@article{discovery10073831,
            year = {2019},
          volume = {76},
          number = {4},
           title = {Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults A 2-Sample Mendelian Randomization Study},
           month = {April},
           pages = {399--408},
         journal = {JAMA Psychiatry},
            note = {This version is the version of record. For information on re-use, please refer to the publisher's terms and conditions.},
       publisher = {AMER MEDICAL ASSOC},
            issn = {2168-6238},
             url = {https://doi.org/10.1001/jamapsychiatry.2018.4175},
          author = {Choi, KW and Chen, C-Y and Stein, MB and Klimentidis, YC and Wang, M-J and Koenen, KC and Smoller, JW and Wray, NR and Ripke, S and Mattheisen, M and Trzaskowski, M and Byrne, EM and Abdellaoui, A and Adams, MJ and Agerbo, E and Air, T and Andlauer, TFM and Bacanu, S-A and Baekvad-Hansen, M and Beekman, ATF and Bigdeli, TB and Binder, EB and Blackwood, DHR and Bryois, J and Buttenschon, HN and Bybjerg-Grauholm, J and Cai, N and Castelao, E and Hvarregaard, J and Christensen, JH and Clarke, T-K and Coleman, JRI and Colodro-Conde, L and Couvy-Duchesne, B and Craddock, N and Crawford, GE and Davies, G and Deary, IJ and Degenhardt, F and Derks, EM and Direk, N and Dolan, CV and Dunn, EC and Eley, TC and Escott-Price, V and Kiadeh, FFH and Finucane, HK and Forstner, AJ and Frank, J and Gaspar, HA and Gill, M and Goes, FS and Gordon, SD and Grove, J and Hall, LS and Hansen, CS and Hansen, TF and Herms, S and Hickie, IB and Hoffmann, P and Homuth, G and Horn, C and Hottenga, J-J and Hougaard, DM and Ising, M and Jansen, R and Jorgenson, E and Knowles, JA and Kohane, IS and Kraft, J and Kretzschmar, W and Krogh, J and Kutalik, Z and Li, Y and Lind, PA and MacIntyre, DJ and MacKinnon, DF and Maier, RM and Marchini, J and McGrath, P and McGuffin, P and Medland, SE and Mehta, D and Middeldorp, CM and Mihailov, E and Milaneschi, Y and Milani, L and Mondimore, FM and Montgomery, GW and Mostafavi, S and Mullins, N and Nauck, M and Ng, B and Nivard, MG and Nyholt, DR and O'Reilly, PF and Oskarsson, H and Owen, MJ and Painter, JN and Pedersen, CB and Pedersen, MG and Peterson, RE and Pettersson, E and Peyrot, WJ and Pistis, G and Posthuma, D and Quiroz, JA and Qvist, P and Rice, JP and Riley, BP and Rivera, M and Saeed, S and Schoevers, R and Schulte, EC and Shen, L and Shi, J and Shyn, SI and Sigurdsson, E and Sinnamon, GCB and Smit, JH and Smith, DJ and Stefansson, H and Steinberg, S and Streit, F and Strohmaier, J and Tansey, KE and Teismann, H and Teumer, A and Thompson, W and Thomson, PA and Thorgeirsson, TE and Traylor, M and Treutlein, J and Trubetskoy, V and Uitterlinden, AG and Umbricht, D and Van der Auwera, S and van Hemert, AM and Viktorin, A and Visscher, PM and Wang, Y and Webb, BT and Weinsheimer, SM and Wellmann, J and Willemsen, G and Witt, SH and Wu, Y and Xi, HS and Yang, J and Zhang, F and Arolt, V and Baune, BT and Berger, K and Boomsma, DI and Cichon, S and Dannlowski, U and De Geus, EJC and DePaulo, JR and Domenici, E and Domschke, K and Esko, T and Grabe, HJ and Hamilton, SP and Hayward, C and Heath, AC and Kendler, KS and Kloiber, S and Lewis, G and Li, QS and Lucae, S and Madden, PAF and Magnusson, PK and Martin, NG and McIntosh, AM and Metspalu, A and Mors, O and Mortensen, PB and Nordentoft, M and Noethen, MM and O'Donovan, MC and Paciga, SA and Pedersen, NL and Penninx, BWJH and Perlis, RH and Porteous, DJ and Potash, JB and Preisig, M and Rietschel, M and Schaefer, C and Schulze, TG and Smoller, JW and Stefansson, K and Tiemeier, H and Uher, R and Volzke, H and Weissman, MM and Werge, T and Lewis, CM and Levinson, DF and Breen, G and Borglum, AD and Sullivan, PF},
        abstract = {Importance: Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity. / Objective: To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference. / Design, Setting, and Participants: This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018. / Main Outcomes and Measures: MDD and physical activity. / Results: GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95\% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity ({\ensuremath{\beta}} = ?0.08 in mean acceleration per MDD vs control status; 95\% CI, ?0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95\% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity ({\ensuremath{\beta}} = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95\% CI, ?0.008 to 0.05; P = .15). / Conclusions and Relevance: Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.}
}