Date Published: February 22, 2017
Publisher: Public Library of Science
Author(s): Oliver van Hecke, Lynne J. Hocking, Nicola Torrance, Archie Campbell, Sandosh Padmanabhan, David J. Porteous, Andrew M. McIntosh, Andrea V. Burri, Haruka Tanaka, Frances M. K. Williams, Blair H. Smith, Monica Uddin.
Depression and chronic pain are the two most important causes of disability (Global Burden of Disease Study 2013). They occur together more frequently than expected and both conditions have been shown to be co-morbid with cardiovascular disease. Although shared socio-demographic risk factors (e.g. gender, deprivation) might explain the co-morbidity of these three conditions, we hypothesised that these three long-term, highly prevalent conditions co-occur and may be due to shared familial risk, and/or genetic factors.
We employed three different study designs in two independent cohorts, namely Generation Scotland and TwinsUK, having standardised, validated questionnaire data on the three traits of interest. First, we estimated the prevalence and co-occurrence of chronic pain, depression and angina among 24,024 participants of a population-based cohort of extended families (Generation Scotland: Scottish Family Health Study), adjusting for age, gender, education, smoking status, and deprivation. Secondly, we compared the odds of co-morbidity in sibling-pairs with the odds in unrelated individuals for the three conditions in the same cohort. Lastly, examination of similar traits in a sample of female twins (TwinsUK, n = 2,902), adjusting for age and BMI, allowed independent replication of the findings and exploration of the influence of additive genetic (A) factors and shared (C) and non-shared (E) environmental factors predisposing to co-occurring chronic widespread pain (CWP) and cardiovascular disease (hypertension, angina, stroke, heart attack, elevated cholesterol, angioplasty or bypass surgery). In the Generation Scotland cohort, individuals with depression were more than twice as likely to have chronic pain as those without depression (adjusted OR 2·64 [95% CI 2·34–2·97]); those with angina were four times more likely to have chronic pain (OR 4·19 [3·64–4·82]); those with depression were twice as likely to have angina (OR 2·20 [1·90–2·54]). Similar odds were obtained when the outcomes and predictors were reversed and similar effects seen among sibling pairs; depression in one sibling predicted chronic pain in the other (OR 1·34 [1·05–1·71]), angina predicted chronic pain in the other (OR 2·19 [1·63–2·95]), and depression, angina (OR 1·98 [1·49–2·65]). Individuals with chronic pain and angina showed almost four-fold greater odds of depression compared with those manifesting neither trait (OR 3·78 [2·99–4·78]); angina showed seven-fold increased odds in the presence of chronic pain and depression (OR 7·76 [6·05–9·95]) and chronic pain nine-fold in the presence of depression and angina (OR 9·43 [6·85–12·98]). In TwinsUK, the relationship between CWP and depression has been published (R = 0.34, p<0.01). Considering the CWP-cardiovascular relationship, the most suitable model to describe the observed data was a combination of A, C and E, with a small but significant genetic predisposition, shared between the two traits (2·2% [95% CI 0·06–0·23]). We found an increased co-occurrence of chronic pain, depression and cardiovascular disease in two independent cohorts (general population-based cohort, twins cohort) suggesting a shared genetic contribution. Adjustment for known environmental influences, particularly those relating to socio-economic status (Generation Scotland: age, gender, deprivation, smoking, education; Twins UK: age,BMI) did not explain the relationship observed between chronic pain, depression and cardiovascular disease. Our findings from two independent cohorts challenge the concept of traditional disease boundaries and warrant further investigation of shared biological mechanisms.
The prevalence of painful conditions co-occurring with other chronic diseases has been under-recognised until recently [1, 2]. For example, chronic pain is common, affecting approximately 1 in 5 adults in the general population across Europe . Chronic pain with sleep disturbance  shows a strong association with anxiety and depression  and longitudinal studies suggest the associated overall disease burden among individuals with co-morbidities, co-prescribing and co-occurrence of disability all lead to greater challenges in managing each condition in turn .
This is the first, large-scale study to examine the three important traits of chronic pain, cardiovascular disease and depression, where the findings have been reproduced to some extent in a second, independent population sample. While a genetic component has long been recognised in each of the three conditions individually, it has been thought that social risk factors such as poverty and deprivation were likely to underlie their co-occurrence. To our surprise, even adjusting for socio-economic status and other environmental risk factors, we found significant odds ratios for co-occurrence. This led us to model chronic pain and cardiovascular disease in twins, and to show a small but significant shared genetic predisposition.
We have shown that chronic pain, cardiovascular disease, and depression coexist in individuals and across families even after adjusting for known environmental risk factors. The presence of one trait significantly increases the risk of manifesting another, both in siblings and twins. Pairs of traits offer even higher risks of manifesting the third. Twin modelling shows that pairs of traits have shared genetic predisposition which would account for their co-occurrence. Future work should aim to identify the genetic variants involved, as better understanding of the biological pathways will clarify the underlying pathogenetic mechanisms as well as having the potential to provide novel targets for intervention.