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JAMA Psychiatry | Original Investigation

Assessment of Bidirectional Relationships


Between Physical Activity and Depression Among Adults
A 2-Sample Mendelian Randomization Study
Karmel W. Choi, PhD; Chia-Yen Chen, PhD; Murray B. Stein, MD, MPH; Yann C. Klimentidis, PhD;
Min-Jung Wang, MSc; Karestan C. Koenen, PhD; Jordan W. Smoller, MD, ScD; for the Major Depressive Disorder
Working Group of the Psychiatric Genomics Consortium

Editorial
IMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk Supplemental content
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 (β = −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 (β = 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). Author Affiliations: Author
affiliations are listed at the end of this
article.
CONCLUSIONS AND RELEVANCE Using genetic instruments identified from large-scale GWAS,
Group Information: Members of the
robust evidence supports a protective relationship between objectively assessed—but not
Major Depressive Disorder Working
self-reported—physical activity and the risk for MDD. Findings point to the importance of Group of the Psychiatric Genomics
objective measurement of physical activity in epidemiologic studies of mental health and Consortium are listed at the end
support the hypothesis that enhancing physical activity may be an effective prevention of this article.

strategy for depression. Corresponding Author: Karmel Choi,


PhD, Psychiatric and
Neurodevelopmental Genetics Unit,
Center for Genomic Medicine,
Massachusetts General Hospital,
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.4175 185 Cambridge St, Boston, MA 02114
Published online January 23, 2019. (kwchoi@mgh.harvard.edu).

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Research Original Investigation Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults

D
epression is a common psychiatric condition that rep-
resents a leading cause of disability worldwide.1 De- Key Points
spite this, efforts to prevent depression have been chal-
Question Does physical activity have a potential causal role
lenging, with few established protective factors, particularly in reducing risk for depression?
modifiable targets for prevention. One promising target is
Findings In this 2-sample mendelian randomization study using
physical activity, defined broadly as musculoskeletal move-
genetic instruments from large-scale genome-wide association
ment resulting in energy expenditure.2 The relationship be-
studies to support potential causal inference, higher levels of
tween physical activity and depression has received much at- physical activity (indexed by objective accelerometer data) were
tention in recent years. For example, meta-analytic data from linked to reduced odds for major depression.
randomized clinical trials3 have suggested that physical ac-
Meaning Findings strengthen empirical support for physical
tivity is linked to reduced depressive symptoms in at-risk
activity as an effective prevention strategy for depression.
populations, and prospective studies4,5 have demonstrated as-
sociations between higher levels of physical activity and de-
creased risk for later depression. sociation studies (GWAS), which have recently become available
Although such findings point to a potential protective role for physical activity12 and major depressive disorder (MDD).13
of physical activity for depression, several questions remain. First, Herein, we apply bidirectional MR to assess the potential causal
does physical activity causally influence risk for depression—or relationship of physical activity with the risk for depression, and
is this better explained by reverse causation? Some studies6,7 vice versa. Furthermore, we examine genetic instruments for
show that depression may also lead to reduced physical activ- physical activity assessed subjectively via self-report and objec-
ity, but few studies have simultaneously tested both directional tively using wearable accelerometers.
relationships. Second, does measurement of physical activity
matter? Literature to date has relied mostly on self-reported mea-
sures of activity,5 which may be subject to confounding by par-
ticipant mood, memory inaccuracy, and social desirability bias.8
Methods
Third, does the relationship between physical activity and de- This study relied on deidentified summary-level data that have
pression persist when potential confounding is minimized? Al- been made publically available; ethical approval had been ob-
though randomized clinical trials minimize confounding from tained in all original studies. Summary data were available for
unaccounted variables by design, they are intensive to conduct a combined sample of 611 583 adult participants, with corre-
and have been of relatively limited size, with a mean of fewer than sponding GWAS sample sizes detailed below. Data were ana-
60 participants per trial.3,9,10 More critically, randomized clini- lyzed for this study from May 10 through July 31, 2018.
cal trials have focused on treating symptoms in depressed indi-
viduals rather than testing preventive effects of physical activ- Data Sources and Instruments
ity on depression, which has population-wide implications but Physical Activity
requires large samples unselected for depression. The most con- We drew on summary statistics from a recent GWAS of physical
vincing evidence to date that physical activity is associated with activity conducted among UK Biobank Study participants.12 This
a reduced risk for depression comes from meta-analyses of pro- GWAS examined the following 2 continuous physical activity
spective studies,5 which are high quality yet still limited by the phenotypes: (1) self-reported moderate-to-vigorous physical
breadth of behavioral, social, and genetic confounders that can- activity (in standardized units of inverse-normalized metabolic-
not be fully ruled out in observational designs. equivalent minutes per week) and (2) objective accelerometer-
Mendelian randomization (MR) is an alternative method for based activity, specifically overall mean acceleration (in milli-
potential causal inference that treats genetic variation as a natu- gravities across at least 72 hours of wrist-worn accelerometer
ral experiment in which individuals are essentially assigned to wear). The GWAS for self-reported activity (n = 377 234) identi-
higher vs lower mean levels of a nongenetic exposure during their fied 9 independent genome-wide significant single-nucleotide
lifetime.11 Because genetic variants are considered to be allocated polymorphisms (SNPs), although SNP-based heritability was
randomly before birth, they are relatively independent of envi- modest at approximately 5%.12 The GWAS for accelerometer-
ronmental factors and established well before onset of disease, based activity (n = 91 084) identified only 2 independent genome-
thereby minimizing issues of residual confounding and reverse wide significant SNPs, although SNP-based heritability was
causation that limit typical observational studies. If an exposure estimated much higher at 14%. These heritability estimates sug-
such as physical activity causally influences an outcome such as gest that SNPs beyond those currently identified as genome-wide
depression, then a variant that affects physical activity should significant may contribute to variation in physical activity. Given
be expected to influence depression to a proportional degree, pro- this, we used the following 2 sets of genetic instruments: (1) only
vided no separate pathway exists by which this variant can affect SNPs previously reported as genome-wide significant and (2) top
depression, a phenomenon known as horizontal pleiotropy. Un- SNPs meeting a more relaxed threshold (P < 1 × 10−7). This method
der these conditions, variants strongly associated with an expo- of relaxing the statistical threshold for genetic instruments has
sure of interest may serve as proxies, or instruments, for estimat- been used in psychiatric MR research when few significant SNPs
ing potential causal relationship with an outcome (Figure 1). In are available.14,15 When the more relaxed threshold was used, we
a 2-sample MR design, instruments can be extracted from sum- clumped SNPs for independence (ie, when SNPs were correlated
mary statistics of large-scale, nonoverlapping genome-wide as- at r2 > 0.001, only 1 representative SNP was retained) based on

