. 2017 Dec;10(6):e001838.

doi: 10.1161/CIRCGENETICS.117.001838.

Heritability of Atrial Fibrillation

Affiliations

¹ From the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (L.-C.W., S.H.C., D.K., J.G.S. P.-R.L., M.C., C.R., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.); Department of Cardiology, Clinical Sciences, Lund University, Sweden (J.G.S.); Department of Heart Failure and Valvular Disease, Skane University Hospital, Lund, Sweden (J.G.S.); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (P.-R.L.); Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (K.L.L., J.D., E.J.B.); Boston University School of Public Health, Boston, MA (K.L.L., J.D., E.J.B.); Boston University School of Medicine, Boston, MA (E.J.B.); and Cardiovascular Research Center (L.-C.W., D.K., J.G.S., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.) and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA.
² From the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (L.-C.W., S.H.C., D.K., J.G.S. P.-R.L., M.C., C.R., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.); Department of Cardiology, Clinical Sciences, Lund University, Sweden (J.G.S.); Department of Heart Failure and Valvular Disease, Skane University Hospital, Lund, Sweden (J.G.S.); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (P.-R.L.); Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (K.L.L., J.D., E.J.B.); Boston University School of Public Health, Boston, MA (K.L.L., J.D., E.J.B.); Boston University School of Medicine, Boston, MA (E.J.B.); and Cardiovascular Research Center (L.-C.W., D.K., J.G.S., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.) and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA. slubitz@mgh.harvard.edu.

PMID: 29237688
PMCID: PMC5966046
DOI: 10.1161/CIRCGENETICS.117.001838

Heritability of Atrial Fibrillation

Lu-Chen Weng et al. Circ Cardiovasc Genet. 2017 Dec.

. 2017 Dec;10(6):e001838.

doi: 10.1161/CIRCGENETICS.117.001838.

Authors

Affiliations

¹ From the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (L.-C.W., S.H.C., D.K., J.G.S. P.-R.L., M.C., C.R., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.); Department of Cardiology, Clinical Sciences, Lund University, Sweden (J.G.S.); Department of Heart Failure and Valvular Disease, Skane University Hospital, Lund, Sweden (J.G.S.); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (P.-R.L.); Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (K.L.L., J.D., E.J.B.); Boston University School of Public Health, Boston, MA (K.L.L., J.D., E.J.B.); Boston University School of Medicine, Boston, MA (E.J.B.); and Cardiovascular Research Center (L.-C.W., D.K., J.G.S., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.) and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA.
² From the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (L.-C.W., S.H.C., D.K., J.G.S. P.-R.L., M.C., C.R., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.); Department of Cardiology, Clinical Sciences, Lund University, Sweden (J.G.S.); Department of Heart Failure and Valvular Disease, Skane University Hospital, Lund, Sweden (J.G.S.); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (P.-R.L.); Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (K.L.L., J.D., E.J.B.); Boston University School of Public Health, Boston, MA (K.L.L., J.D., E.J.B.); Boston University School of Medicine, Boston, MA (E.J.B.); and Cardiovascular Research Center (L.-C.W., D.K., J.G.S., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.) and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA. slubitz@mgh.harvard.edu.

PMID: 29237688
PMCID: PMC5966046
DOI: 10.1161/CIRCGENETICS.117.001838

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, h²_g ) 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 h²_g using a variance components method with variants having a minor allele frequency ≥1%. We evaluated h²_g in age, sex, and genomic strata of interest. The h²_g 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 further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF.

Keywords: atrial fibrillation; epidemiology; genome-wide association study; genomics; medical records.

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Figures

**Figure 1**
Manhattan plot demonstrating associations between tested variants and AF. Known AF loci are shown in blue, and loci uniquely associated with AF in the UK Biobank are shown in red.

**Figure 2**
Regional association plots for loci uniquely associated with AF in the UK Biobank. Panel A displays associations at chromosome 5q31, and panel B at 12p12.

**Figure 3**
SNP-heritability of AF in clinical and genomic strata.Error bars represent the 95% confidence intervals for the *h²_g* estimates. Early-onset AF was defined as that occurring prior to age 65, and older-onset AF as occurring after age 65. Low frequency variants were SNPs with minor allele frequencies between 1%–5%, and common variants with frequencies ≥ 5%. GWAS loci were comprised of the 23 top SNPs from a prior independent association study ± 500 kilobases (kb). AF genes included 37 putative AF susceptibility genes ± 5 kb. AF, cardiac arrhythmia, and cardiomyopathy genes included 82 putative susceptibility genes ± 5 kb. The numbers of individuals and variants included in each stratum are provided in Supplemental Table 7.

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Comment in

Genome-Wide Association Studies Revealing the Heritability of Common Atrial Fibrillation: Is Bigger Always Better?
Clauss S, Sinner MF, Kääb S. Clauss S, et al. Circ Cardiovasc Genet. 2017 Dec;10(6):e002005. doi: 10.1161/CIRCGENETICS.117.002005. Circ Cardiovasc Genet. 2017. PMID: 29237694 No abstract available.

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Heritability of Atrial Fibrillation

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