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

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.

A genome-wide association study finds novel genetic associations with broadly-defined headache in UK Biobank (N = 223,773)

“…Consistent with previous studies from our group, we found strong evidence to support a shared genetic aetiology of pain with psychological traits, indicating a vulnerability to depression and other negative mood states (42,43). In addition, we found a negative correlation with factors associated with a longer duration of education.…”

Genome-wide Association Study of Multisite Chronic Pain in UK Biobank

“…MCP showed moderate positive genetic correlation with a range of psychiatric disorders including MDD, SCZ, and PTSD, along with traits anxiety and neuroticism. The magnitude of genetic correlation between MCP and MDD was similar to that shown for von Korff chronic pain grade (a chronic pain phenotype) and MDD by McIntosh et al via a mixed-modelling approach (ρ = 0.53) (McIntosh et al, 2016). This is in line with previous observations of association and indicates that shared genetic risk factors exist between MCP and a range of psychiatric disorders, most notably MDD, and that the genetic correlation between MCP and MDD matches with that between MDD and von Korff CPG, a validated chronic-pain questionnaire-derived phenotype (Von Korff et al, 1992).…”

“…Chronic pain and chronic pain disorders are often comorbid with psychiatric and neurodevelopmental disorders (Gureje et al, 2008). This has been observed for Major Depressive Disorder (MDD) (Nicholl et al, 2014;McIntosh et al, 2016), post-traumatic stress-disorder (PTSD) (Shipherd et al, 2007;Dunn et al, 2011;Phifer et al, 2011;Outcalt et al, 2015;Akhtar et al, 2018), schizophrenia (Watson, Chandarana and Merskey, 1981;de Almeida et al, 2013;Engels et al, 2014) and bipolar disorder (BD) (Nicholl et al, 2014;Stubbs et al, 2015). There are also reported differences in the perception of pain and interoception (sensing and integration of bodily signals) for people with schizophrenia (Lévesque et al, 2012;Urban-Kowalczyk, Pigońska and Śmigielski, 2015), anorexia nervosa (AN) (Strigo et al, 2013;Bär et al, 2015;Bischoff-Grethe et al, 2018) and autism spectrum disorders (ASD) (Clarke, 2015;Gu et al, 2018), with some evidence of an increase in pain thresholds for AN and ASD.…”

“…Chronic pain, conventionally defined as pain lasting longer than 3 months, has high global prevalence (~30%) (Elzahaf et al, 2012), imposes a significant socioeconomic burden, and contributes to excess mortality (Hocking et al, 2012;Vos et al, 2015).. It is often associated with both specific and non-specific medical conditions such as cancers, HIV/AIDS, fibromyalgia and musculoskeletal conditions (Merskey and Bogduk, 1994;Greene, 2010;Vellucci, 2012), and can be classified according to different grading systems, such as the Von Korff chronic pain grade (Von Korff et al, 1992).. Several aspects of chronic pain, such as chronic pain grade and back pain, have been studied from the genetic point of view, and several have been shown to be complex traits with moderate heritability (Hocking et al, 2012;McIntosh et al, 2016). In part due to the heterogeneity of pain assessment and pain experience, there are very few large-scale genetic studies of chronic pain and no genome-wide significant genetic variants have yet been identified (Mogil, 2012;Zorina-Lichtenwalter et al, 2016).…”

Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals

“…These traits are known to often co-occur with BP and twin studies have suggested that they share underlying genetic factors 17 , with similar genetic correlations also seen for other pain phenotypes. [55][56][57] Our results confirm a recent twin report of genetic correlation of sleep disturbance with BP. 58 Overall, the analysis of genetic correlations provides evidence for shared molecular pathways underlying BP and traits considered as BP risk factors, thus providing basis for identification of causal links between them.…”