Genome-wide by trait interaction analyses with neuroticism reveal chronic pain-associated depression as a distinct genetic subtype.

The frequent co-occurrence of chronic pain (CP) and depression is a well-known phenomenon, supported by both the high prevalence of major depression among CP patients and studies describing a substantial genetic correlation between the two phenotypes. Neuroticism, a trait characterised by maladaptive stress responses and a tendency to experience negative emotions, has been linked to both depression and the experience of pain. This study aimed to determine whether depression associated with CP represents a genetically distinct subtype and to explore the role of neuroticism in modulating genetic susceptibility to depression. To address these questions, we performed genome-wide association analyses for current depression utilising the UK Biobank dataset, followed by genome-wide by trait interaction analyses to assess the interaction effect of neuroticism, and polygenic risk score analyses to compare predictions. Our findings suggest that CP-related depression is a valid subtype of depression. In association with current depression, we identified a total of 49 novel genetic risk polymorphisms meeting the genome-wide significance threshold, including variants involved in synaptic plasticity and transcriptional regulation. Additionally, our results support that neuroticism has a prominent role in modulating the genetic risk of current depression independently of CP, which highlights the importance of considering personality traits and stress factors in understanding the genetic background of complex and heterogeneous phenotypes like depression.