@article{Nielsen2017,
title = {Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development},
author = {Jonas B. Nielsen and Lars G. Fritsche and Wei Zhou and Tanya M. Teslovich and Oddgeir L. Holmen and Stefan Gustafsson and Maiken E. Gabrielsen and Ellen M. Schmidt and Robin Beaumont and Brooke N. Wolford and Maoxuan Lin and Chad M. Brummett and Michael H. Preuss and Lena Refsgaard and Erwin P. Bottinger and Sarah E. Graham and Ida Surakka and Yunhan Chu and Anne Heidi Skogholt and Håvard Dalen and Alan P. Boyle},
url = {https://www.sciencedirect.com/science/article/pii/S0002929717304925},
year = {2017},
date = {2017-12-28},
journal = {American Journal of Human Genetics},
abstract = {Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.},
keywords = {atrial fibrillation, genetics},
pubstate = {published},
tppubtype = {article}
}

@article{Weng2017b,
title = {Heritability of Atrial Fibrillation.},
author = {LC Weng and SH Choi and D Klarin and JG Smith and PR Loh and M Chaffin and C Roselli and OL Hulme and KL Lunetta and J Dupuis and EJ Benjamin and C Newton-Cheh and S Kathiresan and PT Ellinor and SA Lubitz},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29237688},
year = {2017},
date = {2017-12-10},
journal = {Circulation},
abstract = {BACKGROUND:

Previous reports have implicated multiple genetic loci associated with AF, but the contributions of genome-wide variation to AF susceptibility have not been quantified.
METHODS AND RESULTS:

We assessed the contribution of genome-wide single-nucleotide polymorphism variation to AF risk (single-nucleotide polymorphism heritability, h2g ) using data from 120 286 unrelated individuals of European ancestry (2987 with AF) in the population-based UK Biobank. We ascertained AF based on self-report, medical record billing codes, procedure codes, and death records. We estimated h2g using a variance components method with variants having a minor allele frequency ≥1%. We evaluated h2g in age, sex, and genomic strata of interest. The h2g for AF was 22.1% (95% confidence interval, 15.6%-28.5%) and was similar for early- versus older-onset AF (≤65 versus >65 years of age), as well as for men and women. The proportion of AF variance explained by genetic variation was mainly accounted for by common (minor allele frequency, ≥5%) variants (20.4%; 95% confidence interval, 15.1%-25.6%). Only 6.4% (95% confidence interval, 5.1%-7.7%) of AF variance was attributed to variation within known AF susceptibility, cardiac arrhythmia, and cardiomyopathy gene regions.
CONCLUSIONS:

Genetic variation contributes substantially to AF risk. The risk for AF conferred by genomic variation is similar to that observed for several other cardiovascular diseases. Established AF loci only explain a moderate proportion of disease risk, suggesting that furt},
keywords = {17488, atrial fibrillation, genetics},
pubstate = {published},
tppubtype = {article}
}

@article{Weng2017,
title = {Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation.},
author = {LC Weng and SR Preis and OL Hulme and MG Larson and SH Choi and B Wang and L Trinquart and DD McManus and L Staerk and H Lin and KL Lunetta and PT Ellinor and EJ Benjamin and SA Lubitz },
url = {https://www.ncbi.nlm.nih.gov/pubmed/29129827},
year = {2017},
date = {2017-11-12},
journal = {Circulation},
abstract = {Background -The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. Methods -We estimated lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of approximately 1,000 AF-associated single nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. Results -Among 4,606 participants without AF at age 55 years, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF after age 55 years was 37.1%, and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at age 55 years, those in low polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval [CI], 15.4%-29.1%), whereas those in high risk tertiles had a risk of 48.2% (95% CI, 41.3%-55.1%). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P value <0.001). Conclusions -In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible, and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.},
keywords = {17488, atrial fibrillation, genetics},
pubstate = {published},
tppubtype = {article}
}

@article{Jani2017b,
title = {Multimorbidity and co-morbidity in atrial fibrillation and effects on survival: findings from UK Biobank cohort},
author = { Bhautesh Dinesh Jani and Barbara I Nicholl and Ross McQueenie and Derek T Connelly and Peter Hanlon and Katie I Gallacher and Duncan Lee and Frances S Mair},
url = {https://academic.oup.com/europace/article/doi/10.1093/europace/eux322/4582725},
year = {2017},
date = {2017-11-02},
journal = {Europace},
abstract = {To examine the number and type of co-morbid long-term health conditions (LTCs) and their associations with all-cause mortality in an atrial fibrillation (AF) population.

