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Testing Causal Bidirectional Influences between Physical Activity and Depression using Mendelian Randomization

By Karmel Choi, Chia-Yen Chen, Murray B. Stein, Yann Klimentidis, Min-Jung Wang, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Karestan C. Koenen, Jordan W Smoller

Posted 08 Jul 2018
bioRxiv DOI: 10.1101/364232 (published DOI: 10.1001/jamapsychiatry.2018.4175)

Background: Burgeoning evidence from randomized controlled trials and prospective cohort studies suggests that physical activity protects against depression, pointing to a potential modifiable target for prevention. However, the direction of this inverse association is not clear: physical activity may reduce risk for depression, and/or depression may result in decreased physical activity. Here, we used bidirectional two-sample Mendelian randomization (MR) to test causal influences between physical activity and depression. Methods: For genetic instruments, we selected independent top SNPs associated with major depressive disorder (MDD, N = 143,265) and two physical activity phenotypes - self-reported (N = 377,234) and objective accelerometer-based (N = 91,084) - from the largest available, non-overlapping genome-wide association results. We used two sets of genetic instruments: (1) only SNPs previously reported as genome-wide significant, and (2) top SNPs meeting a more relaxed threshold (p < 1x10-7). For each direction of influence, we combined the MR effect estimates from each instrument SNP using inverse variance weighted (IVW) meta-analysis, along with other standard MR methods such as weighted median, MR-Egger, and MR-PRESSO. Results: We found evidence for protective influences of accelerometer-based activity on MDD (IVW odds ratio (OR) = 0.74 for MDD per 1 SD unit increase in average acceleration, 95% confidence interval (CI) = 0.59-0.92, p = .006) when using SNPs meeting the relaxed threshold (i.e., 10 versus only 2 genome-wide significant SNPs, which provided insufficient data for sensitivity analyses). In contrast, we found no evidence for negative influences of MDD on accelerometer-based activity (IVW b = 0.04 change in average acceleration for MDD versus control status, 95% CI = -0.43-0.51, p = .87). Furthermore, we did not see evidence for causal influences between self-reported activity and MDD, in either direction and regardless of instrument SNP criteria. Discussion: We apply MR for the first time to examine causal influences between physical activity and MDD. We discover that objectively measured - but not self-reported - physical activity is inversely associated with MDD. Of note, prior work has shown that accelerometer-based physical activity is more heritable than self-reported activity, in addition to being more representative of actual movement. Our findings validate physical activity as a protective factor for MDD and point to the importance of objective measurement of physical activity in epidemiological studies in relation to mental health. Overall, this study supports the hypothesis that enhancing physical activity is an effective prevention strategy for depression.

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