An epigenomic and omics approach to neurodevelopmental disorders

Abstract

© 2020 Namitha MohandasNeurodevelopmental disorders such as cerebral palsy (CP) and epilepsy are some of the most prevalent childhood neurological disorders caused by damage to the growth and development of the brain. Early life environments predispose children to later health outcomes evidenced by the developmental origins of health and disease (DOHaD) phenomenon. Epigenetics, which refers to modifications of DNA without change in DNA sequence, is one way by which environmental exposures may contribute to development of disease. DNA methylation, arguably the most highly studied epigenetic mark, has been correlated with early life environmental exposures and have implications in both disease mechanisms as well as clinical biomarkers of neurodevelopmental diseases. These modifications most likely originate in utero, in line with the DOHaD hypothesis. The study of monozygotic (MZ) twins, in which genetics, age, sex, parental factors and shared environment are controlled for, helps in distinguishing the extent of effect of genetics and environment. Discordance for neurodevelopmental disorders has been recorded in MZ twins indicating a potential role of non-shared factors in disease risk. The aim of this PhD was to utilise the discordant MZ twin model to understand epigenetic changes associated with neurodevelopmental disorders. Genome-wide DNA methylation was measured within MZ twin cohorts discordant for CP or epilepsy using Illumina’s Infinium HumanMethylation450 and EPIC arrays. Statistical and bioinformatics pipelines were applied to evaluate the association of DNA methylation data to disease phenotypes. As detailed in Chapter Three of this thesis, DNA methylation analysis of CP-discordant twin pairs provides the first evidence that environmentally mediated differential methylation in genes involved in known processes such as hypoxia and inflammation, and processes such as cell adhesion, may contribute to the development of CP. As detailed in Chapter Four, an epigenome-wide analysis of epilepsy discordant MZ twin pairs revealed distinct patterns of DNA methylation within subtypes of epilepsies of unknown cause. Differentially methylated genes within epilepsy subtypes included those with a role in metabolic pathways, voltage-gated channel signalling and neurotransmitter processes. This research paves the way for future larger studies, as understanding DNA methylation profiles associated with neurodevelopmental disorders, may facilitate biomarkers for earlier diagnosis. This could lead to possible intervention strategies for patients suffering from a broad spectrum of disorders. Analysing epigenetic data from disease discordant twins provides an elegant study design and has the power to explore non-shared environmental factors that further refine models of disease mechanisms and biomarkers. The findings of this thesis suggest that epigenetic factors may play a role regulating biological pathways that underlie neurodevelopmental disorders, some of which arise as early as the prenatal period. Replication in other larger and similar cohorts of discordant twin pairs may provide novel targets for biomarker development, thereby allowing for early interventions and helping the health of children