Epigenetics in psychiatry, also called neuroepigenetics, faces a wall of difficulties. In psychiatry, there are diverse methods for examining the structure and function of the brain, but from an epigenomic perspective, actual brain tissue is required for such examination. Although genetic sequences and polymorphisms can be obtained from the brain or peripheral tissues like blood and saliva, examination of brain epigenomics requires brain tissue. It is well known that the human brain cannot be easily obtained. Consequently, peripheral surrogate tissues have been used, resulting in limited progress compared to other epigenetic studies, such as cancer research. This is a key difficulty in this field and is referred to as the dilemma of tissue specificity.
Why is the epigenetic perspective of psychiatry important?
Studies have attempted to identify the genes responsible for various psychiatric disorders by identifying genetic polymorphisms and mutations. One large study compared 37,000 patients with schizophrenia to 113,000 controls. However, after many years and attempts at research, it is now believed that it is difficult to fully explain the prevalence and severity of psychiatric disorders using only genetic sequences. We now know that the impact of the environment after birth is significant. This is another aspect of research of interest to the author. Particularly, the author is interested in investigating the consequences of child maltreatment on brain development. For example, the severity of depressive symptoms among patients diagnosed with depression has been found to differ when underlying childhood experiences of maltreatment are present. Thus, there is a growing consensus on the importance of studying psychiatric disorders and the human mind, taking into account the influence of “Nurture” and “Nature.” Epigenetics, including DNA methylation, has been the major focus of attention as an indicator that reflects this “Nurture.”
What have we been doing to date?
Again, Neuroepigenetics faces the dilemma of tissue specificity. Many studies have used peripheral surrogate tissues such as blood or saliva. In addition, some studies have attempted to overcome this dilemma by researching postmortem brain tissue obtained from brain banks. Against this adversity, four databases that would provide correlations of DNA methylation between the brain and peripheral tissues of the same individual have been published. These four databases were created by research groups in the United Kingdom, Canada, the United States, and Germany but were not created with Asian samples. By browsing these databases, users can see the extent to which the peripheral DNA methylation sites they want to look up correlate with brain DNA methylation. This may not be the best breakthrough yet, but it still represents a major step forward in this field.
Let’s develop a public database for Asians!
In recent years, open data and open science waves have accelerated in science. The trend is not to hold valuable research data in the hands of a single research group alone but to make it as public as possible so that it can be made available for secondary use by many researchers worldwide for various purposes. The author sympathizes and agrees with the altruistic efforts that scientists can make and decides to develop a public database that can empower many Asian researchers.
What did we find?
Partial brain tissue resected from 19 patients with brain diseases that clinically required neurosurgery was allowed for use in this study. Blood, saliva, and buccal epithelial tissues were obtained from the patients to conduct DNA methylation microarray analysis of all four tissues. Microarray is a major technique that comprehensively measures DNA methylation across the genome. The method we used was designed to cover 850,000 methylation sites. An online database (AMAZE-CpG) was constructed from the data obtained from the samples and is now available to the public (https://snishit-amaze-cpg.web.app/). This allows users to see correlations between the brain and peripheral tissues for any given methylation site of the genes of interest. This database will be beneficial in interpreting future research results from Japanese and Asian populations, as DNA methylation is also known to be affected by differences in genetic sequences, including racial differences and the influence of the environment. Indeed, a comparison with the three databases of previous studies also showed that there could be considerable discrepancies in the results between the databases, although not all effects are because of race. We have explained and discussed these topics in detail in our scientific article published in Translational Psychiatry titled “Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and their blood, saliva, and buccal epithelial tissues.”
What is next?
As a next step, we would like to expand this database to include a whole-genome version. Based on microarray data, the current database covers only approximately 3% of the estimated 28 million methylation sites in the genome. We would also like to update the database to a larger scale, as the accumulation of sample size also affects the accuracy.
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