Background The antinuclear antibody (ANA)-positive asymptomatic individuals are at higher risk of developing systemic lupus erythematosus (SLE). However, the genetic burden for SLE in preclinical ANA-positive phase remains largely unknown. In this study, we analyzed SLE-specific polygenic risk scores (PRSs) from a prospective cohort comprising Korean individuals with preclinical autoantibodies, SLE, or none of these conditions to understand the effect of SLE-risk genetic variants on the development of ANA. Methods The PRS for SLE was calculated from genome-wide variants data obtained from 349 individuals with preclinical autoimmunity, 2,057 patients with SLE, and 33,596 healthy controls based on the known risk effects of 180 SLE-risk variants. Preclinical autoantibodies-positive individuals who were diagnosed by rheumatologists, tested positive for at least one among ANA, rheumatoid factor (RF), or anti-cyclic citrullinated peptide autoantibody (anti-CCP). Differences in PRSs among phenotypic groups were assessed using ANOVA with adjustment for genotypic principal components and sex while controlling for the family-wise error rate. Results There was a significant increase in the SLE PRS in the preclinical ANA-positive group (ANA titers ≥ 1:160) compared to healthy controls (p=2.69x10−5) and the preclinical ANA-negative group with preclinical autoimmunity (positive for RF or anti-CCP) (p=2.42x10−²), although their SLE genetic burden was significantly weaker than patients with SLE (p=7.48x10−²5). In addition, SLE PRSs were gradually increased according to the level of ANA titers in a stratified analysis (p=2.38x10−³, figure 1). In contrast, the presence of anti-CCP autoantibodies (irrelevant to SLE) in the preclinical stage was not associated with high SLE PRSs. Conclusions This study demonstrated that the genetic burden for SLE contributes to the preclinical development of ANA. Abstract LO-042 Figure 1 Polygenic risk scores (PRSs) for SLE were plotted based on the following phenotypes: healthy controls, preclinical autoimmunity, and SLE. The individuals with preclinical autoimmunity were divided into four groups according to antinuclear antibody (ANA) titers Figure omitted. See PDF