Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort

Abstract

While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16% to 24%, p<0.0001), but a genetic risk score that is strongly associated with CHD risk was not associated with depression. An increase of one standard deviation in the CH D genetic risk score was associated with 71% higher CHD risk, but 1% higher depression risk (95% CI 0% to 3%; p=0.11). Mendelian randomization analyses suggested that triglycerides, interleukin-6 (IL-6), and C-reactive protein (CRP) are likely causal risk factors for depression. The odds ratio for depression per standard deviation increase in genetically-predicted triglycerides was 1.18 (95% CI 1.09 to 1.27; p=2×10-5); per unit increase in genetically-predicted log-transformed I L-6 was 0.74 (95% CI 0.62 to 0.89; p=0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07 to 1.29; p=0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. I L-6, CRP and triglycerides, are likely to be causally linked with depression, so could be targets for treatment and prevention of depression.

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

“…This effect was found to be independent of pleiotropic effects with neuroticism. In contrast to a previous MR analysis in UK Biobank 21 , we found little evidence for an association of C-reactive protein with risk of depression. Likewise, in contrast to some observational analyses, there was little evidence of association of interleukin-1 receptor antagonist with risk of MDD 10 .…”

“…Further, an emerging body of longitudinal studies have reported links between measured IL-6 levels and risk of depression across different populations 14,16,43,44 . Finally, a causal role of IL6 in depression is in agreement with a recent MR study investigating the associations between genetically proxied serum inflammatory markers and risk of depression in UK Biobank, suggesting a strong causal role of IL-6 in increasing the risk of probable lifetime major depression (moderate/severe) (OR per unit increase in log-transformed IL-6: 0.74, 95% CI: 0.62–0.89) 21 . It is important to note that there was some case overlap between our analysis and this previous UK Biobank analysis (there was approximately 10.5% case overlap in the UK Biobank) 21 .…”

“…Finally, a causal role of IL6 in depression is in agreement with a recent MR study investigating the associations between genetically proxied serum inflammatory markers and risk of depression in UK Biobank, suggesting a strong causal role of IL-6 in increasing the risk of probable lifetime major depression (moderate/severe) (OR per unit increase in log-transformed IL-6: 0.74, 95% CI: 0.62–0.89) 21 . It is important to note that there was some case overlap between our analysis and this previous UK Biobank analysis (there was approximately 10.5% case overlap in the UK Biobank) 21 . However, this degree of overlap is unlikely to have substantially contributed to the replication of this IL-6 finding.…”

“…In a Danish general population sample there was limited evidence to suggest a causal effect of genetically proxied CRP on either hospitalisation with depression (N cases=1,145) or antidepressant medication use (N cases= 8,621) 20 . By contrast, in a subsample of the UK Biobank study participants presenting with probable moderate/severe lifetime depression, as defined by self-report (N cases= 14,701), there was strong evidence of a positive causal effect of both CRP and IL-6 on risk of depression 21 . However, deriving conclusions on the possible causal effects of inflammatory markers on risk of depression when synthesising these studies is challenging given: i. the limited to modest sample size of some of the studies, e.g.…”

“…variable outcome definitions employed (e.g. depressive episode, depressive disorder 20 , probable moderate or severe lifetime major depression 21 ), and iii. differing methods of case ascertainment e.g.…”