauterborn
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.affiliation: Departments of Psychiatry & Human Behavior, University of California, Irvine, Calif., USA; Departments of Anatomy & Neurobiology, University of California, Irvine, Calif., USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
authors.affiliation: Departments of Anatomy & Neurobiology, University of California, Irvine, Calif., USA; Departments of Neurobiology & Behavior, University of California, Irvine, Calif., USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gall
authors.affiliation: Departments of Psychiatry & Human Behavior, University of California, Irvine, Calif., USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Sequeira
authors.affiliation: Departments of Psychiatry & Human Behavior, University of California, Irvine, Calif., USA.
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
keywords: Antipsychotic drug; Dendritic spines; Fluorescence deconvolution tomography; Genome; Induced pluripotent stem cell; Mitochondria; Polygenic disorder; Proteome; Schizophrenia; Transcriptome