LAUSR

ABSTRACT Missing aspects of the heritability of chronic neuropathic pain, as a complex adult-onset trait, may be hidden within rare variants with low effect on disease risk, unlikely to be resolved by a single-variant approach. To identify new risk genes, we performed a next-generation sequencing of 107 pain genes and collapsed the rare variants through gene-wise aggregation analysis. The optimal unified sequence kernel association test was applied to 169 patients with painful neuropathy, 223 patients with nociplastic pain (82 diagnosed with chronic widespread pain and 141 with fibromyalgia), and 216 healthy controls. Frequency and features of variants in TRPA1, which was the most significant gene, were further validated in 2 independent cohorts of 140 patients with chronic pain (90 with painful neuropathy and 50 with chronic widespread pain) and 34 with painless neuropathy. The effect of aminoacidic changes were modeled in silico according to physicochemical characteristics. TRPA1 was significantly enriched of rare variants which significantly discriminated chronic pain patients from healthy controls after Bonferroni correction (P = 6.7 × 10-4, ρ = 1), giving a risk of 4.8-fold higher based on the simple burden test (P = 0.0015, OR = 4.8). Among the 32 patients harboring TRPA1 variants, 24 (75%) were diagnosed with nociplastic pain, either fibromyalgia (12; 37.5%) or chronic widespread pain (12; 37.5%), whereas 8 (25%) with painful neuropathy. Irrespective of the clinical diagnosis, 12 patients (38%) complained of itch and 10 (31.3%) of cold-induced or cold-accentuated pain, mostly episodic. Our study widens the spectrum of channelopathy-related chronic pain disorders and contributes to bridging the gap between phenotype and targeted therapies based on patients' molecular profile.