Elsevier

Journal of Psychiatric Research

Volume 84, January 2017, Pages 221-226
Journal of Psychiatric Research

Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder

https://doi.org/10.1016/j.jpsychires.2016.09.027Get rights and content

Abstract

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged.

Introduction

It is increasingly recognized that the role of mitochondrial genetics expands substantially beyond the hereditary mitochondrial disorders. Mitochondrial DNA (mtDNA) is a 16.6 kb circular molecule located in the mitochondrion; the mtDNA encodes for 13 oxidative phosphorylation proteins, 22 transfer tRNAs, and 12S and 16S ribosomal rRNA genes (Sequeira et al., 2015), (Wallace, 2005). Each cell contains between 100 and 1000 mitochondria and each mitochondrion contains a variable number of mtDNA molecules. Compared to genomic DNA, mtDNA has several unique features including: (1) maternal inheritance with negligible recombination rate, (2) heteroplasmy (a mixture of mutated and wild-type mtDNA), (3) high mutation rates (∼10 times higher than nuclear genomic DNA) due to lack of protective histones and ineffective DNA repair systems and (4) continuous exposure to mutagenic effects of oxygen radicals generated as a side product of oxidative phosphorylation (Chinnery and Turnbull, 1999, Li et al., 2012, Miyazono et al., 2002, Samuels et al., 2013, Szczepanowska and Trifunovic, 2015, Wallace and Chalkia, 2013).

Variations in mitochondrial function have been implicated in a number of complex, multi-factorial diseases, including bipolar disorder (Andreazza and Young, 2014a, Clay et al., 2011, de Sousa et al., 2014, Sequeira et al., 2015). Investigations of mitochondrial function in bipolar disorder have focused on energy production (Andreazza et al., 2007) with studies suggesting: a decrease in complex I subunits associated with production of reactive oxygen species (ROS) (Scola et al., 2013), post-mortem reduction of hippocampal gene expression of mitochondrial proteins regulating oxidative phosphorylation and the ATP dependent proteasome degradation (Konradi et al., 2004), and MR spectroscopic increase in gray matter lactate and glutamate with corresponding decreased intracellular pH and decreased adenosine diphosphate which are markers of a shift from oxidative phosphorylation toward glycolysis (Dager et al., 2004, Dager et al., 2008, Frye et al., 2007, Stork and Renshaw, 2005, Weber et al., 2013).

Several lines of evidence suggest that mtDNA sequence variation may contribute to risk of BD. MtDNA single nucleotide variants (SNVs), deletions, copy number variations and haplogroups (haplotypes that are shared among a group with a common maternal ancestor) have been associated with overall BD risk or related phenotypes (Chang et al., 2014, Kato and Takahashi, 1996, Kazuno et al., 2009, Munakata et al., 2004). In addition, multiple primary mitochondrial disorders, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), have associated symptoms of mood and psychosis (Bijarnia-Mahay et al., 2015, Magner et al., 2014, Anglin et al., 2012a, Dejean de la Batie et al., 2014). However, the findings of most mtDNA studies of BD have thus far failed to replicate, which has been attributed to small sample size, methodological problems, and the heterogeneity of bipolar disorder (Anglin et al., 2012b, Leboyer et al., 1998). BD sub-phenotypes such as early disease onset, psychosis, and rapid cycling may represent more genetically homogeneous subgroups of the disease, and may provide greater statistical power for detecting genetic variation underlying BD subtypes (Saunders et al., 2008). For example, rapid cycling (defined by DSM-5 as 4 or more mood episodes per year) bipolar disorder has been associated with genetic variation in catecholamine degradation (Catechol-O-methyltransferase or COMT), circadian clock gene regulation (CRY2), and brain derived neurotrophic factor (BDNF) (Kirov et al., 1998, Muller et al., 2006, Sjoholm et al., 2010). Similarly, nuclear genome variants associated with early-onset BD and psychosis in BD have also been identified (Hamshere et al., 2009, Nassan et al., 2015). These studies demonstrate the potential value of investigating the role of mtDNA variation in bipolar sub-phenotypes.

The aim of this study was to utilize mtDNA sequencing to evaluate the association of BD clinical sub-phenotypes (rapid cycling, psychosis, and adolescent illness onset) with mitochondrial haplogroups. Phenotypic associations with mtDNA single nucleotide variants (SNVs) were also explored.

Section snippets

Study subjects

Patients with BD were selected from the Mayo Clinic Bipolar Disorder Biobank (Frye et al., 2015). The study was IRB approved at all participating sites and each participant provided informed consent. At enrollment, patients provided blood samples and completed a patient questionnaire to assess demographic characteristics and health-related behaviors. In addition, a clinical questionnaire was used to collect information related to clinical features of the illness. Among those collected through

Results

As presented in Table 1, the median age of the subjects was 42 years (range 18–79) with the majority being female (63%) and Caucasian (92%). The phenotypes of interest included history of rapid cycling (60%), history of psychosis (49%), and adolescent age of illness onset (28%).

A total of 1154 SNVs passed quality control criteria for sequencing mapping and variant calling, including 1136 SNVs with 1 variant allele, 17 SNVs with 2 variant alleles, and 1 SNV with 3 variant alleles among the 224

Discussion

In this study, mtDNA sequence data from 224 BPI patients was analyzed to test for association with several BD sub-phenotypes (psychosis, rapid cycling, and age of onset). While in-depth DNA sequencing analyses have been applied in nuclear genome, there is little literature in psychiatric research using this technique for the mitochondrial genome, and none correlating with BD sub-phenotypes. Haplogroup analysis revealed that patients belonging to haplogroup U (including K sublineage) had higher

Conflict of interest

None to declare.

Contributors

MAF, ER, MN, DO, WEH, and JMB participated in the design of the study and drafting initial manuscript. ER, GJ, JME, and JMB performed bioinformatics/statistical analysis. All authors contributed to interpret the results, review references, and draft the manuscript, and approved the final manuscript.

Role of the funding source

None to declare.

Acknowledgements

This study was funded by the Marriott Foundation and Mayo Clinic Center for Individualized Medicine. We are grateful to the patients who have participated in this study.

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  • Cited by (0)

    Presented in part at the Annual Meeting of the International Society of Bipolar Disorder June 5, 2015 Toronto Canada.

    1

    These authors contributed equally.

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