© 2017 van Hecke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: 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. Methods and findings: 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 siblingpairs 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 fourfold 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]). Conclusion: 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.