Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke

Grétarsdóttir, Sólveig; Þorleifsson, Guðmar; Manolescu, Andrei; Styrkársdóttir, Unnur; Helgadóttir, Anna; Gschwendtner, Andreas; Kostulas, Konstantinos; Kuhlenbäumer, Gregor; Bevan, Steve; Jónsdóttir, Þorbjörg; Bjarnason, Hjördis; Saemundsdottir, Jona; Palsson, Stefan; Arnar, Davíð O.; Hólm, Hilma; Þorgeirsson, Guðmundur; Valdimarsson, Einar Már; Sveinbjörnsdóttir, Sigurlaug; Gieger, Christian; Berger, Klaus; Wichmann, H‐Erich; Hillert, Jan; Markus, Hugh S.; Gulcher, Jeffrey R.; Ringelstein, E. Bernd; Kong, Augustine; Dichgans, Martin; Guðbjartsson, Daníel F.; Þorsteinsdóttir, Unnur; Stefánsson, Kári

doi:10.1002/ana.21480

Cited by 257 publications

(202 citation statements)

References 31 publications

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“…13,14,[35][36][37] Importantly, in the largest meta-analysis to date, all associations were with ischaemic stroke subtypes, and these showed much stronger association than in an analysis with all ischaemic stroke (κ = 1.24, 1.23, 1.19, and 1.11 for rs2107595 (HDAC9), rs6843082 (PITX2), rs879324 (ZFHX3), and rs2383207 (9p21), respectively). 13 Further to this, analyses of early onset cases suggest even stronger associations with young onset cases at these loci.…”

Section: Discussionmentioning

confidence: 91%

Homogeneous case subgroups increase power in genetic association studies

2014

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Genome-wide association studies of clinically defined cases against controls have transformed our understanding of the genetic causes of many diseases. However, there are limitations to the simple clinical definitions used in these studies, and GWAS analyses are beginning to explore more refined phenotypes in subgroups of the existing data sets. These analyses are often performed ad hoc without considering the power requirements to justify such analyses. Here we derive expressions for the relative power of such subgroup analyses and determine the genotypic relative risks (GRRs) required to achieve equivalent power to a full analysis for relevant scenarios. We show that only modest increases in GRRs may be required to offset the reduction in power from analysing fewer cases, implying that analyses of more genetically homogenous case subgroups may have the potential to identify further associations. We find that, for lower genotypic relative risks in the full sample, subgroup analyses of more homogeneous cases have relatively more power than for higher index genotypic relative risks and that this effect is stronger for rare as opposed to common variants. As GWA studies are likely to have now identified the majority of SNPs with stronger effects, these results strongly advocate a renewed effort to identify phenotypically homogeneous disease groups, in which power to detect genetic variants with small effects will be greater. These results suggest that analysis of case subsets could be a powerful strategy to uncover some of the hidden heritability for common complex disorders, particularly in identifying rarer variants of modest effect.

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Section: Discussionmentioning

confidence: 91%

Homogeneous case subgroups increase power in genetic association studies

2014

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“…Variants in two genes associated with atrial fibrillation, PITX2 and ZFHX3, were found to be independent risk factors for ischaemic stroke; 14,15 further analysis determined that these associations were specific to the development of cardioembolic stroke. 16 PITX2 encodes a transcription factor regulated by β-catenin, whereas ZFHX3 encodes a zinc finger protein.…”

Section: Early Studiesmentioning

confidence: 98%

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

Markus

Bevan

2014

Nat Rev Neurol

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| The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings.

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“…18,19 The third and fifth most significant phenotypes in this PheWAS were atrial fibrillation codes (ICD9 427.31, P ¼ 2.1 Â 10 À4 ; ICD9 427.3, P ¼ 2.8 Â 10 À4 ; Figure 1d). This SNP has also been reported to be associated with ischemic stroke, 20 but the associations for the ICD9 codes describing cerebrovascular disease (ICD9 430-438) were not significant.…”

Section: Control Snpsmentioning

confidence: 87%

Phenome-wide association studies (PheWASs) for functional variants

Mayer

Ivacic

et al. 2014

Eur J Hum Genet

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The genome-wide association study (GWAS) is a powerful approach for studying the genetic complexities of human disease. Unfortunately, GWASs often fail to identify clinically significant associations and describing function can be a challenge. GWAS is a phenotype-to-genotype approach. It is now possible to conduct a converse genotype-to-phenotype approach using extensive electronic medical records to define a phenome. This approach associates a single genetic variant with many phenotypes across the phenome and is called a phenome-wide association study (PheWAS). The majority of PheWASs conducted have focused on variants identified previously by GWASs. This approach has been efficient for rediscovering gene-disease associations while also identifying pleiotropic effects for some single-nucleotide polymorphisms (SNPs). However, the use of SNPs identified by GWAS in a PheWAS is limited by the inherent properties of the GWAS SNPs, including weak effect sizes and difficulty when translating discoveries to function. To address these challenges, we conducted a PheWAS on 105 presumed functional stop-gain and stop-loss variants genotyped on 4235 Marshfield Clinic patients. Associations were validated on an additional 10 640 Marshfield Clinic patients. PheWAS results indicate that a nonsense variant in ARMS2 (rs2736911) is associated with age-related macular degeneration (AMD). These results demonstrate that focusing on functional variants may be an effective approach when conducting a PheWAS.

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Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke

Cited by 257 publications

References 31 publications

Homogeneous case subgroups increase power in genetic association studies

Homogeneous case subgroups increase power in genetic association studies

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

Phenome-wide association studies (PheWASs) for functional variants

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