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

Abstract

Objective: 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. Methods: To 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. Results: In 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. Conclusion: Our study identified suggestive risk genes and pathways for IP and CIDP. Functional analysis should be conducted to further confirm these associations.