Chronic 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 Findings
Using 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.
Genetic 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.
Andrew M. McIntosh and colleagues investigate the genetic and environmental factors associated with chronic pain and and major depressive disorder.
Why Was This Study Done?
Genetic factors and the environment you share with your nuclear family, siblings, or spouse may determine your risk of chronic pain.
Depression is also associated with chronic pain, but whether this relationship is explained by shared genetic factors, environment, or both is not known.
We sought to investigate these issues using genetic data and family environmental information from Generation Scotland: Scottish Family Health Study and UK Biobank.
What Did the Researchers Do and Find?
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.
Shared genetic and environmental factors also partly explained the association between chronic pain and depression.
Finally, we found evidence showing that the genetic contribution to chronic pain arises through the combined effect of many different genetic risk factors and that the cumulative effects of genetic risk factors for depression increased an individual’s chance of having chronic pain.
What Do These Findings Mean?
Both genetic factors and chronic pain in a partner or spouse contribute to the risk of chronic pain for an individual.
Chronic pain is caused by an accumulation of many small genetic effects and is associated with some of the same genetic and environmental risk factors that confer risk of depression.