Next-Generation Genome-Wide Association Studies

MacRae, Calum A.; Vasan, Ramachandran S.

doi:10.1161/circgenetics.111.960765

Cited by 37 publications

(38 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inherent heterogeneity of aging-related traits is one of the key problems in these studies. 26,40,82 GWAS typically follow a reductionist approach to overcome this problem, and the basis of this approach is to select more homogeneous sub-phenotypes. For example, one common strategy is to focus on endophenotypes that can be in a causative pathway to a trait in question.…”

Section: Etiologic Complexity Of Aging-related Traitsmentioning

confidence: 99%

See 1 more Smart Citation

Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

Kulminski

2013

Rejuvenation Research

View full text Add to dashboard Cite

Discovering the genetic origin of aging-related traits could greatly advance strategies aiming to extend health span. The results of genome-wide association studies (GWAS) addressing this problem are controversial, and new genetic concepts have been fostered to advance the progress in the field. A limitation of GWAS and new genetic concepts is that they do not thoroughly address specifics of aging-related traits. Integration of theoretical concepts in genetics and aging research with empirical evidence from different disciplines highlights the conceptual problems in studies of genetic origin of aging-related traits. To address these problems, novel approaches of systemic nature are required. These approaches should adopt the non-deterministic nature of linkage of genes with aging-related traits and, consequently, reinforce research strategies for improving our understanding of mechanisms shaping genetic effects on these traits. Investigation of mechanisms will help determine conditions that activate specific genetic variants or profiles and explore to what extent these conditions that shape genetic effects are conserved across human lives and generations.

show abstract

Section: Etiologic Complexity Of Aging-related Traitsmentioning

confidence: 99%

“…82 A clear limitation of this strategy is that it does not guarantee etiologic homogeneity because of limited knowledge about etiology of aging-related traits. 82 Current GWAS following trait-specific mechanisms do not typically address the role of life course in aging-related traits.…”

Section: Etiologic Complexity Of Aging-related Traitsmentioning

confidence: 99%

Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

Kulminski

2013

Rejuvenation Research

View full text Add to dashboard Cite

show abstract

“…15) As well as its versatile applications towards improved detection of genetic changes in patients with cardiovascular disease and exploration of novel genotype-phenotype correlations, [15][16][17] NGS will enable the prediction of clinical outcomes and the development of individualized treatments (personalized medicine) by revealing the interactions of multiple gene mutations in patients with inherited cardiovascular disease.…”

mentioning

confidence: 99%

A Novel Truncating <i>LMNA</i> Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

et al. 2018

View full text Add to dashboard Cite

SummaryThe cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM. Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular diseaseassociated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.(Int Heart J 2018; 59: 531-541)

show abstract

“…13 We previously developed and validated CT angiography (CTA)-based image analysis methods and showed that using highly standardized image analysis protocols, the reproducibility of this technique is excellent 6,14 . In addition, we have also validated this CTA technique against intravascular ultrasonography with radiofrequency backscatter analysis, 7,15 near-infrared spectroscopy, 6 and fractional flow reserve.…”

Section: Discussionmentioning

confidence: 99%

Precision phenotyping, panomics, and system-level bioinformatics to delineate complex biologies of atherosclerosis: Rationale and design of the “Genetic Loci and the Burden of Atherosclerotic Lesions” study

Vörös¹,

Maurovich-Horvat²,

Marvasty³

et al. 2014

Journal of Cardiovascular Computed Tomography

View full text Add to dashboard Cite

By design, this is a hypothesis-free unbiased discovery study collecting a large number of biologically related factors to examine biological associations between genomic, proteomic, metabolomic, lipidomic, and phenotypic factors of atherosclerosis. The Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828) is a prospective, multicenter, international observational study of atherosclerotic coronary artery disease. Approximately 7500 patients are enrolled and undergo non-contrast-enhanced coronary calcium scanning by CT for the detection and quantification of coronary artery calcium, as well as coronary artery CT angiography for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. In addition, patients undergo whole genome sequencing, DNA methylation, whole blood-based transcriptome sequencing, unbiased proteomics based on mass spectrometry, as well as metabolomics and lipidomics on a mass spectrometry platform. The study is analyzed in 3 subsequent phases, and each phase consists of a discovery cohort and an independent validation cohort. For the primary analysis, the primary phenotype will be the presence of any atherosclerotic plaque, as detected by cardiac CT. Additional phenotypic analyses will include per patient maximal luminal stenosis defined as 50% and 70% diameter stenosis. Single-omic and multi-omic associations will be examined for each phenotype; putative biomarkers will be assessed for association, calibration, discrimination, and reclassification.

show abstract

Next-Generation Genome-Wide Association Studies

Cited by 37 publications

References 33 publications

Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

A Novel Truncating <i>LMNA</i> Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

Precision phenotyping, panomics, and system-level bioinformatics to delineate complex biologies of atherosclerosis: Rationale and design of the “Genetic Loci and the Burden of Atherosclerotic Lesions” study

Contact Info

Product

Resources

About