Genome-Wide Meta-Analysis Identifies Genetic Risk Loci for Mono- and Polyneuropathies in 983,477 Individuals

Peripheral neuropathies are common neurological disorders affecting sensory, autonomic, and motor nerves, with an estimated prevalence exceeding 2% in the general population. Typical symptoms include numbness and distal limb muscle weakness, resulting from somatosensory nerve damage. Here, we investigate the genetic architecture of mono- and polyneuropathies and their relationships with comorbid traits using data from FinnGen and the UK Biobank. Our genome-wide association study (GWAS) and meta-analysis identified 48 genome-wide significant (p < 5 × 10 −8 ) independent loci and 66 fine-mapped signals. These included associations with genes involved in neurotransmitter signaling ( HTR3A ), immune function ( HLA-DQB1 , BCL11A ), extracellular matrix remodeling ( COL11A1 , ADAMTS17 , LOXL4 ), axon guidance and neural development ( DCC , ETV1 , NEGR1 ), and carpal tunnel syndrome ( DIRC3 ). Phenome-wide association studies (PheWAS), genetic correlation, and Mendelian randomization analyses supported shared genetic links with sleep problems, chronic pain, and psychiatric disorders. Together, our results highlight a strong polygenic basis for neuropathies and confirm their complex comorbid relationships with sleep, pain, psychiatric, and autoimmune traits. Author approval All authors have seen and approved the manuscript.