Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes

Abstract

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci, genes and pathways. We first focused on CIDP, and 516 CIDP cases and 403,545 controls were included in the GWAS analysis. We also investigated genetic risk for inflammatory polyneuropathy (IP), in which we performed a GWAS study using FinnGen data and combined the results with GWAS from UK biobank (UKBB) using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. Stratified analyses by gender were performed. Mendelian randomization (MR), colocalization, and transcriptome-wide association study (TWAS) analyses were performed to identify associated genes. Gene-set analyses were conducted to identify associated pathways. We identified one genome-wide significant locus at 20q13.33 for CIDP risk among women; the top variant located at the intron region of gene CDH4. Sex-combined MR, colocalization and TWAS analyses identified three candidate pathogenic genes for CIDP, five genes for IP. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Sex-stratified analyses identified three genes for IP among males; and two genes for IP among females. Our study identified suggestive risk genes and pathways for CIDP and IP. Functional analysis should be conducted to further confirm these associations.