Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

Jb, Nielsen; Rb, Thorolfsdottir; Lg, Fritsche; Zhou, Wei; Mw, Skov; Se, Graham; Tj, Herron; McCarthy, SE; Em, Schmidt; Sveinbjörnsson, Garðar; Surakka, Ida; Mr, Mathis; Yamazaki, Masatoshi; Rd, Crawford; Me, Gabrielsen; Ah, Skogholt; Ol, Holmen; Ma, Lin; Wolford, Brooke N.; Dey, Ranjan Kumar; Dalen, Håvard; Sulem, Patrick; Jh, Chung; Jd, Backman; Do, Arnar; Þorsteinsdóttir, Unnur; Baras, Aris; Ó'Dúshláine, Colm; Holst, Anders G.; Wen, Xiaoquan; Hornsby, Whitney E.; Fe, Dewey; Boehnke, Michael; Kheterpal, Sachin; S, Lee; Hm, Kang; Hólm, Hilma; Kitzman, Jacob O.; Ja, Shavit; Jalife, José; Cm, Brummett; Tm, Teslovich; Dj, Carey; Df, Gudbjartsson; Stefánsson, Kāri; Gr, Abecasis; Hveem, Kristian; Cj, Willer

doi:10.1101/242149

Cited by 16 publications

(21 citation statements)

References 51 publications

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“…In recent pre-publication results, Nielsen et al, reported 111 loci from 60,620 AF cases and more than 970,000 referents, 15 including more than 18,000 AF cases from our prior report. 8 We therefore performed a preliminary meta-analysis for the top loci in nonoverlapping participants from these two large efforts with a resulting total of over 93,000 AF cases and more than 1 million referents.…”

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confidence: 54%

“…We meta-analyzed 111 variants from externally reported 15 provisional loci within predominantly non-overlapping samples from the Broad AF Study, BBJ, EGCUT, PHB, SiGN and the Vanderbilt AF Registry with METAL (released on 2011–03-25). 52 The predominantly nonoverlapping samples included a total of 32,957 AF cases and 83,546 referents, with minimal overlap from the studies MGH AF, BBJ and AFLMU.…”

Section: Methodsmentioning

confidence: 99%

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Multi-ethnic genome-wide association study for atrial fibrillation

et al. 2018

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Atrial fibrillation (AF) affects over 33 million individuals worldwide1 and has a complex heritability.2 We conducted the largest meta-analysis of genome-wide association studies for AF to date, consisting of over half a million individuals including 65,446 with AF. In total, we identified 97 loci significantly associated with AF including 67 of which were novel in a combined-ancestry analysis, and 3 in a European specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait loci (eQTL) analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

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confidence: 54%

Section: Methodsmentioning

confidence: 99%

Multi-ethnic genome-wide association study for atrial fibrillation

et al. 2018

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“…In our MR analyses using methods robust to the inclusion of invalid 33 . However, the effect estimates of heart rate reduction on atrial fibrillation are similar when using the GWAS results from Nielsen et al which include both population-based and clinical cohorts 12 . The possibility that the effect is greater in healthy patients is also supported by the previously described association between low heart rate during physical activity and the increased incidence of atrial fibrillation 34 .…”

Section: Effect Of Hcn4 On Atrial Fibrillationmentioning

confidence: 80%

“…We used hospitalization data between GRCh37. We also used the largest available meta-analysis of genome-wide association studies (GWAS) with summary statistics reporting the effect of the HCN4 rs8038766 variant on stroke, atrial fibrillation, CAD, myocardial infarction and heart failure (Supplementary methods) [10][11][12][13][14] .…”

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confidence: 99%

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A genetic model of ivabradine recapitulates results from randomized clinical trials

Legault

Sandoval

Provost

et al. 2020

Preprint

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Background. Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a mutation in HCN4, ivabradine's drug target, on safety and efficacy endpoints. Methods. We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. Results. Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P=9.3 × 10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P=0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P=0.61). Conclusion. Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.

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Separating the genetics of childhood and adult obesity: a validation study of genetic scores for body mass index in adolescence and adulthood in the HUNT Study

Brandkvist

Bjørngaard

Ødegård

et al. 2020

Human Molecular Genetics

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From a life-course perspective, genetic and environmental factors driving childhood obesity may have a lasting influence on health later in life. However, how obesity trajectories vary throughout the life-course remains unknown. Recently, Richardson et al. created powerful early life and adult gene scores for BMI in a comprehensive attempt to separate childhood and adult obesity. The childhood score was derived using questionnaire-based data administered to adults aged 40-69 regarding their relative body size at age 10, making it prone to recall and misclassification bias. We therefore attempted to validate the childhood and adult scores using measured BMI data in adolescence and adulthood among 66 963 individuals from the HUNT Study in Norway from 1963 to 2019. The predictive performance of the childhood score was better in adolescence and early adulthood while the predictive performance of the adult score was better in adulthood. In the age group 12-15.9 years, the variance explained by the childhood polygenic risk score was 6.7% versus 2.4% for the adult polygenic risk score. In the age group 24-29.9 years, the variance explained by the adult PRS was 3.9% versus 3.6% for the childhood PRS. Our findings support that genetic factors driving BMI differ at young age and in adulthood. Within the framework of multivariable Mendelian randomization, the validated childhood gene score can now be used to determine the consequence of childhood obesity on later disease.

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Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

Cited by 16 publications

References 51 publications

Multi-ethnic genome-wide association study for atrial fibrillation

Multi-ethnic genome-wide association study for atrial fibrillation

A genetic model of ivabradine recapitulates results from randomized clinical trials

Separating the genetics of childhood and adult obesity: a validation study of genetic scores for body mass index in adolescence and adulthood in the HUNT Study

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