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Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults Original Investigation Research

from MR analysis, which did not change the pattern of findings;


Figure 1. Mendelian Randomization (MR) Model
thus, results using the full set of SNPs were reported.
Unmeasured For each direction of potential influence, we combined MR
confounders
estimates using inverse variance–weighted (IVW) meta-analysis,
U which essentially translates to a weighted regression of SNP-
outcome effects on SNP-exposure effects where the intercept is
constrained to zero. Again, results can be biased if instrument
B1 B2
SNPs show horizontal pleiotropy, influencing the outcome
Z X Y
through causal pathways other than the exposure, thereby vio-
Genetic Exposure Outcome
variants lating instrumental variable assumptions.16 We therefore com-
B3
pared IVW results with other established MR methods whose es-
timates are known to be relatively robust to horizontal pleiotropy,
B2 indicates the causal relationship of interest to be estimated, where
B2 = B1/B3. B1 and B3 represent estimated direct effects of a genetic variant on
although at the cost of reduced statistical power.17 These meth-
the exposure (eg, physical activity) and outcome (eg, depression), respectively. ods include the weighted median approach, which selects
Solid paths are theorized to exist; dashed paths are theorized to be the median MR estimate as the causal estimate,18 and MR Egger
nonsignificant according to MR assumptions.
regression, which allows the intercept to be freely estimated
as an indicator of average pleiotropic bias.16 We also applied
MR-PRESSO (Pleiotropy Residual Sum and Outlier)19 to detect and
European ancestry reference data from the 1000 Genomes Proj- correct for any outliers reflecting likely pleiotropic biases for all
ect. Where SNPs for the exposure phenotype were not available reported results. Effect estimates are reported in β values where
in the summary statistics of the outcome phenotype, we replaced the outcome was continuous (ie, self-reported or objectively as-
them with overlapping proxy SNPs in high-linkage disequilibrium sessed physical activity levels) and converted to ORs where the
(r2 > 0.80) identified using the LDproxy search on the online plat- outcome was dichotomous (ie, MDD status).
form LDlink (https://ldlink.nci.nih.gov/). Resulting lists of To assess robustness of significant results, we conducted fur-
instrument SNPs for each phenotype are given in eTables 1 to 4 ther tests for horizontal pleiotropy using meta-analytic methods
in the Supplement. to detect heterogeneous outcomes, including leave-1-SNP-out
analyses, the modified Cochran Q statistic, and the MR Egger in-
Depression tercept test of deviation from the null.20 These tests vary in their
We drew on summary statistics from the largest and most re- assumptions but essentially capture the extent to which the ef-
cent GWAS for MDD, defined as a lifetime diagnosis of major fect for 1 or more instrument SNP is exaggerated in magnitude,
depression based primarily on structured assessments by as would be the case if that SNP not only acted through the hy-
trained interviewers, clinician-administered checklists, or pothesized pathway, but through other unaccounted causal path-
medical record review.13 Overall, this case-control GWAS iden- ways. Finally, we looked up each instrument SNP and their prox-
tified 44 independent genome-wide significant SNPs for MDD. ies (r2 > 0.80) in the PhenoScanner GWAS database (version 2;
For the MR analysis, we used meta-analytic results for MDD http://phenoscanner.medschl.cam.ac.uk) to assess any previous
that left out UK Biobank samples, because the physical activ- associations (P < 1 × 10−5) with potential confounding traits and
ity GWAS was also conducted in the UK Biobank, and without assessed the effects of manually removing these SNPs from the
23andMe samples owing to general access constraints. This MR analysis to rule out possible pleiotropic effects.
elimination resulted in a GWAS meta-analytic subsample of
143 265. As instruments, we used independent clumped SNPs
meeting a relaxed threshold (P < 1 × 10−6) to account for the
reduced meta-analytic subsample, with similar procedures for
Results
identifying proxy SNPs as needed. The resulting list of instru- Accelerometer-Based Physical Activity and Depression
ment SNPs is found in eTable 5 in the Supplement. We found evidence of a protective causal relationship between
accelerometer-based physical activity with MDD (IVW OR, 0.74
Statistical Analysis for MDD per 1-SD unit increase in mean acceleration; 95% CI,
Mendelian randomization analyses were conducted in the R com- 0.59-0.92; P = .006); weighted median and MR Egger analysis
puting environment using the TwoSampleMR package (R Proj- yielded similar pattern of effects (Table 1), with 10 SNPs meet-
ect for Statistical Computing). This package harmonizes expo- ing the relaxed statistical threshold (Figure 2). The MR estimate
sure and outcome data sets containing information on SNPs, was not statistically significant with only 2 genome-wide signifi-
alleles, effect sizes (odds ratios [ORs] converted to β statistics by cant SNPs (IVW OR, 1.12; 95% CI, 0.72-1.75; P = .60) (eTable 6 and
log transformation), standard errors, P values, and effect allele eFigure 1 in the Supplement), which provided insufficient data
frequencies for selected exposure instruments. Herein, we al- for alternative MR methods and sensitivity analyses. For the 10
lowed the forward strand of ambiguous SNPs to be inferred where SNPs, MR-PRESSO did not detect any potential outliers. Further-
possible based on allele frequency information; however, strand- more, analyses leaving out each SNP revealed that no single SNP
ambiguous SNPs with intermediate effect allele frequencies drove these results but rather reflected an overall combined pat-
(>0.42) were considered unresolvable. We also conducted sen- tern of opposite relationships with physical activity vs MDD
sitivity analyses where strand-ambiguous SNPs were excluded (eFigure 2 in the Supplement). Similarly, the modified Q statis-

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Research Original Investigation Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults

Table 1. MR Results for the Relationship Between Accelerometer-Based Activity Effect and MDD

Method OR (95% CI)a P Value No. of SNPs


IVWb 0.74 (0.59-0.92) .006 10
Weighted medianb 0.71 (0.53-0.95) .02 10
MR Eggerb 0.57 (0.22-1.48) .28 10
b
Abbreviations: IVW, inverse variance–weighted; MDD, major depressive No MR-PRESSO (Pleiotropy Residual Sum and Outlier) outliers were detected.
disorder; MR, mendelian randomization; OR, odds ratio; SNP, single-nucleotide P < 1 × 10−7 for top SNPs.
polymorphism.
a
Indicates odds for MDD per 1-SD increase in mean acceleration.

