Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants identifies multiple variants including CADM2 and APOE

Klimentidis, Yann C.; Raichlen, David A.; Bea, Jennifer W.; Garcia, David O.; Wineinger, Nathan E.; Mandarino, Lawrence J.; Alexander, Gene E.; Chen, Zhao; Going, Scott B.

doi:10.1038/s41366-018-0120-3

Cited by 300 publications

(384 citation statements)

References 83 publications

(75 reference statements)

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“…We previously observed 5 using MR that while objective measures of physical activity (not included here) are linked to reduced odds of depression, selfreport measures of physical activity do not necessarily show these patterns. Objective measures of physical activity-reflecting a broad tendency for movement/activity-have demonstrated higher heritability 33 and may yield more powerful genetic instruments in an MR framework.…”

Section: Discussionmentioning

confidence: 99%

A two-stage approach to identifying and validating modifiable factors for the prevention of depression

Choi¹,

Stein²,

Nishimi³

et al. 2019

Preprint

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Background: Although depression is recognized as the leading cause of disability worldwide, decades of research have identified few actionable preventive factors. Using phenotypic and genomic data from the UK Biobank, we took advantage of a unique opportunity to screen a wide range of potentially modifiable factors that could offset known risk factors for depression. Methods:We curated baseline data on more than 100 lifestyle and environmental factors in participants' lives, including behavioral (e.g., exercise, sleep, media use, diet), social (e.g., support, activities), and environmental (e.g., greenspace, pollution) variables. In a follow-up survey, participants reported on their traumatic life experiences and mental health, including depression. Polygenic risk scores for depression were generated based on large-scale genomewide association results. Excluding those meeting criteria for depression at baseline, we identified at-risk individuals at high predicted probability (> 90th percentile) for clinically significant depression at follow-up based on their (i) polygenic risk, or (ii) reported traumatic life events. Using a factors-wide design corrected for multiple testing and adjusted for potential confounders, we identified modifiable factors associated with follow-up depression in the full sample and among at-risk individuals. Using a two-sample Mendelian randomization (MR) design, we then examined which significant factors showed potential causal influences on depression risk, or vice versa. Results: A range of baseline modifiable factors were prospectively associated with follow-up depression, including factors related to social engagement, physical activity, media use, and diet. MR follow-up analyses provided further support for the effects of social support-seeking, TV use, and other factors on depression risk. Conclusion:As the field increasingly quantifies the role of genetic factors in complex conditions such as depression, knowledge of modifiable factors that could offset one's genetic risk has MODIFIABLE FACTORS FOR DEPRESSION 3 become highly relevant. Here, we present an approach to screening for potentially modifiable factors that may offset the risk of depression in general and among at-risk individuals. In light of the burden of disease associated with depression and the urgent need for actionable preventive strategies, this approach could help prioritize candidates for follow-up studies including clinical trials for depression prevention.

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Section: Discussionmentioning

confidence: 99%

A two-stage approach to identifying and validating modifiable factors for the prevention of depression

Choi¹,

Stein²,

Nishimi³

et al. 2019

Preprint

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“…Summary-level data were obtained from a recently published GWAS on accelerometer-measured physical activity conducted within UK Biobank 10 . In this GWAS, the regression models were adjusted for age, sex, the first ten genomic principal components, center, season (month), and genotyping chip.…”

Section: Data On Physical Activitymentioning

confidence: 99%

“…We used a two-sample MR framework to examine potential causal associations between objective accelerometer-measured physical activity and risks of breast and colorectal cancer using genetic variants associated with accelerometer-measured physical activity identified from a recent genome-wide association study (GWAS) 10 . We examined the associations of these genetic variants with risks of breast cancer 11 and colorectal cancer 12 .…”

Section: Introductionmentioning

confidence: 99%

Physical activity and risks of breast and colorectal cancer: A Mendelian randomization analysis

Papadimitriou

Dimou

Tsilidis

et al. 2019

Preprint

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Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomization analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.42 to 0.84, P-value=0.003) and colorectal cancer (OR: 0.66, 95% CI: 0.53 to 0.82, P-value=2*E -4 ). We found similar magnitude inverse associations by breast cancer subtype and by colorectal cancer anatomical site. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

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“…For exercise, twin studies investigating leisure‐time physical activity (LTPA), physical activity (PA), physical inactivity (PI) and sedentary behaviors have yielded heritability estimates ranging from ~25 to 85% in humans . In addition, recent genome‐wide association studies of exercise behaviors identified a few genes reaching significance . These include genes highly expressed in the mesolimbic system of the brain, including DRD2 , SLC9A9 and GABRG3 .…”

Section: Role Of Genetics In Auds and Exercisementioning

confidence: 99%

“…[95][96][97][98] In addition, recent genome-wide association studies of exercise behaviors identified a few genes reaching significance. 99,100 These include genes highly expressed in the mesolimbic system of the brain, including DRD2, SLC9A9 and GABRG3. 99,100 DRD2 codes for the dopamine D2 receptor and was identified as significant in genome-wide association studies of both alcohol and exercise behaviors.…”

Section: Role Of Genetics In Auds and Exercisementioning

confidence: 99%

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

Booher

Martínez

Ehringer

2020

Genes Brain and Behavior

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Alcohol use disorders (AUDs) lead to early death and many devastating consequences for individuals, families and society. Currently, few effective treatments are available, but emerging research suggests exercise might be beneficial in some individuals. To develop the most effective exercise treatment program, more research on intensity, type, timing, stage of addiction, drug involved, sex of subject and subject population is needed. This review highlights the complexity of the interaction between alcohol behaviors and exercise, with a focus on the role of sex and genetics. Moreover, we describe a variety of rodent models used to investigate the neuronal physiology changes that underlie alcohol consumption and exercise. Specifically, current data indicate that moderate exercise may ameliorate neuronal damage caused by alcohol consumption. Additionally, we describe studies of rodent models in the context of hedonic substitution to draw broad conclusions about shared underlying neurobiological mechanisms. Until recently, most studies in rodents were performed only in males, and few studies have utilized different genetic strains of mice or rats. Comparing similar behavioral paradigms across sex and strain, it has become clear that major sex and genetic differences exist for each behavioral context alone (alcohol consumption and exercise) and combined. Therefore, future research in this area should be developed with careful study design and attention to address both of these factors.

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Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants identifies multiple variants including CADM2 and APOE

Cited by 300 publications

References 83 publications

A two-stage approach to identifying and validating modifiable factors for the prevention of depression

A two-stage approach to identifying and validating modifiable factors for the prevention of depression

Physical activity and risks of breast and colorectal cancer: A Mendelian randomization analysis

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

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