Previous studies on pain symptoms have suggested that pain mainly involves peripheral, spinal and central effects, including various factors that affect nociceptive perception, inflammatory response, and the neural pathways of pain centers and pain signals in the brain.36,37 In addition, a large number of studies have found that there are complex interactions and common genetic risk factors between depression and pain symptoms.12,38 Such as, some studies have found that depression can affect changes in multiple brain regions, most commonly in areas such as prefrontal cortex(PFC), anterior cingulate cortex (ACC), hippocampus and amygdala, where gray matter volume loss and alterations in activity similar to those that occur in chronic pain.38,39Neuroimaging studies have also revealed the close relationship between brain regions (somatosensory, IC ACC, PFC and thalamus) involved in the integration of pain sensation and emotions and the regions regulated by depression.40These common influencing factors may cause differences in pain susceptibility genes between depression patients and the general population. However, to our knowledge, studies exploring the genetic mechanisms of pain in patients with depression are limited, and the corresponding susceptibility genes remain unclear. Therefore, we conducted GWAS studies on different pain phenotypes in patients with depression, and identified three candidate genes associated with different pain phenotypes. These candidate genes not only have multiple functions affecting psychiatric disorders, nervous system development and neurogenesis, but it is noteworthy that some genes are also involved in physiological processes affecting pain symptoms, such as ADGRF1 identified for neck or shoulder pain, SLC9A9 gene for MCP and TRIOBP for stomach or abdominal pain.
ADGRF1 (adhesion G protein-coupled receptors) is a group of specific target receptors for synaptic amides that are highly expressed in neural stem cells and the brain during development.41Its ligand, N-Docosahexaenoylamine (Synaptamide), is an endocannabinoid metabolite. This signaling pathway can not only by influencing the neurogenic and synaptic genes expression, induction of neurogenesis of hippocampus and cortex neurons and synapses, and the neuronal differentiation of neural stem cells, can also ring through cyclic adenosine monophosphate (cAMP) to transmit anti-inflammatory signals, inhibiting the expression of pro-inflammatory genes and pro-inflammatory cytokines.41,42 Because of these biological functions, synaptamide play a role in improving cognitive function and neuronal plasticity in neuropathic pain.43 What’s more, Park et al. demonstrated the immunomodulatory effects of ADGRF1 in the brain and in the periphery, and jointly promoted the anti-neuroinflammatory effects of synaptamide in systemic inflammatory conditions. These results suggest that ADGRF1 mediated inhibition of innate immune cell activation may be a novel therapeutic strategy for controlling brain and/or peripheral inflammation and related diseases.44
SLC9A9(solute carrier family 9, member A9) mainly encodes sodium/proton exchanger 9(NHE9), It is expressed in many brain tissues and modulates luminal pH of circulating endosomes, which are important organelles for synaptic transmission and plasticity.45 And SLC9A9 pathway is associated with long-term potentiation, which underlies cognitive functions that are frequently disrupted in learning and memory, ADHD, and ASD.46 Previous studies have found that changes in SLC9A9 gene expression and protein function are associated with a variety of human diseases, such as ADHD, ASD et al.47 In addition, a protein-protein interaction network pathway analysis showed that SLC9A9 is also involved in oxidative stress, nociception and other functions.46 Since there are multiple overlapping factors between the functions involved in ADGRF1 and SLC9A9 and the influencing factors of pain symptoms, we speculate that two genes are associated with the pain in patients with depression by influencing the factors of pain symptoms. Further studies are still needed to verify our speculation.
TRIOBP gene primarily encodes TRIO and F-actin binding proteins, which are involved in neural tissue development and control actin cytoskeleton organization, cell motility and cell growth.48 Among them, several studies have implicated that TRIOBP-1 is involved in schizophrenia by forming protein aggregates in the brain.49 At present, studies of TRIIOBP gene are limited, and further studies are needed to confirm its possible etiological association with pain symptoms.
