Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

被引：12

作者：

Jaworek, Thomas ^{[1
]}

Xu, Huichun ^{[1
]}

Gaynor, Brady J. ^{[1
]}

Cole, John W. ^{[2
,6
]}

Rannikmae, Kristiina ^{[7
]}

Stanne, Tara M. ^{[8
]}

Tomppo, Liisa ^{[9
]}

Abedi, Vida ^{[10
]}

Amouyel, Philippe ^{[11
,12
,13
,14
]}

Armstrong, Nicole D. ^{[15
]}

Attia, John ^{[16
]}

Bell, Steven ^{[17
]}

Benavente, Oscar R. ^{[22
]}

Boncoraglio, Giorgio B. ^{[23
]}

Butterworth, Adam ^{[18
,19
,20
,21
,24
,25
]}

Carcel-Marquez, Jara ^{[26
]}

Chen, Zhengming ^{[27
]}

Chong, Michael ^{[29
,30
]}

Cruchaga, Carlos ^{[32
]}

Cushman, Mary ^{[35
]}

Danesh, John ^{[18
,19
,20
,21
,24
,25
,36
]}

Debette, Stephanie ^{[37
,38
]}

Duggan, David J. ^{[39
]}

Durda, Jon Peter ^{[33
,34
,40
]}

Engstrom, Gunnar ^{[41
]}

Enzinger, Chris ^{[43
]}

Faul, Jessica D. ^{[44
]}

Fecteau, Natalie S. ^{[2
]}

Fernandez-Cadenas, Israel ^{[26
,45
]}

Gieger, Christian ^{[46
,47
]}

Giese, Anne-Katrin ^{[48
]}

Grewal, Raji P. ^{[49
]}

Grittner, Ulrike ^{[50
]}

Havulinna, Aki S. ^{[51
]}

Heitsch, Laura ^{[52
,53
]}

Hochberg, Marc C. ^{[3
,4
]}

Holliday, Elizabeth ^{[16
]}

Hu, Jie ^{[57
]}

Ilinca, Andreea ^{[42
,58
]}

Irvin, Marguerite R. ^{[15
]}

Jackson, Rebecca D. ^{[59
]}

Jacob, Mina A. ^{[60
]}

Rabionet, Raquel ^{[61
,62
,63
]}

Jimenez-Conde, Jordi ^{[64
]}

Johnson, Julie A. ^{[65
,66
,67
]}

Kamatani, Yoichiro ^{[68
]}

Kardia, Sharon L. R. ^{[71
]}

Koido, Masaru

Kubo, Michiaki ^{[69
,70
,72
,73
]}

Lange, Leslie

机构：

[1] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA

[2] Univ Maryland, Dept Neurol, Diabet & Nutr, Baltimore, MD 21201 USA

[3] Univ Maryland, Div Rheumatol & Clin Immunol, Baltimore, MD 21201 USA

[4] Univ Maryland, Dept Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA

[5] Univ Maryland, Inst Genome Sci, Baltimore, MD 21201 USA

[6] VA Maryland Hlth Care Syst, Baltimore, MD USA

[7] Univ Edinburgh, Usher Inst, Med Informat Ctr, Edinburgh, Midlothian, Scotland

[8] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Lab Med, Gothenburg, Sweden

[9] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland

[10] Geisinger Hlth Syst, Dept Mol & Funct Genom, Danville, PA USA

[11] Univ Lille, LabEx DISTALZ, RID AGE Risk Factors & Mol Determinants Aging Rel, U1167, Lille, France

[12] Inserm, U1167, Lille, France

[13] Ctr Hosp Univ Lille, Lille, France

[14] Inst Pasteur, Lille, France

[15] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA

[16] Univ Newcastle, Sch Med & Publ Hlth, Callaghan, NSW, Australia

[17] Univ Cambridge, Stroke Res Grp, Cambridge, England

[18] Univ Cambridge, Dept Clin Neurosci, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England

[19] Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Ctr Res Excellence, Cambridge, England

[20] Univ Cambridge, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Genom, Cambridge, England

[21] Univ Cambridge, Cambridge, England

[22] Univ British Columbia, Dept Neurol, Vancouver, BC, Canada

[23] Fdn IRCCS Ist Neurol Carlo Besta, Dept Cerebrovasc Dis, Milan, Italy

[24] Hlth Data Res UK Cambridge, Cambridge, England

[25] Wellcome Genome Campus, Cambridge, England

[26] Biomed Res Inst St Pau IIB St Pau, Stroke Pharmacogen & Genet Grp, Barcelona, Spain

[27] Univ Oxford, Nuffield Dept Populat Hlth, MRC Populat Hlth Res Unit, Oxford, England

[28] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

[29] McMaster Univ, DBCVS Res Inst, Dept Pathol & Mol Med, Populat Hlth Res Inst, Hamilton, ON, Canada

[30] Thrombosis & Atherosclerosis Res Inst TaARI, Hamilton, ON, Canada

[31] Washington Univ, Sch Med, Dept Neurol, St Louis, MO USA

[32] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO USA

[33] Univ Vermont, Larner Coll Med, Dept Med, Burlington, VT USA

[34] Univ Vermont, Larner Coll Med, Lab Clin Biochem Res, Burlington, VT USA

[35] Univ Vermont, Larner Coll Med, Dept Med, Burlington, VT USA

[36] Wellcome Sanger Inst, Dept Human Genet, Hinxton, England

[37] Univ Bordeaux, Inserm Bordeux Populat Hlth Res Ctr, UMR 1219, Bordeaux, France

[38] Bordeaux Univ Hosp, Inst Neurodegenerat Dis, Dept Neurol, Bordeaux, France

[39] Affiliate City Hope, Translat Genom Res Inst, Quantitat Med & Syst Biol Div, Phoenix, AZ USA

[40] Lab Clin Biochem Res, Malmo, Sweden

[41] Dept Clin Sci, Malmo, Sweden

[42] Lund Univ, Dept Clin Sci, Neurol, Lund, Sweden

[43] Med Univ Graz, Dept Neurol, Graz, Austria

[44] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA

[45] Fundacio Docencia & Recerca MutuaTerrassa, Stroke Pharmacogen & Genet, Terrassa, Spain

[46] Helmholtz Zentrum Munchen German Res Ctr Environm, Unit Mol Epidemiol, Neuherberg, Germany

[47] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol, Neuherberg, Germany

[48] Univ Klinikum Hamburg Eppendorf, Kopf & Neurozentrum, Klin & Poliklin Neurol, Hamburg, Germany

[49] St Francis Med Ctr, Neurosci Inst, Trenton, NJ USA

[50] Charite Univ Med Ctr, Dept Biostat & Clin Epidemiol, Berlin, Germany

来源：

NEUROLOGY | 2022年 / 99卷 / 16期

关键词：

ABO BLOOD-GROUP; GENOME-WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; LOCUS; GENOTYPE;

D O I：

10.1212/WNL.0000000000201006

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

引用

页码：E1738 / E1754

页数：17

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