This study identifies a novel age-specific genetic hotspot for ischemic stroke at chromosome 19p13.12 in Han Chinese, and together with enrichment of subtype-specific rare pathogenic variants, reveals a distinct genetic architecture underlying early-onset stroke in East Asians.
Key Findings
Results
A novel risk locus on chromosome 19p13.12 near CYP4F3 was robustly associated with early-onset ischemic stroke in Han Chinese.
The lead SNP rs541118668 (CYP4F3) showed OR 1.69, 95% CI 1.44–1.98; p = 6.86 × 10⁻¹¹
Analysis compared 5,546 early-onset IS cases vs 143,017 controls (mean age: 52.7 vs 40.6 years; female: 45.6% vs 58.7%)
Early-onset IS was defined as ages 18–54 years
The novel SNPs clustered on chromosome 19p13.12
PheWAS of the risk variants revealed explicit associations with cerebrovascular diseases and no associations with other diseases
Results
In the all-IS GWAS, the CYP4F3 locus and 6 other loci were significantly associated with ischemic stroke, including one previously reported East Asian locus near FGF5.
All-IS analysis included 21,544 cases vs 267,198 controls (mean age: 69.5 vs 53.7 years; female: 43.2% vs 55.5%)
Seven loci total reached genome-wide significance in the all-IS analysis
The previously reported rs12509595 (near FGF5) showed OR 1.06, 95% CI 1.04–1.08; p = 2.74 × 10⁻⁸ in East Asians
Data were drawn from the Taiwan Precision Medicine Initiative database across 16 medical centers
Results
Novel SNPs at chromosome 19p13.12 were specifically associated with the small vessel occlusion (SVO) subtype of ischemic stroke.
Association with SVO subtype was validated in an independent IS cohort of n = 716 patients (p < 0.05)
Subtype classification used the TOAST etiologic classification system
Fine-mapping and linkage disequilibrium patterns were investigated to explore functional relevance
Results
Pathway enrichment analysis implicated CYP4F3 in lipid metabolism and inflammatory responses as mechanisms underlying the novel stroke risk locus.
Enrichment pathway analysis was conducted to explore functional relevance of stroke-associated variants
CYP4F3 was implicated in both lipid metabolism and inflammatory response pathways
PheWAS showed associations of risk variants were specific to cerebrovascular diseases
Results
15.6% of unrelated early-onset ischemic stroke probands carried likely pathogenic rare variants identified by whole-exome sequencing.
28 of 180 unrelated probands with early-onset IS carried likely pathogenic variants (15.6%)
16 of 85 sporadic stroke probands (18.8%) and 12 of 87 familial stroke probands (13.8%) carried likely pathogenic variants
Probands were consecutive and unrelated early-onset sporadic and/or familial stroke cases
Rare variants were particularly enriched in those with SVO subtype: NOTCH3, HTRA1, HBB, GJA1, and GP1BA
Rare pathogenic variants associated with cerebral venous infarction included PROS1 and F2
Discussion
The genetic architecture of early-onset ischemic stroke in Han Chinese is distinct from that identified in European populations and older age groups.
Prior GWASs have identified common genetic risk loci for IS primarily in European populations older than 55 years
The CYP4F3 locus represents an age-specific genetic hotspot not previously reported
The study used the Taiwan Precision Medicine Initiative database including individuals from general outpatient clinics
Both common variant (GWAS) and rare variant (whole-exome sequencing) approaches were used to characterize the genetic architecture
What This Means
This research suggests that stroke occurring in younger adults (ages 18–54) in Taiwan has a unique genetic basis compared to stroke in older adults or in European populations. The researchers analyzed genetic data from tens of thousands of Han Chinese individuals and discovered a previously unknown region of the genome — near a gene called CYP4F3 on chromosome 19 — that significantly increases the risk of early-onset stroke. This gene appears to be involved in how the body processes fats and manages inflammation. The association was particularly strong for a type of stroke caused by blockage of small blood vessels in the brain.
In addition to this common genetic variant, the study also used a technique called whole-exome sequencing to look for rare but highly impactful genetic mutations in 180 young stroke patients. They found that about 1 in 6 of these patients carried a likely disease-causing mutation in genes already known to affect blood vessel health or blood clotting (such as NOTCH3, HTRA1, HBB, GJA1, GP1BA, PROS1, and F2). These rare variants were especially common in patients whose stroke was caused by small vessel disease or blockage of the veins in the brain.
These findings matter because they suggest that stroke in younger East Asian adults has a distinct genetic profile that is not captured by studies focused on older or European populations. Identifying these genetic risk factors could eventually help clinicians identify young people at elevated risk before they have a stroke, and may point toward biological pathways — like lipid metabolism and inflammation — that could be targeted for prevention or treatment.
Wang Y, Liu K, Gan Y, Chi N, Lu L, Chou C, et al.. (2026). Identification of Novel Genetic Risk Variants Associated With Early-Onset Ischemic Stroke in Taiwan.. Neurology. https://doi.org/10.1212/WNL.0000000000218126