Circulation

ORIGINAL RESEARCH ARTICLE

Clinical Application of a Novel Genetic Risk

Score for Ischemic Stroke in Patients With
Cardiometabolic Disease

BACKGROUND: Genome-wide association studies have identified single- Nicholas A. Marston ,

nucleotide polymorphisms that are associated with an increased risk of stroke. MD, MPH*
We sought to determine whether a genetic risk score (GRS) could identify Parth N. Patel, MD*
subjects at higher risk for ischemic stroke after accounting for traditional clinical ⁝
risk factors in 5 trials across the spectrum of cardiometabolic disease. Steven A. Lubitz , MD,
MPH†
METHODS: Subjects who had consented for genetic testing and who were of Marc S. Sabatine , MD,
European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with MPH†
Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Christian T. Ruff , MD,
Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular MPH†
Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54
(Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using
Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER
Downloaded from http://ahajournals.org by on November 23, 2023

(Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With

Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide
polymorphisms associated with ischemic stroke was used to calculate a GRS in
each patient and identify tertiles of genetic risk. A Cox model was used to calculate
hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk
factors.

RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an
ischemic stroke over a median follow-up period of 2.5 years. After adjusting for
clinical risk factors, a higher GRS was strongly and independently associated with
increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in
the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had
adjusted hazard ratios of 1.15 (95% CI, 0.98–1.36) and 1.24 (95% CI 1.05–1.45)
for ischemic stroke, respectively. Stratification into subgroups revealed that the
performance of the GRS appeared stronger in the primary prevention cohort with an
*Drs Marston and Patel contributed
adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04–1.53), equally.
in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81–1.41) in subjects
†Drs Lubitz, Sabatine, and Ruff
with previous stroke. In an exploratory analysis of patients with atrial fibrillation and contributed equally.
CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke The full author list is available on page 476.
and an absolute risk equivalent to those with CHA2DS2-VASc score of 3.
Key Words: atrial fibrillation
◼ ischemic stroke ◼ genetics
CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic ◼ genomics ◼ stroke
disease, a 32–single-nucleotide polymorphism GRS was a strong, independent
Sources of Funding, see page 476
predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-
VASc scores, the GRS identified patients with risk comparable to those with © 2020 American Heart Association, Inc.

