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. 2025 Jul 22;105(2):e213832.
doi: 10.1212/WNL.0000000000213832. Epub 2025 Jun 27.

Genetic Risk and Prognosis of the First Incident Stroke Survivors: Findings from China Kadoorie Biobank and UK Biobank

Yuting Han  1 , Hongjing Shi  1 , Canqing Yu  1   2   3 , Pei Pei  2 , Ling Yang  4 , Iona Y Millwood  4 , Robin G Walters  4 , Yiping Chen  4 , Huaidong Du  4 , Meiyu Guan  5 , Daniel Avery  4 , Junshi Chen  6 , Zhengming Chen  4 , Liming Li  1   2   3 , Dianjianyi Sun  1   2   3 , Jun Lv  1   2   3   7 ; China Kadoorie Biobank Collaborative Group
Affiliations

Genetic Risk and Prognosis of the First Incident Stroke Survivors: Findings from China Kadoorie Biobank and UK Biobank

Yuting Han et al. Neurology. .

Abstract

Background and objectives: Stroke is known for its poor prognosis. Although genetic instruments have shown promise in stratifying first stroke risk in the general population, it is unknown whether they are associated with stroke prognosis. Our study aims to explore the role of genetic risk of stroke in the progression from stroke-free to first stroke and then to recurrent stroke, subsequent coronary heart disease (CHD), and death in China and the United Kingdom.

Methods: We used data from 2 prospective population-based cohorts, China Kadoorie Biobank (CKB) and UK Biobank (UKB). Participants who were unrelated and free of stroke and CHD at baseline were included. Genetic risks of stroke were quantified using integrative polygenic risk scores (iPRSs), which incorporated summary statistics from multiple genome-wide association studies for stroke outcomes and its subtypes, and vascular-risk traits. We used a multistate model to analyze the roles of genetic risk in the transitions from baseline to first incident stroke and then to recurrent stroke, subsequent CHD, and death.

Results: Our study included 80,908 CKB participants and 380,348 UKB participants, with mean ages (% female) of 54.0 years (58.6%) and 56.1 years (55.4%). During median follow-ups of 11.9 years and 13.4 years in the CKB and UKB, respectively, 13,481 and 5,772 participants had their first stroke, neither experienced a CHD, or died within 28 days. These survivors had 5,707 and 943 recurrent strokes, as well as 1,196 and 418 CHD events, respectively. iPRSs were associated with recurrent stroke and CHD among stroke survivors in both populations. The corresponding hazard ratios (HRs) and 95% CIs per SD of iPRSs were 1.08 (1.05-1.11) and 1.08 (1.02-1.15) in CKB and 1.11 (1.03-1.19) and 1.23 (1.10-1.37) in UKB, respectively. There was no association between iPRSs and mortality risk. When we further divided the first stroke into 4 pathologic subtypes, both populations revealed statistically significant associations between iPRSs and the transitions from first ischemic stroke to recurrent stroke and CHD.

Discussion: Our study shows that the genetic risk of first stroke also influences the prognosis of stroke survivors, indicating that PRS has the potential to improve stroke prognosis.

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Conflict of interest statement

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Study Design
CHD = coronary heart disease; ICH = intracerebral hemorrhage; IS = ischemic stroke; SAH = subarachnoid hemorrhage.
Figure 2
Figure 2. Hazard Ratios (95% CIs) for Transition Pattern A Per SD of the Integrative Polygenic Risk Score
iPRS refers to meta-PRS that incorporates GWASs for stroke and vascular risk factors. Cox models were stratified by age in the five-year group and 10 study regions (for CKB only) and adjusted for sex, principal components of ancestry (the first 5 for CKB and the first 10 for UKB), and genotyping array (for CKB only). CHD = coronary heart disease; CKB = China Kadoorie Biobank; iPRS = integrative polygenic risk score; UKB = UK Biobank.
Figure 3
Figure 3. Cumulative Incidence of Recurrent Stroke and Coronary Heart Disease Since 28 Days After the First Stroke
The cumulative incidence was estimated using the Fine-Gray subdistribution hazard model, with recurrent stroke, coronary heart disease, and death as competing events. Estimations were performed separately for high genetic risk (upper quartile of integrative polygenic risk score) and low genetic risk (lower quartile) according to the integrative polygenic risk score. All covariates were set to the population-average level. The values in the table are cumulative incidences of recurrent stroke and coronary heart disease at each year since the 28 days after the first stroke. CKB = China Kadoorie Biobank; UKB = UK Biobank.
Figure 4
Figure 4. Hazard Ratios (95% CIs) for Transition Pattern B Per SD of Integrative Polygenic Risk Score
iPRS refers to meta-PRS that incorporates GWASs for stroke and vascular risk factors. Cox models were stratified by age in the five-year group and 10 study regions (for CKB only) and adjusted for sex, principal components of ancestry (the first 5 for CKB and the first 10 for UKB), and genotyping array (for CKB only). CHD = coronary heart disease; CKB = China Kadoorie Biobank; ICH = intracerebral hemorrhage; iPRS = integrative polygenic risk score; IS = ischemic stroke; SAH = subarachnoid hemorrhage; UKB = UK Biobank
Figure 5
Figure 5. Cumulative Incidence of Recurrent Stroke and Coronary Heart Disease Since 28 Days After the First Ischemic Stroke
The cumulative incidence was estimated using the Fine-Gray subdistribution hazard model, with recurrent stroke, coronary heart disease, and death as competing events. Estimations were performed separately for high genetic risk (upper quartile of integrative polygenic risk score) and low genetic risk (lower quartile) according to the integrative polygenic risk score. All covariates were set to the population-average level. The values in the table are cumulative incidences of recurrent stroke and coronary heart disease at each year since the 28 days after the first ischemic stroke. CKB = China Kadoorie Biobank; UKB = UK Biobank.
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