References
1. Ellinor PT and Macrae CA. The genetics of atrial fibrillation.J Cardiovasc Electrophysiol . 2003;14:1007-9.
2. Fatkin D, Santiago CF, Huttner IG, Lubitz SA and Ellinor PT. Genetics
of Atrial Fibrillation: State of the Art in 2017. Heart Lung
Circ . 2017;26:894-901.
3. Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H,
Sigurdsson A, Jonasdottir A, Baker A, Thorleifsson G, Kristjansson K,
Palsson A, Blondal T, Sulem P, Backman VM, Hardarson GA, Palsdottir E,
Helgason A, Sigurjonsdottir R, Sverrisson JT, Kostulas K, Ng MC, Baum L,
So WY, Wong KS, Chan JC, Furie KL, Greenberg SM, Sale M, Kelly P, MacRae
CA, Smith EE, Rosand J, Hillert J, Ma RC, Ellinor PT, Thorgeirsson G,
Gulcher JR, Kong A, Thorsteinsdottir U and Stefansson K. Variants
conferring risk of atrial fibrillation on chromosome 4q25.Nature . 2007;448:353-7.
4. Tada H, Shiffman D, Smith JG, Sjogren M, Lubitz SA, Ellinor PT, Louie
JZ, Catanese JJ, Engstrom G, Devlin JJ, Kathiresan S and Melander O.
Twelve-single nucleotide polymorphism genetic risk score identifies
individuals at increased risk for future atrial fibrillation and stroke.Stroke . 2014;45:2856-2862.
5. Lubitz SA, Sinner MF, Lunetta KL, Makino S, Pfeufer A, Rahman R,
Veltman CE, Barnard J, Bis JC, Danik SP, Sonni A, Shea MA, Del Monte F,
Perz S, Muller M, Peters A, Greenberg SM, Furie KL, van Noord C,
Boerwinkle E, Stricker BH, Witteman J, Smith JD, Chung MK, Heckbert SR,
Benjamin EJ, Rosand J, Arking DE, Alonso A, Kaab S and Ellinor PT.
Independent susceptibility markers for atrial fibrillation on chromosome
4q25. Circulation . 2010;122:976-84.
6. Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV,
Schnabel RB, Bis JC, Boerwinkle E, Sinner MF, Dehghan A, Lubitz SA,
D’Agostino RB, Sr., Lumley T, Ehret GB, Heeringa J, Aspelund T,
Newton-Cheh C, Larson MG, Marciante KD, Soliman EZ, Rivadeneira F, Wang
TJ, Eiriksdottir G, Levy D, Psaty BM, Li M, Chamberlain AM, Hofman A,
Vasan RS, Harris TB, Rotter JI, Kao WH, Agarwal SK, Stricker BH, Wang K,
Launer LJ, Smith NL, Chakravarti A, Uitterlinden AG, Wolf PA,
Sotoodehnia N, Kottgen A, van Duijn CM, Meitinger T, Mueller M, Perz S,
Steinbeck G, Wichmann HE, Lunetta KL, Heckbert SR, Gudnason V, Alonso A,
Kaab S, Ellinor PT and Witteman JC. Variants in ZFHX3 are associated
with atrial fibrillation in individuals of European ancestry. Nat
Genet . 2009;41:879-81.
7. Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB,
Thorgeirsson G, Gulcher J, Mathiesen EB, Njolstad I, Nyrnes A, Wilsgaard
T, Hald EM, Hveem K, Stoltenberg C, Kucera G, Stubblefield T, Carter S,
Roden D, Ng MC, Baum L, So WY, Wong KS, Chan JC, Gieger C, Wichmann HE,
Gschwendtner A, Dichgans M, Kuhlenbaumer G, Berger K, Ringelstein EB,
Bevan S, Markus HS, Kostulas K, Hillert J, Sveinbjornsdottir S,
Valdimarsson EM, Lochen ML, Ma RC, Darbar D, Kong A, Arnar DO,
Thorsteinsdottir U and Stefansson K. A sequence variant in ZFHX3 on
16q22 associates with atrial fibrillation and ischemic stroke. Nat
Genet . 2009;41:876-8.
8. Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK,
Sinner MF, de Bakker PI, Mueller M, Lubitz SA, Fox E, Darbar D, Smith
NL, Smith JD, Schnabel RB, Soliman EZ, Rice KM, Van Wagoner DR, Beckmann
BM, van Noord C, Wang K, Ehret GB, Rotter JI, Hazen SL, Steinbeck G,
Smith AV, Launer LJ, Harris TB, Makino S, Nelis M, Milan DJ, Perz S,
Esko T, Kottgen A, Moebus S, Newton-Cheh C, Li M, Mohlenkamp S, Wang TJ,
Kao WH, Vasan RS, Nothen MM, MacRae CA, Stricker BH, Hofman A,
Uitterlinden AG, Levy D, Boerwinkle E, Metspalu A, Topol EJ, Chakravarti
A, Gudnason V, Psaty BM, Roden DM, Meitinger T, Wichmann HE, Witteman
JC, Barnard J, Arking DE, Benjamin EJ, Heckbert SR and Kaab S. Common
variants in KCNN3 are associated with lone atrial fibrillation.Nat Genet . 2010;42:240-4.
9. Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV,
Arking DE, Muller-Nurasyid M, Krijthe BP, Lubitz SA, Bis JC, Chung MK,
Dorr M, Ozaki K, Roberts JD, Smith JG, Pfeufer A, Sinner MF, Lohman K,
Ding J, Smith NL, Smith JD, Rienstra M, Rice KM, Van Wagoner DR, Magnani
JW, Wakili R, Clauss S, Rotter JI, Steinbeck G, Launer LJ, Davies RW,
Borkovich M, Harris TB, Lin H, Volker U, Volzke H, Milan DJ, Hofman A,
Boerwinkle E, Chen LY, Soliman EZ, Voight BF, Li G, Chakravarti A, Kubo
M, Tedrow UB, Rose LM, Ridker PM, Conen D, Tsunoda T, Furukawa T,
Sotoodehnia N, Xu S, Kamatani N, Levy D, Nakamura Y, Parvez B, Mahida S,
Furie KL, Rosand J, Muhammad R, Psaty BM, Meitinger T, Perz S, Wichmann
HE, Witteman JC, Kao WH, Kathiresan S, Roden DM, Uitterlinden AG,
Rivadeneira F, McKnight B, Sjogren M, Newman AB, Liu Y, Gollob MH,
Melander O, Tanaka T, Stricker BH, Felix SB, Alonso A, Darbar D, Barnard
J, Chasman DI, Heckbert SR, Benjamin EJ, Gudnason V and Kaab S.
Meta-analysis identifies six new susceptibility loci for atrial
fibrillation. Nat Genet . 2012;44:670-5.
10. Shaffer F and Ginsberg JP. An Overview of Heart Rate Variability
Metrics and Norms. Front Public Health . 2017;5:258.
11. Shaffer F, McCraty R and Zerr CL. A healthy heart is not a
metronome: an integrative review of the heart’s anatomy and heart rate
variability. Front Psychol . 2014;5:1040.
12. Katritsis DG and Josephson ME. Electrophysiological Testing for the
Investigation of Bradycardias. Arrhythm Electrophysiol Rev .
2017;6:24-28.
13. Di Biase L, Santangeli P, Anselmino M, Mohanty P, Salvetti I, Gili
S, Horton R, Sanchez JE, Bai R, Mohanty S, Pump A, Cereceda Brantes M,
Gallinghouse GJ, Burkhardt JD, Cesarani F, Scaglione M, Natale A and
Gaita F. Does the left atrial appendage morphology correlate with the
risk of stroke in patients with atrial fibrillation? Results from a
multicenter study. J Am Coll Cardiol . 2012;60:531-8.
14. Habibi M, Chahal H, Greenland P, Guallar E, Lima JAC, Soliman EZ,
Alonso A, Heckbert SR and Nazarian S. Resting Heart Rate, Short-Term
Heart Rate Variability and Incident Atrial Fibrillation (from the
Multi-Ethnic Study of Atherosclerosis (MESA)). Am J Cardiol .
2019;124:1684-1689.