higher CHA2DS2-VASc scores. https://www.ahajournals.org/journal/circ

470 February 2, 2021 Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927

 Marston et al
Clinical Perspective
What Is New?
• This is the first study to show that a genetic risk
score remains an independent predictor of isch-
emic stroke in subjects who are older and have
established cardiometabolic disease.
• The genetic risk score demonstrated stronger risk
prediction in subjects without previous stroke and
in those with a lower burden of clinical risk factors.
What Are the Clinical Implications?
• Genetics may help refine stroke prediction in
patients at apparent low clinical risk.
• Further studies should focus on whether patients
with atrial fibrillation and CHA2DS2-VASc scores of
0 to 1 but high genetic risk would benefit from
anticoagulation therapy.
I
schemic stroke, a sudden neurological deficit caused
by an interruption of cerebral blood flow, remains a
leading cause of morbidity and mortality worldwide.1
Although several traditional risk factors such as hyper-
tension, diabetes, and heart failure exhibit strong asso-
ciations with ischemic stroke, a substantial proportion
of ischemic stroke risk remains unexplained.2–4 Multiple
lines of evidence suggest that heritable factors may
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contribute to the development of ischemic stroke,5,6
with some reports estimating that 30% to 40% of
variability in ischemic stroke risk can be explained by
genetic variation.7 Over the past decade, advances in
molecular genetics have better defined the genetic ar-
chitecture underlying risk for ischemic stroke, bringing
further attention to this underappreciated component
of stroke susceptibility.8
Genetic risk scores represent a method of sum-
mating an individual’s genetic propensity for a given
phenotype and have garnered interest for their po-
tential to improve risk prediction in many common
diseases.9–11 Despite promise in other conditions, early
attempts at using a genetic risk score (GRS) for isch-
emic stroke showed limited predictive ability,12–14 pos-
sibly because of the fewer number of stroke suscep-
tibility loci identified and the biological heterogeneity
of ischemic stroke. In the wake of the MEGASTROKE
meta-analysis of genome-wide association studies,15
multiple groups have developed genetic risk scores
with increased predictive power.16,17 Whether a GRS
can predict ischemic stroke risk across a diverse group
of patients with cardiovascular disease, after fully ad-
justing for clinical risk factors including atrial fibrilla-
tion, is still not known.
We sought to determine whether a GRS could iden-
tify subjects at higher risk for ischemic stroke after
Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927
Novel Genetic Risk Score Predicts Ischemic Stroke
accounting for traditional clinical risk factors in 5 tri-
ORIGINAL RESEARCH
als across the spectrum of cardiometabolic disease. We
quantified the level of risk conferred by each genetic
ARTICLE
risk tertile, compared the magnitude of risk provided by
high genetic risk with that provided by well-established
clinical risk factors, and investigated GRS performance
across key subgroups. Last, we explored whether genet-
ic risk classification could refine stroke risk prediction in
patients with atrial fibrillation, with specific attention to
those with lower CHA2DS2-VASc scores in whom high
genetic risk might inform the decision about initiating
anticoagulation.
METHODS
Study Design and Population
We performed a genetic cohort analysis pooling individ-
ual patient-level data from 5 cardiovascular clinical trials:
ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor
Xa Next Generation in Atrial Fibrillation),18 SOLID-TIMI 52
(Stabilization of Plaques Using Darapladib),19 SAVOR-TIMI
53 (Saxagliptin Assessment of Vascular Outcomes Recorded
in Patients with Diabetes Mellitus),20 PEGASUS-TIMI 54
(Prevention of Cardiovascular Events in Patients With
Prior Heart Attack Using Ticagrelor Compared to Placebo
on a Background of Aspirin),21 and FOURIER (Further
Cardiovascular Outcomes Research With PCSK9 Inhibition
in Patients With Elevated Risk).22 The study population rep-
resents a broad spectrum of cardiovascular disease including
established atherosclerosis, previous myocardial infarction,
diabetes, and atrial fibrillation. Brief descriptions of each
trial are listed in the Appendix in the Data Supplement.
Patients who consented for genetic analysis, passed qual-
ity control, and were of European ancestry were included.
Baseline characteristics for each trial are listed in Table I in
the Data Supplement.
Study protocols were approved by the institutional
review board or ethics committee at each participating site.
All subjects provided written informed consent. We encour-
age parties interested in collaboration and data sharing
to contact the corresponding author directly for further
discussions.
Genotyping and Imputation
Methods for genotyping and imputation have previously
been published.11 Genotyping was performed using the
Illumina Multi-Ethnic Genotyping Array (ENGAGE AF-TIMI
48, SAVOR-TIMI 53, and PEGASUS-TIMI 54), Affymetrix
Biobank Array (SOLID-TIMI 52), and Infinium Global Array
(FOURIER). Preimputation quality control was performed
using PLINK v2.0,23 followed by imputation using the
Michigan Imputation server24 and TOPMed Freeze5 refer-
ence panel.25 Postimputation quality control was performed,
followed by identification of patients with European ances-
try using the 1000 Genomes phase 3 v5 reference panel26
and ADMIXTURE tool.27
February 2, 2021 471
 Marston et al
Genetic Risk Score
ORIGINAL RESEARCH
The GRS for ischemic stroke was based on all 32 genome-