Methods and results

Community cohort participants (UK Biobank n = 502 637) aged 37–73 years were recruited between 2006 and 2010. Self-reported LTCs (n = 42) identified in people with AF at baseline. All-cause mortality was available for a median follow-up of 7 years (interquartile range 76–93 months). Hazard ratios (HRs) examined associations between number and type of co-morbid LTC and all-cause mortality, adjusting for age, sex, socio-economic status, smoking, and anticoagulation status. Three thousand six hundred fifty-one participants (0.7% of the study population) reported AF; mean age was 61.9 years. The all-cause mortality rate was 6.7% (248 participants) at 7 years. Atrial fibrillation participants with ≥4 co-morbidities had a six-fold higher risk of mortality compared to participants without any LTC. Co-morbid heart failure was associated with higher risk of mortality [HR 2.96, 95% confidence interval (CI) 1.83–4.80], whereas the presence of co-morbid stroke did not have a significant association. Among non-cardiometabolic conditions, presence of chronic obstructive pulmonary disease (HR 3.31, 95% CI 2.14–5.11) and osteoporosis (HR 3.13, 95% CI 1.63–6.01) was associated with a higher risk of mortality.

Conclusion

Survival in middle-aged to older individuals with self-reported AF is strongly correlated with level of multimorbidity. This group should be targeted for interventions to optimize their management, which in turn may potentially reduce the impact of their co-morbidities on survival. Future AF clinical guidelines need to place greater emphasis on the issue of co-morbidity.},
keywords = {14151, atrial fibrillation, featured, morbidity},
pubstate = {published},
tppubtype = {article}
}

@article{Verweij2017,
title = {Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure.},
author = {N Verweij and RN Eppinga Y Hagemeijer P van der Harst },
url = {https://www.ncbi.nlm.nih.gov/pubmed/28584231},
year = {2017},
date = {2017-06-05},
journal = {Scientific Reports},
abstract = {Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <× 10-5 in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 × 10-8) including 15 novel loci. These novel loci include multiple genes that are involved in angiogenesis (TGFB1, ITGB5, CDH13 and RHOA) and 2 independent variants in the TGFB1 locus. We also identified SGEF as a candidate gene in one of the novel CAD loci. SGEF was previously suggested as a therapeutic target based on mouse studies. The genetic risk score of CAD predicted recurrent CAD events and cardiovascular mortality. We also identified significant genetic correlations between CAD and other cardiovascular conditions, including heart failure and atrial fibrillation. In conclusion, we substantially increased the number of loci convincingly associated with CAD and provide additional biological and clinical insights.},
keywords = {9628, atrial fibrillation, featured, genetics},
pubstate = {published},
tppubtype = {article}
}

@article{Christophersen2017,
title = {Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation},
author = {Ingrid E Christophersen, Michiel Rienstra, Carolina Roselli, Xiaoyan Yin, Bastiaan Geelhoed, John Barnard, Honghuang Lin, Dan E Arking, Albert V Smith, Christine M Albert, Mark Chaffin, Nathan R Tucker, Molong Li, Derek Klarin, Nathan A Bihlmeyer, Siew-Kee Low, Peter E Weeke, Martina Müller-Nurasyid, J Gustav Smith, Jennifer A Brody, Maartje N Niemeijer, Marcus Dörr, Stella Trompet, Jennifer Huffman, Stefan Gustafsson et al.},
url = {https://www.nature.com/ng/journal/v49/n6/full/ng.3843.html},
year = {2017},
date = {2017-04-17},
journal = {Nature Genetics},
abstract = {Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death1, 2. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups3, 4, 5, 6, 7. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.},
keywords = {15293, atrial fibrillation},
pubstate = {published},
tppubtype = {article}
}