MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

Abstract

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.

Keywords: :

• DNA methylation
• COMT
• schizophrenia
• intermediate phenotype
• fMRI

10.4161/epi.29223

Disclosure of Potential Conflicts of Interest

Veit Roessner has received lecture fees from Eli Lilly, Janssen-Cilag, Medice, Novartis and was a member of advisory boards of Eli Lilly, Novartis. Dr Calhoun has received research support from the National Institutes of Health, National Science Foundation, Department of Energy, has done some consultation, has performed grant reviews for the National Institutes of Health and other agencies; has guest-edited journal sections; has given academic lectures in various scientific venues; and has generated books or book chapters for publishers of various texts. All other authors declare no biomedical financial interests or other potential conflict of interests.

Acknowledgments

This work was supported by the National Institutes of Health (NIH/NCRR P41RR14075, K08 MH068540), the Department of Energy (DE-FG02-99ER62764), the MIND Research Network, Morphometry BIRN (1U24, RR021382A), Function BIRN (U24RR021992-01, NIH.NCRR MO1 RR025758-01), the National Institute of General Medical Sciences and the National Institute of Biomedical Imaging and Bioengineering (NIGMS P20-GM103472 and NIBIB 2R01-EB000840 to V.C.), and the National Association for Research in Schizophrenia and Affective Disorders (NARSAD award to S.E.).