Polygenic risk scores for prediction of immune checkpoint inhibitor thyroid toxicity in diverse populations

BACKGROUND: Immune checkpoint inhibitor (ICI)-induced thyroiditis is a common immune-related adverse event (irAE) linked to improved survival. Polygenic risk scores (PRSs) for autoimmune hypothyroidism predict thyroid irAEs in European-ancestry patients; performance in non-European populations is unclear. METHODS: In the Veterans Affairs Million Veteran Program (2011-2023), we identified ICI-treated patients with germline genotyping and a chemotherapy-treated control cohort, excluding those with thyroid disease or prior thyroid-directed treatments. Harmonized ancestry and race (HARE) defined Non-Hispanic White (NHW) and Black (NHB) groups. Thyroid irAEs within one year were defined using laboratory criteria capturing both hyperthyroid and hypothyroid phases. We compared two PRSs: a published European-derived PRS, and an updated PRS selected across multiple GWAS sources and methods (including MVP multi-ancestry GWAS) to maximize discrimination in African-ancestry individuals in a held-out test set. HARE-stratified multivariable Cox models estimated time to thyroiditis; a 6-month landmark analysis assessed overall survival. RESULTS: The ICI cohort included 4,289 patients (3,473 NHW; 816 NHB). The baseline PRS was associated with thyroiditis in NHW (adjusted hazard ratio [aHR] per SD 1.33, 95% CI 1.19-1.50) but not NHB patients or controls. The updated PRS improved risk stratification in NHW (aHR 1.45, 1.28-1.63) and predicted thyroiditis in NHB patients (aHR 1.48, 1.11-1.98), but not in controls. Thyroiditis within 6 months was associated with improved survival, but neither PRS was. CONCLUSIONS: Germline polygenic liability to hypothyroidism predicts ICI-induced thyroiditis in NHW and NHB patients when PRSs are selected via ancestry-stratified validation. Careful exploration of the dataset-method space is critical for equitable PRS development.