Genetic correlations between pain phenotypes and depression and neuroticism

Abstract

19Correlations between pain phenotypes and psychiatric traits such as depression and 20 the personality trait of neuroticism are not fully understood. The purpose of this study 21 was to identify whether eight pain phenotypes, depressive symptoms, major 22 depressive disorders, and neuroticism are correlated for genetic reasons. Eight pain 23 phenotypes were defined by a specific pain-related question in the UK Biobank 24 questionnaire. First we generated genome-wide association summary statistics on 25 each pain phenotype, and estimated the common SNP-based heritability of each trait 26 using GCTA. We then estimated the genetic correlation of each pain phenotype with 27 depressive symptoms, major depressive disorders and neuroticism using the the 28 cross-trait linkage disequilibrium score regression (LDSC) method integrated in the 29 LD Hub. Third, we used the LDSC software to calculate genetic correlations among 30 pain phenotypes. All pain phenotypes were heritable, with pain all over the body 31showing the highest heritability (h 2 =0.31, standard error=0.072). All pain phenotypes, 32 except hip pain and knee pain, had significant and positive genetic correlations with 33 depressive symptoms, major depressive disorders and neuroticism. The largest 34 genetic correlations occurred between neuroticism and stomach or abdominal pain 35 (rg=0.70, P=2.4 x 10 -9 ). In contrast, hip pain and knee pain showed weaker evidence 36 of shared genetic architecture with these negative emotional traits. In addition, many 37 pain phenotypes had positive and significant genetic correlations with each other 38 indicating shared genetic mechanisms. Pain at a variety of body sites is heritable 39 and genetically correlated with depression and neuroticism. This suggests that pain, 40 neuroticism and depression share partially overlapping genetic risk factors. 41 experience of pain could help our understanding of its aetiology and prevention, and 56 might also offer opportunities for personalised medicine and drug targeting based on 57 identified genetic variants. Although some genetic studies have focused on pain in 58 specific body sites and have suggested possible genetic variants associated with 59 pain phenotypes, 5 the overall understanding of the genetic contributions of pain 60 remain unclear. Current limitations in our knowledge include: 1. the extent to which 61 pain as a phenotype is determined by additive genetic components mainly 62represented by single nucleotide polymorphisms (SNPs); 2. whether the genetic 63 mechanisms of pain in different body sites or in different disorders are similar or 64 different; and 3. whether the genetic connections between pain phenotypes and 65 other common co-morbidities are similar or different. Addressing these questions 66 brings further challenges when the severity and the frequency of pain are taken into 67 account. 68 4 Mental health disorders are among the commonest co-morbidities of pain. 6-7 69Depression was ranked as the third most important cause of disability worldwide, 70 a...

Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain conditions

“…It is likely that the locus tagged by rs7628207 contains regulatory elements that influence transcription of adjacent genes. Interestingly, RNF123 gene expression has been linked to the risk of major depression 30 , and major depressive disorders are genetically correlated with pain 25 . As the AMIGO3 gene transcript (the CNS-related gene bearing the GIP1associated SNP rs7628207 in its intron) was not present among the list of probes analyzed in the GTEx 31 and Westra projects 32 , we could not infer pleiotropy.…”

“…As a result, even very large genome-wide association studies provide only a limited number of replicated loci and rather low SNP-based heritability. Evidence from recent studies indicates that pain at different anatomical sites shares a common genetic component [24][25][26] . This suggests that combining several pain phenotypes in a single analytical framework may facilitate the discovery of common genetic factorschronic musculoskeletal pain genes and pathways.…”

“…Indeed, different chronic pain conditions may have common biological pathways such as those related to pain perception and processing. Several studies have provided evidence for shared genetic factors between conditions manifesting chronic pain 24 as well as pain at different anatomical sites 25,26 . However, to the best of our knowledge, no study yet published has explicitly identified these genetic factors.…”

Preclinical Considerations about Affective Disorders and Pain: A Broadly Intertwined, yet Often Under-Explored, Relationship Having Major Clinical Implications

“…Lately, there is also an increasing trend in the current literature regarding the etiology of neuroticism, and also its connections with the risk of affective disorders and pain vulnerability, evidencing the mediator role of personality for pain and affective disorders [ 165 ]. Thus, neuroticism was described as a stable, genetically-based dimension of temperament, which can be viewed as a consequence or response to elevated stress, being related to the psychological profile of every individual and based on a multitude of endo- and exogenous factors fulfilling the role of amplifiers [ 166 ].…”

“…Therefore, genetic correlations were performed for example, by linkage disequilibrium score regression method in a UK cohort that consisted of 151,922–226,683 individuals. By estimating the genetic correlation of 8 pain phenotypes with other psychiatric traits, Meng et al [ 166 ] demonstrated that all pain phenotypes are heritable (h2 = 0.31) and they have a strong and positive correlation with other pervasive low moods by sharing to some extent a similar mechaniscistic pattern.…”