Limits...
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.

Show MeSH

Related in: MedlinePlus

Forest plot for the associations between rs11984041 and large vessel stroke in discovery and replication collectionsThe blue lines show the 95% confidence intervals of the log odds-ratio (OR) for each cohort, with the area of each square proportional to the inverse of the standard error. The diamonds indicate the 95% confidence interval for, from top to bottom, the discovery summary (combined British and German discovery collections), combined across collections within each of the three replication stages, the replication summary (combined across all three replication stages) and the overall summary (all discovery and replication collections combined). Evidence was combined across collections via an inverse-variance weighted fixed-effect meta-analysis. There was no evidence of heterogeneity of effect across collections (P = 0.92).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3303115&req=5

Figure 2: Forest plot for the associations between rs11984041 and large vessel stroke in discovery and replication collectionsThe blue lines show the 95% confidence intervals of the log odds-ratio (OR) for each cohort, with the area of each square proportional to the inverse of the standard error. The diamonds indicate the 95% confidence interval for, from top to bottom, the discovery summary (combined British and German discovery collections), combined across collections within each of the three replication stages, the replication summary (combined across all three replication stages) and the overall summary (all discovery and replication collections combined). Evidence was combined across collections via an inverse-variance weighted fixed-effect meta-analysis. There was no evidence of heterogeneity of effect across collections (P = 0.92).

Mentions: Thirty-eight previously unreported loci showed potential association for all stroke or one of the stroke subtypes in the discovery samples, and we further investigated these loci in the European replication samples by genotyping 43 SNPs covering these loci as well as 7 SNPs to cover the previously reported loci (Supplementary Table 2). Thirteen of these previously unreported loci and the previously reported loci were taken forward to replication in the American samples with genotyping of 20 SNPs covering these regions (Supplementary Table 3). Most replication samples were genotyped using Sequenom assays; for those previously typed with GWAS chips we used genotype imputation where the SNP was not directly typed (see Supplementary Tables 2 and 3 and Online Methods). A SNP at chromosome 7p21.1 (rs11984041) showed evidence of association with large vessel stroke in the discovery data (P=1.07×10−5) and in the joint European and US replication data in the same direction (one-sided P=7.9×10−5). As a further check, we investigated this SNP in three further collections of large vessel cases and matched controls (735 cases, 28583 controls in total), which we refer to as Stage 3 replication (see Online Methods for details). The Stage 3 data also showed evidence in the same direction (one-sided P=2.25×10−4). Together, the combined discovery and three-stage replication data provide strong evidence for association (P=1.87×10−11) and suggest each copy of the A allele increases risk of large vessel stroke by approximately 1.4 fold (Table 2 and Figure 2). This SNP is within the final intron of the gene HDAC9. The risk allele (A) frequency was 9.29% and 8.78% in the UK and German discovery controls respectively.


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)

Forest plot for the associations between rs11984041 and large vessel stroke in discovery and replication collectionsThe blue lines show the 95% confidence intervals of the log odds-ratio (OR) for each cohort, with the area of each square proportional to the inverse of the standard error. The diamonds indicate the 95% confidence interval for, from top to bottom, the discovery summary (combined British and German discovery collections), combined across collections within each of the three replication stages, the replication summary (combined across all three replication stages) and the overall summary (all discovery and replication collections combined). Evidence was combined across collections via an inverse-variance weighted fixed-effect meta-analysis. There was no evidence of heterogeneity of effect across collections (P = 0.92).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303115&req=5

Figure 2: Forest plot for the associations between rs11984041 and large vessel stroke in discovery and replication collectionsThe blue lines show the 95% confidence intervals of the log odds-ratio (OR) for each cohort, with the area of each square proportional to the inverse of the standard error. The diamonds indicate the 95% confidence interval for, from top to bottom, the discovery summary (combined British and German discovery collections), combined across collections within each of the three replication stages, the replication summary (combined across all three replication stages) and the overall summary (all discovery and replication collections combined). Evidence was combined across collections via an inverse-variance weighted fixed-effect meta-analysis. There was no evidence of heterogeneity of effect across collections (P = 0.92).
Mentions: Thirty-eight previously unreported loci showed potential association for all stroke or one of the stroke subtypes in the discovery samples, and we further investigated these loci in the European replication samples by genotyping 43 SNPs covering these loci as well as 7 SNPs to cover the previously reported loci (Supplementary Table 2). Thirteen of these previously unreported loci and the previously reported loci were taken forward to replication in the American samples with genotyping of 20 SNPs covering these regions (Supplementary Table 3). Most replication samples were genotyped using Sequenom assays; for those previously typed with GWAS chips we used genotype imputation where the SNP was not directly typed (see Supplementary Tables 2 and 3 and Online Methods). A SNP at chromosome 7p21.1 (rs11984041) showed evidence of association with large vessel stroke in the discovery data (P=1.07×10−5) and in the joint European and US replication data in the same direction (one-sided P=7.9×10−5). As a further check, we investigated this SNP in three further collections of large vessel cases and matched controls (735 cases, 28583 controls in total), which we refer to as Stage 3 replication (see Online Methods for details). The Stage 3 data also showed evidence in the same direction (one-sided P=2.25×10−4). Together, the combined discovery and three-stage replication data provide strong evidence for association (P=1.87×10−11) and suggest each copy of the A allele increases risk of large vessel stroke by approximately 1.4 fold (Table 2 and Figure 2). This SNP is within the final intron of the gene HDAC9. The risk allele (A) frequency was 9.29% and 8.78% in the UK and German discovery controls respectively.

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