Figure 2. Mendelian Randomization (MR) Plots for Relationship of Accelerometer-Based Activity With Major Depressive Disorder (MDD)

A Scatterplot B Forest plot

0.02 IVW SNP β (95% CI)


Weighted median rs113871181 0.02 (–0.06 to 0.09)
MR Egger
rs59499656 0.01 (–0.07 to 0.09)
0 rs12522261 –0.02 (–0.10 to 0.07)
SNP Effect on MDD

rs11012732 –0.04 (–0.12 to 0.05)


rs12045968 –0.04 (–0.13 to 0.04)
–0.02 rs9293503 –0.06 (–0.14 to 0.03)
rs1550435 –0.06 (–0.15 to 0.03)
rs148193266 –0.07 (–0.15 to 0.01)
–0.04 rs34517439 –0.07 (–0.16 to 0.02)
rs6775319 –0.08 (–0.17 to 0.01)
IVW (combined) –0.04 (–0.06 to –0.01)
–0.06
0.1 0.2 0.3 0.4 0.5 0.6 0.7 –0.2 –0.1 0 0.1
SNP Effect on PA MR Effect Size for PA on MDD, β (95% CI)

A, Scatterplot of single-nucleotide polymorphism (SNP) potential effects on MR-estimated effects sizes. Data are expressed as raw β values with 95% CI.
physical activity (PA) vs MDD, with the slope of each line corresponding to P < 1 × 10−7 for top SNPs. IVW indicates inverse variance–weighted method.
estimated MR effect per method. B, Forest plot of individual and combined SNP

Table 2. MR Results for the Relationship Between MDD and Accelerometer-Based Activity Abbreviations: IVW, inverse
a variance–weighted; MDD, major
Method β (95% CI) P Value SNPs
depressive disorder; MR, mendelian
Main modelb randomization; OR, odds ratio;
IVW −0.08 (−0.47 to 0.32) .70 15 SNP, single-nucleotide
Weighted median −0.07 (−0.62 to 0.48) .82 15 polymorphism.
a
Indicates change in mean
MR Egger −0.13 (−2.11 to 1.86) .90 15
acceleration per MDD vs control
With outlier status.
IVW 0.05 (−0.41 to 0.51) .83 16 b
Indicates model with MR-PRESSO
Weighted median −0.04 (−0.59 to 0.51) .98 16 (Pleiotropy Residual Sum and
Outlier) outlier (rs78676209)
MR Egger 1.05 (−0.96 to 3.06) .33 16
removed. P < 1 × 10−6 for top SNPs.

tic indicated no notable heterogeneity (Q = 6.01; P = .74) across In the other direction, across all MR methods, we found no
instrument SNP effects. The MR Egger intercept test further sug- evidence of causal relationships of MDD with accelerometer-
gested no horizontal pleiotropy (intercept, 0.008; standard error, based activity (Table 2). MR-PRESSO detected 1 outlier, and
0.02; P = .60). In the PhenoScanner database, we identified 2 of MR estimates remained null after removal of this outlier (IVW
the 10 SNPs for accelerometer-based activity nominally associ- β = −0.08 in mean acceleration per MDD vs control status;
ated with depression-relevant traits (ie, rs59499656 with body 95% CI, −0.47 to 0.32; P = .70). The weighted median and MR
mass index and rs9293503 with educational attainment). How- Egger yielded a similar pattern of effects (Table 2 and Figure 3).
ever, removing both SNPs did not change the pattern of results.
When we further mapped SNPs to known genes in public data- Self-reported Physical Activity and Depression
bases and examined whether any genes have been implicated In contrast, we found no statistically significant evidence of a
in GWAS of relevant traits, removing SNPs produced no substan- relationship between self-reported activity and MDD, regard-
tive change in results (eMethods 1, which includes eFigure 3 and less of instrument SNP threshold (outlier-adjusted IVW
eTables 6 and 7, in the Supplement). OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent

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Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults Original Investigation Research

Figure 3. Mendelian Randomization (MR) Plots for Relationship of Major Depressive Disorder (MDD) With Accelerometer-Based Activity

A Scatterplot B Forest plot


IVW
Weighted median SNP β (95% CI)
MR Egger rs2060886 1.25 (–0.35 to 2.86)
rs4811079 0.95 (–0.58 to 2.48)
0.3
rs1460943 0.64 (–0.87 to 2.16)
rs2451828 0.63 (–0.90 to 2.15)
0.2 rs34382743 0.47 (–1.13 to 2.07)
rs6832890 0.29 (–1.20 to 1.78)
rs17499892 0.22 (–1.25 to 1.69)
SNP Effect on PA

0.1 rs4776768 –0.05 (–1.64 to 1.53)


rs586275 –0.10 (–1.54 to 1.35)
rs1081458 –0.39 (–1.97 to 1.19)
0 rs1950829 –0.42 (–1.74 to 0.89)
rs12658032 –0.63 (–1.99 to 0.74)
rs1025145 –1.14 (–2.73 to 0.46)
–0.1 rs1936365 –1.25 (–2.67 to 0.17)
rs7546987 –1.32 (–2.93 to 0.30)
IVW (combined) –0.08 (–0.47 to 0.32)
–0.2
0 0.05 0.10 0.15 0.20 –3 –2 –1 0 1 2 3
SNP Effect on MDD MR Effect Size for MDD on PA, β (95% CI)

