Methodological challenges and opportunities in epigenome-wide association studies for psychiatric disorders

Psychiatric disorders have a prevalence of one in eight. The biologic etiology of these disorders remains unclear. Psychiatric disorders are believed to have a genetic and environmental component that interact through epigenetics. DNA methylation is a stable and the most studied epigenetic mark in the context of psychiatric disorders. In recent years, there has been great interest in performing hypothesis-generating epigenome-wide association studies (EWAS) to identify DNA methylation sites significantly associated with psychiatric disorders. For most psychiatric disorders, EWAS have been able to identify DNA methylation sites, which can either point toward underlying molecular mechanisms or serve as biomarkers. Even though the field of psychiatric epigenetics appears promising, several challenges need to be addressed to optimize the performance of EWAS, thereby enabling the identification of potential molecular mechanisms and meaningful biomarkers. At the same time, these challenges present opportunities to enhance our understanding of the molecular mechanisms underlying the association of epigenetic markers and psychiatric disorders. In this chapter, we will discuss these challenges and opportunities in detail and conclude the chapter with future directions for EWAS in psychiatric disorders with a focus on cross-tissue comparisons.