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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

International Stroke Genetics Consortium (ISGC)Wellcome Trust Case Control Consortium 2 (WTCCC2)Bellenguez C, Bevan S, Gschwendtner A, Spencer CC, Burgess AI, Pirinen M, Jackson CA, Traylor M, Strange A, Su Z, Band G, Syme PD, Malik R, Pera J, Norrving B, Lemmens R, Freeman C, Schanz R, James T, Poole D, Murphy L, Segal H, Cortellini L, Cheng YC, Woo D, Nalls MA, Müller-Myhsok B, Meisinger C, Seedorf U, Ross-Adams H, Boonen S, Wloch-Kopec D, Valant V, Slark J, Furie K, Delavaran H, Langford C, Deloukas P, Edkins S, Hunt S, Gray E, Dronov S, Peltonen L, Gretarsdottir S, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Boncoraglio GB, Parati EA, Attia J, Holliday E, Levi C, Franzosi MG, Goel A, Helgadottir A, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Worrall BB, Kittner SJ, Mitchell BD, Kissela B, Meschia JF, Thijs V, Lindgren A, Macleod MJ, Slowik A, Walters M, Rosand J, Sharma P, Farrall M, Sudlow CL, Rothwell PM, Dichgans M, Donnelly P, Markus HS - Nat. Genet. (2012)

Bottom Line: We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry.Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls.We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, UK.

ABSTRACT
Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

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Genetic heterogeneity of different stroke sub-types for the 4 loci with significant associations: HDAC9, PITX2, 9p21(CDKN2A/CDKN2B) and ZFHX3Bar plots show the posterior probabilities on the models of association: no effect in any subtype (Null), same effect in all subtypes, correlated effects across subtypes or subtype specific effects (see main text). Models are a priori assumed to be equally likely. Bayes factors, which compare the evidence (marginal likelihood) between any pair of models, can be calculated as the ratio of the posterior probability assigned to each model as reported under each bar of the plot. Accompanying density plots show the marginal posterior distribution on the odds ratio of the risk allele for each stroke subtype assuming a model of correlated effects (see methods for specification of priors). These analyses were performed using both discovery and replication samples (stage 1 & 2).
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Figure 3: Genetic heterogeneity of different stroke sub-types for the 4 loci with significant associations: HDAC9, PITX2, 9p21(CDKN2A/CDKN2B) and ZFHX3Bar plots show the posterior probabilities on the models of association: no effect in any subtype (Null), same effect in all subtypes, correlated effects across subtypes or subtype specific effects (see main text). Models are a priori assumed to be equally likely. Bayes factors, which compare the evidence (marginal likelihood) between any pair of models, can be calculated as the ratio of the posterior probability assigned to each model as reported under each bar of the plot. Accompanying density plots show the marginal posterior distribution on the odds ratio of the risk allele for each stroke subtype assuming a model of correlated effects (see methods for specification of priors). These analyses were performed using both discovery and replication samples (stage 1 & 2).

Mentions: Standard statistical tests of association between rs11984041 and each of cardioembolic and small vessel stroke are not significant (discovery plus 2-stage replication p = 0.12, OR = 1.10, 95% CI = 0.98 – 1.23, and p = 0.06, OR = 1.13, 95% CI = 1.00 – 1.28 respectively). A non-significant result could simply be due to a lack of power: lack of significance in itself cannot rule out an effect in these subtypes. We investigated this potential genetic heterogeneity further by formally comparing different statistical models for the effect of the SNP on the different stroke subtypes. The models we compared were: (i) a model in which the variant has no effect on risk for any of the subtypes (“” model); (ii) a model in which the SNP has the same effect on each subtype (“same effects” model); (iii) three models, in each of which the SNP has an effect on one subtype, and no effect for the other two subtypes (“LVD”, “SVD” and “CE” models respectively for the effect only in large vessel, small vessel, and cardioembolic stroke); and (iv) a “correlated effects” model allowing different, but correlated, effects for each subtype. We undertook the model comparison in a Bayesian statistical framework (see Online Methods for details), for our new association around HDAC9, as well as for the previously reported associations we confirmed as listed in Table 2. The results, based on the discovery and the first two stages of the replication, are shown in Figure 3.


Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

International Stroke Genetics Consortium (ISGC)Wellcome Trust Case Control Consortium 2 (WTCCC2)Bellenguez C, Bevan S, Gschwendtner A, Spencer CC, Burgess AI, Pirinen M, Jackson CA, Traylor M, Strange A, Su Z, Band G, Syme PD, Malik R, Pera J, Norrving B, Lemmens R, Freeman C, Schanz R, James T, Poole D, Murphy L, Segal H, Cortellini L, Cheng YC, Woo D, Nalls MA, Müller-Myhsok B, Meisinger C, Seedorf U, Ross-Adams H, Boonen S, Wloch-Kopec D, Valant V, Slark J, Furie K, Delavaran H, Langford C, Deloukas P, Edkins S, Hunt S, Gray E, Dronov S, Peltonen L, Gretarsdottir S, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Boncoraglio GB, Parati EA, Attia J, Holliday E, Levi C, Franzosi MG, Goel A, Helgadottir A, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Worrall BB, Kittner SJ, Mitchell BD, Kissela B, Meschia JF, Thijs V, Lindgren A, Macleod MJ, Slowik A, Walters M, Rosand J, Sharma P, Farrall M, Sudlow CL, Rothwell PM, Dichgans M, Donnelly P, Markus HS - Nat. Genet. (2012)

Genetic heterogeneity of different stroke sub-types for the 4 loci with significant associations: HDAC9, PITX2, 9p21(CDKN2A/CDKN2B) and ZFHX3Bar plots show the posterior probabilities on the models of association: no effect in any subtype (Null), same effect in all subtypes, correlated effects across subtypes or subtype specific effects (see main text). Models are a priori assumed to be equally likely. Bayes factors, which compare the evidence (marginal likelihood) between any pair of models, can be calculated as the ratio of the posterior probability assigned to each model as reported under each bar of the plot. Accompanying density plots show the marginal posterior distribution on the odds ratio of the risk allele for each stroke subtype assuming a model of correlated effects (see methods for specification of priors). These analyses were performed using both discovery and replication samples (stage 1 & 2).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3303115&req=5

Figure 3: Genetic heterogeneity of different stroke sub-types for the 4 loci with significant associations: HDAC9, PITX2, 9p21(CDKN2A/CDKN2B) and ZFHX3Bar plots show the posterior probabilities on the models of association: no effect in any subtype (Null), same effect in all subtypes, correlated effects across subtypes or subtype specific effects (see main text). Models are a priori assumed to be equally likely. Bayes factors, which compare the evidence (marginal likelihood) between any pair of models, can be calculated as the ratio of the posterior probability assigned to each model as reported under each bar of the plot. Accompanying density plots show the marginal posterior distribution on the odds ratio of the risk allele for each stroke subtype assuming a model of correlated effects (see methods for specification of priors). These analyses were performed using both discovery and replication samples (stage 1 & 2).
Mentions: Standard statistical tests of association between rs11984041 and each of cardioembolic and small vessel stroke are not significant (discovery plus 2-stage replication p = 0.12, OR = 1.10, 95% CI = 0.98 – 1.23, and p = 0.06, OR = 1.13, 95% CI = 1.00 – 1.28 respectively). A non-significant result could simply be due to a lack of power: lack of significance in itself cannot rule out an effect in these subtypes. We investigated this potential genetic heterogeneity further by formally comparing different statistical models for the effect of the SNP on the different stroke subtypes. The models we compared were: (i) a model in which the variant has no effect on risk for any of the subtypes (“” model); (ii) a model in which the SNP has the same effect on each subtype (“same effects” model); (iii) three models, in each of which the SNP has an effect on one subtype, and no effect for the other two subtypes (“LVD”, “SVD” and “CE” models respectively for the effect only in large vessel, small vessel, and cardioembolic stroke); and (iv) a “correlated effects” model allowing different, but correlated, effects for each subtype. We undertook the model comparison in a Bayesian statistical framework (see Online Methods for details), for our new association around HDAC9, as well as for the previously reported associations we confirmed as listed in Table 2. The results, based on the discovery and the first two stages of the replication, are shown in Figure 3.

Bottom Line: We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry.Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls.We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, UK.

ABSTRACT
Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Show MeSH
Related in: MedlinePlus