wide associated single-nucleotide polymorphisms (SNPs) from
ARTICLE
MEGASTROKE,15 listed in Table II in the Data Supplement. In
cases where the risk variant was not available, proxy SNPs
were used to complete the set of 32 SNPs.28,29 With the use
of PLINK v2.0, the GRS was calculated for each patient by
multiplying the imputed allelic dosage with the variant-spe-
cific weight (β-coefficient for the association between the
SNP and ischemic stroke) based on MEGASTROKE,15 and then
summing across all variants. Patients were assigned into low,
intermediate, and high genetic risk for ischemic stroke based
on tertiles.
Clinical End Point and Follow-Up
The end point of interest was ischemic stroke. In each trial,
ischemic stroke was formally adjudicated by an independent
clinical end point committee blinded to treatment assign-
ment. The median follow-up across trials ranged from 2.2
to 2.9 years.
Statistical Analysis
Individual patient-level data were pooled from the 5 clinical
trials. Analyses were performed in the overall genetic cohort,
primary versus secondary prevention cohorts, clinical sub-
groups of interest, the ENGAGE AF-TIMI 48 trial (all with atrial
fibrillation), and across a range of CHADSVASc scores in those
with and without atrial fibrillation.30 Time-to-event data were
used to create Kaplan-Meier curves. Cox proportional hazard
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models were used to calculate hazard ratios (HRs) for ischemic
stroke across genetic risk categories. Schoenfeld residuals
were used to test proportional hazards assumptions that were
met. Analyses were adjusted for age, sex, genetic ancestry (by
principal components 1–5), and clinical comorbidities includ-
ing hypertension, hyperlipidemia, diabetes, smoking, vascular
disease, congestive heart failure, and atrial fibrillation. A trend
test was used to assess the difference in ischemic stroke across
genetic risk categories. With the use of the components of
the Revised Framingham Stroke Risk Score31 and geographic
region (given the global nature of these trials) for the base
model in the overall cohort, the Harrell C-index was used
to determine whether the addition of genetics (genetic risk
score and genetic ancestry) improved discrimination between
patients who experienced stroke and those who did not. The
C-index was also assessed in patients with a CHA2DS2-VASc
score of 2, along with the ability of the GRS to reclassify risk
using the net reclassification improvement at event rate.32 The
95% confidence interval for net reclassification improvement
was calculated by a resampling method. All P values were
2-sided and assessed at a threshold of 0.05.
RESULTS
Study Cohort
Across the 5 trials studied, 51 288 subjects were eli-
gible to be included in this analysis. The average age
of the study population was 65.9 years, and 28.3%
were female. Most subjects (81.7%) had coronary or
472 February 2, 2021
Novel Genetic Risk Score Predicts Ischemic Stroke
peripheral artery disease. Many had traditional clinical
risk factors for stroke, including hypertension (82.3%),
hyperlipidemia (60.2%), and diabetes (41.9%). A
smaller percentage of the cohort had previous transient
ischemic attack or stroke (14.0%), were current smok-
ers (18.2%), had atrial fibrillation (28.4%), or had a his-
tory of congestive heart failure (29.1%). A total of 960
subjects had an ischemic stroke over a median follow-
up of 2.5 years.
Identification of Genetic Risk Groups
Baseline characteristics by genetic risk tertile are shown
in the Table. Subjects in the highest tertile of the GRS
were more likely to be female, have had a previous
stroke, and have comorbidities associated with stroke
including hypertension, atrial fibrillation, and conges-
tive heart failure. The relative contribution of each trial
to each tertile of genetic risk is listed in Table I in the
Data Supplement.
Genetic Risk Predicts Ischemic Stroke
The Kaplan-Meier event rates for ischemic stroke at 3
years in the low, intermediate, and high GRS groups
were 1.95% (n=272), 2.24% (n=322), and 2.56%
(n=366), respectively (Figure 1). After adjusting for
clinical risk factors, a higher GRS remained strongly
associated with increased risk for ischemic stroke (P
trend=0.009). In comparison with patients in the low-
est GRS tertile, those in the middle tertile had an adjust-
ed HR of 1.15 (95% CI, 0.98–1.36) for ischemic stroke
and those in the top tertile had an adjusted HR of 1.24
(95% CI, 1.05–1.45). The magnitude of risk conferred
by a high GRS was comparable to the individual risk
provided from smoking, diabetes, or hypertension (Fig-
ure I in the Data Supplement). Addition of the GRS to a
Cox model of clinical variables from the Revised Fram-
ingham Stroke Risk Score plus geographic region did
not significantly increase the C-index (0.64 [0.62–0.66]
versus 0.65 [0.63–0.66]).
Among subgroups, the performance of the GRS
was stronger in the 44 095 subjects without previous
stroke (adjusted HR of top tertile versus lowest tertile,
1.27 [95% CI, 1.04–1.53]; Figure 2), with no clear
predictive utility in the 7193 subjects with previous
stroke (adjusted HR, 1.06 [95% CI, 0.81–1.41]). In
addition, risk prediction with the GRS was better in
subjects without diabetes (Pinteraction=0.002) or conges-
tive heart failure (Pinteraction=0.04) in comparison with
subjects with those conditions (Figure II in the Data
Supplement). The GRS demonstrated similar predic-
tive power across subgroups of sex and age, and in
those with and without vascular disease and atrial fi-
brillation.
Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927
 Marston et al Novel Genetic Risk Score Predicts Ischemic Stroke

