Olivera Story Jovanova1, Ivana Nedeljkovic1, Derek Spieler2,3, Rosie M Walker4,5, Chunyu Liu6,7,8, Michelle Luciano4,9, Jan Bressler10, Jennifer Brody11, Amanda J Drake12, Kathryn L Evans4,5, Rahul Gondalia13, Sonja Kunze2,14, Brigitte Kuhnel2,14, Jari Lahti15, Rozenn N Lemaitre11, Riccardo E Marioni4,9, Brenton Swenson11,16, Jayandra Jung Himali6,8,17, Hongsheng Wu18, Yun Li19,20,21, Allan F McRae22,23, Tom C Russ4,24,25, James Stewart13,26, Zhiying Wang10, Guosheng Zhang19,20,21, Karl-Heinz Ladwig2,3, Andre G Uitterlinden1,27, Xiuqing Guo28, Annette Peters2,14, Katri Räikkönen15, John M Starr4,24, Melanie Waldenberger2,14, Naomi R Wray22,23, Eric A Whitsel13,29, Nona Sotoodehnia11, Sudha Seshadri6,17, David J Porteous4,5, Joyce van Meurs27, Thomas H Mosley30, Andrew M McIntosh4,31, Michael M Mendelson6,7,32, Daniel Levy6,7, Lifang Hou33, Johan G Eriksson34, Myriam Fornage10,35, Ian J Deary4,9, Andrea Baccarelli36, Henning Tiemeier1,37,38, Najaf Amin1. 1. Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands. 2. Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany. 3. Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie des Klinikums Rechts der Isar der Technischen Universität München, Munich, Germany. 4. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom. 5. Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. 6. The Framingham Heart Study, Framingham, Massachusetts. 7. The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland. 8. Boston University School of Public Health, Boston, Massachusetts. 9. Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom. 10. Human Genetics Center, University of Texas Health Science Center at Houston. 11. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle. 12. University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. 13. Department of Epidemiology, University of North Carolina at Chapel Hill. 14. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany. 15. Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 16. Institute for Public Health Genetics, School of Public Health, University of Washington, Seattle. 17. Boston University School of Medicine, Boston, Massachusetts. 18. Computer Science and Networking, Wentworth Institute of Technology, Boston, Massachusetts. 19. Department of Genetics, University of North Carolina at Chapel Hill. 20. Department of Biostatistics, University of North Carolina at Chapel Hill. 21. Department of Computer Science, University of North Carolina at Chapel Hill. 22. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. 23. Queensland Brain Institute, The University of Queensland, Brisbane, Australia. 24. Alzheimer Scotland Dementia Research Centre, Edinburgh, United Kingdom. 25. Centre for Dementia Prevention, University of Edinburgh, Edinburgh, United Kingdom. 26. Carolina Population Center, University of North Carolina at Chapel Hill. 27. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 28. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Harbor-University of California Los Angeles (UCLA) Medical Center. 29. Department of Medicine, University of North Carolina at Chapel Hill. 30. MIND Center, University of Mississippi Medical Center, Jackson. 31. Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, United Kingdom. 32. Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 33. Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 34. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. 35. Institute of Molecular Medicine, University of Texas Health Science Center at Houston. 36. Department of Environmental Health Sciences, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts. 37. Department of Child and Adolescent Psychiatry, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands. 38. Department of Social and Behavioral Science, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Abstract
Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression. Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.
Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-InfiniumHuman Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression. Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.
Authors: Marc Jan Bonder; René Luijk; Daria V Zhernakova; Matthijs Moed; Patrick Deelen; Martijn Vermaat; Maarten van Iterson; Freerk van Dijk; Michiel van Galen; Jan Bot; Roderick C Slieker; P Mila Jhamai; Michael Verbiest; H Eka D Suchiman; Marijn Verkerk; Ruud van der Breggen; Jeroen van Rooij; Nico Lakenberg; Wibowo Arindrarto; Szymon M Kielbasa; Iris Jonkers; Peter van 't Hof; Irene Nooren; Marian Beekman; Joris Deelen; Diana van Heemst; Alexandra Zhernakova; Ettje F Tigchelaar; Morris A Swertz; Albert Hofman; André G Uitterlinden; René Pool; Jenny van Dongen; Jouke J Hottenga; Coen D A Stehouwer; Carla J H van der Kallen; Casper G Schalkwijk; Leonard H van den Berg; Erik W van Zwet; Hailiang Mei; Yang Li; Mathieu Lemire; Thomas J Hudson; P Eline Slagboom; Cisca Wijmenga; Jan H Veldink; Marleen M J van Greevenbroek; Cornelia M van Duijn; Dorret I Boomsma; Aaron Isaacs; Rick Jansen; Joyce B J van Meurs; Peter A C 't Hoen; Lude Franke; Bastiaan T Heijmans Journal: Nat Genet Date: 2016-12-05 Impact factor: 38.330
Authors: David M Howard; Oliver Pain; Ryan Arathimos; Miruna C Barbu; Carmen Amador; Rosie M Walker; Bradley Jermy; Mark J Adams; Ian J Deary; David Porteous; Archie Campbell; Patrick F Sullivan; Kathryn L Evans; Louise Arseneault; Naomi R Wray; Michael Meaney; Andrew M McIntosh; Cathryn M Lewis Journal: Hum Mol Genet Date: 2022-02-21 Impact factor: 6.150