Reciprocal interaction between depression and pain: results from a comprehensive bidirectional Mendelian randomization study and functional annotation analysis

To understand a putative causal link for depression and pain, we retrieved summary statistics from genome-wide association studies conducted for pain at 7 different body sites (N = 151,922-226,683) and major depression disorder (MDD, N-case/control = 246,363/561,190). We conducted a bidirectional Mendelian randomization analysis using distinct genome-wide association studies-identified single nucleotide polymorphisms for each trait as instrumental variables and performed several sensitivity analyses to verify Mendelian randomization assumptions. We also conducted functional annotation analysis using 396 tissue-specific annotations from the roadmap project. Across 7 different body sites, genetic predisposition to depression was associated with pain at the neck/shoulder (odds ratio [OR] = 1.08 per one log-unit increase in depression risk, 95% confidence interval [CI]: 1.06-1.10), back (OR = 1.05, 95% CI: 1.04-1.07), abdominal/stomach (OR = 1.03, 95% CI: 1.02-1.04), as well as headache (OR = 1.10, 95% CI: 1.07-1.12), but not with pain on the face, hip, and knee. In the reverse direction, genetically instrumented multisite chronic pain (OR = 1.78 per one increment in the number of pain site, 95% CI: 1.51-2.11) and headache (OR = 1.55 per one log-unit increase in headache risk, 95% CI = 1.13-2.10) were associated with MDD. Functional annotation analysis showed differential clustering patterns where depression clustered closely with headache and neck/shoulder pain, exhibiting substantial brain tissue enrichment. Our study indicates that depression is a causal risk factor for headache and pain localized at neck/shoulder, back, and abdominal/stomach, rather than pain at face, hip, and knee, and suggests common neurological pathologies underlying the development of depression, headache, and neck/shoulder pain.

Automated summary

This study found a causal link between depression and pain at the neck/shoulder, back, abdominal/stomach, and headache, but not with pain on the face, hip, and knee. Genetically instrumented multisite chronic pain and headache were also associated with major depression disorder. Functional annotation analysis showed that depression clustered closely with headache and neck/shoulder pain, exhibiting substantial brain tissue enrichment.