Exploring the early drivers of pain in Parkinson’s disease

Pain is a common and complex non-motor symptom in people with Parkinson's disease (PWP). Little is known about the genetic drivers of pain in PWP, and progress in its study has been challenging. Here, we conducted two genome-wide association studies (GWAS) to identify genetic variants associated with pain experienced during the earliest stages of Parkinson's disease. The study population consisted of 4,159 PWP of European ancestry who were mapped to five previously-described, longitudinal pain trajectories. In the first GWAS, the extreme pain trajectories (highest burden versus no significant pain over time) were compared, and in the second GWAS, a multinomial approach was undertaken. While no variant reached genome-wide significance, we identified promising associations, such as rs117108018 (OR_GWAS-Extreme=8.96, p_GWAS-Extreme=2.5 × 10^{- 7}), a brain/nerve eQTL for L3MBTL3 and EPB41L2, and rs61881484 (p_{GWAS-Multinomial}=2 × 10^{- 7}), which intersects a transcription factor peak targeting CREB1, critical in sensory neuron synaptic plasticity and neuropathic pain regulation. Gene-based tests implicated CTNNB1 (p_GWAS-Extreme=3.2 × 10^{- 5}), KLK7 (p_GWAS-Extreme=7 × 10^{- 5}), and SLITRK3 (p_{GWAS-Multinomial}=3.2 × 10^{- 5}), which have been associated with neurodevelopment. At the pathway-level, there was an enrichment for genes involved in neurotransmitter regulation and opioid dependence. This study implicates neuropathic pain mechanisms as prominent drivers of elevated pain in PWP, suggests potential therapeutic genetic targets for further research.