Genome-Wide Significant Loci: How Important Are They?

Björkegren, Johan; Kovacic, Jason C.; Dudley, Joel T.; Schadt, Eric E.

doi:10.1016/j.jacc.2014.12.033

Cited by 124 publications

(85 citation statements)

References 93 publications

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“…114 A molecular network is based on interactions among diverse molecules, including genes, proteins, and metabolites. These can include interactions between proteins, effects on gene regulation, coexpression, and various functional interactions.…”

Section: Systems Genetics Approach To Understanding the Genetic Basismentioning

confidence: 99%

Genetics of Coronary Artery Disease

McPherson

Tybjærg‐Hansen

2016

Circulation Research

327

203

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Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genomewide significance (P<5×10 −8 ) have been identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (q<0.05) and together explain 28% of the estimated heritability of CAD. These data have been used successfully to create genetic risk scores that can improve risk prediction beyond conventional risk factors and identify those individuals who will benefit most from statin therapy. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk in epidemiological studies. In contrast to genome-wide association studies, whole-exome sequencing has provided valuable information directly relevant to genes with known roles in plasma lipoprotein metabolism but has, thus far, failed to identify other rare coding variants linked to CAD. Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been limited progress in understanding the function of the novel loci; the majority of which are in noncoding regions of the genome. (Circ Res. 2016;118:564-578.

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Section: Systems Genetics Approach To Understanding the Genetic Basismentioning

confidence: 99%

Genetics of Coronary Artery Disease

McPherson

Tybjærg‐Hansen

2016

Circulation Research

327

203

View full text Add to dashboard Cite

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“…However, individuals with a high genetic risk score appear to have a larger benefit from statin treatment than those with low genetic risk (Hughes et al , 2012; Mega et al , 2015; Schunkert & Samani, 2015). Further, stimulating input in this field might come from systems medicine approaches (Bjoerkegren et al , 2015). For example, an integrative analysis revealed an enrichment of CAD‐associated variants in differentially co‐expressed microRNA–mRNA pairs (Huan et al , 2013).…”

Section: Precision Medicinementioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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“…1 , Назаренко М. с. 1,2,3 , Пузырев В. П. 1,3 В обзоре рассмотрены существующие представления о структурной изменчи-вости генома соматических клеток как компоненты, связанной с атеросклеро-зом.…”

Section: структурная вариабельность генома лейкоцитов и клеток артериunclassified

“…1,2,3 , Пузырев В. П. 1,3 В обзоре рассмотрены существующие представления о структурной изменчи-вости генома соматических клеток как компоненты, связанной с атеросклеро-зом. Приведены результаты собственного исследования о спектре вариаций числа копий участков ДНК в лейкоцитах периферической крови и клетках артерий при их атеросклеротическом поражении у человека.…”

Section: структурная вариабельность генома лейкоцитов и клеток артериunclassified

“…Несмотря на активное проведение исследований в области генетики атеросклероза и его клинических осложнений, список генов, изменчи-вость которых может быть фактором риска развития и прогрессии данных заболеваний, относительно небольшой, а однонуклеотидный полиморфизм объ-ясняет лишь малую долю наследуемости данных заболеваний. Исследования ассоциаций выявляют генетическую детерминированность факторов риска атеросклероза (дислипидемия и артериальная гипер-тензия) и, следовательно, ранних этапов атерогенеза, но не проясняют всего спектра молекулярных меха-низмов патологических изменений, происходящих в стенке артерий при развитии сосудистых осложне-ний [3,4].…”

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