Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

Original languageEnglish (US)
Pages (from-to)e002338
JournalCirculation. Genomic and precision medicine
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2019

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Genetic Loci
Stroke

Keywords

  • atherosclerosis
  • cerebral hemorrhage
  • chromosome
  • dementia
  • haplotype

Cite this

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls. / NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC).

In: Circulation. Genomic and precision medicine, Vol. 12, No. 7, 01.07.2019, p. e002338.

Research output: Contribution to journalArticle

NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC) 2019, 'Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls', Circulation. Genomic and precision medicine, vol. 12, no. 7, pp. e002338. https://doi.org/10.1161/CIRCGEN.118.002338
NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC). / Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls. In: Circulation. Genomic and precision medicine. 2019 ; Vol. 12, No. 7. pp. e002338.
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title = "Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls",
abstract = "BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.",
keywords = "atherosclerosis, cerebral hemorrhage, chromosome, dementia, haplotype",
author = "{NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)} and Matthew Traylor and Anderson, {Christopher D.} and Rutten-Jacobs, {Loes C.A.} and Falcone, {Guido J.} and Comeau, {Mary E.} and Hakan Ay and Sudlow, {Cathie L.M.} and Huichun Xu and Mitchell, {Braxton D.} and Cole, {John W.} and Kathryn Rexrode and Jordi Jimenez-Conde and Reinhold Schmidt and Grewal, {Raji P.} and Sacco, {Ralph L} and Marta Ribases and Tatjana Rundek and Jonathan Rosand and Martin Dichgans and Lee, {Jin Moo} and Langefeld, {Carl D.} and Kittner, {Steven J.} and Markus, {Hugh S.} and Daniel Woo and Rainer Malik",
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T1 - Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

AU - NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)

AU - Traylor, Matthew

AU - Anderson, Christopher D.

AU - Rutten-Jacobs, Loes C.A.

AU - Falcone, Guido J.

AU - Comeau, Mary E.

AU - Ay, Hakan

AU - Sudlow, Cathie L.M.

AU - Xu, Huichun

AU - Mitchell, Braxton D.

AU - Cole, John W.

AU - Rexrode, Kathryn

AU - Jimenez-Conde, Jordi

AU - Schmidt, Reinhold

AU - Grewal, Raji P.

AU - Sacco, Ralph L

AU - Ribases, Marta

AU - Rundek, Tatjana

AU - Rosand, Jonathan

AU - Dichgans, Martin

AU - Lee, Jin Moo

AU - Langefeld, Carl D.

AU - Kittner, Steven J.

AU - Markus, Hugh S.

AU - Woo, Daniel

AU - Malik, Rainer

PY - 2019/7/1

Y1 - 2019/7/1

N2 - BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

AB - BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

KW - atherosclerosis

KW - cerebral hemorrhage

KW - chromosome

KW - dementia

KW - haplotype

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U2 - 10.1161/CIRCGEN.118.002338

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