A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke

Guðbjartsson, Daníel F.; Hólm, Hilma; Grétarsdóttir, Sólveig; Þorleifsson, Guðmar; Walters, G. Bragi; Þorgeirsson, Guðmundur; Gulcher, Jeffrey R.; Mathiesen, Ellisiv B.; Njølstad, Inger; Nyrnes, Audhild; Wilsgaard, Tom; Hald, Erin Mathiesen; Hveem, Kristian; Stoltenberg, Camilla; Kucera, Gayle; Stubblefield, Tanya; Carter, Shannon; Roden, Dan M.; Ng, Maggie; Baum, Larry; So, Wing Yee; Wong, Ka Sing; Chan, Juliana C.N.; Gieger, Christian; Wichmann, H‐Erich; Gschwendtner, Andreas; Dichgans, Martin; Kuhlenbäumer, Gregor; Berger, Klaus; Ringelstein, E. B.; Bevan, Steve; Markus, Hugh S.; Kostulas, Konstantinos; Hillert, Jan; Sveinbjörnsdóttir, Sigurlaug; Valdimarsson, Einar Már; Løchen, Maja‐Lisa; Ronald, C.; Darbar, Dawood; Kong, Augustine; Arnar, Davíð O.; Þorsteinsdóttir, Unnur; Stefánsson, Kári

doi:10.1038/ng.417

Cited by 432 publications

(344 citation statements)

References 11 publications

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“…24 Therefore, population-based or genome-wide studies have been used to identify many AF risk loci. 25,26,27,28,29,30 The genes at these loci encode transcription factors and ion channels, and many are without a clear relation to AF at the present time.…”

Section: Section 2: Definitions Mechanisms and Rationale For Af Ablmentioning

confidence: 99%

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

Calkins,

Kuck,

Cappato

et al. 2012

Heart Rhythm

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Section: Section 2: Definitions Mechanisms and Rationale For Af Ablmentioning

confidence: 99%

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

Calkins,

Kuck,

Cappato

et al. 2012

Heart Rhythm

1,763

1,468

View full text Add to dashboard Cite

“…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: 99%

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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“…AF may be rarely inherited in a Mendelian fashion [37] but it has recently become apparent that, even in sporadic AF, there is a significant heritability, with an odds ratio of 1.7-3.6, depending upon population and correction for other influences [38,39]. The majority of the genetic risk of AF appears to be conferred by a locus on chromosome 4 (4q25) [40], with a smaller but significant risk conferred by SNPs at 16q21 [41]. The 4q25 locus is adjacent to the gene encoding the transcription factor PITX2.…”

Section: Genome-wide Association Studies: Getting Closer To the Genetmentioning

confidence: 99%

“…PITX2 is required for normal cardiac development, with the PITX2c isoform being expressed mainly in the left atrium [42]. This suggests that homozygous SNPs at 4q25 induce subtle abnormalities in PITX2 expression or function, perhaps causing subclinical morphological abnormalities that predispose to postnatal AF, which in turn lead to an increased risk of ischaemic stroke [41,43]. Even with the greater power of GWAS, the complexity of cardiovascular diseases makes it extremely difficult to determine robust associations in large heterogeneous cohorts of patients.…”

Section: Genome-wide Association Studies: Getting Closer To the Genetmentioning

confidence: 99%

The genetics of cardiovascular disease: new insights from emerging approaches

Chico¹,

Milo²,

Crossman³

2009

The Journal of Pathology

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The prospect that sequencing the human genome would see rapid translation of a greater understanding of cardiovascular genetics into novel diagnostics and therapeutics has so far met with only limited success. However, diverse technological advances and exploitation of novel animal models of cardiovascular development and disease are providing ever more insight into cardiovascular diseases and development, and bring closer the prospect of 'postgenomic' diagnostics and therapies. Here we review some of these emerging approaches (genome wide association studies, deep sequencing, microRNA regulation, and zebrafish as a model of cardiovascular disease and development) and discuss their potential for finally fulfilling the promise of application to clinical cardiovascular medicine.

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A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke

Cited by 432 publications

References 11 publications

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

Phenome-wide association studies (PheWASs) for functional variants

The genetics of cardiovascular disease: new insights from emerging approaches

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