Investigating the shared genetic architecture and causal relationship between pain and neuropsychiatric disorders

Abstract

Background: Pain often occurs in parallel with many neuropsychiatric disorders.However, the underlying mechanisms and potential causality have not been well studied. Methods:We collected the genome-wide association study (GWAS) summary statistics of 26 common pain and neuropsychiatric disorders with sample size ranging from 17,310 to 482,730 in European population. The genetic correlation between pair of pain and neuropsychiatric disorders, as well as the relevant cell types were investigated by linkage disequilibrium (LD) score regression analyses. Then transcriptome-wide association study (TWAS) was applied to identify the potential shared genes by integrating the gene expression information and GWAS. In addition, Mendelian randomization (MR) analyses were conducted to infer the potential causality between pain and neuropsychiatric disorders.Results: Among the 169 pairwise pain and neuropsychiatric disorders, 55 pairs showed significant (P < 1.54×10 −4 ) positive correlations (median rg = 0.43) and 9 pairs showed negative correlations (median rg = −0.31). MR analyses identified 26 significant (P < 1.48×10 −4 ) likely causal associations, for instance, neuroticism and insomnia were risk 2 / 29 factors for most of short-term pain, multisite chronic pain was risk factor for neuroticism, insomnia, major depressive disorder and attention deficit/hyperactivity disorder, and vice versa. The signals of pain and neuropsychiatric disorders tended to be enriched in the functional regions of cell types from central nervous system (CNS).A total of 19 genes shared in at least one pain and neuropsychiatric disorder pair were identified by TWAS integrating the gene expression information of CNS. The shared genes included AMT, NCOA6 and UNC45A which involved in glycine degradation, insulin secretion and cell proliferation, respectively, suggesting pain and neuropsychiatric disorders might share neuronal signaling-related, metabolism-related and proliferation-related pathogenic mechanisms. Conclusion:Our findings provided the evidence of shared genetic structure, causality and potential shared pathogenic mechanisms between pain and neuropsychiatric disorders, and enhanced our understanding of the comorbidities of pain and neuropsychiatric disorders.

Genetic relationships between chronic pain, psychopathologies, and neuroticism

“…Internalizing disorders show the highest genetic correlation with the crosscondition chronic pain factor, which is consistent with previous reports [80,58,19]. It has likewise been previously shown that the internalizing disorders we considered here have high comorbidity with chronic pain.…”

“…On the other hand, bipolar disorder has been reported to be highly comorbid with chronic pain [109, 10,92]. There is evidence from two studies that it is genetically correlated with multisite pain [59,19], which is defined in both studies as the count of chronic pain sites across the body, using self-report in the UKBB. We used the same dataset and questionnaire, but we did not construct a phenotype using the count of pain sites, because as a measure of pain widespreadness it was of limited utility for determining shared cross-condition genetic risk (see [127] for a detailed discussion of our reasons).…”

“…This seemingly protective effect may be due to schizophrenia patients under-reporting chronic pain [110]. There is also evidence for a genetic correlation between schizophrenia and chronic multi-site pain (or count of pain sites, as above) [19].…”

“…Of the compulsive thought disorders, anorexia has been reported to be comorbid with abdominal pain [97] and migraine [87] but not to have genetic correlations with chronic pain [19]. There is evidence that OCD is comorbid 12 with chronic pain from population-based but not clinic-based studies [23].…”

Shared genetic architecture and causality between autism spectrum disorder and irritable bowel syndrome, pain, and fatigue

“…Some of these methods have been applied previously to investigate the genetic overlap between ASD and pain. For example, one study investigated causality between pain and neuropsychiatric disorders including ASD using MR, but did not nd a causal relationship between pain and ASD 20 . Another study found that the PRS of ASD was associated with low pain tolerance, suggesting that a higher genetic risk of ASD might be associated with more severe pain symptoms 25 .…”