title: Chronic pain, depression and cardiovascular disease linked through a shared genetic predisposition: Analysis of a family-based cohort and twin study.
abstract: 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.
  
  
  RESULTS
  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]).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Population Health Sciences, School of Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Oliver
authors.identifier: http://orcid.org/0000-0002-6229-5057
authors.initials: O
authors.lastname: van Hecke
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.|Generation Scotland, Centre for Genomics and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.affiliation: Division of Population Health Sciences, School of Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0002-7856-7408
authors.initials: N
authors.lastname: Torrance
authors.affiliation: Generation Scotland, Centre for Genomics and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Archie
authors.identifier: http://orcid.org/0000-0003-0198-5078
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Generation Scotland, Centre for Genomics and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Generation Scotland, Centre for Genomics and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Genomics and Molecular Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Generation Scotland, Centre for Genomics and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew M
authors.identifier: http://orcid.org/0000-0002-0198-4588
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Institute of Psychology, University of Zurich, Zurich, Switzerland.|Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.|Dept of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Burri
authors.affiliation: Mie Prefectural College of Nursing, Tsu, Mie, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Dept of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Frances M K
authors.initials: FM
authors.lastname: Williams
authors.affiliation: Division of Population Health Sciences, School of Medicine, University of Dundee, Dundee, United Kingdom.|Generation Scotland, Centre for Genomics and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Blair H
authors.identifier: http://orcid.org/0000-0002-5362-9430
authors.initials: BH
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D000787:Angina Pectoris / Q000453:epidemiology / Q000235:genetics*; D059350:Chronic Pain / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D015897:Comorbidity; D003866:Depressive Disorder / Q000453:epidemiology / Q000235:genetics*; D004200:Diseases in Twins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D015995:Prevalence; D011795:Surveys and Questionnaires; D014427:Twins / Q000235:genetics