A genome-wide association study identifies novel genetic variants associated with neck or shoulder pain in the UK biobank, 2025, Tao et al.

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A genome-wide association study identifies novel genetic variants associated with neck or shoulder pain in the UK biobank (N = 430,193)

Spoiler: Authors

Yiwen Taoa, Qi Pana, Tengda Caia, Zen Huat Lub, Mainul Haquec, Tania Dottorinid, Lesley A. Colvine, Blair H. Smithe, Weihua Meng

Introduction:
Neck and shoulder pain are prevalent musculoskeletal disorders that significantly affect the quality of life for a substantial portion of the global population. Studies have shown that women are more susceptible than men.

Objective:
This study aims to discover genetic variants associated with neck or shoulder pain through a genome-wide association study (GWAS), using data from 430,193 participants in the UK Biobank.

Methods:
A genome-wide association study was performed adjusting for age, sex, BMI, and 8 population principal components. Significant and independent genetic variants were replicated by FinnGen.

Results:
The primary GWAS revealed 5 significant genetic loci (including 2 novel) associated with neck or shoulder pain, with the most significant single nucleotide polymorphism (SNP) being rs9889282 (P = 2.63 × 10−12) near CA10 on chromosome 17. Two novel significant associations were detected on chromosomes 18 and 14, with the top SNPs being rs4608411 (P = 8.20 × 10−9) near TCF4 and rs370565192 (P = 3.80 × 10−8) in DCAF5, respectively. Our secondary GWAS identified a single novel genetic locus in SLC24A3 among males and 2 genetic loci (including one novel near LINC02770) among females. In the replication stage, the SLC39A8 locus was weakly supported by the FinnGen cohort. The tissue expression analysis revealed a significant association between brain tissues and neck or shoulder pain.

Conclusion:
In summary, this study has identified novel genetic variants for neck or shoulder pain. Sex-stratified GWAS also suggested that sex played a role in the occurrence of the phenotype.

Link | DOI | PDF | PAIN Reports | Open Access

 

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Figure 1 "Manhattan plots of GWAS results for neck or shoulder pain in primary, female, and male analyses."


Figure 2 "The regional plot of locus in the CA10 region from the primary GWAS. Regional plot of the susceptibility locus in the CA10 region based on the primary GWAS association analysis."


Figure 4 "Tissue expression results from GTEx using FUMA. Panel A shows tissue expression results for 30 specific tissue types from GTEx, analyzed with FUMA. Panel B displays results for 53 tissue types."

 

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Higher female prevalence:

Several investigations have shown that the occurrence of neck or shoulder pain is significantly related to age, sex, body mass index, physical ability, psychological pressure, workplace, and whether suffering from diabetes. Mahmud et al. reported that 72% of women and 51% of men suffer from neck pain, indicating that women are more likely to be affected by neck pain than men.

Past GWAS also highlighted CA10:

In a previous genome-wide association study (GWAS) using the UK Biobank, the FOXP2, LINC01572, and CA10 genes were identified to be significantly associated with neck or shoulder pain, with only FOXP2 and LINCO1572 being marginally replicated in another cohort.

CA10 expression:

The expression of CA10 was highest in brain tissues such as cerebellar hemisphere, putamen basal ganglia, and cortex.

More about CA10:

In the primary GWAS, the locus near CA10 on chromosome 17 was the most significantly associated with neck or shoulder pain, with a top SNP of rs9889282 (P = 2.63 × 10−12). CA10 encodes a protein from the zinc metalloenzyme family called carbonic anhydrase, involved in bone resorption and bone mineral solubilization. The protein is also believed to be involved in the development of the brain and the central nervous system. The strong interconnections between carbonic anhydrase activity and neuropathic pain have been suggested. It has been identified that inhibition of carbonic anhydrase activity by intraperitoneal injection of acetazolamide decreased neuropathic pain. For CA10, one study suggested that it may play the role of adaptors, facilitating neurexins' indirect connections with unidentified postsynaptic target molecules, and thus mediating the development of new transsynaptic complexes. As there are not many studies on CA10 in humans, future studies should focus on elucidating the mechanism of CA10 action on neck or shoulder pain.

Tissue expression and associated symptoms:

In the tissue expression analysis, neck or shoulder pain showed a strong correlation with the brain and pituitary categories. The identified brain tissues revealed key signaling pathways related to pain perception (BA24, hypothalamus, amygdala), sensory processing (amygdala, cortex, BA9, basal ganglia), and central neuroendocrine (hypothalamus). These findings align with clinical observations where individuals experiencing chronic neck or shoulder pain often report associated symptoms such as headaches, fatigue, and alterations in mood. The identified brain regions, including the cerebral cortex and amygdala, are known to play crucial roles in emotional processing and stress response. This connection raises questions about the psychosocial aspects influencing the development and persistence of neck or shoulder pain.

 

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A past GWAS about neck and shoulder pain by a lot of the same authors also highlighted CA10. Here is the abstract:

A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank, 2020, Meng et al.

Spoiler: Authors

Meng W, Chan BW, Harris C, Freidin MB, Hebert HL, Adams MJ, Campbell A, Hayward C, Zheng H, Zhang X, Colvin LA, Hales TG, Palmer CNA, Williams FMK, McIntosh A, Smith BH.

Background
Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK.

Methods
A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication.

Results
We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively).

Conclusions
We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

Link | DOI | PDF | Human Molecular Genetics | Open Access

 

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Figures from Meng et al., 2020
Figure 1: "The Manhattan plot of the GWAS on neck or shoulder pain using the UK Biobank cohort (N = 203 309)."


Figure 2: "Tissue expression results on 30 specific tissue types by GTEx in the FUMA."


Figure 3: Tissue expression results on 53 specific tissue types by GTEx in the FUMA.

 

[voner]

The identified brain regions, including the cerebral cortex and amygdala, are known to play crucial roles in emotional processing and stress response. This connection raises questions about the psychosocial aspects influencing the development and persistence of neck or shoulder pain.

?

 

[Hoopoe]

In the tissue expression analysis, neck or shoulder pain showed a strong correlation with the brain and pituitary categories. The identified brain tissues revealed key signaling pathways related to pain perception (BA24, hypothalamus, amygdala), sensory processing (amygdala, cortex, BA9, basal ganglia), and central neuroendocrine (hypothalamus). These findings align with clinical observations where individuals experiencing chronic neck or shoulder pain often report associated symptoms such as headaches, fatigue, and alterations in mood. The identified brain regions, including the cerebral cortex and amygdala, are known to play crucial roles in emotional processing and stress response. This connection raises questions about the psychosocial aspects influencing the development and persistence of neck or shoulder pain.

Common sense tells me that people with genetics that make them more sensitive to pain will experience worse pain, irrespective of the origin of that pain, and thereby more likely to be diagnosed. So in a genetics study of chronic pain, expect to see the genes involved in pain sensitivity.

More common sense and less attempts to build psychosocial theories of chronic pain.