Epigenetic Research in Neuropsychiatric Disorders: the “Tissue Issue”

Kelly M. Bakulski, Alycia Halladay, Valerie W. Hu, Jonathan Mill, M. Daniele Fallin

Evidence has linked neuropsychiatric disorders with epigenetic marks as either a biomarker of disease, biomarker of exposure, or mechanism of disease processes. Neuropsychiatric epidemiologic studies using either target brain tissue or surrogate blood tissue each have methodological challenges and distinct advantages. Brain tissue studies are challenged by small sample sizes of cases and controls, incomplete phenotyping, post-mortem timing, and cellular heterogeneity, but the use of a primary disease relevant tissue is critical. Blood-based studies have access to much larger sample sizes and more replication opportunities, as well as the potential for longitudinal measurements, both prior to onset and during the course of treatments. Yet, blood studies also are challenged by cell-type heterogeneity, and many question the validity of using peripheral tissues as a brain biomarker. Emerging evidence suggests that these limitations to blood-based epigenetic studies are surmountable, but confirmation in target tissue remains important. Epigenetic mechanisms have the potential to help elucidate biology connecting experiential risk factors with neuropsychiatric disease manifestation. Cross-tissue studies as well as advanced epidemiologic methods should be employed to more effectively conduct neuropsychiatric epigenetic research.