Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogenous clinical picture. This study aimed to link genetic SLE predisposition with relevant clinical manifestations using a two-step approach. First, we identified datasets best corresponding to the 11 American College of Rheumatology 1982 (ACR-82) classification criteria for SLE using an ICD-10 code-based search in a large, public database (FinnGen consortium). Mendelian Randomization analysis of these datasets linked genetic SLE predisposition to several SLE-like manifestations: rosacea, OR 1.09(1.03–1.16), polyarthropathies, OR 1.10(1.06–1.14), pleural effusions, OR 1.09(1.04–1.14), and hemolytic anemia, OR 1.32(1.10–1.58). Second, validation was conducted in a clinical SLE cohort comprising 1,487 genotyped Scandinavian patients with detailed medical records. Based on the public datasets, genetic risk scores (GRS) for each relevant manifestation were constructed for each patient. Associations between each GRS and the corresponding ACR-82 criterion were evaluated using sex- and disease duration-adjusted logistic regression. Five of the 11 ACR-82 criteria were associated with their corresponding GRS: arthritis, OR 1.15(1.02–1.31), nephritis, OR 1.15(1.04–1.29), neurology, OR 1.24(1.04–1.47), hematology, OR 1.12(1.00–1.24), and immunology, OR 1.37(1.22–1.56), indicating that our method of using publicly available datasets to construct manifestation-specific GRSs may be useful in predicting SLE outcomes.

CS reports the following competing interests: Bristol-Myers Squibb(BMS) (employee). PP reports the following competing interests: Olink/Thermo Fisher Scientific(employee).LR reports the following competing interests: Ampel Biosolutions (Advisor or Review Panel Member); AstraZeneca (Advisor or Review Panel Member, Speaker/Honoraria); Bayer (Consultant); BMS (Advisor or Review Panel Member); UCB (Advisor or Review Panel Member). DL reports the following competing interests: AstraZeneca (Advisor or Review Panel Member).

This study was supported by the Gustaf Prim Foundation, the Swedish Society for Medical Research (S20-0127), the Swedish Research Council for Medicine and Health, the Swedish Rheumatism Association, King Gustaf V 80‐Year Foundation, the Swedish Society of Medicine, the Agnes and Mac Rudberg Foundation, the Ingegerd Johansson donation, the Gustafsson Foundation, the Selander Foundation and the County Council of Uppsala.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The protocol for this study was approved by the Regional Ethical Review Board, Uppsala (DNR 2009/013 and 2020-05065) and the local ethics committees. Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District have provided ethical approval for the FinnGen project.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All public datasets used in this study are available for download from the FinnGen consortium (https://r5.finngen.fi/). As the data from the clinical cohort includes detailed genetic and clinical information, it cannot be openly shared. However, summary-level data and certain aggregated results may be made available upon reasonable request to qualified researchers, provided that the request complies with the ethical approvals and data sharing policies of the relevant institutions. Please contact the corresponding author for further information.