0783 Genome-Wide Association Study of Restless Legs Syndrome in Chinese Identifies Novel Loci and Enhances Cross-Population Risk Prediction

Abstract Introduction Restless legs syndrome (RLS) displays distinct clinical and genetic characteristics in East Asians, yet large-scale genomic data from China remain limited. To address this gap, we conducted the largest multicenter genome-wide association study of RLS in the Chinese population to define population-specific genetic architecture and phenotype–genotype relationships. Methods This multicenter study was led by Peking University People’s Hospital and included RLS patients from 25 accredited sleep laboratories across 16 provinces in China through the national RLS research network (RLSNC). Genome-wide association analyses, functional annotation, phenotype-wide association screening, genotype–phenotype stratification, and logistic regression models were performed to evaluate genetic effects on PLMI severity, sleep efficiency, and other RLS-relevant traits. Results We performed the largest multicenter GWAS of RLS in China, including 1,584 primary cases and 6,921 matched controls recruited from 25 sleep laboratories across 16 provinces. We identified six genome-wide significant susceptibility loci in the Chinese population, comprising three loci overlapping with signals previously reported in European-ancestry cohorts and three novel Chinese-specific loci—including variants near NTNG1 and additional signals in regulatory regions involved in synaptic function and neuronal excitability—and replicated BTBD9 and GLO1, whereas MEIS1 did not reach genome-wide significance, indicating marked trans-ethnic heterogeneity. NTNG1 (rs4603157) was strongly associated with sleep efficiency, showing a progressive genotype shift from normal to poor and severe categories. BTBD9 (rs3923809) showed a robust association with lower PLMI, with the G allele acting as a protective variant (OR = 0.59). Phenotype–genotype heatmaps revealed two major clusters—PLMI/fatigue (BTBD9/NCOA4) and sleep efficiency (NTNG1)—supporting genetically separable subtypes. These findings define the first high-resolution Chinese RLS genetic map and inform cross-population interpretation and subtype-based risk prediction. Conclusion This large multicenter Chinese GWAS identifies population-specific RLS susceptibility loci and reveals distinct genetic pathways underlying PLMI-dominant and sleep-fragmentation–dominant subtypes. These results refine trans-ethnic interpretation of RLS genetics and provide a foundation for subtype-based precision risk stratification in East Asians. Support (if any) This study was supported by the National Natural Science Foundation of China (NSFC) (Nos. 82400114 and 32441101).