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Hypermethylation in the ZBTB20 gene is associated with major depressive disorder

Matthew N Davies1*, Lutz Krause2, Jordana T Bell1, Fei Gao3, Kirsten J Ward1, Honglong Wu3, Hanlin Lu3, Yuan Liu3, Pei-Chein Tsai1, David A Collier4, Therese Murphy5, Emma Dempster5, Jonathan Mill45, UK Brain Expression Consortium, Alexis Battle7, Sara Mostafavi7, Xiaowei Zhu7, Anjali Henders2, Enda Byrne26, Naomi R Wray26, Nicholas G Martin2, Tim D Spector1 and Jun Wang3

Author Affiliations

1 Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Hospital Campus, Westminster Bridge Road, London SE1 7EH, UK

2 Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia

3 BGI-Shenzhen, Shenzhen 518083, China

4 SGDP Centre, Institute of Psychiatry, King’s College London, London SE5 8AF, UK

5 Medical School, University of Exeter, Exeter EX1 2LU, UK

6 Queensland Brain Institute, University of Queensland, St Lucia, QLD 4072, Australia

7 Stanford University, Stanford, CA 94305, USA

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Genome Biology 2014, 15:R56  doi:10.1186/gb-2014-15-4-r56

Published: 2 April 2014



Although genetic variation is believed to contribute to an individual’s susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder.


Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder.


Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.