Table. Baseline Characteristics by Genetic Risk Score Tertiles

ORIGINAL RESEARCH
Low genetic Intermediate High genetic
Characteristics risk genetic risk risk P value

ARTICLE
Participants 17 096 17 096 17 096
Demographics
 Age, y 66.1 (9.2) 65.9 (9.3) 65.6 (9.2) <0.001
   65–74 y 6521 (38) 6281 (37) 6272 (37) 0.007

   ≥75 y 3306 (19) 3306 (19) 3116 (18) 0.01

 Female sex 4808 (28) 4722 (28) 4989 (29) 0.005

Medical history
 Hypertension 13 749 (80) 14 110 (83) 14 350 (84) <0.001
 Hyperlipidemia 10 379 (61) 10 293 (60) 10 181 (60) 0.09
 Diabetes 7367 (43) 6989 (41) 7118 (42) <0.001
 Smoking 3062 (18) 3118 (18) 3169 (19) 0.33
 Atrial fibrillation 4300 (25) 4721 (28) 5536 (32) <0.001
 Vascular disease 14 107 (83) 14 056 (82) 13 716 (80) <0.001
 Congestive heart failure 4494 (26) 4867 (29) 5552 (33) <0.001
 Stroke/transient ischemic attack 2106 (12) 2453 (14) 2634 (15) <0.001

Values indicate n (%) or average (standard deviation). P values represent χ test for categorical variables and
2

1-way ANOVA for continuous variables.