15. Wang W, Alonso A, Soliman EZ, O’Neal WT, Calkins H, Chen LY,
Diener-West M and Szklo M. Relation of Resting Heart Rate to Incident
Atrial Fibrillation (From ARIC [Atherosclerosis Risk in Communities]
Study). Am J Cardiol . 2018;121:1169-1176.
16. Novak V, Saul JP and Eckberg DL. Task Force report on heart rate
variability. Circulation . 1997;96:1056-7.
17. Bettoni M and Zimmermann M. Autonomic tone variations before the
onset of paroxysmal atrial fibrillation. Circulation .
2002;105:2753-9.
18. Frey MK, Richter B, Gwechenberger M, Marx M, Pezawas T, Schrutka L
and Gossinger H. High incidence of atrial fibrillation after successful
catheter ablation of atrioventricular nodal reentrant tachycardia: a
15.5-year follow-up. Sci Rep . 2019;9:11784.
19. Bauernfeind RA, Wyndham CR, Swiryn SP, Palileo EV, Strasberg B, Lam
W, Westveer D and Rosen KM. Paroxysmal atrial fibrillation in the
Wolff-Parkinson-White syndrome. Am J Cardiol . 1981;47:562-9.
20. Jennings MM and Donahue JK. Connexin Remodeling Contributes to
Atrial Fibrillation. J Atr Fibrillation . 2013;6:839.
21. Thibodeau IL, Xu J, Li Q, Liu G, Lam K, Veinot JP, Birnie DH, Jones
DL, Krahn AD, Lemery R, Nicholson BJ and Gollob MH. Paradigm of genetic
mosaicism and lone atrial fibrillation: physiological characterization
of a connexin 43-deletion mutant identified from atrial tissue.Circulation . 2010;122:236-44.
22. Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A,
Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson
CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM,
Benavente OR, Bevan S, Boncoraglio GB, Brown RD, Jr., Butterworth AS,
Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc
I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan
Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V,
Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert
SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E,
Irvin MR, Jian X, Jimenez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene
KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA,
Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis
CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J,
Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA,
Ninomiya T, O’Donnell MJ, Psaty BM, Pulit SL, Rannikmae K, Reiner AP,
Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI,
Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R,
Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C,
Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U,
Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ,
Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S,
Consortium AF, Cohorts for H, Aging Research in Genomic Epidemiology C,
International Genomics of Blood Pressure C, Consortium I, Starnet, Bis
JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Bjorkegren JLM, Codoni
V, Civelek M, Smith NL, Tregouet DA, Christophersen IE, Roselli C,
Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P,
Elliott P, Chambers JC, Takeuchi F, Johnson AD, BioBank Japan
Cooperative Hospital G, Consortium C, Consortium E-C, Consortium EP-I,
International Stroke Genetics C, Consortium M, Neurology Working Group
of the CC, Network NSG, Study UKYLD, Consortium M, Sanghera DK, Melander
O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT, Jr., Rolfs A,
Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K,
Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM,
Kamatani Y, Debette S and Dichgans M. Multiancestry genome-wide
association study of 520,000 subjects identifies 32 loci associated with
stroke and stroke subtypes. Nat Genet . 2018;50:524-537.
23. Khurram IM, Dewire J, Mager M, Maqbool F, Zimmerman SL, Zipunnikov
V, Beinart R, Marine JE, Spragg DD, Berger RD, Ashikaga H, Nazarian S
and Calkins H. Relationship between left atrial appendage morphology and
stroke in patients with atrial fibrillation. Heart Rhythm .
2013;10:1843-9.
24. Franco D, Sedmera D and Lozano-Velasco E. Multiple Roles of Pitx2 in
Cardiac Development and Disease. J Cardiovasc Dev Dis . 2017;4.
25. Perez FJ, Schubert CM, Parvez B, Pathak V, Ellenbogen KA and Wood
MA. Long-term outcomes after catheter ablation of cavo-tricuspid isthmus
dependent atrial flutter: a meta-analysis. Circ Arrhythm
Electrophysiol . 2009;2:393-401.
