A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke

Elizabeth G. Holliday, Jane Maguire, Tiffany Jane Evans, Jonathan Golledge, Erik Biros, Martin Lewis, Simon Koblar, Jim Jannes, G. J. Hankey, Ross Baker

Research output: Contribution to conferencePoster

Abstract

Introduction Genetic influences upon ischemic stroke risk are supported by the trait’s familial aggregation, higher concordance among monozygotic than dizygotic twins, and the high heritability of intermediate phenotypes such as carotid intima-media thickness. In spite of this evidence, genome-wide association studies (GWAS) have detected few replicable genetic risk factors for ischemic stroke, potentially due to aetiological heterogeneity of this trait. Hypothesis We first assessed the hypothesis that common ischemic stroke subtypes differ in their heritability, defined as the proportion of observed phenotypic variation attributable to genetic variation. The second hypothesis was that GWAS may detect stronger and more replicable genetic associations for distinct stroke subtypes with high heritability, rather than the broad ischemic stroke diagnosis. Methods An Australian, European-ancestry sample of 1230 ischemic stroke cases and 1280 population controls was genotyped for a genome wide association study using the Illumina 610-Quad array. Ischemic stroke subtypes were assigned using TOAST criteria. The proportion of case-control variation attributable to genome wide genetic variation was estimated using a published approach based on linear mixed models. Genome wide association analyses incorporating approximately 2.5 million genotyped and imputed SNPs were subsequently performed using a one-degree of freedom trend test assuming an additive effect of allele dosage. Results Significant evidence for a genetic contribution to ischemic stroke risk was detected (h2=0.39, SE=0.15, p-value = 0.0009), but this was higher and more significant for the large artery atherosclerosis (LAA) subtype (h2=0.66, SE=0.21, p-value = 0.0001). The genetic contributions to small vessel disease and cardioembolic stroke were less significant than for overall ischemic stroke. Genome wide association analyses including 421 LAA cases and 1244 controls detected a novel LAA susceptibility locus on chromosome 6p21.1 (two SNPs with P<5×10-8). The 6p21.1 locus showed markedly diminished association with the broader ischemic stroke phenotype. Conclusions In conclusion, this study detected higher heritability of large artery atherosclerotic stroke than cardioembolic stroke, small vessel disease or broad ischemic stroke. It suggests a genetic risk locus for large artery atherosclerosis on chromosome 6p21.1 and supports the analysis of aetiological subtypes to better identify genetic risk alleles for ischemic stroke.

Conference

ConferenceInternational Stroke Conference
CountryUnited States
CityNew Orleans
Period1/02/123/02/12

