Wouter J Peyrot1, Sandra Van der Auwera2, Yuri Milaneschi3, Conor V Dolan4, Pamela A F Madden5, Patrick F Sullivan6, Jana Strohmaier7, Stephan Ripke8, Marcella Rietschel7, Michel G Nivard4, Niamh Mullins9, Grant W Montgomery10, Anjali K Henders10, Andrew C Heat5, Helen L Fisher9, Erin C Dunn11, Enda M Byrne10, Tracy A Air12, Bernhard T Baune12, Gerome Breen9, Douglas F Levinson13, Cathryn M Lewis9, Nick G Martin14, Elliot N Nelson5, Dorret I Boomsma4, Hans J Grabe2, Naomi R Wray10, Brenda W J H Penninx3. 1. Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, the Netherlands. Electronic address: peyrot.w@gmail.com. 2. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. 3. Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, the Netherlands. 4. Department of Biological Psychology, VU University Medical Center, Amsterdam, the Netherlands. 5. Department of Psychiatry, Washington University Medical School, St. Louis, Missouri. 6. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 7. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 8. Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts. 9. Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. 10. Queensland Brain Institute, University of Queensland, Brisbane, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. 11. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. 12. Discipline of Psychiatry, University of Adelaide, Adelaide, Australia. 13. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California. 14. Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Australia.
Abstract
BACKGROUND: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. METHODS: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. RESULTS: MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). CONCLUSIONS: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.
BACKGROUND: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. METHODS: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. RESULTS:MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). CONCLUSIONS: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.
Authors: Ron de Graaf; Margreet ten Have; Coen van Gool; Saskia van Dorsselaer Journal: Soc Psychiatry Psychiatr Epidemiol Date: 2011-01-01 Impact factor: 4.328
Authors: Cathryn M Lewis; Mandy Y Ng; Amy W Butler; Sarah Cohen-Woods; Rudolf Uher; Katrina Pirlo; Michael E Weale; Alexandra Schosser; Ursula M Paredes; Margarita Rivera; Nicholas Craddock; Mike J Owen; Lisa Jones; Ian Jones; Ania Korszun; Katherine J Aitchison; Jianxin Shi; John P Quinn; Alasdair Mackenzie; Peter Vollenweider; Gerard Waeber; Simon Heath; Mark Lathrop; Pierandrea Muglia; Michael R Barnes; John C Whittaker; Federica Tozzi; Florian Holsboer; Martin Preisig; Anne E Farmer; Gerome Breen; Ian W Craig; Peter McGuffin Journal: Am J Psychiatry Date: 2010-06-01 Impact factor: 18.112
Authors: Gonçalo R Abecasis; David Altshuler; Adam Auton; Lisa D Brooks; Richard M Durbin; Richard A Gibbs; Matt E Hurles; Gil A McVean Journal: Nature Date: 2010-10-28 Impact factor: 49.962
Authors: J G F M Hovens; J E Wiersma; E J Giltay; P van Oppen; P Spinhoven; B W J H Penninx; F G Zitman Journal: Acta Psychiatr Scand Date: 2009-10-30 Impact factor: 6.392
Authors: Christopher C Chang; Carson C Chow; Laurent Cam Tellier; Shashaank Vattikuti; Shaun M Purcell; James J Lee Journal: Gigascience Date: 2015-02-25 Impact factor: 6.524
Authors: Maura Boldrini; Hanga Galfalvy; Andrew J Dwork; Gorazd B Rosoklija; Iskra Trencevska-Ivanovska; Goran Pavlovski; René Hen; Victoria Arango; J John Mann Journal: Biol Psychiatry Date: 2019-01-17 Impact factor: 13.382
Authors: Anton Schulmann; Euijung Ryu; Vanessa Goncalves; Brandi Rollins; Michael Christiansen; Mark A Frye; Joanna Biernacka; Marquis P Vawter Journal: Mol Neuropsychiatry Date: 2019-02-05
Authors: Melisa Chuong; Mark J Adams; Alex S F Kwong; Chris S Haley; Carmen Amador; Andrew M McIntosh Journal: JAMA Psychiatry Date: 2022-09-28 Impact factor: 25.911
Authors: John L Slunecka; Matthijs D van der Zee; Jeffrey J Beck; Brandon N Johnson; Casey T Finnicum; René Pool; Jouke-Jan Hottenga; Eco J C de Geus; Erik A Ehli Journal: Hum Genomics Date: 2021-07-20 Impact factor: 4.639
Authors: Heather C Whalley; Andrew M McIntosh; Xueyi Shen; David M Howard; Mark J Adams; W David Hill; Toni-Kim Clarke; Ian J Deary Journal: Nat Commun Date: 2020-05-08 Impact factor: 14.919
Authors: Monika A Waszczuk; Anna R Docherty; Andrey A Shabalin; Jiaju Miao; Xiaohua Yang; Pei-Fen Kuan; Evelyn Bromet; Roman Kotov; Benjamin J Luft Journal: Psychol Med Date: 2020-10-23 Impact factor: 7.723