Article Figures & Data
- Figure 1
Overview of the present study. (A) Flow chart for the study population; (B) Study design. The current study can be divided into four parts: (1) validation of previous PRSs, (2) development of new PRSs, (3) identification of the optimal PRS for each outcome and (4) validation and evaluation of the optimal PRS for each outcome. aParticipants who had a first or second-degree relative in the sample (kinship coefficient φ>0.125) were removed by using PLINK 1.9. bPlease refer to online supplemental methods for detailed procedures of case-control matching. cSee online supplemental methods and table 3 for details. dSee online supplemental methods and table 4 for details. AS, any stroke; C+T, clumping and thresholding; CAD, coronary heart disease; CKB, China Kadoorie Biobank; GWAS, genome-wide association study; ICH, intracerebral haemorrhage; IS, ischaemic stroke; PRS, polygenic risk score; SAH, subarachnoid haemorrhage; SSF, summary statistics file; TIA, transient ischaemic attack.
- Figure 2
Associations of PRSs with risks of stroke and its subtypes. (A) AS, (B) IS, (C) ICH, (D) SAH. The PRSs reported here are the optimal PRSs for stroke and its subtypes in the training sets (see table 1), which were standardised (0 mean, unit SD) in the testing set. Cox models were stratified by sex and 10 study regions and adjusted for the top 10 principal components of ancestry and array versions, with age as the time scale. The number above the closed square represents the HR. The number of stroke events in women and men has been reported in table 2. The vertical lines indicate 95% CIs. AS, any stroke; ICH, intracerebral hemorrhage; IS, ischaemic stroke; PRS, polygenic risk score; SAH, subarachnoid haemorrhage.
- Figure 3
C statistics evaluating the performance of PRS. The traditional risk prediction models (traditional models) were defined as sex-specific Cox models stratified by 10 study regions, with time on study as the time scale, including models for ischaemic stroke (ICD-10: I63) and models for haemorrhagic stroke (ICD-10: I60–I62).18 Predictors included in traditional models were the same as the ‘CKB-CVD models’, including age, systolic and diastolic blood pressure, use of antihypertensives, current daily smoking, self-reported diabetes and waist circumference. Interactions between age and the other six predictors were also included. The 95% CIs of Harrell’s C and Harrell’s C changes were calculated by 100 bootstrap replications using the BCa method in Stata. CKB, China Kadoorie Biobank; CVD, Cardiovascular disease; ICD, International Classification of Disease; PRS, Polygenic risk score.
- Table 1
The optimal PRSs associated with risks of stroke and its subtypes in the training sets
Outcomes Method PRS source* No of variants ORSD (95% CI) P value Note Any stroke (N=7412 pairs) Previous study PGS002259 448 1.13 (1.09 to 1.16) 1.44×10–11 C+T GCST005838 (p=1×10-6, r2=0) 38 1.11 (1.07 to 1.14) 1.90×10–9 LDpred GCST005838 (ρ=0.01, Ref=1KGP-EAS) 1 017 531 1.14 (1.10 to 1.18) 3.38×10–14 Optimal Ischaemic stroke (N=3844 pairs) Previous study PGS000039 1 563 569 1.07 (1.01 to 1.12) 0.012 C+T GCST90018864 (p=0.02, r2=0.8) 32 158 1.18 (1.13 to 1.24) 3.55×10–11 Optimal LDpred GCST90018864 (ρ=0.01, Ref=1KGP-EUR) 1 017 672 1.17 (1.11 to 1.23) 1.46×10–9 Intracerebral haemorrhage (N=4296 pairs) C+T GCST90018870 (p=0.001, r2=0.2) 1326 1.09 (1.04 to 1.14) 1.37×10–4 LDpred GCST90018870 (ρ=0.1, Ref=1KGP-EUR) 1 017 664 1.10 (1.05 to 1.15) 3.09×10–5 Optimal Subarachnoid haemorrhage (N=359 pairs) C+T GCST90018703 (p=0.4, r2=0) 7899 1.25 (1.06 to 1.47) 9.21×10–3 Optimal LDpred GCST90018923 (ρ=0.01, Ref=1KGP-EUR) 1 017 665 1.15 (0.98 to 1.35) 0.096 The current table only displays the optimal PRS obtained from different strategies (previous study, C+T and LDpred) for each disease outcome. The detailed results of all PRSs can be found in online supplemental table 7.
*'PGS’ indicates the index in the PGS Catalogue. ‘GCST’ indicates the index in the GWAS Catalogue. The information in brackets is the parameter used for developing the PRS.
C+T, clumping and thresholding; EAS, East Asian; EUR, European; 1KGP, 1000 Genomes Project (Phase 3); PRS, polygenic risk score; Ref, reference population.
- Table 2
Characteristics of the testing set
Women Men No of participants 43 170 28 980 Baseline characteristics Age, years 50.6 (42.5–58.3) 51.9 (43.2–60.3) Rural areas 22 449 (52.0) 15 772 (54.4) Array 1 5948 (13.8) 4503 (15.5) Primary school and below 23 605 (54.7) 11 882 (41.0) Daily smokers 915 (2.1) 16 317 (56.3) Body mass index, kg/m2 23.6 (21.4–26.0) 23.3 (21.1–25.7) Waist circumference, cm 78.0 (72.0–84.5) 81.5 (74.5–88.5) Hypertension 14 062 (32.6) 10 653 (36.8) Diabetes 2477 (5.7) 1553 (5.4) Family history of stroke 7619 (17.6) 5075 (17.5) Follow-up Follow-up time, years 12.6 (11.7–13.4) 12.4 (11.4–13.3) Total person-years* 529 498 343 421 Incident events† Any stroke 4763 (11.0) 3751 (12.9) Ischaemic stroke 4254 (9.9) 3253 (11.2) Intracerebral haemorrhage 600 (1.4) 593 (2.0) Subarachnoid haemorrhage 87 (0.2) 45 (0.2) Data are presented as n (%) or median (25th–75th percentile) unless otherwise specified.
*Person-years were calculated as the time from the baseline date to the first of the following: death, lost to follow-up or the global censoring date (31 December 2018).
†Only the first event was counted.
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