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Association Between Promoter Methylation of Serotonin Transporter Gene and Depressive Symptoms: A Monozygotic Twin Study

Zhao, Jinying MD, PhD; Goldberg, Jack PhD; Bremner, James D. MD; Vaccarino, Viola MD, PhD

doi: 10.1097/PSY.0b013e3182924cf4
Original Articles

Objective Epigenetic mechanisms have been implicated in the pathogenesis of psychiatric disorders. The serotonin transporter gene (SLC6A4) is a key candidate gene for depression. We examined the association between SLC6A4 promoter methylation variation and depressive symptoms using 84 monozygotic twin pairs.

Methods DNA methylation level in the SLC6A4 promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The number of current depressive symptoms was assessed using the Beck Depressive Inventory II (BDI-II). The association between methylation variation and depressive symptoms was examined using matched twin-pair analyses, adjusting for body mass index, smoking, physical activity, and alcohol consumption. Multiple testing was controlled by adjusted false discovery rate (q value).

Results Intrapair difference in DNA methylation variation at 10 of the 20 studied CpG sites is significantly correlated with intrapair difference in BDI scores. Linear regression using intrapair differences demonstrates that intrapair difference in BDI score was significantly associated with intrapair differences in DNA methylation variation after adjusting for potential confounders and correction for multiple testing. On average, a 10% increase in the difference in mean DNA methylation level was associated with 4.4 increase in the difference in BDI score (95% confidence interval = 0.9–7.9, p = .01).

Conclusions This study provides evidence that variation in methylation level within the promoter region of the serotonin transporter gene is associated with variation in depressive symptoms in a large sample of monozygotic twin pairs. This relationship is not confounded by genetic and shared environment. The 5-HTTLPR genotype also does not modulate this association.

From the Department of Epidemiology (J.Z.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana; Department of Epidemiology (J.G.), University of Washington, Seattle, Washington; Department of Psychiatry and Behavioral Sciences (J.D.B.), School of Medicine, and Department of Epidemiology (V.V.), School of Public Health, Emory University, Atlanta, Georgia.

Address correspondence and reprint requests to Jinying Zhao, MD, PhD, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2000-SL18, New Orleans, LA 70112. E-mail:

Received for publication February 22, 2012; revision received February 16, 2013.

Copyright © 2013 by American Psychosomatic Society
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