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. 2016 Sep 2;12(9):e1006284.
doi: 10.1371/journal.pgen.1006284. eCollection 2016 Sep.

Whole Exome Sequencing in Atrial Fibrillation

Steven A Lubitz  1   2 , Jennifer A Brody  3 , Nathan A Bihlmeyer  4 , Carolina Roselli  2 , Lu-Chen Weng  2   5 , Ingrid E Christophersen  2   5   6 , Alvaro Alonso  7 , Eric Boerwinkle  8   9 , Richard A Gibbs  9 , Joshua C Bis  3 ; NHLBI GO Exome Sequencing Project; L Adrienne Cupples  10   11 , Peter J Mohler  12 , Deborah A Nickerson  13 , Donna Muzny  9 , Marco V Perez  14 , Bruce M Psaty  15   16 , Elsayed Z Soliman  17 , Nona Sotoodehnia  3   18 , Kathryn L Lunetta  11 , Emelia J Benjamin  11   19   20   21 , Susan R Heckbert  3   22 , Dan E Arking  4 , Patrick T Ellinor  1   2 , Honghuang Lin  11   23
Affiliations

Whole Exome Sequencing in Atrial Fibrillation

Steven A Lubitz et al. PLoS Genet. .

Abstract

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

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Conflict of interest statement

PTE is a principal investigator on a grant from Bayer HealthCare to the Broad Institute. BMP serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

Figures

Fig 1
Fig 1. Manhattan plot of common variant associations with atrial fibrillation.
Fig 2
Fig 2. Statistical power with current sample size and α = 5x10-7.
See this image and copyright information in PMC

References

    1. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114(2):119–25. . - PubMed
    1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370–5. . - PubMed
    1. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82(8A):2N–9N. . - PubMed
    1. Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study. The Rotterdam Study. Stroke. 1997;28(2):316–21. . - PubMed
    1. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920–5. . - PubMed

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