Karssen, L. C. | bioRxiv Science

bioRxiv2019

Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain at different anatomic sites

Chronic musculoskeletal pain has a negative impact on all aspects of human life. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. In this research, we aimed to reduce phenotype heterogeneity and reveal genes and pathways shared by chronic musculoskeletal pain at four locations: back, neck/shoulder, hip, and knee. Our study was based on the results of genome-wide association studies performed using UK Biobank data with a total sample size of 456,000 individuals. We applied principal component analysis based on the matrix of genetic covariances between the studied pain traits and constructed four genetically independent phenotypes (GIPs). The leading GIP (GIP1) explains the largest proportion of the genetic variance of and covariance between the analyzed phenotypes (78.4%), and the later GIPs (GIP2-4) explain progressively less. We identified and replicated five loci associated with GIP1 and one locus associated with GIP2. The genes decisively prioritized for the GIP1-associated loci were SLC39A8, ECM1, and FOXP2. For the remaining two GIP1-associated loci, we proposed several candidates (AMIGO3, BSN, RBM6, FAM212A, RNF123, UBA7 and MIR7114, NSMF, NOXA1, GRIN1), but were unable to prioritize any of them convincingly. The most likely causal gene in the locus associated with GIP2 was GDF5. For GIP1, gene set/tissue/cell type enrichment analyses identified multiple terms related to the nervous system. Genetic correlations analysis revealed a genetic overlap between GIP1 and osteoarthritis as well as a set of anthropometric (such as overweight and waist circumference), sociodemographic (such as age of first birth and college completion) and psychiatric/personality (such as depressive symptoms and neuroticism) traits. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and likely reflecting pain perception and processing.

genomics↗

bioRxiv2018

Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals

Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large GWAS (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated three BP associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disc problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least two strong molecular axes of BP genesis, one related to structural/anatomic factors such as intervertebral disk problems and anthropometrics; and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of LBP.

genetics↗