A, Scatterplot of single-nucleotide polymorphism (SNP) effects on MDD vs their MR-estimated effects sizes. Data are expressed as raw β values with 95% CI.
effects on physical activity (PA), with slope of each line corresponding to IVW indicates inverse variance–weighted method.
estimated MR effect per method. B, Forest plot of individual and combined SNP

minutes of moderate-to-vigorous activity [95% CI, 0.87-1.90; Self-report measures of activity may be affected by mood states
P = .21] for 24 top SNPs; IVW OR, 1.45 for MDD per 1-SD increase and cognitive biases that also affect mental health, making it
in metabolic-equivalent minutes of moderate-to-vigorous ac- difficult to ascertain whether observed associations are true
tivity [95% CI, 0.57-3.37; P = .48] for 6 genome-wide signifi- or simply artifacts of a common liability. For example, indi-
cant SNPs) (eTables 9-11 and eFigures 4 and 5 in the Supple- viduals vulnerable to depression may perceive themselves as
ment), or between MDD and self-reported activity (for 14 top more inactive and disengaged than their peers or compen-
SNPs, outlier-adjusted IVW β = 0.02 in standardized metabolic- sate by overreporting activity. Although this does not invali-
equivalent minutes of moderate-to-vigorous activity for MDD date the utility of self-reported measures, verifying their con-
vs control status; 95% CI, −0.008 to 0.05; P = .15) (eTable 12 clusions with objective measures is essential. Prior work has
and eFigure 6 in the Supplement). indicated that objectively measured physical activity is more
heritable12 and hence may be closer to biological processes that
could directly affect depression, as well as more powerfully in-
strumented by SNPs in the MR context.24 Only 1 prior study,25
Discussion to our knowledge, has incorporated genetic information, using
Depression is a common and debilitating condition, with a high a twin-based design, to assess the relationship between physi-
societal burden of morbidity and mortality.21 As such, identi- cal activity and depression. Contrary to our study, it did not
fication of effective strategies for preventing depression has yield evidence of such a relationship, perhaps owing to self-
substantial implications for improving population health. Re- report measures and restricted definition of physical activity
cent evidence has suggested that physical activity may pro- as leisure exercise (ie, intentionally performed to improve or
tect against the risk for depression.3-5 However, if the relation- maintain fitness) vs physical activity more broadly.2
ship between physical activity and depression is not causal, We estimated a moderate but significant reduction of MDD
recommendations to promote physical activity, while benefi- risk per 1-SD increase in objectively measured physical activ-
cial for other health outcomes, would yield limited results for ity. One SD of objectively measured physical activity in the
depression. To strengthen causal inference, we apply a geneti- UK Biobank Study has been reported to be approximately 8
cally informed method. Using MR with genetic instruments se- milligravities (or 0.08 m/s 2 ) of acceleration in a mean 5-
lected from large-scale GWAS, we find evidence supporting a second window of analyzed accelerometer data. 12,26 Al-
potential causal relationship between physical activity and a though no straightforward translation of these values into
reduced risk for depression. energy expenditure or step-based metrics is available, an 8-mil-
Our results extend current literature in a number of ways. ligravity increase in mean acceleration is roughly what we
First, we examined self-reported and objectively measured might observe in a 24-hour period if—for example—a person
(ie, accelerometer-based) physical activity and discovered that replaced sedentary behavior with 15 minutes of vigorous ac-
findings on the relationship with depression are specific to ob- tivity (eg, running); just more than 1 hour of moderate physi-
jectively measured—but not self-reported—activity. Meta- cal activity (eg, fast walking); or some combination of light ac-
analytic data have shown that self-report and objective mea- tivity (eg, standing, stretching, easy chores) and more vigorous
sures can yield discrepant estimates of physical activity.8,22,23 activity (eFigure 7 and eTable 13 in the Supplement).

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Research Original Investigation Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults

Second, it has remained unclear to date whether inverse tivity in relation to depression, whereas recent work has
associations between physical activity and depression are ow- revealed complicated associations between the type, dura-
ing potentially to a protective relationship between physical tion, frequency, and intensity of physical activity and mental
activity and depression and/or a relationship between depres- health29 that could affect the size and direction of observed
sion and reduced physical activity. Using bidirectional MR, we MR estimates but could not be assessed in the present study.
found evidence of only 1 direction of this relationship, where Fourth, SNPs associated with physical activity were identi-
physical activity demonstrated a potential causal relation- fied in the UK Biobank Study, which consists of individuals aged
ship with depression, while depression does not appear to have 40 to 70 years, whereas samples in the MDD GWAS included
a such a relationship with physical activity. Other factors may a wider range of age groups. Physical activity in younger in-
better explain the observed depression-activity relationship7 dividuals may be influenced by other variants that share dif-
rather than depression directly compromising physical activ- ferent associations with MDD, although such GWAS data are
ity. For example, underlying conditions such as chronic pain not yet available. Moreover, we do not have demographic data
could interfere with activity and lead to depression. How- on all of the GWAS participants, such as age and sex, which lim-
ever, our MR analyses may not be currently powered to de- its clinical generalizability of these findings to other popula-
tect small effects (for calculations, see eMethods 2 in the tions. Finally, we cannot interpret effect sizes in the same way
Supplement) that may become apparent when future discov- as a clinical trial in which individuals are assigned to a dis-
ery GWAS are expanded. crete program of physical activity of defined length, because
MR estimates reflect lifelong effects of assignment to genetic
Limitations variants. However, our MR estimate is notably similar in mag-
This study has several limitations. First, although we drew on nitude to those of recent meta-analytic observational data.5
the largest available GWAS, some identified few genome- Despite these limitations, our application of MR repre-
wide significant SNPs, which could result in relatively weak sents a test of whether genetic instruments provide indepen-
genetic instruments. To address this, we applied statistical cri- dent support for potentially protective relationships be-
teria to include additional SNPs as instruments. This ap- tween physical activity and depression risk. Our novel
proach has been used in other MR studies where currently triangulation of genetic variants as instruments for causal
known genome-wide significant SNPs are limited.14,15 Sec- inference30 obviates typical challenges for observational re-
ond, despite selecting strongly associated SNPs, common SNPs search while strengthening evidence from such studies.3-5
do not yet explain much total variance in complex traits27 and Stronger evidence of causal relationships is of great impor-
so cannot be considered exact proxies of the exposure. In ad- tance because few modifiable factors for preventing depres-
dition, because we do not yet know the biological action of sion are known. If physical activity truly reduces risk for de-
these SNPs, it is impossible to fully rule out pleiotropic mecha- pression, it would be useful to promote physical activity not
nisms without detailed functional follow-up of these loci, only in the population at large, where this can yield public
although we conducted the most up-to-date array of sensitiv- health returns at the level of human productivity and re-
ity analyses to rule out horizontal pleiotropy. Although hori- duced health care burden, but also for individuals at risk for
zontal pleiotropy is a concern for MR inference, vertical plei- developing new depression, such as adolescents or those fac-
otropy—in which an exposure acts on an outcome via other ing depressogenic exposures, such as violence-exposed indi-
variables along the same causal pathway—is acceptable.17 For viduals or workers in high-stress environments.
example, if physical activity causally reduces body mass in-
dex, and then body mass index causally affects MDD, this rep-
resents vertical pleiotropy for which we should not unneces-
sarily penalize the MR estimate.24 However, it is reassuring that
Conclusions
our observed MR estimate was robust across sensitivity analy- This study leverages MR to support causal inference regard-
ses, suggesting negligible bias from evident sources of pleiot- ing putative protective factors in mental health. Our findings
ropy. Third, we used summary GWAS data for MDD and not validate a potential protective relationship between physical
for depressive symptoms in individuals with or without MDD. activity and depression and point to the importance of objec-
Although meta-analyses have shown that physical activity is tive measurement of physical activity in epidemiologic stud-
associated with improved symptoms in individuals with ies of mental health. Overall, this study supports the hypoth-
depression,9,10,28 our study was not designed to address this esis that enhancing physical activity is an effective prevention
issue. Also, we only considered overall levels of physical ac- strategy for depression.

