Prospective Blood Transcriptomics Study in a Motor Vehicle Collision Cohort Identified a Protective Function of the SAMD15 Gene Against Chronic Pain

Traumatic brain injuries following motor vehicle collisions (MVCs) are ubiquitous. Surprisingly, there are no correlates between concussion impact force and long-term pain outcomes. To study the molecular underpinnings of chronic pain after MVC, we assembled a prospective cohort of 36 subjects that experienced MVC and suffered documented mild traumatic brain injuries. For each participant, a first blood sample was drawn within 72 hours of the collision, then a second one at the 6-month mark. Pain was also assessed at the second blood draw to determine if pain became chronic or resolved. Blood samples enabled transcriptomics analyses for immune cells. At the transcriptome-wide level, we found that Sterile Alpha Motif Domain Containing 15 (SAMD15) mRNA was significantly upregulated with time in subjects who resolved their pain whereas unregulated in those with persistent pain. Using several large publicly available datasets, such as the UK Biobank and the GTeX portal, we then linked elevated SAMD15 gene expression, elevated neutrophils cell counts, and decreased risk for chronic pain to increased dosage of the T allele at SNP rs4903580, situated within SAMD15's gene locus. The causality between the components of our model was established and supported by Mendelian randomization. Overall, our results support the role of SAMD15 as a potential gene effector for neutrophil-dependent chronic pain development. PERSPECTIVE: This article highlights the potential protective role of the SAMD15 gene against chronic pain following a mild traumatic brain injury. The expression of the gene is associated with a SNP rs4903580, which is itself associated with neutrophils counts as well as chronic pain in large genetic studies.