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

Abstract

ObjectiveChronic 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. MethodsTo increase power, we first included all patients with a diagnosis of inflammatory polyneuropathy (IP) as cases. We performed a GWAS study using FinnGen R10 individual 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. The second GWAS focused on CIDP patients and a total of 516 CIDP cases and 403,545 controls were included in the analysis. Stratified analyses by gender were also performed for both IP and CIDP. We performed gene-level analyses using transcriptome-wide mendelian randomization (TWMR) analysis, colocalization analysis, transcriptome-wide association study (TWAS) using S-PrediXcan and MAGMA to identify genes associated with IP and CIDP. Gene-set analyses were conducted using MAGMA to identify pathways that are related to IP and CIDP. ResultsIn GWAS study, we identified one genome-wide significant loci at 20q13.33 for CIDP risk among women; the top variant located at the intron region of gene CDH4. TWMR, colocalization and S-PrediXcan analyses identified DGKQ, GLDC, IDUA, SLAMF9 and TMEM175 as candidate pathogenic genes for IP; genes DIRAS1, GNG7, and SLC39A3 for CIDP; genes DIRAS1, DCTN1, and ME1 for IP among males; and genes DIRAS1 and ME1 for IP among women. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. ConclusionOur study identified suggestive risk genes and pathways for IP and CIDP. Functional analysis should be conducted to further confirm these associations.