26. Koerber SM, Turagam MK, Gautam S, Winterfield J, Wharton JM,
Lakkireddy D and Gold MR. Prophylactic pulmonary vein isolation during
cavotricuspid isthmus ablation for atrial flutter: A meta-analysis.Pacing Clin Electrophysiol . 2019;42:493-498.
27. Hucker WJ, Saini H, Lubitz SA and Ellinor PT. Atrial Fibrillation
Genetics: Is There a Practical Clinical Value Now or in the Future?Can J Cardiol . 2016;32:1300-1305.
28. Roberts JD, Hsu JC, Aouizerat BE, Pullinger CR, Malloy MJ, Kane JP,
Olgin JE and Marcus GM. Impact of a 4q25 genetic variant in atrial
flutter and on the risk of atrial fibrillation after cavotricuspid
isthmus ablation. J Cardiovasc Electrophysiol . 2014;25:271-277.
29. Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM,
Almgren P, Alonso A, Anderson CD, Aragam KG, Arking DE, Barnard J, Bartz
TM, Benjamin EJ, Bihlmeyer NA, Bis JC, Bloom HL, Boerwinkle E, Bottinger
EB, Brody JA, Calkins H, Campbell A, Cappola TP, Carlquist J, Chasman
DI, Chen LY, Chen YI, Choi EK, Choi SH, Christophersen IE, Chung MK,
Cole JW, Conen D, Cook J, Crijns HJ, Cutler MJ, Damrauer SM, Daniels BR,
Darbar D, Delgado G, Denny JC, Dichgans M, Dorr M, Dudink EA, Dudley SC,
Esa N, Esko T, Eskola M, Fatkin D, Felix SB, Ford I, Franco OH, Geelhoed
B, Grewal RP, Gudnason V, Guo X, Gupta N, Gustafsson S, Gutmann R,
Hamsten A, Harris TB, Hayward C, Heckbert SR, Hernesniemi J, Hocking LJ,
Hofman A, Horimoto A, Huang J, Huang PL, Huffman J, Ingelsson E, Ipek
EG, Ito K, Jimenez-Conde J, Johnson R, Jukema JW, Kaab S, Kahonen M,
Kamatani Y, Kane JP, Kastrati A, Kathiresan S, Katschnig-Winter P,
Kavousi M, Kessler T, Kietselaer BL, Kirchhof P, Kleber ME, Knight S,
Krieger JE, Kubo M, Launer LJ, Laurikka J, Lehtimaki T, Leineweber K,
Lemaitre RN, Li M, Lim HE, Lin HJ, Lin H, Lind L, Lindgren CM, Lokki ML,
London B, Loos RJF, Low SK, Lu Y, Lyytikainen LP, Macfarlane PW,
Magnusson PK, Mahajan A, Malik R, Mansur AJ, Marcus GM, Margolin L,
Margulies KB, Marz W, McManus DD, Melander O, Mohanty S, Montgomery JA,
Morley MP, Morris AP, Muller-Nurasyid M, Natale A, Nazarian S, Neumann
B, Newton-Cheh C, Niemeijer MN, Nikus K, Nilsson P, Noordam R, Oellers
H, Olesen MS, Orho-Melander M, Padmanabhan S, Pak HN, Pare G, Pedersen
NL, Pera J, Pereira A, Porteous D, Psaty BM, Pulit SL, Pullinger CR,
Rader DJ, Refsgaard L, Ribases M, Ridker PM, Rienstra M, Risch L, Roden
DM, Rosand J, Rosenberg MA, Rost N, Rotter JI, Saba S, Sandhu RK,
Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA, Seppala I,
Shaffer C, Shah S, Shalaby AA, Shim J, Shoemaker MB, Siland JE, Sinisalo
J, Sinner MF, Slowik A, Smith AV, Smith BH, Smith JG, Smith JD, Smith
NL, Soliman EZ, Sotoodehnia N, Stricker BH, Sun A, Sun H, Svendsen JH,
Tanaka T, Tanriverdi K, Taylor KD, Teder-Laving M, Teumer A, Theriault
S, Trompet S, Tucker NR, Tveit A, Uitterlinden AG, Van Der Harst P, Van
Gelder IC, Van Wagoner DR, Verweij N, Vlachopoulou E, Volker U, Wang B,
Weeke PE, Weijs B, Weiss R, Weiss S, Wells QS, Wiggins KL, Wong JA, Woo
D, Worrall BB, Yang PS, Yao J, Yoneda ZT, Zeller T, Zeng L, Lubitz SA,
Lunetta KL and Ellinor PT. Multi-ethnic genome-wide association study
for atrial fibrillation. Nat Genet . 2018;50:1225-1233.
30. Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham
SE, Herron TJ, McCarthy S, Schmidt EM, Sveinbjornsson G, Surakka I,
Mathis MR, Yamazaki M, Crawford RD, Gabrielsen ME, Skogholt AH, Holmen
OL, Lin M, Wolford BN, Dey R, Dalen H, Sulem P, Chung JH, Backman JD,
Arnar DO, Thorsteinsdottir U, Baras A, O’Dushlaine C, Holst AG, Wen X,
Hornsby W, Dewey FE, Boehnke M, Kheterpal S, Mukherjee B, Lee S, Kang
HM, Holm H, Kitzman J, Shavit JA, Jalife J, Brummett CM, Teslovich TM,
Carey DJ, Gudbjartsson DF, Stefansson K, Abecasis GR, Hveem K and Willer
CJ. Biobank-driven genomic discovery yields new insight into atrial
fibrillation biology. Nat Genet . 2018;50:1234-1239.
31. Nielsen JB, Fritsche LG, Zhou W, Teslovich TM, Holmen OL, Gustafsson
S, Gabrielsen ME, Schmidt EM, Beaumont R, Wolford BN, Lin M, Brummett
CM, Preuss MH, Refsgaard L, Bottinger EP, Graham SE, Surakka I, Chu Y,
Skogholt AH, Dalen H, Boyle AP, Oral H, Herron TJ, Kitzman J, Jalife J,
Svendsen JH, Olesen MS, Njolstad I, Lochen ML, Baras A, Gottesman O,
Marcketta A, O’Dushlaine C, Ritchie MD, Wilsgaard T, Loos RJF, Frayling
TM, Boehnke M, Ingelsson E, Carey DJ, Dewey FE, Kang HM, Abecasis GR,
Hveem K and Willer CJ. Genome-wide Study of Atrial Fibrillation
Identifies Seven Risk Loci and Highlights Biological Pathways and
Regulatory Elements Involved in Cardiac Development. Am J Hum
Genet . 2018;102:103-115.
32. Weng LC, Choi SH, Klarin D, Smith JG, Loh PR, Chaffin M, Roselli C,
Hulme OL, Lunetta KL, Dupuis J, Benjamin EJ, Newton-Cheh C, Kathiresan
S, Ellinor PT and Lubitz SA. Heritability of Atrial Fibrillation.Circ Cardiovasc Genet . 2017;10.
Figure Title and Legends
Figure 1: Heart Rate (A) and Heart Rate Variability (B as Stratified by
Atrial Fibrillation Genetic Risk Quartiles. BPM = beats per minutes; HR
= heart rate; SDNN= standard deviation of NN intervals; RMSDD =Root Mean
Square of the Successive Differences. * = P <0.05; n = 86.
Figure 2: Cardiac Conduction (A) and Atrioventricular Physiology (B) as
Stratified by Atrial Fibrillation Genetic Risk Quartiles. HV =
His-Ventricle Conduction time; * = P <0.05; n = 181.
Figure 3: AF Free Survival After CTI Ablation Stratified by Genetic Risk
Score. Probability of atrial fibrillation over time (days) in follow up
as stratified by genetic risk score in the post CTI population. Genetic
risk score is stratified into quartiles ranging from Low to High genetic
risk.
Figure 4: Left Atrial Appendage Morphology and AF Genetic Risk. (A)
Appendage morphology (percent chicken wing), appendage os (circumference
in cm) and indexed appendage volume stratified by polygenic risk of AF
quartiles. (B) Appendage morphology (percent chicken wing), appendage os
(circumference in cm) and indexed appendage volume stratified by
RS2200733 single nucleotide variant carrier status. * = P
<0.05
Table 1. Single Nucleotide Variants Comprising an AF Polygenic Risk
Score