Abstract

Schizophrenia (SZ) is a severe, complex, and common mental disorder with high heritability (80%), an adult age of onset, and high discordance (∼50%) in monozygotic twins (MZ). Extensive studies on familial and non-familial cases have implicated a number of segregating mutations and de novo changes in SZ that may include changes to the mitochondrial genome. Yet, no single universally causal variant has been identified, highlighting its extensive genetic heterogeneity. This report specifically focuses on the assessment of changes in the mitochondrial genome in a unique set of monozygotic twins discordant (MZD) for SZ using blood. Genomic DNA from six pairs of MZD twins and two sets of parents (N = 16) was hybridized to the Affymetrix Human SNP Array 6.0 to assess mitochondrial DNA copy number (mtDNA-CN). Whole genome sequencing (WGS) and quantitative polymerase chain reaction (qPCR) was performed for a subset of MZD pairs and their parents and was also used to derive mtDNA-CN estimates. The WGS data were further analyzed to generate heteroplasmy (HP) estimates. Our results show that mtDNA-CN estimates for within-pair and mother-child differences were smaller than comparisons involving unrelated individuals, as expected. MZD twins showed discordance in mtDNA-CN estimates and displayed concordance in directionality of differences for mtDNA-CN across all technologies. Further, qPCR performed better than Affymetrix in estimating mtDNA-CN based on relatedness. No reliable differences in HP were detected between MZD twins. The within-MZD differences in mtDNA-CN observed represent postzygotic somatic changes that may contribute to discordance of MZ twins for diseases, including SZ.