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

Abstract

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 # Corresponding author. * These authors contributed equally to this work. AUTHOR CONTRIBUTIONS MF and YT contributed to the design of the study, carried out statistical analysis, produced the figures, and first draft of the manuscript; LC provided statistical and computational support; MP and PS analysed CHARGE dataset and contributed to interpretation of the results; YA and FW conceived and oversaw the study, contributed to the design and interpretation of the results; all co-authors contributed to the final manuscript revision. COMPETING FINANCIAL INTERESTS YSA and LCK are owners of Maatschap PolyOmica, a private organization, providing services, research and development in the field of computational and statistical (gen)omics. Other authors declare no conflicts of interest.

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

“…Slc39a8 mutant zebrafish exhibit vertebral abnormalities, impaired growth, and decreased motor activity, and a missense GIP1-associated polymorphism rs13107325 in the SLC39A8 gene has previously been associated with the increased risk of osteoarthritis 54 and severe adolescent idiopathic scoliosis 57 . Thus, similar to findings from our recent study of back pain 45 , genetic factors underlying chronic musculoskeletal pain comprise biological, social, and psychological components.…”

“…Traits that displayed the strongest genetic correlations with GIP1 were osteoarthritis (rg = 0.65), age of first birth (rg = −0.56), depressive symptoms (rg = 0.54), and college completion (rg = 0.54). Overall, the pattern of genetic correlations with GIP1 was very similar to that observed for back pain in our previous study 45 . GIP2 was genetically correlated only with osteoarthritis (inverse genetic correlation, rg = −0.30) and obesity-related traits, and GIP4 only with hip circumference ( Supplementary Data 11b, c).…”

Genetic, lifestyle and environmental risk factors for chronic pain revealed through GWAS

“…Using Complex Traits Genetics Virtual Lab (CTG-VL) [18], we explored whether those SNPs have been previously associated to other traits. We observed that rs10660361 was also identified by a recent GWAS on back pain (P-value = 7.77×10 −8 ) [25] and multisite chronic pain (P-value = 1.9×10 −9 ) [36]. However, rs113313884 was only associated with multisite chronic pain at a suggestive level (P-value = 6.9×10 −3 ) highlighting the importance of studying phenotypes using different definitions.…”

“…Evidence for the role of genetic factors in CP comes from twin and family studies [38] where its heritability is estimated to be as high as 60% [11,37]. More recently, large-scale genome-wide association studies (GWAS) have identified multiple genetic variants associated with chronic back pain [25,75] and multisite chronic pain [36] as further evidence of a genetic contribution to CP. However, their causal relationship has yet to be adequately examined.…”

The Musculoskeletal Knowledge Portal: Making Omics Data Useful to the Broader Scientific Community

“…The development of high‐throughput genotyping technologies and large biobank collections, complemented with rapid methodological advances in statistical genetics, has enabled hypothesis‐free genome‐wide association studies (GWAS), which have identified hundreds of genetic variants across many loci associated with musculoskeletal conditions such as fracture, ( 7,8 ) osteoarthritis, ( 9 ) and sarcopenia, and their related endophenotypes including bone mineral density, ( 10–13 ) lean mass, ( 14 ) grip strength ( 15,16 ) and even back pain. ( 17 ) As large‐scale whole‐genome (WGS) and exome sequencing data become available, even more variants will be identified. ( 18 ) These studies provide a fertile ground for understanding the biologic pathways underlying the genetic architecture of musculoskeletal traits.…”