Polygenic Risk Scores Linked to Specific SLE Manifestations, With Matthew Dapas, PhD

In an interview with HCPLive, Matthew Dapas, PhD, of Northwestern University, discussed recent findings on polygenic risk scores for systemic lupus erythematosus (SLE), presented at the American College of Rheumatology Convergence (ACR) 2025. The study evaluated associations between genetic risk and clinical features derived from electronic health records across more than 32,000 participants in the Electronic Medical Records and Genomics Network.

One advantage of this study was the large database. The polygenic risk score was derived using summary statistics from a genome-wide association study of 6748 lupus cases and 11,516 controls of European ancestry.

“The reality of the genetics of these diseases is that it's not one gene that causes a disease, but it's actually a constellation of very small effects that just are enough to tip the scales in one direction or the other,” Dapas told HCPLive. “So, to identify those really small effects, you need really large databases. There's a number of large efforts, and [in] the United States… where we're trying to generate whole genome sequencing for millions of individuals to derive new discoveries and genetics because the more the more people you have in a database, the more accurate model you can build, more effective the implementation of that model will be in a clinical setting, and the better outcomes that leads.”

In the Northwestern cohort (n = 1061), the polygenic risk score predicted SLE with an area under the receiver operating characteristic curve of 0.724 and was significantly associated with both localized and systemic lupus (P = 1.6×10^-9) and systemic lupus erythematosus (P = 3.0×10^-9). Additional nominal associations were observed for cardiac complications (P = 2.8×10^-3) and impaired renal function (P = 4.6×10^-3), with enrichment for circulatory system (P = 9.7×10^-5) and hematopoietic traits (P = 3.2×10^-2).

Genetic risk was further associated with several individual Systemic Lupus International Collaborating Clinics criteria, including acute cutaneous lupus, thrombocytopenia, leukopenia, and low complement levels. Low complement was observed in 55% of patients in the highest polygenic risk score decile, compared with 30% in the lowest decile, suggesting that greater genetic risk may be linked to specific immunological features.

Dapas emphasized that although polygenic risk scores are not yet part of routine clinical practice, they have the potential to support risk assessment. Dapas noted that high-quality clinical data and patient evaluation, combined with expanding genomic databases, can help train risk models.

“I anticipate that's something that will become routine in the not-too-distant future,” he said. “One important thing to keep in mind, as a medical geneticist, [is that] we rely so much on that fundamental interaction between clinician and patient.”

He said this helps us train genetic risk models, which rely on accurate phenotyping and accurate classification

“Logging of data into a database that is then used for research is so essential, because without accurate workups of patients, it all kind of falls apart,” Dapas said. “In all my work, I work closely with a team of clinicians, and it really is kind of a symbiotic relationship. It's a whole network of individuals with different sets of expertise, working together to try and improve outcomes for patients with the disease. I appreciate what the clinicians do, and I hope, through this work and other geneticists, that we can collectively move the needle on some of these diseases.”

Dapas has no relevant reported disclosures.

References

1. Forrest N, Tuteja S, Pacheco J, Mitrovic V, Ramsey-Goldman R, Walunas T, Dapas M. Polygenic risk of lupus is differentially associated with individual EHR-derived classification criteria [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/polygenic-risk-of-lupus-is-differentially-associated-with-individual-ehr-derived-classification-criteria/. Accessed November 24, 2025.

2. Dapas M. Polygenic Risk Scores Reveal Genetic Drivers of Lupus Heterogeneity, With Matthew Dapas, PhD. HCPLive. November 24, 2025. https://www.hcplive.com/view/polygenic-risk-scores-reveal-genetic-drivers-lupus-heterogeneity-matthew-dapas-phd. Accessed December 3, 2025.