Exploratory Analysis in ENGAGE AF-TIMI value from the GRS in subjects with fewer risk factors (P
48 trend=0.02; Figure IV in the Data Supplement).
When comparing the degree of risk stratification pro-
A total of 11 187 patients from the overall cohort were
vided by CHA2DS2-VASc in patients with differing levels
enrolled in ENGAGE AF-TIMI 48, a trial of patients with
of genetic risk, there was a steeper gradient present in
atrial fibrillation and a CHADS2 score of 2 or higher
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patients with lower genetic risk, ranging from a 0.6%

who were treated with anticoagulation. Of these, 395
(3.5%) had an ischemic stroke over a median follow-
up of 2.8 years. Even after adjusting for components of
the CHA2DS2-VASc score, patients with a high GRS were
at 29% greater risk of ischemic stroke (adjusted HR,
1.29 [95% CI, 1.01–1.64]; P=0.045) than those with
a low GRS (Figure III in the Data Supplement). The mag-
nitude of risk was beyond that of multiple components
of the CHA2DS2-VASc score such as vascular disease,
congestive heart failure, diabetes, and hypertension.
Among this atrial fibrillation cohort, the predictive
ability of the GRS was significantly stronger in patients
with lower CHA2DS2-VASc scores (P trend=0.04), includ-
ing a 4-fold increased risk in patients with a CHA2DS2-
VASc score of 2 (HR, 3.97 [95% CI, 1.04–15.2]; Fig-
ure 3). More specifically, high genetic risk identified
one-third of patients with a CHA2DS2-VASc score of
2 who had a risk of ischemic stroke equivalent to pa-
tients with a CHA2DS2-VASc score of 3. When the GRS
was applied to patients with a CHA2DS2-VASc score
of 2, the C-index went from 0.68 (0.58–0.77) to 0.84
(0.77–0.91), and the net reclassification improvement
was 0.32 (0.04–0.69), with 33% of those without
stroke correctly reclassified to a lower-risk group (Ta-
ble III in the Data Supplement). A sensitivity analysis in
patients without atrial fibrillation from the other 4 tri-
als demonstrated a similar trend of greater prognostic
rate of stroke in patients with a CHA2DS2-VASc score of
2 to a 5.5% rate of stroke in patients with a CHA2DS2-
VASc score >5 (P trend<0.001). In patients with high
genetic risk, a more modest increase in absolute stroke
risk was observed, ranging from 2.8% in patients with
a CHA2DS2-VASc score of 2 to 5.1% in those with scores
>5 (P trend=0.01; Figure V in the Data Supplement).
DISCUSSION
With 51 288 patients and 960 incident ischemic
strokes, this study represents one of the largest pro-
spective analyses of stroke genetics to date. Such data
provide a unique opportunity to study the clinical value
of an ischemic stroke GRS at scale and across a diverse
patient population. In this study, we demonstrate that
a 32-SNP GRS predicts ischemic stroke in patients with
a wide range of cardiometabolic diseases, appears to
have greater utility in those without previous stroke,
and can potentially refine stroke risk in patients with
atrial fibrillation and lower CHA2DS2-VASc scores, sug-
gesting a potential role for genetic risk scores in thera-
peutic decision making.
In patients who are older and have cardiovascular
risk factors, it is not clear whether a genetic predis-
position still plays a role in ischemic stroke. However,

Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927 February 2, 2021 473

 Marston et al Novel Genetic Risk Score Predicts Ischemic Stroke
ORIGINAL RESEARCH
ARTICLE

Figure 1. Kaplan-Meier event rates for ischemic stroke by tertile of genetic risk score at 3 years.
Int. indicates intermediate; and KM, Kaplan-Meier.

