Schizophrenia Genomics

This web page was produced as an assignment for an undergraduate course at Davidson College.

Figure 1. Embroidery by a person diagnosed with schizophrenia.
Those diagnosed with schizophrenia typically suffer from delusions, hallucinations,
and/or disorganized speech. Image courtesy of Wikimedia Commons.

Genomic-epigenomic Interactions Driving Risk for Schizophrenia
Schizophrenia is a neuropsychiatric disorder that is clinically well characterized but has a poorly understood neuropathology. It is believed to be in part of genetic origin, and increased risk for schizophrenia may be acquired during early development, despite the fact that the disease does not typically manifest until adulthood (Jablensky, 2010). In January of 2016, two separate genomics research projects conducted in two separate labs were evaluated, and their results were taken together to draw new conclusions about the potential epigenomic influence on the etiology of schizophrenia. The two studies employed slightly different techniques to investigate the effect the changes in DNA methylation occurring in the prenatal to postnatal transition during development may have on brain development of those with and without schizophrenia. Furthermore, the studies sought to assess the influence of variations in DNA sequence on DNA methylation via identification of methylation quantitative trait loci (meQTLs), genomic loci where genotypic variation may affect patterns of DNA methylation (Smith et al., 2014).

Simultaneous Hypothesis Driven and Discovery Science
In both studies, the researchers were testing a hypothesis. The most heavily supported hypothesis to describe the pathology of schizophrenia, the neurodevelopmental hypothesis, postulates that risk for schizophrenia is at least in part a result of abnormalities in early brain development (Fatemi & Folsom, 2009). Additionally epigenetic dysregulation of gene expression have been associated with a variety of neurodevelopmental disorders, including schizophrenia. Both studies examined the relationship between the epigenomic regulation, specifically DNA methylation, and genetic risk for schizophrenia. This information led the researchers in both studies to test the hypothesis that DNA methylation changes in prefrontal cortex will occur in development as early as the prenatal to postnatal transition.
However, the researchers in both studies were also doing discovery science at least to an extent, as they each sought to identify loci where genotype may be influencing DNA methylation, and perhaps the subsequent level of risk for schizophrenia. In these experiments specifically, the researchers were only driven by the hypothesis that genotype may influence DNA methylation. The exploration of where in the genome this may occur and to what extent was purely discovery science in both studies.

Take Home Message
Genomic technology has allowed us to examine the interaction between epigenomic regulation in the form of DNA methylation and predisposition to a neuropsychiatric disease. DNA methylation, or lack thereof, can change rates of gene expression, thus altering the development of the tissue in which the genes are expressed. When dysregulation occurs during a critical developmental time point in a particular tissue, the development of that tissue may be altered or hindered in some way. When this epigenomic dysregulation occurs in the brain, it is not surprising that risk for a neuropsychiatric condition such as schizophrenia may be the result. It is important to note that DNA methylation is not the only form of epigenomic regulation, but it is the one that has been most heavily implicated in the neuropathology of schizophrenia to date. Furthermore, there are specific genomic sequences that influence the epigenome. Those that influence DNA methylation levels are meQTLs. Thus, one of the biggest overall takeaways from these two studies is that they highlight both the interconnectedness of the genome and epigenome and the complexity of the interactions between them.

I think the projects discussed in this article are valuable on two levels. First, they utilize genomic technology to uncover new and valuable information about the genetic component of the etiology of schizophrenia. Ultimately, the findings can help us narrow down the developmental time window in which humans become most susceptible to increasing their risk of later developing schizophrenia and potentially identify genomic locations that serve as markers for genetic risk for the development of schizophrenia in adulthood. Neither of the projects absolutely determined the manner in which the genome, epigenome, and interactions between the two may influence risk of schizophrenia, nor did they claim to. However, both projects provide evidence that there is likely a genomic-epigenomic component to the etiology of the disease. Although there is much more work to be done, the steps taken in these two projects are important ones for initiating additional research into the genomic-epigenomic interactions that may impact an individual's risk for developing schizophrenia.
Second, these studies demonstrate the immense value genomics brings to furthering our understanding of complex biological processes. These two projects sought to examine the potential effect of genomic variations on epigenomic regulation and in turn on variations in gene expression during early brain development that may later contribute to the development of schizophrenia. In doing so, they made a valuable impact on our understanding of the biological basis of a disease that has been clinically characterized for over a generation, but never fully understood from a neuroscientific standpoint (Jablensky, 2010). Thus, the studies highlight the widespread potential of genomic research to shed light on the biological mechanisms and genetic bases of diseases, functions, and processes that have to date remained scientific mysteries.

References

Fatemi SH, Folsom TD. 2009. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull. 35(3):528-548

Jablensky A. 2010. The diagnostic concept of schizophrenia: its history, evolution, and future prospects.

Smith AK, Kilaru V, Kocak M, Almli LM, Mercer KB, Ressler KJ, Tylavsky FA, Conneely KN. 2014. Methylation quantative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type.