<p>Large-scale genetic studies of treatment-resistant depression (TRD) have been performed majority on European ancestry cohorts, potentially missing important population-specific biological insights. Understanding the genetic predisposition for TRD across populations could provide insights for etiologic heterogeneity. Conducting a cohort study of 106,796 unrelated participants using Taiwan Biobank (TWBB), we investigated the association of polygenic score (PGS) with the development of TRD among patients with depression and explore the concordance of the PGS association between East Asian and European populations. Three binary outcomes were defined, including TRD vs. non-major depressive disorder (MDD), treatment responsive MDD (trMDD) vs. non-MDD, and TRD vs. trMDD. Six PGSs belong to personality domains (nervous, worry, guilty feelings, neuroticism, tense, and worry embarrassment) and compulsive PGS were associated with TRD vs. trMDD in TWBB. The pattern of association was consistent across TRD definitions with different dose, duration, and interrupted window for antidepressant treatment. The estimated strength of PGS association in TWBB is consistent with that in All of US (AoU) (meta-analytic R² was 68% for TRD vs. non-MDD, 81% for trMDD vs. non-MDD, and 77% for TRD vs. trMDD). PGSs for temperament and education were associated with TRD vs. trMDD in AoU but not in TWBB. There was a moderate to high trans-ancestry concordance for the genetic estimates with TRD, while PGS association for specific traits were not transferable between East Asian and European populations. Genetic research across ancestries and geographic regions is crucial to learn population-specific etiology.</p>