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

Abstract

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.

A meta‐review of “lifestyle psychiatry”: the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders

“…For disordered sleeping, a two-sample MR study found evidence that self-reported difficulties in falling or staying asleep increase the risk for bipolar disorder (OR=1.79, 95% CI: 1.40-2.29, p<0.001), an effect which was consistent across multiple sensitivity methods to test for pleiotropy, whereas no evidence was found for depression, ADHD or schizophrenia 76 . However, the study by Choi et al 34 did find evidence for self-reported inadvertent daytime napping as a risk factor for the onset of depression (OR=1.34, 95% CI: 1.17-1.53, p=0.00002), consistent across pleiotropy robust sensitivity methods (see Table 8).…”

“…Two MR studies examined the causal relations between physical activity and depression 33,34 . Choi et al 34 applied a factor-wide design to Wray et al's GWAS 35 , corrected for multiple testing and adjusted for potential confounders, to identify a broad spectrum of modifiable risk factors potentially implicated in major depression.…”

“…Two MR studies examined the causal relations between physical activity and depression 33,34 . Choi et al 34 applied a factor-wide design to Wray et al's GWAS 35 , corrected for multiple testing and adjusted for potential confounders, to identify a broad spectrum of modifiable risk factors potentially implicated in major depression. MR analysis of the available variables related to physical activity found some evidence that self-reported cycling or swimming may causally decrease depression risk, although only at a nominal level of significance (which did not survive correction for multiple testing).…”

“…The only eligible MR study found to examine causal relations between diet and incident mental illness was the aforementioned analysis by Choi et al 34 , which also examined multiple dietary factors, including salt intake, lamb intake, inconsistent dietary patterns, multivitamin supplement use, tea intake, and cereal intake. There was no firm evidence that any of these factors influenced the risk of developing depression, apart from an unexpected effect of multivitamin supplementation use on increased risk (OR=1.28, 95% CI: 1.11-1.47, p=0.0006), which however was not consistent across sensitivity methods (see Table 6).…”

“…Three MR studies assessed the causal role of sleep-related variables on risk for mental illness. Two of these were from the aforementioned two-sample MR studies of physical activity, which also measured sleep time using self-reported 34 and objective 39 measures. There was no evidence for causal associations between hours of sleep with depression, schizophrenia or bipolar disorder.…”