ARTICLE INFORMATION Massachusetts (Choi, Wang, Koenen, Smoller); Department of Psychiatry, University of California,
Accepted for Publication: November 5, 2018. Psychiatric and Neurodevelopmental Genetics Unit, San Diego, La Jolla (Stein); Veterans Affairs
Center for Genomic Medicine, Massachusetts Psychiatry Service, San Diego Healthcare System,
Published Online: January 23, 2019. General Hospital, Boston (Choi, Chen, Koenen, San Diego, California (Stein); Department of
doi:10.1001/jamapsychiatry.2018.4175 Smoller); Stanley Center for Psychiatric Research, Epidemiology and Biostatistics, Mel and Enid
Author Affiliations: Department of Psychiatry, Broad Institute, Boston, Massachusetts (Choi, Zuckerman College of Public Health, University of
Massachusetts General Hospital, Boston (Choi, Chen, Koenen, Smoller); Analytic and Translational Arizona, Tucson (Klimentidis); BIO5 Institute,
Koenen, Smoller); Department of Epidemiology, Genetics Unit, Center for Genomic Medicine, University of Arizona, Tucson (Klimentidis).
Harvard T. H. Chan School of Public Health, Boston, Massachusetts General Hospital, Boston (Chen);

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Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults Original Investigation Research