we found that a GRS is a significant and independent this population. The performance of the GRS was even
predictor of ischemic stroke risk, even in patients with more robust when applied to patients without diabetes
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cardiometabolic disease and a median age of 66 years.
More precisely, those in the top third of the GRS car-
ried a 24% greater risk of ischemic stroke than those
in the lowest third of the GRS. To put this degree of
risk into perspective, high genetic risk was similar to
the risk provided by several well-established clinical risk
factors such as smoking, diabetes, and hypertension in
or heart failure and, more broadly, demonstrated stron-
ger risk prediction in patients with a lower burden of
clinical risk factors.
Beyond the independent and additive value of genet-
ics in determining ischemic stroke risk, a second ques-
tion of interest is whether genetics can also identify in-
creased risk for recurrent ischemic stroke. Although only

Figure 2. Hazard ratios for top tertile of genetic risk score in patients with and without previous stroke.
Hazard ratios are adjusted for age, sex, hypertension, hyperlipidemia, smoking, diabetes, atrial fibrillation, coronary artery disease, and congestive heart failure. In
all groups, 95% confidence intervals are shown. GRS indicates genetic risk score; and HR, hazard ratio.

474 February 2, 2021 Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927

 Marston et al
Figure 3. Proportion of individuals with ischemic stroke in anticoagulated patients with atrial fibrillation stratified by CHA2DS2-VASc score and
genetic risk in ENGAGE AF-TIMI 48.
Median follow-up of 2.8 years. ENGAGE AF-TIMI 48 indicates Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation; and HR, hazard ratio.
14% of the overall cohort had previous stroke, this sub-
group of subjects accounted for 31% of the ischemic
strokes during the follow-up period. We found that the
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32-SNP GRS was unable to predict recurrent stroke in
this secondary prevention population. Conversely, the
predictive value of genetic risk was far stronger in pa-
tients without previous stroke. These findings imply that
the GRS used in this study may be most useful for strati-
fying risk for a first-ever stroke. Determining whether
primary and secondary strokes have varying genetic
drivers will require additional investigation.
Although identifying increased stroke risk from a GRS
may be valuable, the low absolute event rates in the
general cardiometabolic population limit the ability of
the GRS to change clinical practice. However, applica-
tion of the GRS in patients with atrial fibrillation could be
considered to help determine who should receive anti-
coagulation. We tested whether genetics could enhance
stroke risk stratification in an exploratory analysis of the
ENGAGE AF-TIMI 48 trial and found that GRS perfor-
mance was greatest when applied to patients with low-
er CHA2DS2-VASc scores. Specifically, in patients with a
CHA2DS2-VASc score of 2, there was a 4-fold increased
risk of stroke in those with high genetic risk. This trans-
lated to an absolute stroke risk equivalent to patients
with a CHA2DS2-VASc score of 3, identifying a group of
patients whose stroke risk is underappreciated.
Patients with a CHA2DS2-VASc score of 1 often pres-
ent the greatest challenge clinically regarding anticoag-
ulation management, and the addition of genetic risk
Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927
Novel Genetic Risk Score Predicts Ischemic Stroke
ORIGINAL RESEARCH
ARTICLE
could provide greater clarity in such situations. Although
the ENGAGE AF-TIMI 48 trial had very few patients with
low CHA2DS2-VASc scores, and all were on anticoagula-
tion, our findings suggest that high genetic risk confers
a multiple fold higher stroke risk that could help guide
management. Further studies are needed to validate
these findings and ultimately address whether such pa-
tients with low CHA2DS2-VASc scores, but high genetic
risk would benefit from anticoagulation therapy.
Limitations
Our study has several limitations. First, we specifically
studied subjects enrolled in 5 clinical trials across the
spectrum of cardiometabolic disease and, therefore,
our findings may not be fully applicable to a an un-
selected general population. In addition, our analysis
was limited to subjects who were of European ancestry
and had consented to genetic testing. Further data will
be required before extrapolating genetic risk prediction
to more diverse populations. Regarding our investiga-
tion in ENGAGE AF-TIMI 48, the proportion of patients
in the trial with lower CHA2DS2-VASc scores was lim-
ited. Therefore, the confidence intervals for the mag-
nitude of increased risk in those with a high GRS were
wide, and thus our results in this population should be
viewed as exploratory. Future research efforts should
focus on genotyping other large cohorts of subjects
with atrial fibrillation to validate these findings in this
subgroup of interest. Last, our study does not explore
February 2, 2021 475
 Marston et al
the biological heterogeneity of stroke and the relative
ORIGINAL RESEARCH
contributions of large-artery atherosclerotic stroke, car-
dioembolic stroke, and small-vessel stroke to the isch-
ARTICLE
emic stroke phenotype. Although it is likely that each of
these stroke subtypes contributed to the overall rates of
ischemic stroke found in our study, attempts at genetic
risk prediction across subtypes would require deeper
stroke phenotyping and would likely be underpowered
because of the small number of genetic loci that are
known to be associated with each stroke subtype. As
such, in this study, we elected to apply a GRS com-
prising the 32 SNPs that had achieved genome-wide
significance for stroke or any ischemic stroke subtype
to predict all ischemic stroke. Many of these SNPs are
closely associated with blood pressure, hyperlipidemia,
coronary artery disease, atrial fibrillation, and venous
thromboembolism, suggesting that the GRS used in
this study incorporates these various biological mech-
anisms. We anticipate that further advances in stroke
genetics will reveal additional loci that can refine efforts
toward genetic risk prediction of stroke subtypes in the
future.
Conclusion
Across 5 large clinical trials of subjects with cardiometabol-
ic disease, a 32-SNP GRS was a strong, independent pre-
dictor of ischemic stroke. The predictive value of the GRS
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appeared strongest in subjects without previous stroke
and in subjects with fewer clinical risk factors. Moreover,
in patients with atrial fibrillation but lower CHA2DS2-VASc
scores, the GRS identified patients with risk comparable
