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Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.

TitleRare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.
Publication TypeJournal Article
Year of Publication2015
AuthorsAuer PL, Nalls M, Meschia JF, Worrall BB, Longstreth WT, Seshadri S, Kooperberg C, Burger KM, Carlson CS, Carty CL, Chen W-M, L Cupples A, DeStefano AL, Fornage M, Hardy J, Hsu L, Jackson RD, Jarvik GP, Kim DS, Lakshminarayan K, Lange LA, Manichaikul A, Quinlan AR, Singleton AB, Thornton TA, Nickerson DA, Peters U
Secondary AuthorsRich SS
Corporate AuthorsNational Heart, Lung, and Blood Institute Exome Sequencing Project
JournalJAMA Neurol
Volume72
Issue7
Pagination781-8
Date Published2015 Jul
ISSN2168-6157
KeywordsAged, Brain Ischemia, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle Proteins, National Heart, Lung, and Blood Institute (U.S.), Nuclear Proteins, Open Reading Frames, Palmitoyl-CoA Hydrolase, Stroke, United States
Abstract

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

DOI10.1001/jamaneurol.2015.0582
Alternate JournalJAMA Neurol
PubMed ID25961151
PubMed Central IDPMC4673986
Grant ListN01-HC-25195 / HC / NHLBI NIH HHS / United States
N01 HC-55016 / HC / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
5R00-HG004316 / HG / NHGRI NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
N01-HC48049 / HC / NHLBI NIH HHS / United States
R01 NS042733 / NS / NINDS NIH HHS / United States
UL1-RR025014 / RR / NCRR NIH HHS / United States
N01 HC095170 / HC / NHLBI NIH HHS / United States
N01-HC48050 / HC / NHLBI NIH HHS / United States
P50 HL084946 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01-NS39987 / NS / NINDS NIH HHS / United States
N01 HC-95171 / HC / NHLBI NIH HHS / United States
F32 HL083714 / HL / NHLBI NIH HHS / United States
N01 HC-55015 / HC / NHLBI NIH HHS / United States
N01 HC-55021 / HC / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
R00 HG004316 / HG / NHGRI NIH HHS / United States
RC2 HL101779 / HL / NHLBI NIH HHS / United States
U01 HL066583 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
R21 HL077916 / HL / NHLBI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
HL077916 / HL / NHLBI NIH HHS / United States
N01HC48049 / HL / NHLBI NIH HHS / United States
R01-HG004738 / HG / NHGRI NIH HHS / United States
HHSN268201100004I / HL / NHLBI NIH HHS / United States
N01-HC48048 / HC / NHLBI NIH HHS / United States
K23-AR52742 / AR / NIAMS NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
RC2-HL101779 / HL / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
N01 HC055018 / HC / NHLBI NIH HHS / United States
U01 HL089897 / HL / NHLBI NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
N01 HC095172 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
RC2-HL102924 / HL / NHLBI NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
Z01 AG000954 / ImNIH / Intramural NIH HHS / United States
M01-RR07122 / RR / NCRR NIH HHS / United States
K23 AR052742 / AR / NIAMS NIH HHS / United States
N01 HC095171 / HC / NHLBI NIH HHS / United States
NS17950 / NS / NINDS NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01 HL089856 / HL / NHLBI NIH HHS / United States
N01 HC-55020 / HC / NHLBI NIH HHS / United States
P50-HL084946 / HL / NHLBI NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
U01-HL089856 / HL / NHLBI NIH HHS / United States
N01 HC055019 / HC / NHLBI NIH HHS / United States
RC2 HL101651 / HL / NHLBI NIH HHS / United States
HR-46002 / HR / NHLBI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
N01HC-55017 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
F32-HL083714 / HL / NHLBI NIH HHS / United States
N01HC95095 / HL / NHLBI NIH HHS / United States
N01-HC48047 / HC / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01 NS039987 / NS / NINDS NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
R01HL105756 / HL / NHLBI NIH HHS / United States
R01 HL095396 / HL / NHLBI NIH HHS / United States
N01 HC-95172 / HC / NHLBI NIH HHS / United States
UL1 RR025014 / RR / NCRR NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
R01AG023629 / AG / NIA NIH HHS / United States
U01-HL089897 / HL / NHLBI NIH HHS / United States
N01-HC-95160 / HC / NHLBI NIH HHS / United States
Z01-AG000954-7 / AG / NIA NIH HHS / United States
N01 HC055015 / HC / NHLBI NIH HHS / United States
N01 HC055021 / HC / NHLBI NIH HHS / United States
M01 RR007122 / RR / NCRR NIH HHS / United States
R01-HL068890 / HL / NHLBI NIH HHS / United States
R02-HL095396 / HL / NHLBI NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
024156 / / PHS HHS / United States
N01HC48050 / HL / NHLBI NIH HHS / United States
R01HL087652 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
UL1 TR002319 / TR / NCATS NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HL-69197 / HL / NHLBI NIH HHS / United States
N01HC48047 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
N01-HC-95161 / HC / NHLBI NIH HHS / United States
U01 HG004738 / HG / NHGRI NIH HHS / United States
N01 HC055020 / HC / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
U01HL080295 / HL / NHLBI NIH HHS / United States
UL1 TR000423 / TR / NCATS NIH HHS / United States
HL-76285 / HL / NHLBI NIH HHS / United States
R01HL103612 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01-HC-95166 / HC / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01-NS42733 / NS / NINDS NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01 HR046002 / HR / NHLBI NIH HHS / United States
RC2-HL066583 / HL / NHLBI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
N01 HC055016 / HC / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
HHSN268201100004C / WH / WHI NIH HHS / United States
N01 HC-95170 / HC / NHLBI NIH HHS / United States
RC2-HL101651 / HL / NHLBI NIH HHS / United States
R01 HL068890 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
N01HC48048 / HL / NHLBI NIH HHS / United States
N01-HC95095 / HC / NHLBI NIH HHS / United States
N01-HC-95167 / HC / NHLBI NIH HHS / United States
R01HL120393 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
N01 HC-55019 / HC / NHLBI NIH HHS / United States
R01 HL076285 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States