Among the candidate genes associated with different pain phenotypes identified by PWAS, several candidate genes, such as P2RX7 and SIRPA, are associated with biological mechanisms that influence pain symptoms or participate in the pain process. P2RX7 (purinergic receptor P2X 7) is a non-selective cationic channel activated by extracellular ATP. It is mainly expressed in the peripheral and central nervous system and immune system. Activation of P2RX7 not only contributes to pro-inflammatory response to injury or bacterial invasion and mediates apoptosis, but also plays a role in chronic inflammation and neuropathic pain.50 Such as, an animal study revealed that P2RX7 may promote pain modulation through its effect on peripheral tissue damage and altered central nervous system processing in clinical pain states.51 Kambur's study reinforces this evidence and suggests that P2RX7 gene and genetic variants may be involved in regulating human pain sensitivity.50 In addition, previous studies have found that the P2RX7 variant is associated with a higher risk of psychiatric disorders such as bipolar disorder and depression, and that the P2RX7 receptor is involved in psychosis related pathways, such as synaptic plasticity, neurotransmission, and immune regulation.52
It is worth noting that SIRPA gene was overlapping genes in two PWAS studies with different reference weights. SIRPA gene mainly encodes proteins that are members of the signal-regulatory-protein (SIRP) family, which are involved in signal transduction mediated by various growth factor receptors. Previous studies have found that cleavage of signal-regulatory-protein α (SIRPα) is related to enhanced inflammatory signaling,53 CD47 is a demonstrated ligand for this receptor protein, and its signaling pathway, CD47-SIRPα, is involved in the regulation of immune homeostasis and neuronal networks.54 What's more, Haiyue Zhang et al revealed the importance of CD47 and SIRPα in the neuroinflammatory process of central nervous system diseases.55 Overall, P2RX7 has been shown to be directly involved in the regulation of chronic pain, while SIRPA is mainly involved in the biological process of influencing factors of pain symptoms, so it can be speculated that they may influence pain symptoms by regulating and participating in inflammatory responses. Further studies are needed to confirm our speculation. In addition, among the numerous candidate genes identified in the PWAS study, many genes are also associated with psychiatric disorders, nervous system development, and neuronal conduction. For example, PPM1F56 and GSTM357 et al.
In the calculation results of genetic correlation with different psychiatric disorders, we found that ADHD, and PTSD were significantly positively correlated with different pain phenotypes, reflecting the possible common genetic structure. It is particularly noteworthy that the genetic positive correlation between ADHD and MCP phenotype was consistent with the significant association gene (SLC9A9) identified in the GWAS of MCP. SLC9A9 gene pathway is associated with long-term potentiation, which is the basis of cognitive functions that are frequently disrupted in ADHD.46 This further indicates that ADHD and MCP phenotype share the common genetic structure, and also reflects pleiotropy, in which specific genetic alleles may increase the risk of both phenotypes.58
In addition, enrichment analysis revealed that significant genes were associated with multiple biological processes and functional pathways. Some of these related biological processes and functional pathways can directly or indirectly affect pain symptoms. For example, sulfur compound metabolism process, previous studies have found that sulfur compounds (such as hydrogen sulphide) can relieve pain symptoms and inflammation59, so significant genes may regulate the pain of patients with depression by participating in sulfur compound metabolism process, What’s more, some studies have also found that signal release and chemical synaptic transmission are involved in the biological process of pain symptoms60, and the biological relationship between other pathways and pain symptoms needs to be further studied.
Overall, one advantage of our study is the use of a large sample size from the UK Biobank, which can eliminate statistical noise by overcoming potential confounding factors such as selection biases and heterogeneity. In addition, compared with previous pain GWAS studies, our research focused more on multiple pain phenotypes in patients with depression. Based on GWAS, PWAS study and LDSC analysis were further used to explore the potential biological mechanisms related to pain in patients with depression from the perspective of protein expression level and genetics.
Nevertheless, it is worth noting that our research has some limitations. First, all data in our research were derived from the UK Biobank, and the research participants were limited to depression patients of European descent. When applying the research results to different populations, the impact of genetic backgrounds differences on the results should be considered, Secondly, because the phenotyping of pain in the UK Biobank was based on a specific non-standard pain-related questionnaire, it may result in pain phenotypes being broadly defined and not filtered by other potentially relevant information about the nature, duration or intensity of pain. Finally, genes significantly associated with pain symptoms were identified in our study, and while previous studies have suggested that they play a role in neurological function and disease, there is no direct evidence that they are involved in pain symptoms, and further research is needed to confirm this.
In summary, through GWAS and PWAS analysis, we found several susceptibility genes significantly associated with pain phenotype in patients with depression, What’s more, LDSC analysis found that there was a significant genetic correlation between different pain phenotypes and ADHD and PTSD, suggesting that there may be a common genetic structure. These findings contribute to the understanding of the biological mechanism of pain phenotype in patients with depression and provide new clues for the study of its pathogenesis.