Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.

Stroke
Authors
Keywords
Abstract

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

Year of Publication
2014
Journal
Stroke
Volume
45
Issue
2
Pages
394-402
Date Published
2014 Feb
ISSN
1524-4628
URL
DOI
10.1161/STROKEAHA.113.002938
PubMed ID
24436234
PubMed Central ID
PMC4006951
Links
Grant list
N01HC55020 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01 HC055022 / HC / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
N01 HC085086 / HC / NHLBI NIH HHS / United States
U01 HG 004446 / HG / NHGRI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
Z01 AG000015 / AG / NIA NIH HHS / United States
UL1RR033176 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
R01 NS45012 / NS / NINDS NIH HHS / United States
R01 NS045012 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 NS042733 / NS / NINDS NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
Z01 AG000015-50 / AG / NIA NIH HHS / United States
095626 / Wellcome Trust / United Kingdom
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HHSN268201100010C / HL / NHLBI NIH HHS / United States
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U01 NS069208 / NS / NINDS NIH HHS / United States
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N01-HC-55015 / HC / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
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Z01 AG-000954-06 / AG / NIA NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
085475/B/08/Z / Wellcome Trust / United Kingdom
N01 HC055015 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / PHS HHS / United States
N01 HC055021 / HC / NHLBI NIH HHS / United States
N01 HC085084 / HC / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
U01 HG004436 / HG / NHGRI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
Z01 AG007380-03 / Intramural NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / PHS HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / PHS HHS / United States
U01 NS069208-01 / NS / NINDS NIH HHS / United States
N01 HC055020 / HC / NHLBI NIH HHS / United States
HHSN268200782096C / PHS HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01 HC085079 / HC / NHLBI NIH HHS / United States
HHSN268201100006C / PHS HHS / United States
HL-093029 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
Z01 AG000954-06 / Intramural NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
U54 RR020278 / RR / NCRR NIH HHS / United States
N01 HC055016 / HC / NHLBI NIH HHS / United States
085475/Z/08/Z / Wellcome Trust / United Kingdom
Z01 AG000954 / AG / NIA NIH HHS / United States
R01 NS-39987 / NS / NINDS NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States