Author Contributions: Dr Choi had full access to all Initiative for Integrative Psychiatric Research, and Berghofer Medical Research Institute; Nese Direk,
the data in the study and takes responsibility for the Centre for Integrated Register-based Research and Department of Epidemiology, Erasmus MC,
integrity of the data and the accuracy of the data National Centre for Register-Based Research, Rotterdam, the Netherlands; Conor V. Dolan,
analysis. Aarhus University; Tracy M. Air, Discipline of Department of Biological Psychology & EMGO+
Concept and design: Choi, Chen, Stein, Koenen, Psychiatry, University of Adelaide, Adelaide, Institute for Health and Care Research, Vrije
Smoller. Australia; Till F. M. Andlauer, Department of Universiteit Amsterdam; Erin C. Dunn, Department
Acquisition, analysis, or interpretation of data: Choi, Translational Research in Psychiatry, Max Planck of Psychiatry and Psychiatric and
Stein, Klimentidis, Wang, Koenen, Smoller. Institute of Psychiatry, and Munich Cluster for Neurodevelopmental Genetics Unit, Massachusetts
Drafting of the manuscript: Choi, Stein, Klimentidis. Systems Neurology (SyNergy), Munich, Germany; General Hospital, Boston, and Stanley Center for
Critical revision of the manuscript for important Silviu-Alin Bacanu, Department of Psychiatry, Psychiatric Research, Broad Institute; Thalia C. Eley,
intellectual content: All authors. Virginia Commonwealth University, Richmond; MRC Social Genetic and Developmental Psychiatry
Statistical analysis: Choi, Chen. Marie Bækvad-Hansen, iPSYCH, The Lundbeck Centre, King’s College London; Valentina
Obtained funding: Smoller. Foundation Initiative for Integrative Psychiatric Escott-Price, Neuroscience and Mental Health,
Administrative, technical, or material support: Research, and Center for Neonatal Screening, Cardiff University; Farnush Farhadi Hassan Kiadeh,
Klimentidis, Wang, Smoller. Department for Congenital Disorders, Statens Bioinformatics, University of British Columbia,
Supervision: Koenen, Smoller. Serum Institut, Copenhagen, Denmark; Aartjan T. F. Vancouver, British Columbia, Canada; Hilary K.
Conflict of Interest Disclosures: Dr Stein reported Beekman, Department of Psychiatry, Vrije Finucane, Department of Epidemiology, Harvard T.
consulting for Actelion, Aptinyx, Inc, Dart Universiteit Medical Center and GGZ inGeest, H. Chan School of Public Health, Boston, and
Neuroscience, LLC, Healthcare Management Amsterdam; Tim B. Bigdeli, Department of Department of Mathematics, Massachusetts
Technologies, Janssen Pharmaceuticals, Inc, Psychiatry, Virginia Commonwealth University, Institute of Technology, Cambridge; Andreas J.
Neurocrine Biosciences, Oxeia Biopharmaceuticals, and Virginia Institute for Psychiatric and Behavior Forstner, Institute of Human Genetics and
Pfizer, and Resilience Therapeutics in the past Genetics, Richmond; Elisabeth B. Binder, Life&Brain Center, Department of Genomics,
3 years; owning founders’ shares in Resilience Department of Translational Research in Psychiatry, University of Bonny, and Department of Psychiatry
Therapeutics; and having stock options in Max Planck Institute of Psychiatry, and Department and Human Genomics Research Group and
Resilience Therapeutics and Oxeia of Psychiatry and Behavioral Sciences, Emory Department of Biomedicine, University of Basel,
Biopharmaceticals. Dr Smoller reported being an University School of Medicine, Atlanta, Georgia; Basel, Switzerland; Josef Frank, Department of
unpaid member of the Scientific Advisory Board of Douglas H. R. Blackwood, Division of Psychiatry, Genetic Epidemiology in Psychiatry, Central
Psy Therapeutics, Inc, and of the Bipolar/ University of Edinburgh; Julien Bryois, Department Institute of Mental Health, Medical Faculty
Depression Research Community Advisory Panel of of Medical Epidemiology and Biostatistics, Mannheim, Heidelberg University, Mannheim,
23andMe. No other disclosures were reported. Karolinska Institutet; Henriette N. Buttenschøn, Germany; Héléna A. Gaspar, MRC Social Genetic
iSEQ, Centre for Integrative Sequencing, and and Developmental Psychiatry Centre, King’s
Funding/Support: This study was supported in Department of Clinical Medicine, Translational College London; Michael Gill, Department of
part by grant T32MH017119 from the NIMH Neuropsychiatry Unit, Aarhus University, abd Psychiatry, Trinity College Dublin, Dublin, Ireland;
(Dr Choi); Tepper Family Massachusetts General iPSYCH, The Lundbeck Foundation Initiative for Fernando S. Goes, Department of Psychiatry and
Hospital Research Scholar funding (Dr Smoller); the Integrative Psychiatric Research; Jonas Behavioral Sciences, The Johns Hopkins University,
Demarest Lloyd Jr Foundation (Dr Smoller); and Bybjerg-Grauholm, iPSYCH, The Lundbeck Baltimore, Maryland; Scott D. Gordon, Department
grant K24MH094614 from the NIMH (Dr Smoller). Foundation Initiative for Integrative Psychiatric of Genetics and Computational Biology, QIMR
Role of the Funder/Sponsor: The funding sources Research, and Center for Neonatal Screening, Berghofer Medical Research Institute; Jakob Grove,
had no role in the design and conduct of the study; Department for Congenital Disorders, Statens Department of Biomedicine and iSEQ, Centre for
collection, management, analysis, and Serum Institut; Na Cai, Human Genetics, Wellcome Integrative Sequencing, and Bioinformatics
interpretation of the data; preparation, review, or Trust Sanger Institute, Cambridge, Great Britain, Research Centre, Aarhus University, and iPSYCH,
approval of the manuscript; and decision to submit and Statistical Genomics and Systems Genetics, The Lundbeck Foundation Initiative for Integrative
the manuscript for publication. European Bioinformatics Institute, Cambridge, Psychiatric Research; Lynsey S. Hall, Division of
Group Information: Members of the Major Great Britain; Enrique Castelao, Department of Psychiatry, University of Edinburgh, and Institute of
Depressive Disorder Working Group of the Psychiatry, University Hospital of Lausanne, Prilly, Genetic Medicine, Newcastle University, Newcastle
Psychiatric Genomics Consortium include the Switzerland; Jane Hvarregaard Christensen, upon Tyne, Great Britain; Christine Søholm Hansen,
following: Naomi R. Wray, Institute for Molecular Department of Biomedicine, iSEQ, Centre for iPSYCH, The Lundbeck Foundation Initiative for
Bioscience and Queensland Brain Institute, The Integrative Sequencing, Aarhus University, and Integrative Psychiatric Research, and Center for
University of Queensland, Brisbane, Australia; iPSYCH, The Lundbeck Foundation Initiative for Neonatal Screening, Department for Congenital
Stephan Ripke, Analytic and Translational Genetics Integrative Psychiatric Research; Toni-Kim Clarke, Disorders, Statens Serum Institut; Thomas F.
Unit, Massachusetts General Hospital, Boston, Division of Psychiatry, University of Edinburgh; Hansen, Danish Headache Centre, Department of
Department of Psychiatry and Psychotherapy, Jonathan R. I. Coleman, MRC Social Genetic and Neurology, Rigshospitalet, Glostrup, Institute of
Universitätsmedizin Berlin Campus Charité Mitte, Developmental Psychiatry Centre, King’s College Biological Psychiatry, Mental Health Center Sct.
Berlin, Germany, and Medical and Population London, London, Great Britain; Lucía Hans, Mental Health Services Capital Region of
Genetics, Broad Institute, Cambridge, Great Britain; Colodro-Conde, Genetics and Computational Denmark, Copenhagen, and iPSYCH, The Lundbeck
Manuel Mattheisen, Centre for Psychiatry Research, Biology, QIMR Berghofer Medical Research Foundation Initiative for Psychiatric Research;
Department of Clinical Neuroscience, and Centre Institute, Herston, Australia; Baptiste Stefan Herms, Institute of Human Genetics and
for Psychiatry Research, Department of Clinical Couvy-Duchesne, Centre for Advanced Imaging and Life&Brain Center, Department of Genomics,
Neuroscience, Karolinska Institutet, Stockholm, Queensland Brain Institute, The University of University of Bonn, and University of Basel; Ian B.
Sweden, Department of Biomedicine and iSEQ, Queensland, Saint Lucia, Australia; Nick Craddock, Hickie, Brain and Mind Centre, University of Sydney,
Centre for Integrative Sequencing, Aarhus Psychological Medicine, Cardiff University, Cardiff, Sydney, Australia; Per Hoffmann, Institute of
University, Aarhus, Denmark, and iPSYCH, The Great Britain; Gregory E. Crawford, Center for Human Genetics and Life&Brain Center,
Lundbeck Foundation Initiative for Integrative Genomic and Computational Biology and Department of Genomics, University of Bonn, and
Psychiatric Research, Denmark; Maciej Trzaskowski, Department of Pediatrics, Division of Medical University of Basel; Georg Homuth, Interfaculty
Institute for Molecular Bioscience, The University of Genetics, Duke University, Durham, North Carolina; Institute for Genetics and Functional Genomics,
Queensland; Enda M. Byrne, Institute for Molecular Gail Davies, Centre for Cognitive Ageing and Department of Functional Genomics, University
Bioscience, The University of Queensland; Abdel Cognitive Epidemiology, University of Edinburgh; Medicine and Ernst Moritz Arndt University
Abdellaoui, Department of Biological Psychology Ian J. Deary, Centre for Cognitive Ageing and Greifswald, Greifswald, Germany; Carsten Horn,
and EMGO+ Institute for Health and Care Research, Cognitive Epidemiology, University of Edinburgh; Roche Pharmaceutical Research and Early
Vrije Universiteit Amsterdam, Amsterdam, the Franziska Degenhardt, Institute of Human Genetics Development, Pharmaceutical Sciences, Roche
Netherlands; Mark J. Adams, Division of Psychiatry, and Life&Brain Center, Department of Genomics, Innovation Center Basel, F. Hoffmann-La Roche Ltd,
University of Edinburgh, Edinburgh, Great Britain; University of Bonn, Bonn, Germany; Eske M. Derks, Basel; Jouke-Jan Hottenga, Department of
Esben Agerbo, iPSYCH, The Lundbeck Foundation Genetics and Computational Biology, QIMR Biological Psychology and EMGO+ Institute for

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Research Original Investigation Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults

