Genome-wide association study identifies novel genetic variants associated with widespread pain in the UK Biobank, 2025, Pan

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Genome-wide association study identifies novel genetic variants associated with widespread pain in the UK Biobank, 2025, Pan

Abstract

Objectives:
Widespread pain is a hallmark characteristic of fibromyalgia, commonly affecting older individuals. This study aimed to identify novel genetic variants associated with widespread pain by utilizing the extensive UK Biobank dataset.

Methods:
We conducted a primary genome-wide association study (GWAS) using a novel definition of widespread pain, defined as pain experienced all over the body during the past month. Sex-stratified GWAS analysis approach was also performed to analyze the impact of sex on widespread pain.

Results:
The primary GWAS identified one novel significant genetic locus (rs34691025, p = 1.76 × 10−8) on chromosome 5q13.2 within the ARHGEF28 gene and several loci that approached genome-wide significance. The sex-stratified GWAS outputs revealed biological difference widespread pain between males and females, with a novel locus identified in the female-specific analysis within the LRMDA gene on chromosome 10. Genetic Correlation analysis demonstrated significant genetic correlations between widespread pain and other phenotypes, including joint disorders and spondylosis. The PheWAS revealed associations between the significant genetic variants with hearing disorders and cardiovascular diseases. A two-sample Mendelian randomization analysis found no significant causal association between hearing loss and widespread pain.

Conclusions:
Our study advances the understanding of the genetic factors contributing to widespread pain, highlighting notable differences between males and females and identifying a novel genetic locus associated with this condition.

LINK | PDF | Sage Journals - Molecular Pain

 

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The main repeated SNP's in Table 3 with highest p-values is for variants on gene ARHGEF28, I looked up the gene on GeneCards (link) to determine function.

Molecular function for ARHGEF28 Gene according to UniProtKB/Swiss-Prot
Function
* Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors.
* Functions in axonal branching, synapse formation and dendritic morphogenesis.
* Functions also in focal adhesion formation, cell motility and B-lymphocytes activation.
* May regulate NEFL expression and aggregation and play a role in apoptosis (By similarity). ARG28_HUMAN,Q8N1W1

Interesting that ARHGEF28 is a gene that has function for brain signalling related stuff (synapse formation and dendritic morphogenesis) and B-cell activation. In the JE hypothesis thread we were wondering about possible links between immune cells and synapses and this seems to be one such link in a disease group that incorporates fibromyalgia.

 

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Participants could select from the following options:
(1) Headache,
(2) Facial pain,
(3) Neck or shoulder pain,
(4) Back pain,
(5) Stomach or abdominal pain,
(6) Hip pain,
(7) Knee pain,
(8) Pain all over the body,
(9) None of the above,
(10) Prefer not to say
(UK Biobank Questionnaire field ID: 6159). Multiple selections were allowed.

Cases of widespread pain were identified by the selection of “Pain all over the body,” regardless of other choices.
Controls were those who chose “None of the above.”

Male Cases = 1885, Control = 80,228
Female Cases = 2732, Control = 87,385