to those with higher CHA2DS2-VASc scores.
ARTICLE INFORMATION
Received October 3, 2020; accepted November 11, 2020.
The Data Supplement is available with this article at https://www.ahajournals.
org/doi/suppl/10.1161/CIRCULATIONAHA.120.051927.
This manuscript was sent to Prof Gianluigi Condorelli, Senior Guest Editor,
for review by expert referees, editorial decision, and final disposition.
This work was presented as an abstract at the American Heart Association
Scientific Sessions, November 13 to November 17, 2020.
Authors
Nicholas A. Marston , MD, MPH; Parth N. Patel, MD; Frederick K. Kamanu ,
PhD; Francesco Nordio, PhD; Giorgio M. Melloni , PhD; Carolina Roselli ,
MS; Yared Gurmu, PhD; Lu-Chen Weng, PhD; Marc P. Bonaca , MD, MPH;
Robert P. Giugliano , MD, SM; Benjamin M. Scirica , MD, MPH; Michelle
L. O’Donoghue , MD, MPH; Christopher P. Cannon, MD; Christopher D.
Anderson , MD, MMSc; Deepak L. Bhatt , MD, MPH; Philippe Gabriel Steg ,
MD; Marc Cohen , MD; Robert F. Storey , MD, DM; Peter Sever, PhD;
­Anthony C. Keech, MD; Itamar Raz , MD; Ofri Mosenzon, MD; Elliott M.
Antman, MD; Eugene Braunwald , MD; Patrick T. Ellinor , MD, PhD; Steven
A. Lubitz , MD, MPH; Marc S. Sabatine , MD, MPH; Christian T. Ruff ,
MD, MPH
Correspondence
Nicholas Marston, MD, MPH, 60 Fenwood Rd, Boston, MA 02115. Email nmar-
ston@bwh.harvard.edu
476 February 2, 2021
Novel Genetic Risk Score Predicts Ischemic Stroke
Affiliations
TIMI Study Group, Boston, MA (N.A.M., F.K.K., F.N., G.M.M., R.P.G., B.M.S.,
M.L.O’D., E.M.A., E.B., M.S.S., C.T.R.). Division of Cardiovascular Medicine
(N.A.M., F.K.K., F.N., G.M.M., R.P.G, B.M.S., M.L.O’D., C.P.C., D.L.B., E.M.A.,
E.B., M.S.S., C.T.R.), Department of Medicine (P.N.P.), Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA. Takeda Pharmaceuticals, Cam-
bridge, MA (F.N.). Cardiovascular Disease Initiative, Broad Institute of MIT and
Harvard, Cambridge, MA (C.R., L.-C.W., P.T.E., S.A.L.). US Food and Drug
Administration, Silver Spring, MD (Y.G.). CPC Clinical Research, Aurora, CO
(M.P.B.). Center for Genomic Medicine, Massachusetts General Hospital, Bos-
ton (C.D.A.). Hospital Bichat-Claude Bernard, Paris, France (P.G.S.). Newark
Beth Israel Medical Center, NJ (M.C.). University of Sheffield Medical School,
United Kingdom (R.F.S.). Imperial College London, United Kingdom (P.S.). NHM-
RC Clinical Trials Centre, Sydney, Australia (A.C.K.). Hebrew University Hospital,
Jerusalem, Israel (I.R., O.M.).
Acknowledgments
Drs Marston and Patel contributed to study design, literature search, statisti-
cal analysis, data interpretation, figures, and drafting of the manuscript. Drs
Kamanu, Nordio, and Melloni, C. Roselli, and Drs Gurmu and Weng contrib-
uted to data preparation, study design, and statistical analysis. Drs Bonaca,
Giugliano, Scirica, O’Donoghue, Cannon, Anderson, Bhatt, Steg, Cohen, Sto-
rey, Sever, Keech, Raz, Mosenzon, Antman, and Braunwald contributed to
data interpretation and critical review of the manuscript. Drs Ellinor, Lubitz,
Sabatine, and Ruff contributed to study design, statistical analysis, data in-
terpretation, figures, and critical review of the manuscript. Drs Sabatine and
Ruff are the guarantors of this work and, as such, had full access to all the
data in the study and take responsibility for the integrity of the data and the
accuracy of the data analysis.
Sources of Funding
The trials were funded by Amgen, AstraZeneca, Daiichi Sankyo, and GlaxoS-
mithKline.
Disclosures
Dr Marston reports grant support from the National Institutes of Health and
involvement in clinical trials with Amgen, Pfizer, Novartis, and AstraZeneca
without personal fees, payments, or increase in salary. Dr Nordio is now em-
ployed by Takeda Pharmaceuticals. C. Roselli is supported by a grant from
Bayer AG to the Broad Institute focused on the development of therapeutics for
cardiovascular disease. Dr Gurmu is now employed at the Food and Drug Ad-
ministration. Dr Weng reports support from the American Heart Association
(18SFRN34110082). Dr Bonaca discloses grant support from Amgen, AstraZen-
eca, Bayer, Sanofi and consulting fees from Amgen, AstraZeneca, Bayer, Sanofi.
Dr Giugliano reports grants from Amgen and Daiichi Sankyo, during the con-
duct of the study; personal fees from Akcea, American College of Cardiology,
Bristol Myers Squibb, CVS Caremark, GlaxoSmithKline, Janssen, Lexicon Merck,
Pfizer, and Servier; grants and personal fees from Amarin, Amgen, and Daiichi
Sankyo outside the submitted work; and an institutional research grant to the
TIMI Study Group at Brigham and Women’s Hospital for research he is not di-
rectly involved in from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare
Pharmaceuticals, Inc, BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia,
Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals,
Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr Scirica re-
ports research grants from AstraZeneca, Eisai, Novartis, and Merck and consult-
ing fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr
Reddy’s Laboratories, Eisai, Elsevier Practice Update Cardiology, GlaxoSmith-
Kline, Lexicon, Merck, Novo Nordisk, Sanofi, and St Jude’s Medical; and has
equity in Health [at] Scale. Dr O’Donoghue reports institutional research grants
from Amgen, Janssen, The Medicines Company, Eisai, GlaxoSmithKline, and
Astra Zeneca. Dr Cannon reports research grants from Amgen, Boehringer-In-
gelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo
Nordisk, and Pfizer; consulting fees from Aegerion, Alnylam, Amarin, Amgen,
Applied Therapeutics, Ascendia, BI, BMS, Corvidia, Eli Lilly, HLS Therapeutics,
Innovent, Janssen, Kowa, Merck, Pfizer, Rhoshan, and Sanofi. Dr Anderson re-
ports grants from the National Institutes of Health (R01NS103924,
R01NS069763), the American Heart Association (18SFRN34250007), and Mas-
sachusetts General Hospital, sponsored research support from Bayer AG, and
consulting fees for ApoPharma, Inc. Dr Bhatt discloses the following relation-
ships: Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice
Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx
Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927
 Marston et al
Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute,
Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Asso-
ciation Quality Oversight Committee; Data Monitoring Committees: Baim Insti-
tute for Clinical Research (formerly Harvard Clinical Research Institute, for the
PORTICO trial (Portico Re-sheathable Transcatheter Aortic Valve System US IDE
Trial), funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for
the ExCEED trial (Efficacy of Secukinumab Compared to Adalimumab in Pa-
tients With Psoriatic Arthritis), funded by Edwards), Contego Medical (Chair,
PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting
Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo
Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Com-
pared to Standard Care After Heart Valve Replacement Using a Catheter in Pa-
tients With Atrial Fibrillation], funded by Daiichi Sankyo), Population Health
Research Institute; Honoraria: American College of Cardiology (Senior Associ-
ate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation
Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Re-
search Institute; RE-DUAL PCI clinical trial (Evaluation of Dual Therapy With
Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo
a PCI With Stenting) steering committee funded by Boehringer Ingelheim; AE-
GIS-II (Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome)
executive committee funded by CSL Behring), Belvoir Publications (Editor in
Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Trans-
lation Research Group (clinical trial steering committees), Duke Clinical Re-
search Institute (clinical trial steering committees, including for the PRO-
NOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus
Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Dis-
ease), funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal
of Invasive Cardiology), Journal of the American College of Cardiology (Guest
Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex,
Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Popu-
lation Health Research Institute (for the COMPASS [Rivaroxaban for the Preven-
tion of Major Cardiovascular Events in Coronary or Peripheral Artery Disease]
operations committee, publications committee, steering committee, and US
national coleader, funded by Bayer), Slack Publications (Chief Medical Editor,
Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secre-
tary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology
(Deputy Editor), National Cardiovascular Data Registry (NCDR)-ACTION Registry
Steering Committee (Chair), VA CART Research and Publications Committee
Downloaded from http://ahajournals.org by on November 23, 2023
(Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca,
Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring,
Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia,
Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Pfizer, PhaseBio, PLx
Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company;
Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to
Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific,
CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardi-
ology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr Steg re-
ports research grants from Amarin, Bayer, Sanofi, and Servier; speaking or con-
sulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Idorsia, Novartis, Novo-Nordisk,
Pfizer, Regeneron, Sanofi, and Servier. Dr Cohen discloses honoraria for Speak-
ers Bureau and advisory Boards (moderate) from AstraZeneca. Dr Storey reports
research grants, consultancy fees, and honoraria from AstraZeneca; consulting
fees and honoraria from Bayer and Bristol Myers Squibb/Pfizer; research grants
and consultancy fees from Cytosorbents, GlyCardial Diagnostics, and Thrombo-
serin; consultancy fees from Amgen, Haemonetics, Hengrui, Idorsia, PhaseBio,
Portola and Sanofi Aventis; honoraria from Intas Pharmaceuticals and Med-
scape. Dr Sever reports research grants and honoraria for speakers’ bureau
Amgen and Pfizer. Dr Keech reports grants and personal fees from Abbott and
Mylan; personal fees from Amgen, AstraZeneca, Pfizer, and Bayer; grants from
Sanofi and Novartis, outside the submitted work. Dr Raz received personal fees
from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Concenter Bio-
Pharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis,
Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FutuRx, Insuline Medical, Medial
EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novar-
tis, Teva, GlucoMe, and DarioHealth. Dr Mosenzon reports serving on Advisory
Boards for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer
Ingelheim, Novartis, AstraZeneca, BOL Pharma; Research grant support through
Hadassah Hebrew University Hospital: Novo Nordisk, AstraZeneca and Bristol-
Myers Squibb; Speaker’s Bureau: AstraZeneca and Bristol-Myers Squibb, Novo
Nordisk, Eli Lilly, Sanofi, Novartis, Merck Sharp & Dohme, Boehringer Ingelheim.
Dr Antman reports receiving grant support through his institution from Daiichi
Sankyo. Dr Braunwald reports research grants through the Brigham and Wom-
en’s Hospital from Astra Zeneca, Daiichi Sankyo, Merck, and Novartis.
Circulation. 2021;143:470–478. DOI: 10.1161/CIRCULATIONAHA.120.051927
Novel Genetic Risk Score Predicts Ischemic Stroke
Consultancies with Amgen, Cardurion, MyoKardia, NovoNordisk, Boehringer-
Ingelheim/Lilly, IMMEDIATE, and Verve. Uncompensated consultancies and lec-
ORIGINAL RESEARCH
tures with The Medicines Company. Dr Ellinor reports grants and personal fees
from Bayer AG, personal fees from Novartis and Quest Diagnostics, outside the
ARTICLE
submitted work. Dr Lubitz is supported by National Institutes of Health grant
1R01HL139731 and American Heart Association 18SFRN34250007. He re-
ceives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG,
Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers
Squibb/Pfizer and Bayer AG. Dr Sabatine reports research grant support
through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer,
Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Develop-
ment, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark
Pharmaceuticals, Takeda; Consulting for Amgen, Anthos Therapeutics, Astra-
Zeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM
Therapeutics, Intarcia, Ionis, Janssen Research and Development, Medicines
Company, MedImmune, Merck, Novartis; Dr Sabatine is a member of the TIMI
Study Group, which has also received institutional research grant support
through Brigham and Women’s Hospital from: Abbott, Aralez, Roche, and Zora
Biosciences. Dr Ruff reports grants from Boehringer Ingelheim, Daiichi Sankyo,
MedImmune, National Institute of Health; personal fees from Bayer, Bristol My-
ers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MedImmune, Pfizer,
Portola, Anthos, outside the submitted work; Dr Ruff is a member of the TIMI
Study Group, which has received institutional research grant support through
Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca,
Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoS-
mithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark
Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Bioscienc-
es. The other authors report no disclosures.
Supplemental Materials
Supplemental Methods
Data Supplement Tables I–III
Data Supplement Figures I–V
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