Article Text
PDF
Abstract
Background Despite recent advances in systemic lupus erythematosus (SLE) genetics, genetic contribution to development of neuropsychiatric SLE (NPSLE), which is one of the devastating complications of SLE, has yet to be defined. We investigated genetic contributions to NPSLE using a genome-wide association study (GWAS).
Methods We recruited 1,205 SLE patients from Hanyang BAE lupus cohort (enrollment from 1998 to June 2021; June 2022 as final follow-up) and performed GWAS using Korean Chip with imputation using 1KG reference panels. The 271 patients with NPSLE (22.5%) were defined using Ainiala Criteria that did not include minor NP events (headaches, anxiety), a revised version of American Colleague of Rheumatology (ACR) case definitions for 19 NP syndromes. The association of GWAS data with Ainiala NPSLE or each major event (seizure, psychosis) were analyzed using logistic regression by adjusting for clinical factors.
Results Across all analyses groups, we identified 30 significant genetic loci at suggestive level (P <1x10–6). rs4508395 and rs191085932 were top SNPs in analyses of Ainiala NPSLE and SLE with seizure, respectively (OR [95% CI] = 1.96 [1.51–2.54], P = 3.49x10–7 and OR = 8.26 [3.71 – 18.37], P = 3.51x10–7). In the Ainiala NPSLE analysis group, we mapped 53 genes using variants with P <1x 10–5 and observed that those were significantly associated with differentially expressed genes in nerve tissue and in parts of the brain (adjusted P = 0.044 and 0.040, respectively, figure 1A and 1B). Additionally, those genes were significantly enriched in hippocampal subfield of brain (adjusted P = 1.45x10–3) (figure 1C).
Conclusions We identified genetic variants associated with Ainiala NPSLE which may be functionally related to nerve and brain, providing new ideas for molecular pathogenesis of NPSLE.
Functional analyses for genetic risk loci of NPSLE. Tissue implicated by genetic associations with NPSLE from (A) GTEx data expression data v7, (B) GTEx data expression data v6. (C) Result of gene set enrichment test using genetic associations with NPSLE
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.