Chronic pain is a prevalent disease with increasing clinical challenges. Genome-wide association studies in
chronic pain patients have identified hundreds of common pathogenic variants, yet they only explained a portion of individual variance of
chronic pain. With the advances in next-generation sequencing technologies, it is now feasible to conduct rarer variants studies in large-scale databases. Here, we performed gene-based rare variant analyses in 200,000 human subjects in the UK biobank whole-exome sequencing database for investigating 9 different
chronic pain states and validated our findings in 3 other large-scale databases. Our analyses identified the SLC13A1 gene coding for
sodium/sulfate symporter associated with chronic
back pain and multisite
pain at the genome-wide level and with
chronic headache, knee, and neck and
shoulder pain at the nominal level. Seven loss-of-function rare variants were identified within the gene locus potentially contributing to the development of
chronic pain, with 2 of them individually associated with
back pain and multisite
pain. These 2 rare variants were then tested for replication in 3 other biobanks, and the strongest evidence was found for rs28364172 as an individual contributor. Transcriptional analyses of Slc13a1 in rodents showed substantial regulation of its expression in the dorsal root ganglia and the sciatic nerve in
neuropathic pain assays. Our results stress the importance of the SLC13A1 gene in
sulfate homeostasis in the nervous system and its critical role in preventing
pain states, thus suggesting new therapeutic approaches for treating
chronic pain in a personalized manner, especially in people with mutations in the SLC13A1 gene.