台湾早发性缺血性卒中新遗传风险变异识别

原文

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: We identified a robust association between a novel risk locus and early-onset IS (5,546 cases vs 143,017 controls; mean age: 52.7 vs 40.6 years; female: 45.6% vs 58.7%), including the lead single-nucleotide polymorphism (SNP) rs541118668 (CYP4F3) (OR 1.69, 95% CI 1.44-1.98; p = 6.86 × 10-11). In patients with all IS (21,544 cases vs 267,198 controls; mean age: 69.5 vs 53.7 years; female: 43.2% vs 55.5%), this locus and 6 other loci, including the reported rs12509595 (near FGF5) (OR 1.06, 95% CI 1.04-1.08; p = 2.74 × 10-8) in East Asians, were significantly associated. The novel SNPs clustered on chromosome 19p13.12 and were associated with the small vessel occlusion (SVO) subtype in the independent IS cohort (n = 716, p < 0.05). The PheWASs of the risk variants revealed explicit associations with cerebrovascular diseases and no associations with other diseases. The enrichment pathway implicated CYP4F3 in lipid metabolism and inflammatory responses. Moreover, we discovered that 28 of 180 unrelated probands with early-onset IS (15.6%; 16/85 sporadic and 12/87 familial stroke) carried likely pathogenic variants, particularly those with SVO (NOTCH3, HTRA1, HBB, GJA1, and GP1BA) and cerebral venous infarction (PROS1 and F2). 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.