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October 9, 2025Open Access

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

Key Points

Patients with neuropsychiatric systemic lupus erythematosus exhibited more diverse clinical manifestations.
NPSLE patients had greater organ damage, with a total SDI score showing significant differences compared to non-NPSLE.
Nine loci associated with NPSLE were identified through genome-wide association studies, implicating potential brain region involvement.
The clinical implications suggest that neuropsychiatric involvement extends beyond nervous system symptoms.

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.

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