Biobank-driven genomic discovery yields new insight into atrial fibrillation biology

Jb, Nielsen; Þórólfsdóttir, Rósa B.; Fritsche, Lars G.; Zhou, Wei; Skov, Marianne; Graham, Sarah E.; Herron, Todd J.; McCarthy, Shane; Schmidt, Ellen M.; Sveinbjörnsson, Garðar; Surakka, Ida; Mathis, Michael R.; Yamazaki, Masatoshi; Crawford, Ryan; Gabrielsen, Maiken Elvestad; Skogholt, Anne Heidi; Holmen, Oddgeir L.; Lin, Maoxuan; Wolford, Brooke N.; Dey, Rounak; Dalen, Håvard; Sulem, Patrick; Chung, Jonathan; Backman, Joshua; Arnar, Davíð O.; Þorsteinsdóttir, Unnur; Baras, Aris; Ó'Dúshláine, Colm; Holst, Anders; Wen, Xiaoquan; Hornsby, Whitney E.; Dewey, Frederick E.; Boehnke, Michael; Kheterpal, Sachin; Mukherjee, Bhramar; Lee, Seunggeun; Kang, Hyun Min; Hólm, Hilma; Kitzman, Jacob O.; Shavit, Jordan A.; Jalife, José; Brummett, Chad M.; Teslovich, Tanya M.; Carey, David J.; Guðbjartsson, Daníel F.; Stefánsson, Kāri; Abecasis, Gonçalo R.; Hveem, Kristian; Willer, Cristen J.

doi:10.1038/s41588-018-0171-3

Cited by 579 publications

(525 citation statements)

References 67 publications

Supporting

Mentioning

515

Contrasting

Unclassified

Order By: Relevance

“…There is a significant association between common variants at the TTN locus and AF in other studies. 7,32,34,35 The direction and effect size of the association observed in the current study is similar to that previously reported, but the differences observed in statistical significance may be a reflection of the sample size. In the common variant analysis, there was an association between individuals with early-onset AF and genetic variants at the NAV2 locus, a finding that was observed in two recent meta-analyses for AF.…”

Section: Discussionsupporting

confidence: 90%

“…In the common variant analysis, there was an association between individuals with early-onset AF and genetic variants at the NAV2 locus, a finding that was observed in two recent meta-analyses for AF. 32,35 The neuron navigator 2 gene encodes the Nav2 protein that was originally identified as an all-trans retinoic acid responsive gene in a neuroblastoma cell line. 36 Knockout of the NAV2 gene in mice results in loss of normal development of the glossopharyngeal and vagal cranial nerves and a blunted baroreceptor response.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Choi¹,

Weng²,

Roselli³

et al. 2018

JAMA

Self Cite

149

125

View full text Add to dashboard Cite

Importance Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective To perform large-scale, deep-coverage whole genome sequencing to identify genetic variants related to AF. Design, Setting, Participants The National Heart Lung and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high depth, whole genome sequencing between 2014 and 2017 in 18,526 individuals from the U.S., Mexico, Puerto-Rico, Costa-Rica, Barbados, and Samoa. This case-control study included 2,781 patients with early onset AF from 9 studies and identified 4,959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank and the MyCode Study consisting of 346,546 and 42,782 participants, respectively. Exposures Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures Early-onset AF defined as AF onset < 66 years of age. Due to multiple testing, the significance threshold for the rare variant analysis was P=4.55 X 10−3. Results Among 2,781 early-onset AF cases, 72.1% were male, and the mean age of AF onset was 48.7±10.2 years. Samples underwent whole genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least one LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of cases compared with 1.1% in controls. The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend 4.92×10−4) and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (odds ratio = 5.94; 95% CI, 2.64–13.35; P=1.65×10−5). The association between TTN LOF variants and AF was replicated in an independent 1,582 early-onset AF cases and 41,200 controls (odds ratio = 2.16; 95% CI, 1.19–3.92; P=0.01). Conclusions and Relevance In a case control study, there was a statistically significant association between a LOF variant in the gene TTN and early-onset AF, with the variant present in a small percentage of cases. Further research is required to understand whether this is a causal relationship.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Choi¹,

Weng²,

Roselli³

et al. 2018

JAMA

Self Cite

149

125

View full text Add to dashboard Cite

show abstract

“…The summary association statistics came from recent genome-wide association studies (GWAS) ( Supplementary Table S3, Supplementary Figure 1). [16][17][18][19][20] LDpred was used to account for linkage disequilibrium among loci, 21 with whole-genome sequencing data on 2,690 Finns serving as the LD reference panel. After performing quality control, the final scores were generated with PLINK2 24 by calculating the weighted sum of risk allele dosages for each single nucleotide polymorphism (SNP).…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

Polygenic and clinical risk scores and their impact on age at onset of cardiometabolic diseases and common cancers

Mars

Koskela

Ripatti

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: Polygenic risk scores (PRS) have shown promise in predicting susceptibility to common diseases. However, the extent to which PRS and clinical risk factors act jointly and identify high-risk individuals for early onset of disease is unknown. Methods:We used large-scale biobank data (the FinnGen study; n=135,300), with up to 46 years of prospective follow-up, and the FINRISK study with standardized clinical risk factor measurements to build genome-wide PRSs with >6M variants for coronary heart disease (CHD), type 2 diabetes (T2D), atrial fibrillation (AF), and breast and prostate cancer. We evaluated their associations with first disease events, age at disease onset, and impact together with routinely used clinical risk scores for predicting future disease. Results:Compared to the 20-80 th percentiles, a PRS in the top 2.5% translated into hazard ratios (HRs) for incident disease ranging from 2.03 to 4.28 (p-values 1.96x10 -59 to <1.00x10 -100 ) and the bottom 2.5% into HRs ranging from 0.20 to 0.61. The estimated difference in age at disease onset between top and bottom 2.5% of PRSs was 6 to 13 years. Among early-onset cases, 21.3-32.9% had a PRS in the highest decile and in CHD and AF. Conclusions:The properties of PRS were similar in all five diseases. PRS identified a considerable proportion early-onset cases, and for all ages the performance of PRS was comparable to established clinical risk scores. These findings warrant further clinical studies on application of polygenic risk information for stratified screening or for guiding lifestyle and preventive medical interventions.

show abstract

“…However, CAD loci in liver and endocrine enhancers were instead associated with systolic blood 6 pressure 51 . Similarly CAD loci also associated with waist-to-hip ratio 49,51,52 overlapped adipose but not 7 liver, endocrine, or heart enhancers, and CAD loci associated with HDL cholesterol 53 overlapped liver, 8 adipose, and endocrine enhancer but not heart tissues. 9…”

Section: Partitioning Multifactorial Traits and Trait Combinations Inmentioning

confidence: 94%

Integrative analysis of 10,000 epigenomic maps across 800 samples for regulatory genomics and disease dissection

Boix

Park

Meuleman

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

Biobank-driven genomic discovery yields new insight into atrial fibrillation biology

Cited by 579 publications

References 67 publications

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Polygenic and clinical risk scores and their impact on age at onset of cardiometabolic diseases and common cancers

Integrative analysis of 10,000 epigenomic maps across 800 samples for regulatory genomics and disease dissection

Contact Info

Product

Resources

About