Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation — an epigenetic mechanism both heritable and sensitive to the environment — may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.
Bibliographical noteFunding Information:
We deeply appreciate the invaluable contributions made by the donors and their families. This research is supported by Mayo Foundation for Medical Education and Research , the J. Willard and Alice S. Marriott Foundation, and the James D. and Pamela S. Deal family. The tissue bank is supported by NIGMS Center for Psychiatric Neuroscience COBRE grant P30 GM103328 and NIMH grant R01 MH67996 . We would like to thank the Ulm Foundation and NIAAA grant AA018779 awarded to DSC. We also thank the staff of the Cuyahoga County Medical Examiner's Office, Cleveland, OH, Drs. Herbert Y. Meltzer and Bryan Roth for their assistance in psychiatric assessments, Timothy M. De Jong, Lisa Konick, and Lisa Larkin for their assistance in acquiring written consent and tissues, and the Mayo Clinic Medical Genome Facility Genotyping Core for providing the microarray service.
© 2019 The Authors