Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.

Andrew M Mcintosh ,Caroline Hayward ,Serena Scollen ,Gail Davies ,Toni‐Kim Clarke ,Daniel J Smith ,Jude Gibson ,Amy V Jones ,Meng Wang ,Archie Campbell ,Saskia P Hagenaars ,Eleanor M Wigmore ,David A Hinds ,Lynsey S Hall ,Ana Maria Fernandez-Pujals ,Mark J Adams ,Barbara I Nicholl ,Yanni Zeng ,Ian J Deary ,Chris Haley ,David J Porteous ,Blair H Smith ,Lynne J Hocking

doi:10.1371/journal.pmed.1002090

Abstract

BackgroundChronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.Methods and FindingsUsing family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum β = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 5.68 x 10−2, 95% CI 4.70x10-2 to 6.65x10-2 , p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum β = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2 , p = 4.3x10-4) and UK Biobank (maximum β = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2 , p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes.ConclusionsGenetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.

Highlights

Chronic pain and major depressive disorder (MDD) are highly prevalent and frequently comorbid conditions [1] that complicate chronic physical disease and are leading causes of disability globally [2]
Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD
Using data from the family-based Generation Scotland study, we found that genetic factors and the environment you share with your partner/spouse are important risk factors for the development of chronic pain

Summary

Introduction

Chronic pain and major depressive disorder (MDD) are highly prevalent and frequently comorbid conditions [1] that complicate chronic physical disease and are leading causes of disability globally [2]. The causes of chronic pain and depression are poorly understood, there is evidence of a contribution from genetic factors in each disorder [3,4]. The genetic architecture of chronic pain is, unknown, and while human and animal studies suggest potentially a polygenic contribution of many common variants to differences in liability [9], to our knowledge, this supposition remains unproven. Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We sought to replicate any significant findings in the United Kingdom Biobank study

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Conclusion