Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression.
BACKGROUND: Adolescent depression is a common neuropsychiatric disorder that often continues into adulthood and is associated with a wide range of poor outcomes including suicide. Although numerous studies have looked at genetic markers associated with depression, the role of epigenetic variation remains relatively unexplored. METHODS: Monozygotic (MZ) twins were selected from an adolescent twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. There were 18 pairs of MZ twins identified in which one member scored consistently higher (group mean within the clinically significant range) on self-rated depression than the other. We assessed genome-wide patterns of DNA methylation in twin buccal cell DNA using the Infinium HumanMethylation450 BeadChip from Illumina. Quality control and data preprocessing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. The top differentially methylated DMP was successfully validated by bisulfite-pyrosequencing, and identified DMPs were tested in postmortem brain samples obtained from patients with major depressive disorder (n = 14) and matched control subjects (n = 15). RESULTS: Two reproducible depression-associated DMPs were identified, including the top-ranked DMP that was located within STK32C, which encodes a serine/threonine kinase, of unknown function. CONCLUSIONS: Our data indicate that DNA methylation differences are apparent in MZ twins discordant for adolescent depression and that some of the disease-associated variation observed in buccal cell DNA is mirrored in adult brain tissue obtained from individuals with clinical depression.
This study was funded by a grant awarded by the Psychiatric Reserch Trust (TCE, JM & ELD) G1219 collection waves 1-3 funded by the W T Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship and Career Development Award to Thalia C. Eley. Wave 4 supported by the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry to Alice M. Gregory. We thank the families for their participation as well as numerous staff and students from the Social Genetic Developmental Psychiatry Centre, Institute of Psychiatry, London and Goldsmiths, University of London.
This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.
Vol. 76, pp. 977 - 983
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