Decomposing the genetic background of chronic back pain

Abstract

Chronic back pain (CBP) is a disabling condition with a lifetime prevalence of 40% and a substantial socioeconomic burden. Because of the high heterogeneity of CBP, subphenotyping may be necessary to improve prediction and support personalized treatment for those with CBP. The lack of distinct cellular and molecular markers for CBP complicates the task of subphenotyping. To investigate CBP subphenotypes, we decomposed the genetic background of CBP into a shared genetic background common to other chronic pain conditions (back, neck, hip, knee, stomach, and head pain) and unshared genetic background related only to CBP. We showed that the shared and unshared genetic backgrounds of CBP differ in their biological functions: the first one is likely to control processes mainly in nervous, immune and musculoskeletal systems underlying chronic pain development regardless its site, while the second may contribute more to local processes in spine leading to chronic pain precisely in the back. We identified 18 genes with shared impact across different chronic pain conditions and two genes that were specific for CBP. These findings may contribute to future development of targets and new biomarkers for chronic pain management. Next, among people with CBP, we demonstrated that polygenic risk scores accounting for the shared and unshared genetic backgrounds of CBP may underpin different subphenotypes of CBP cases. These subphenotypes are characterized by varying genetic predisposition to a wide array of medical conditions and interventions such as diabetes mellitus, myocardial infarction, diagnostic endoscopic procedures, and surgery involving muscles, bones, and joints. The proposed genetic decomposition framework holds promise for investigating the genetic underpinnings of other heterogeneous diseases.