Health and Care Research, Vrije Universiteit Developmental Psychiatry Centre, King’s College Universiteit Medical Center and GGZ inGeest;
Amsterdam; David M. Hougaard, iPSYCH, The London; Matthias Nauck, German Centre for Daniel J. Smith, Institute of Health and Wellbeing,
Lundbeck Foundation Initiative for Integrative Cardiovascular Research, Partner Site Greifswald, University of Glasgow, Glasgow, Great Britain;
Psychiatric Research, and Center for Neonatal and Institute of Clinical Chemistry and Laboratory Hreinn Stefansson, deCODE Genetics/Amgen,
Screening, Department for Congenital Disorders, Medicine, University Medicine Greifswald, Reykjavik; Stacy Steinberg, deCODE Genetics/
Statens Serum Institut; Marcus Ising, Max Planck Greifswald, Germany; Bernard Ng, Department of Amgen; Fabian Streit, Department of Genetic
Institute of Psychiatry; Rick Jansen, Department of Statistics, University of British Columbia; Michel G. Epidemiology in Psychiatry, Central Institute of
Psychiatry, Vrije Universiteit Medical Center and Nivard, Department of Biological Psychology and Mental Health, Medical Faculty Mannheim,
GGZ inGeest; Eric Jorgenson, Division of Research, EMGO+ Institute for Health and Care Research, Heidelberg University; Jana Strohmaier,
Kaiser Permanente Northern California, Oakland; Vrije Universiteit Amsterdam; Dale R. Nyholt, Department of Genetic Epidemiology in Psychiatry,
James A. Knowles, Psychiatry and The Behavioral Institute of Health and Biomedical Innovation, Central Institute of Mental Health, Medical Faculty
Sciences, University of Southern California, Queensland University of Technology, Brisbane; Mannheim, Heidelberg University; Katherine E.
Los Angeles; Isaac S. Kohane, Department of Paul F. O’Reilly, MRC Social Genetic and Tansey, College of Biomedical and Life Sciences,
Biomedical Informatics, Harvard Medical School, Developmental Psychiatry Centre, King’s College Cardiff University; Henning Teismann, Institute of
Department of Medicine, Brigham and Women’s London; Hogni Oskarsson, Humus, Reykjavik, Epidemiology and Social Medicine, University of
Hospital, and Informatics Program, Boston Iceland; Michael J. Owen, MRC Centre for Münster, Münster, Germany; Alexander Teumer,
Children’s Hospital, Boston, Massachusetts; Julia Neuropsychiatric Genetics and Genomics, Cardiff Institute for Community Medicine, University
Kraft, Department of Psychiatry and University; Jodie N. Painter, Genetics and Medicine Greifswald; Wesley Thompson, iPSYCH,
Psychotherapy, Universitätsmedizin Berlin Campus Computational Biology, QIMR Berghofer Medical The Lundbeck Foundation Initiative for Integrative
Charité Mitte, Berlin, Germany; Warren W. Research Institute; Carsten Bøcker Pedersen, Psychiatric Research, Institute of Biological
Kretzschmar, Wellcome Trust Centre for Human iPSYCH, The Lundbeck Foundation Initiative for Psychiatry, Mental Health Center Sct. Hans, Mental
Genetics, University of Oxford, Oxford, Integrative Psychiatric Research, and Centre for Health Services Capital Region of Denmark,
Great Britain; Jesper Krogh, Department of Integrated Register-based Research and National Department of Psychiatry, University of California,
Endocrinology at Herlev University Hospital, Centre for Register-Based Research, Aarhus San Diego, and KG Jebsen Centre for Psychosis
University of Copenhagen; Zoltán Kutalik, Institute University; Marianne Giørtz Pedersen, iPSYCH, Research, Norway Division of Mental Health and
of Social and Preventive Medicine, University The Lundbeck Foundation Initiative for Integrative Addiction, Oslo University Hospital, Oslo; Pippa A.
Hospital of Lausanne, and Swiss Institute of Psychiatric Research, and Centre for Integrated Thomson, Medical Genetics Section, Centre for
Bioinformatics, Lausanne, Switzerland; Yihan Li, Register-based Research and National Centre for Genomics and Experimental Medicine, Institute of
Wellcome Trust Centre for Human Genetics; Register-Based Research, Aarhus University; Genetics and Molecular Medicine, University of
Penelope A. Lind, Genetics and Computational Roseann E. Peterson, Department of Psychiatry and Edinburgh; Thorgeir E. Thorgeirsson, deCODE
Biology, QIMR Berghofer Medical Research Virginia Institute for Psychiatric and Behavioral Genetics/Amgen; Matthew Traylor, Clinical
Institute; Donald J. MacIntyre, Division of Genetics, Virginia Commonwealth University; Erik Neurosciences, University of Cambridge,
Psychiatry, Centre for Clinical Brain Sciences, and Pettersson, Department of Medical Epidemiology Cambridge, Great Britain; Jens Treutlein,
Department of Psychiatry and Psychotherapy, and Biostatistics, Karolinska Institutet; Wouter J. Department of Genetic Epidemiology in Psychiatry,
University of Bonn; Dean F. MacKinnon, Peyrot, Department of Psychiatry, Vrije Universiteit Central Institute of Mental Health, Medical Faculty
Department of Psychiatry and Behavioral Sciences, Medical Center and GGZ inGeest; Giorgio Pistis, Mannheim, Heidelberg University; Vassily
The Johns Hopkins University; Robert M. Maier, Department of Psychiatry, University Hospital of Trubetskoy, Department of Psychiatry and
Queensland Brain Institute, The University of Lausanne; Danielle Posthuma, Clinical Genetics and Psychotherapy, Universitätsmedizin Berlin Campus
Queensland; Wolfgang Maier, Department of Complex Trait Genetics, Vrije Universiteit Medical Charité Mitte; André G. Uitterlinden, Internal
Psychiatry and Psychotherapy, University of Bonn; Center, Amsterdam; Jorge A. Quiroz, Solid Medicine, Erasmus MC; Daniel Umbricht, Roche
Jonathan Marchini, Department of Statistics, Biosciences, Boston; Per Qvist, Department of Pharmaceutical Research and Early Development,
University of Oxford; Hamdi Mbarek, Department Biomedicine and iSEQ, Centre for Integrative Neuroscience, Ophthalmology and Rare Diseases
of Biological Psychology and EMGO+ Institute for Sequencing, Aarhus University, and iPSYCH, The Discovery & Translational Medicine Area, Roche
Health and Care Research, Vrije Universiteit Lundbeck Foundation Initiative for Integrative Innovation Center Basel, F. Hoffmann-La Roche Ltd;
Amsterdam; Patrick McGrath, Department of Psychiatric Research; John P. Rice, Department of Sandra Van der Auwera, Department of Psychiatry
Psychiatry, Columbia University College of Psychiatry, Washington University in Saint Louis and Psychotherapy, University Medicine Greifswald;
Physicians and Surgeons, New York, New York; School of Medicine, Saint Louis, Missouri; Brien P. Albert M. van Hemert, Department of Psychiatry,
Peter McGuffin, MRC Social Genetic and Riley, Department of Psychiatry, Virginia Leiden University Medical Center, Leiden, the
Developmental Psychiatry Centre, King’s College Commonwealth University; Margarita Rivera, MRC Netherlands; Alexander Viktorin, Department of
London; Sarah E. Medland, Genetics and Social Genetic and Developmental Psychiatry Medical Epidemiology and Biostatistics, Karolinska
Computational Biology, QIMR Berghofer Medical Centre, King’s College London, and Department of Institutet; Peter M. Visscher, Institute for Molecular
Research Institute; Divya Mehta, Queensland Brain Biochemistry and Molecular Biology II, Institute of Bioscience and Queensland Brain Institute, The
Institute, The University of Queensland, and School Neurosciences, Center for Biomedical Research, University of Queensland; Yunpeng Wang, iPSYCH,
of Psychology and Counseling, Queensland University of Granada, Granada, Spain; Saira Saeed The Lundbeck Foundation Initiative for Integrative
University of Technology, Brisbane; Christel M. Mirza, Department of Epidemiology, Erasmus MC; Psychiatric Research, Institute of Biological
Middeldorp, Department of Biological Psychology Robert Schoevers, Department of Psychiatry, Psychiatry, Mental Health Center Sct. Hans, Mental
and EMGO+ Institute for Health and Care Research, University of Groningen, University Medical Center Health Services Capital Region of Denmark, and KG
Vrije Universiteit Amsterdam, Child and Youth Groningen, Groningen, the Netherlands; Eva C. Jebsen Centre for Psychosis Research, Norway
Mental Health Service, Children’s Health Schulte, Department of Psychiatry and Division of Mental Health and Addiction, Oslo
Queensland Hospital and Health Service, South Psychotherapy and Institute of Psychiatric University Hospital; Bradley T. Webb, Virginia
Brisbane, Australia, and Child Health Research Phenomics and Genomics, Medical Center of the Institute of Psychiatric and Behavioral Genetics,
Centre, The University of Queensland; Evelin University of Munich, Campus Innenstadt, Munich, Virginia Commonwealth University; Shantel Marie
Mihailov, Estonian Genome Center, University of Germany; Ling Shen, Division of Research, Kaiser Weinsheimer, iPSYCH, The Lundbeck Foundation
Tartu, Tartu; Yuri Milaneschi, Department of Permanente Northern California, Oakland; Jianxin Initiative for Integrative Psychiatric Research, and
Psychiatry, Vrije Universiteit Medical Center and Shi, Division of Cancer Epidemiology and Genetics, Institute of Biological Psychiatry, Mental Health
GGZ inGeest; Lili Milani, Estonian Genome Center, National Cancer Institute, Bethesda, Maryland; Center Sct. Hans, Mental Health Services Capital
University of Tartu; Francis M. Mondimore, Stanley I. Shyn, Behavioral Health Services, Kaiser Region of Denmark; Jürgen Wellmann, Institute of
Department of Psychiatry and Behavioral Sciences, Permanente Washington, Seattle; Engilbert Epidemiology and Social Medicine, University of
The Johns Hopkins University; Grant W Sigurdsson, Faculty of Medicine, Department of Münster; Gonneke Willemsen, Department of
Montgomery, Institute for Molecular Bioscience, Psychiatry, University of Iceland, Reykjavik; Grant C. Biological Psychology and EMGO+ Institute for
The University of Queensland; Sara Mostafavi, B. Sinnamon, School of Medicine and Dentistry, Health and Care Research, Vrije Universiteit
Medical Genetics and Statistics, University of British James Cook University, Townsville, Australia; Amsterdam; Stephanie H. Witt, Department of
Columbia; Niamh Mullins, MRC Social Genetic and Johannes H. Smit, Department of Psychiatry, Vrije Genetic Epidemiology in Psychiatry, Central