Cite this

Holliday, E. G., Maguire, J., Evans, T. J., Golledge, J., Biros, E., Lewis, M., ... Baker, R. (2012). A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke. Poster session presented at International Stroke Conference, New Orleans, United States.
Holliday, Elizabeth G. ; Maguire, Jane ; Evans, Tiffany Jane ; Golledge, Jonathan ; Biros, Erik ; Lewis, Martin ; Koblar, Simon ; Jannes, Jim ; Hankey, G. J. ; Baker, Ross. / A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke. Poster session presented at International Stroke Conference, New Orleans, United States.
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title = "A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke",
abstract = "Introduction Genetic influences upon ischemic stroke risk are supported by the trait’s familial aggregation, higher concordance among monozygotic than dizygotic twins, and the high heritability of intermediate phenotypes such as carotid intima-media thickness. In spite of this evidence, genome-wide association studies (GWAS) have detected few replicable genetic risk factors for ischemic stroke, potentially due to aetiological heterogeneity of this trait. Hypothesis We first assessed the hypothesis that common ischemic stroke subtypes differ in their heritability, defined as the proportion of observed phenotypic variation attributable to genetic variation. The second hypothesis was that GWAS may detect stronger and more replicable genetic associations for distinct stroke subtypes with high heritability, rather than the broad ischemic stroke diagnosis. Methods An Australian, European-ancestry sample of 1230 ischemic stroke cases and 1280 population controls was genotyped for a genome wide association study using the Illumina 610-Quad array. Ischemic stroke subtypes were assigned using TOAST criteria. The proportion of case-control variation attributable to genome wide genetic variation was estimated using a published approach based on linear mixed models. Genome wide association analyses incorporating approximately 2.5 million genotyped and imputed SNPs were subsequently performed using a one-degree of freedom trend test assuming an additive effect of allele dosage. Results Significant evidence for a genetic contribution to ischemic stroke risk was detected (h2=0.39, SE=0.15, p-value = 0.0009), but this was higher and more significant for the large artery atherosclerosis (LAA) subtype (h2=0.66, SE=0.21, p-value = 0.0001). The genetic contributions to small vessel disease and cardioembolic stroke were less significant than for overall ischemic stroke. Genome wide association analyses including 421 LAA cases and 1244 controls detected a novel LAA susceptibility locus on chromosome 6p21.1 (two SNPs with P<5×10-8). The 6p21.1 locus showed markedly diminished association with the broader ischemic stroke phenotype. Conclusions In conclusion, this study detected higher heritability of large artery atherosclerotic stroke than cardioembolic stroke, small vessel disease or broad ischemic stroke. It suggests a genetic risk locus for large artery atherosclerosis on chromosome 6p21.1 and supports the analysis of aetiological subtypes to better identify genetic risk alleles for ischemic stroke.",
author = "Holliday, {Elizabeth G.} and Jane Maguire and Evans, {Tiffany Jane} and Jonathan Golledge and Erik Biros and Martin Lewis and Simon Koblar and Jim Jannes and Hankey, {G. J.} and Ross Baker",
note = "Stroke February 2012, Volume 43, Issue Suppl 1; International Stroke Conference ; Conference date: 01-02-2012 Through 03-02-2012",
year = "2012",
month = "2",
language = "English",

}

Holliday, EG, Maguire, J, Evans, TJ, Golledge, J, Biros, E, Lewis, M, Koblar, S, Jannes, J, Hankey, GJ & Baker, R 2012, 'A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke' International Stroke Conference, New Orleans, United States, 1/02/12 - 3/02/12, .

A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke. / Holliday, Elizabeth G.; Maguire, Jane; Evans, Tiffany Jane; Golledge, Jonathan; Biros, Erik; Lewis, Martin; Koblar, Simon; Jannes, Jim; Hankey, G. J.; Baker, Ross.

2012. Poster session presented at International Stroke Conference, New Orleans, United States.

Research output: Contribution to conferencePoster

TY - CONF

T1 - A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke

AU - Holliday, Elizabeth G.

AU - Maguire, Jane

AU - Evans, Tiffany Jane

AU - Golledge, Jonathan

AU - Biros, Erik

AU - Lewis, Martin

AU - Koblar, Simon

AU - Jannes, Jim

AU - Hankey, G. J.

