Yin-Cheng Wang, Kai-Ming Liu, Yu‐Ling Gan, Nai‐Fang Chi, Liang-Suei Lu, Che-Yu Chou, Liang-Yun Wang, Li-Hsin Chang, Ming-Chih Hou, Yun‐Ching Fu, Jeng-Fong Chiou, Ming‐Shiang Wu, Shun‐Fa Yang, See-Tong Pang, Jaw-Yuan Wang, Yi-Ting Tsai, Chih‐Yang Huang, Kuan‐Ming Chiu, Ming Chen, Fu‐Tien Chiang, Chih‐Hung Wang, Wei-Jen Yao, S. Lee, Chi‐Hung Huang, Yo‐Tsen Liu, Shuu-Jiun Wang, Wen‐Ya Ko, Chien-Hsiun Chen, I‐Hui Lee
BACKGROUND AND OBJECTIVES: Genome-wide association studies (GWASs) have identified common genetic risk loci for ischemic stroke (IS), primarily in European populations older than 55 years. We aimed to identify common and rare risk variants associated with early-onset IS (ages 18-54) in Taiwan. METHODS: We conducted GWASs of early-onset and all IS cases, compared with stroke-free controls of Han ethnicity, using the Taiwan Precision Medicine Initiative database, which includes individuals from general outpatient clinics across 16 medical centers. To explore the functional relevance of stroke-associated variants, we investigated fine-mapping and linkage disequilibrium patterns, phenotype correlations using the TOAST etiologic classification in an independent IS cohort, phenome-wide association studies (PheWASs), and pathway enrichment analysis. Furthermore, we examined rare pathogenic variants using whole-exome sequencing in consecutive, unrelated early-onset sporadic and/or familial stroke probands. RESULTS: ). DISCUSSION: Our study identifies a novel age-specific genetic hotspot for IS at chromosome 19p13.12 in Han Chinese. Together with enrichment of subtype-specific rare pathogenic variants, these findings reveal a distinct genetic architecture underlying early-onset stroke in East Asians.