Unveiling the clinical and genetic impact of neuropsychiatric involvement in systemic lupus erythematosus

Abstract

Objectives Despite the clinical significance of neuropsychiatric systemic lupus erythematosus (NPSLE), which is a severe complication of SLE, clinical and genetic studies on NPSLE remain limited. This study aimed to identify the clinical features of NPSLE and explore genetic factors associated with NPSLE in a prospective lupus cohort.

Methods The clinical features, disease activity and organ damage of 1205 Korean patients with SLE were assessed at least annually, and genome-wide genotyping with imputation was performed. The clinical and genetic associations of NPSLE, excluding minor events, and its specific subsets (seizure or psychosis) compared with those of non-NPSLE were analysed using genome-wide association studies (GWASs). The biological relevance of the identified loci was investigated through functional analyses.

Results A total of 271 patients with NPSLE exhibited more clinically diverse manifestations (p=2.40×10−4), especially in patients with seizure (N=84, p=4.86×10−14) and psychosis (N=26, p=8.29×10−5), compared with 934 patients with non-NPSLE. Notably, NPSLE patients significantly had greater organ damage (total Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score: OR 1.49, p=3.28×10−17; non-NP SDI score: OR 1.22, p=7.61×10−5) than patients with non-NPSLE, adjusting for age, sex, hypertension, disease duration and antiphospholipid antibodies. GWAS revealed nine NPSLE-associated loci at a suggestive significance level (p<5×10⁻⁶). The nine nearest mapped genes were exclusively expressed in the brain (adjusted p=5.28×10−4), particularly in the basal ganglia, cortex and hippocampus (adjusted p<0.05).

Conclusions Neuropsychiatric involvement in SLE increases clinical manifestations and extends organ damage beyond the nervous system, with NPSLE-related genetic variants highlighting their potential functional roles in various brain regions.