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Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults Original Investigation Research

Institute of Mental Health, Medical Faculty The Lundbeck Foundation Initiative for Integrative Psychiatry Centre and Department of Medical and
Mannheim, Heidelberg University; Yang Wu, Psychiatric Research, and Centre for Integrated Molecular Genetics, King’s College London; Douglas
Institute for Molecular Bioscience, The University of Register-based Research and National Centre for F. Levinson, Psychiatry and Behavioral Sciences,
Queensland; Hualin S. Xi, Computational Sciences Register-Based Research, Aarhus University; Stanford University, Stanford, California; Gerome
Center of Emphasis, Pfizer Global Research and Bertram Müller-Myhsok, Department of Breen, MRC Social Genetic and Developmental
Development, Cambridge, Massachusetts; Jian Translational Research in Psychiatry, Max Planck Psychiatry Centre and NIHR BRC for Mental Health,
Yang, Institute for Molecular Bioscience and Institute of Psychiatry, Munich Cluster for Systems King’s College London; Anders D. Børglum,
Queensland Brain Institute, The University of Neurology (SyNergy), and University of Liverpool, Department of Biomedicine and iSEQ, Centre for
Queensland; Futao Zhang, Institute for Molecular Liverpool, Great Britain; Merete Nordentoft, Integrative Sequencing, Aarhus University, and
Bioscience, The University of Queensland; Volker iPSYCH, The Lundbeck Foundation Initiative for iPSYCH, The Lundbeck Foundation Initiative for
Arolt, Department of Psychiatry, University of Integrative Psychiatric Research, Mental Health Integrative Psychiatric Research; and Patrick F.
Münster; Bernhard T. Baune, Discipline of Center Copenhagen, Copenhagen University Sullivan, Department of Medical Epidemiology and
Psychiatry, University of Adelaide, Adelaide, Hospital; Markus M Nöthen, Institute of Human Biostatistics, Karolinska Institutet, and
Australia; Klaus Berger, Institute of Epidemiology Genetics and Life&Brain Center, Department of Departments of Genetics and Psychiatry, University
and Social Medicine, University of Münster; Dorret Genomics, University of Bonn; Michael C. of North Carolina at Chapel Hill.
I. Boomsma, Department of Biological Psychology O’Donovan, MRC Centre for Neuropsychiatric
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