Electronic Thesis and Dissertation Repository


Doctor of Philosophy




Dr. Shiva M. Singh


Schizophrenia (OMIM: 181500) is a common, debilitating and life-altering disorder. It affects 1% of the population worldwide and most often presents in early adulthood leading to devastating effects for patients, their families and society. Despite thousands of studies performed on the underlying mechanisms of schizophrenia, the causes of the disease remain unknown. However, what is known is that environmental, genetic and epigenetic factors contribute to the development of this complex disorder. Although a genetic role in schizophrenia is well established, the search for schizophrenia genes using traditional approaches has remained challenging. Interestingly, monozygotic twins show concordance for schizophrenia only 50% of the time and therefore provide a unique scenario for genomic analysis.

This Doctoral thesis examines the genetic and epigenetic contributions to schizophrenia discordance in monozygotic twins. In this thesis, I have identified and characterized genome-wide changes through the use of the Affymetrix SNP 6.0 Microarray, Complete Genomics whole genome sequencing and the Nimblegen Methylation 720k Microarray. Specifically, I have identified genetic and epigenetic differences between monozygotic twins discordant for schizophrenia.

The results show multiple genetic and epigenetic changes between monozygotic twins with discordance for schizophrenia. Some of these differences are patient-specific and others are shared between affected twins in the study. In addition, some of these differences affected genes and others did not. Many of the genes and genomic regions have been previously implicated in schizophrenia and neurodevelopmental disorders. The findings reinforce the concept that individual genomes harbor extensive variability, some inherited and some acquired. Even monozygotic twins are not identical and each individual may be a mosaic; carrying different sequence variations in different cells. The results also suggest that discordance for schizophrenia in monozygotic twins may result from the accumulation of genetic and epigenetic mutations that lead to the disease threshold being met in one twin only. The results argue for the involvement of de novo mutations in genetic individuality and complex disease. Improved understanding of the genomic contributions to schizophrenia is critical for movement towards earlier and more accurate diagnosis, better treatment and further understanding of this complex mental health disorder.