The brain is a gene-dosage sensitive organ in which either under- or overexpression of genes encoding proteins associated with brain function results in a range of congenital neurodevelopmental disorders, suggesting that the brain is extremely sensitive to perturbations in gene regulation, and further indicating the importance of a proper gene expression control in the brain.
Intrinsic epigenetic mechanisms are involved in the controls of gene expression, and are essential for normal development during embryogenesis and for differentiation of neural cells (Takizawa et al., 2001). It has been reported that abnormalities in epigenetic mechanisms can result in a number of congenital neurodevelopmental disorders.
Advances in methodologies for epigenetic analysis, such as Beadchip microarrays and next-generation sequencing, now enable the investigation of the epigenetic status at individual loci, multiple loci, or the whole genome. These new approaches also enable epigenome-wide association studies (EWAS).
Several lines of evidence suggest that epigenetic abnormalities can be induced by environmental factors. Thus, clinical epigenetic research not only needs to target congenital disorders, but must also investigate acquired chronic diseases including common mental and neurodevelopmental disorders, in which epigenomic abnormalities may reside at multiple genomic loci.
We are now in the process of identifying environmentally induced epigenomic changes that can be used as “epigenomic disease signature,” that is, predictive markers for chronic diseases. Realization of this goal will ensure the start of “personalized medicine” or “preemptive medicine.”
In this chapter, we describe epigenetic and epigenomic (genome-wide epigenetic) abnormalities associated with congenital neurodevelopmental disorders. Additionally, we describe environment-induced epigenetic abnormalities, and discuss EWAS on various diseases including neurodevelopmental disorders. We also discuss personalized medicine as a goal of EWAS.
Congenital neurodevelopmental disorders with epigenetic abnormalities
Genomic imprinting disorders
Genomic imprinting is an epigenetic phenomenon that was initially discovered in mammals, and results in the monoallelic, parent-of-origin expression of some genes. These inherited maternal and paternal imprints are erased in the germ line and a new imprinting pattern is established according to the sex of the individual.