AU - Baker, Ross

N1 - Stroke February 2012, Volume 43, Issue Suppl 1

PY - 2012/2

Y1 - 2012/2

N2 - Introduction Genetic influences upon ischemic stroke risk are supported by the trait’s familial aggregation, higher concordance among monozygotic than dizygotic twins, and the high heritability of intermediate phenotypes such as carotid intima-media thickness. In spite of this evidence, genome-wide association studies (GWAS) have detected few replicable genetic risk factors for ischemic stroke, potentially due to aetiological heterogeneity of this trait. Hypothesis We first assessed the hypothesis that common ischemic stroke subtypes differ in their heritability, defined as the proportion of observed phenotypic variation attributable to genetic variation. The second hypothesis was that GWAS may detect stronger and more replicable genetic associations for distinct stroke subtypes with high heritability, rather than the broad ischemic stroke diagnosis. Methods An Australian, European-ancestry sample of 1230 ischemic stroke cases and 1280 population controls was genotyped for a genome wide association study using the Illumina 610-Quad array. Ischemic stroke subtypes were assigned using TOAST criteria. The proportion of case-control variation attributable to genome wide genetic variation was estimated using a published approach based on linear mixed models. Genome wide association analyses incorporating approximately 2.5 million genotyped and imputed SNPs were subsequently performed using a one-degree of freedom trend test assuming an additive effect of allele dosage. Results Significant evidence for a genetic contribution to ischemic stroke risk was detected (h2=0.39, SE=0.15, p-value = 0.0009), but this was higher and more significant for the large artery atherosclerosis (LAA) subtype (h2=0.66, SE=0.21, p-value = 0.0001). The genetic contributions to small vessel disease and cardioembolic stroke were less significant than for overall ischemic stroke. Genome wide association analyses including 421 LAA cases and 1244 controls detected a novel LAA susceptibility locus on chromosome 6p21.1 (two SNPs with P<5×10-8). The 6p21.1 locus showed markedly diminished association with the broader ischemic stroke phenotype. Conclusions In conclusion, this study detected higher heritability of large artery atherosclerotic stroke than cardioembolic stroke, small vessel disease or broad ischemic stroke. It suggests a genetic risk locus for large artery atherosclerosis on chromosome 6p21.1 and supports the analysis of aetiological subtypes to better identify genetic risk alleles for ischemic stroke.

AB - Introduction Genetic influences upon ischemic stroke risk are supported by the trait’s familial aggregation, higher concordance among monozygotic than dizygotic twins, and the high heritability of intermediate phenotypes such as carotid intima-media thickness. In spite of this evidence, genome-wide association studies (GWAS) have detected few replicable genetic risk factors for ischemic stroke, potentially due to aetiological heterogeneity of this trait. Hypothesis We first assessed the hypothesis that common ischemic stroke subtypes differ in their heritability, defined as the proportion of observed phenotypic variation attributable to genetic variation. The second hypothesis was that GWAS may detect stronger and more replicable genetic associations for distinct stroke subtypes with high heritability, rather than the broad ischemic stroke diagnosis. Methods An Australian, European-ancestry sample of 1230 ischemic stroke cases and 1280 population controls was genotyped for a genome wide association study using the Illumina 610-Quad array. Ischemic stroke subtypes were assigned using TOAST criteria. The proportion of case-control variation attributable to genome wide genetic variation was estimated using a published approach based on linear mixed models. Genome wide association analyses incorporating approximately 2.5 million genotyped and imputed SNPs were subsequently performed using a one-degree of freedom trend test assuming an additive effect of allele dosage. Results Significant evidence for a genetic contribution to ischemic stroke risk was detected (h2=0.39, SE=0.15, p-value = 0.0009), but this was higher and more significant for the large artery atherosclerosis (LAA) subtype (h2=0.66, SE=0.21, p-value = 0.0001). The genetic contributions to small vessel disease and cardioembolic stroke were less significant than for overall ischemic stroke. Genome wide association analyses including 421 LAA cases and 1244 controls detected a novel LAA susceptibility locus on chromosome 6p21.1 (two SNPs with P<5×10-8). The 6p21.1 locus showed markedly diminished association with the broader ischemic stroke phenotype. Conclusions In conclusion, this study detected higher heritability of large artery atherosclerotic stroke than cardioembolic stroke, small vessel disease or broad ischemic stroke. It suggests a genetic risk locus for large artery atherosclerosis on chromosome 6p21.1 and supports the analysis of aetiological subtypes to better identify genetic risk alleles for ischemic stroke.

M3 - Poster

ER -

Holliday EG, Maguire J, Evans TJ, Golledge J, Biros E, Lewis M et al. A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke. 2012. Poster session presented at International Stroke Conference, New Orleans, United States.