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Chronic Back Pain Linked to Three Loci in New Genome-Wide Analysis

NEW YORK (GenomeWeb) – Researchers have linked three loci to chronic back pain in a genome-wide analysis.

An international team of researchers conducted a genome-wide association study meta-analysis of more than 441,000 individuals with and without chronic back pain. Back pain, they noted is the top worldwide cause of years lived with disability. As the researchers reported today in PLOS Genetics, they homed in on three loci associated with the condition. These loci implicated potential roles for skeletal and spinal cord development-linked pathways in the chronic pain condition.

"The results of our genome‐wide association study point to multiple pathways that may influence risk for chronic back pain," first author Pradeep Suri, an assistant professor and physician at the University of Washington, said in a statement.

In the discovery phase of their analysis, the researchers drew upon 29,531 cases and 128,494 controls of European ancestry from 15 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) populations and the UK Biobank who had undergone genotyping. The case individuals reported experiencing chronic back pain, though the definition varied a little from cohort to cohort.

In this phase, the researchers identified one locus with genome-wide significance, rs12310519, and four loci with suggestive significance, all of which they then assessed in the replication phase of their study.

In a separate cohort of 283,752 cases and controls from the UK Biobank who were not part of the initial analysis, the researchers confirmed the association at rs12310519 in the intronic region of SOX5, though not the other loci.

However, in combined meta-analysis of all cases and controls two of the three loci with suggestive significance in the discovery cohort reached significance, as did the SOX5 locus.

The strongest association with chronic back pain was at the locus in SOX5, which encodes a transcription factor involved in embryonic development. In mice, SOX5 inactivation leads to defects in cartilage and skeletogenesis, while the inactivation of both SOX5 and SOX6 — with which it works closely — leads to severe chondrodysplasia, the researchers noted.

They also found that the lead SNP at SOX5 overlaps with potential regulatory regions for chondrogenic cells, and, in a previous GWAS, was strongly associated with imaging-detected lumbar intervertebral disc degeneration. This suggested to the researchers that this variant could influence back pain by affecting skeletal development.

Another of the loci the researchers found falls at an intergenic region between CCDC26, which encodes a long non-coding RNA, and GSDMC, which encodes gasdermin C. The researchers noted that this SNP was associated with lumbar surgery for sciatica due to intervertebral disc herniation, and this intrigued them as lumbar disc herniation has been implicated in back pain.

Additionally, they noted that gasdermin C is associated with differential methylation patterns in osteoarthritis-related cartilage and subchondral bone cartilage. This suggested that this variant could affect chronic back pain via cartilage, osteoarthritis, or lumbar disc degeneration, the researchers said.

The third locus the investigators linked to chronic back pain was an intronic variant in the DCC gene. DCC encodes a transmembrane protein that acts as a receptor for netrin-1, an axonal guidance molecule. This variant might affect spinal cord development to influence back pain, or, as both DCC and chronic back pain are linked to depression, it could be due to pleiotropy, they noted.

"Chronic back pain is linked to changes in mood, and the role of the central nervous system in the transition from acute to chronic back pain is well‐recognized. However, the top two genetic variants we identified suggest causes implicating the peripheral structures, such as the spine," Suri said. "We expect that further large‐scale genetic studies will reveal the importance of both peripheral and central contributors to the complex experience of chronic back pain."