Genome-wide meta-analysis identifies genetic risk loci for mono- and polyneuropathies in 983 477 individuals

TL;DR

This study identifies 48 genetic loci linked to peripheral neuropathies and reveals shared genetic links with sleep, pain, and psychiatric disorders.

Contribution

The study reports 48 genome-wide significant loci and provides new insights into the polygenic basis and comorbid genetic relationships of neuropathies.

Findings

48 genome-wide significant loci and 66 fine-mapped credible sets were identified for neuropathies.

Genetic links between neuropathies and sleep problems, chronic pain, and psychiatric disorders were confirmed.

Key genes involved include those related to neurotransmitter signaling, immune function, and neural development.

Abstract

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 credible sets. 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). Public variant association data across cohorts, genetic correlation, and Mendelian randomization analyses supported shared genetic links of neuropathies with sleep problems, chronic pain, and psychiatric disorders. Together, our results highlight a strong polygenic basis for neuropathies and further confirm their genetic comorbid relationships with sleep, pain, psychiatric, and autoimmune traits.

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