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Metabolic syndrome (MetS) is a collection of cardiovascular risk factors; however, the high prevalence and heterogeneity impede effective clinical management. We conducted unsupervised clustering on individuals from UK Biobank to reveal endotypes. Five MetS subgroups were identified: Cluster 1 (C1): non-descriptive, Cluster 2 (C2): hypertensive, Cluster 3 (C3): obese, Cluster 4 (C4): lipodystrophy-like, and Cluster 5 (C5): hyperglycemic. For all of the endotypes, we identified the corresponding cardiometabolic traits and their associations with clinical outcomes. Genome-wide association studies (GWASs) were conducted to identify associated genotypic traits. We then determined endotype-specific genotypic traits and constructed polygenic risk score (PRS) models specific to each endotype. GWAS of each MetS clusters revealed different genotypic traits. C1 GWAS revealed novel findings of TRIM63 , MYBPC3 , MYLPF , and RAPSN . Intriguingly, C1, C3, and C4 were associated with genes highly expressed in brain tissues. MetS clusters with comparable phenotypic and genotypic traits were identified in Taiwan Biobank., Competing Interests: All authors declare no competing interests., (© 2024 Institute of Biomedical Sciences, Academia Sinica, Taiwan.)

To explore the complex genetic architecture of common diseases and traits, we conducted comprehensive PheWAS of ten diseases and 34 quantitative traits in the community-based Taiwan Biobank (TWB). We identified 995 significantly associated loci with 135 novel loci specific to Taiwanese population. Further analyses highlighted the genetic pleiotropy of loci related to complex disease and associated quantitative traits. Extensive analysis on glycaemic phenotypes (T2D, fasting glucose and HbA 1c ) was performed and identified 115 significant loci with four novel genetic variants (HACL1, RAD21, ASH1L and GAK). Transcriptomics data also strengthen the relevancy of the findings to metabolic disorders, thus contributing to better understanding of pathogenesis. In addition, genetic risk scores are constructed and validated for absolute risks prediction of T2D in Taiwanese population. In conclusion, our data-driven approach without a priori hypothesis is useful for novel gene discovery and validation on top of disease risk prediction for unique non-European population., (© 2022. The Author(s).)