Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain

Abstract

Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (rg = 0.299 ± 0.026, p = 9.10 × 10–31), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (βOA→MD = 0.09, SE = 0.02, z-score p-value < 1.02 × 10–5; βMD→OA = 0.19, SE = 0.026, p < 2.67 × 10–13), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (Pmeta ≤ 5 × 10–8), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted “mechanosensory behavior” genes (GO:0007638; Pgene_set = 2.45 × 10–8) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.

A shared genetic signature for common chronic pain conditions and its impact on biopsychosocial traits

“…Conversely, chronic facial pain increased the risk of seeking care for depression (i.e., pain → depression only [Supplementary Table S7]). These findings are broadly consistent with other genetic studies concerning depression and chronic pain, which have shown genetic causal relationships between chronic pain and depression, spanning both depression → pain pathways [54][55][56][57][58] and pain → depression pathways. 20,52,55,59 Taken together, our results and previous findings 19,20,27,54,55 raise further intriguing hypotheses, such as that either or both causal directions may exist on a patient sub-group basis.…”

“…These findings are broadly consistent with other genetic studies concerning depression and chronic pain, which have shown genetic causal relationships between chronic pain and depression, spanning both depression → pain pathways [54][55][56][57][58] and pain → depression pathways. 20,52,55,59 Taken together, our results and previous findings 19,20,27,54,55 raise further intriguing hypotheses, such as that either or both causal directions may exist on a patient sub-group basis. 52 Our LCV results also implicate a history of trauma or stressincluding death of a close relative in last two years; being adopted as a child; sexual assault; marital separation; and military serviceas genetic causal factors for various chronic pain types.…”

“…Conversely, chronic facial pain increased the risk of seeking care for depression (i.e., pain → depression only [Supplementary Table S7]). These findings are broadly consistent with other genetic studies of complex traits concerning depression and chronic pain, which have shown: (i) genetic correlations between depression-related traits and various pain conditions 7,9,30 ; and (ii) genetic causal relationships between chronic pain and depression, spanning both depression → pain pathways 30,31 and pain → depression pathways. 8,30 Taken together, the current study’s results and previous findings 8,30,31 raise further intriguing hypotheses, such as either or both causal directions may exist on a patient sub-group basis, 23 which may even change over time as their condition/comorbidities further develop.…”

Depression in Osteoarthritis: Current Understanding

“…Recently, Barowsky et al used cross-disorder genome-wide genetic data analysis to examine the etiological relationship between OA and MDD. 67 After a series of pleiotropic analyses, the findings suggest that OA and MDD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. 67 This suggests that the two diseases may share a common genetic risk mechanism.…”

“… 67 After a series of pleiotropic analyses, the findings suggest that OA and MDD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. 67 This suggests that the two diseases may share a common genetic risk mechanism. In addition, Boer et al conducted a genome-wide association study meta-analysis across 826,690 individuals (177,517 with OA) and found that OA shares genetic components with multiple traits, including depressive symptoms.…”