SMR Analysis Integrating GWAS and eQTL Data Reveals UHRF1BP1 and SNRPC as Potential Drug Targets for Low Back Pain

Low back pain (LBP) is a leading cause of disability worldwide with limited effective pharmacotherapies. We aimed to identify novel therapeutic candidate targets for LBP through integrative genomics.

We employed summary-data-based Mendelian randomization (SMR) with GWAS data from FinnGen (13,178 cases/164,682 controls) and tissue-specific expression quantitative trait loci (eQTLs) from peripheral blood (Westra cohort: n = 5,311; 15,636 genes) and brain tissue (UKBEC: n = 134; 16,309 genes). Heterogeneity in dependent instruments (HEIDI) analysis validated causal associations. Candidate targets were further assessed by pathway enrichment, drug prediction, and phenome-wide association studies (PheWAS).

Peripheral blood eQTLs identified four genes associated with LBP (P_SMR < 3.2×10^-, HEIDI P > 0.05): BTN2A3P, GFPT1, UHRF1BP1, SNRPC; brain eQTLs identified four genes associated with LBP (P_SMR < 3.07×10^-, HEIDI P > 0.05): CHST3, DCC, UHRF1BP1, SNRPC. Cross-tissue integration prioritized UHRF1BP1 and SNRPC as consensus candidates. Drug prediction suggested levamisole and taxifolin as potential UHRF1BP1-modulating compounds. PheWAS indicated low pleiotropic risk, with associations mainly with hypertension and celiac disease.

This multi-omics framework prioritizes UHRF1BP1 (involved in epigenetic regulation) and SNRPC (RNA splicing modulator) as mechanistically novel, genetically supported candidate targets for LBP, providing a foundation for future experimental validation and therapeutic development.