Title | Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Cheng Y-C, Stanne TM, Giese A-K, Ho WKee, Traylor M, Amouyel P, Holliday EG, Malik R, Xu H, Kittner SJ, Cole JW, O'Connell JR, Danesh J, Rasheed A, Zhao W, Engelter S, Grond-Ginsbach C, Kamatani Y, Lathrop M, Leys D, Thijs V, Metso TM, Tatlisumak T, Pezzini A, Parati EA, Norrving B, Bevan S, Rothwell PM, Sudlow C, Slowik A, Lindgren A, Walters MR, Jannes J, Shen J, Crosslin D, Doheny K, Laurie CC, Kanse SM, Bis JC, Fornage M, Mosley TH, Hopewell JC, Strauch K, Müller-Nurasyid M, Gieger C, Waldenberger M, Peters A, Meisinger C, M Ikram A, Longstreth WT, Meschia JF, Seshadri S, Sharma P, Worrall B, Jern C, Levi C, Dichgans M, Boncoraglio GB, Markus HS, Debette S, Rolfs A, Saleheen D |
Secondary Authors | Mitchell BD |
Corporate Authors | WTCCC-2 Consortium |
Journal | Stroke |
Volume | 47 |
Issue | 2 |
Pagination | 307-16 |
Date Published | 2016 Feb |
ISSN | 1524-4628 |
Keywords | Adult, African Continental Ancestry Group, Age of Onset, Aged, Asian Continental Ancestry Group, Brain Ischemia, Chromosomes, Human, Pair 10, Computer Simulation, DNA, Intergenic, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Serine Endopeptidases, Stroke |
Abstract | BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke. |
DOI | 10.1161/STROKEAHA.115.011328 |
Alternate Journal | Stroke |
PubMed ID | 26732560 |
PubMed Central ID | PMC4729659 |
Grant List | R01HL105756 / HL / NHLBI NIH HHS / United States N01 HC055021 / HC / NHLBI NIH HHS / United States U01HL080295 / HL / NHLBI NIH HHS / United States N01HC55020 / HL / NHLBI NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States N01 HC055022 / HC / NHLBI NIH HHS / United States R01-HL073410 / HL / NHLBI NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States Z01-AG000954 / AG / NIA NIH HHS / United States G0800270 / MRC_ / Medical Research Council / United Kingdom R01 HL103612 / HL / NHLBI NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States R01 HL089650 / HL / NHLBI NIH HHS / United States UL1TR000124 / TR / NCATS 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 HG004438 / HG / NHGRI NIH HHS / United States RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom U01 HG004446 / HG / NHGRI NIH HHS / United States P30-DK072488 / DK / NIDDK NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States N01HC55018 / HL / NHLBI NIH HHS / United States R01-NS39987 / NS / NINDS NIH HHS / United States R01-HL085251 / HL / NHLBI NIH HHS / United States 095626 / WT_ / Wellcome Trust / United Kingdom R01HL59367 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States Z01 AG000015 / ImNIH / Intramural NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States WT095219MA / WT_ / Wellcome Trust / United Kingdom HHSN268201100005G / HL / NHLBI NIH HHS / United States U01 HL096917 / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States R01 HL085251 / HL / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States 104040 / WT_ / Wellcome Trust / United Kingdom RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom N01 HC055018 / HC / NHLBI NIH HHS / United States R01DK063491 / DK / NIDDK NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States U01-NS069208 / NS / NINDS NIH HHS / United States / DH_ / Department of Health / United Kingdom R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC55022 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States Z01 AG000954 / ImNIH / Intramural NIH HHS / United States HHSN268200625226C / / PHS HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States HL093029 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom N01HC55015 / HL / NHLBI NIH HHS / United States R01 HL093029 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States WTCCC2-Munich / WT_ / Wellcome Trust / United Kingdom R01 HL105756 / HL / NHLBI NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States U01-HG004436 / HG / NHGRI NIH HHS / United States Z01-AG000015-50 / AG / NIA NIH HHS / United States N01 HC055019 / HC / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States P30 DK072488 / DK / NIDDK NIH HHS / United States U01-HL096917 / HL / NHLBI NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States U01 NS069208 / NS / NINDS NIH HHS / United States R01 NS039987 / NS / NINDS NIH HHS / United States R01HL089650 / HL / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States R01-NS45012 / NS / NINDS NIH HHS / United States WT084724MA / WT_ / Wellcome Trust / United Kingdom N01HC55016 / HL / NHLBI NIH HHS / United States R01AG023629 / AG / NIA NIH HHS / United States 085475/B/08/Z / WT_ / Wellcome Trust / United Kingdom N01 HC055015 / HC / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States R01HL087652 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States U01 HG004436 / HG / NHGRI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States N01HC55019 / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States OSRP2/1006 / DMT_ / The Dunhill Medical Trust / United Kingdom N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States WTCCC2 / WT_ / Wellcome Trust / United Kingdom / WT_ / Wellcome Trust / United Kingdom HHSN268201200036C / HL / NHLBI NIH HHS / United States N01 HC055020 / HC / NHLBI NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States R01HL103612 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States N01HC55021 / HL / NHLBI NIH HHS / United States U01-HG004438 / HG / NHGRI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States R01 HL073410 / HL / NHLBI NIH HHS / United States R01-NS42733 / NS / NINDS NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States WTCCC2-UK / WT_ / Wellcome Trust / United Kingdom FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom G1001799 / WT_ / Wellcome Trust / United Kingdom N01 HC055016 / HC / NHLBI NIH HHS / United States 085475/Z/08/Z / WT_ / Wellcome Trust / United Kingdom U01-HG004446 / HG / NHGRI NIH HHS / United States R01HL120393 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States |