Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

Moritz F. Sinner, Nathan R. Tucker, Kathryn L. Lunetta, Kouichi Ozaki, J. Gustav Smith, Stella Trompet, Joshua C. Bis, Honghuang Lin, Mina K. Chung, Jonas B. Nielsen, Steven A. Lubitz, Bouwe P. Krijthe, Jared W. Magnani, Jiangchuan Ye, Michael H. Gollob, Tatsuhiko Tsunoda, Martina Müller-Nurasyid, Peter Lichtner, Annette Peters, Elena Dolmatova & 35 others Michiaki Kubo, Jonathan D. Smith, Bruce M. Psaty, Nicholas L. Smith, J. Wouter Jukema, Daniel I. Chasman, Christine M. Albert, Yusuke Ebana, Tetsushi Furukawa, Peter W. Macfarlane, Tamara B. Harris, Dawood Darbar, Marcus Dörr, Anders G. Holst, Jesper H. Svendsen, Albert Hofman, Andre G. Uitterlinden, Vilmundur Gudnason, Mitsuaki Isobe, Rainer Malik, Martin Dichgans, Jonathan Rosand, David R. Van Wagoner, Emelia J. Benjamin, David J. Milan, Olle Melander, Susan R. Heckbert, Ian Ford, Yongmei Liu, John Barnard, Morten S. Olesen, Bruno H.C. Stricker, Toshihiro Tanaka, Stefan Kääb, Patrick T. Ellinor

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Background-Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results-To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10-16), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10-8), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10-11), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10-9). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10-25) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10-9). The top singlenucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10-19), GJA1 (P=2.66×10-6), and TBX5 (P=1.36×10-5). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions-We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

Original languageEnglish
Pages (from-to)1225-1235
Number of pages11
JournalCirculation
Volume130
Issue number15
DOIs
Publication statusPublished - 01-01-2014

Fingerprint

Atrial Fibrillation
Confidence Intervals
Genes
Quantitative Trait Loci
Proxy
Zebrafish
Action Potentials
Cardiac Arrhythmias
Heart Failure
Stroke
Pharmacology
Population

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Sinner, M. F., Tucker, N. R., Lunetta, K. L., Ozaki, K., Smith, J. G., Trompet, S., ... Ellinor, P. T. (2014). Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation, 130(15), 1225-1235. https://doi.org/10.1161/CIRCULATIONAHA.114.009892
Sinner, Moritz F. ; Tucker, Nathan R. ; Lunetta, Kathryn L. ; Ozaki, Kouichi ; Smith, J. Gustav ; Trompet, Stella ; Bis, Joshua C. ; Lin, Honghuang ; Chung, Mina K. ; Nielsen, Jonas B. ; Lubitz, Steven A. ; Krijthe, Bouwe P. ; Magnani, Jared W. ; Ye, Jiangchuan ; Gollob, Michael H. ; Tsunoda, Tatsuhiko ; Müller-Nurasyid, Martina ; Lichtner, Peter ; Peters, Annette ; Dolmatova, Elena ; Kubo, Michiaki ; Smith, Jonathan D. ; Psaty, Bruce M. ; Smith, Nicholas L. ; Jukema, J. Wouter ; Chasman, Daniel I. ; Albert, Christine M. ; Ebana, Yusuke ; Furukawa, Tetsushi ; Macfarlane, Peter W. ; Harris, Tamara B. ; Darbar, Dawood ; Dörr, Marcus ; Holst, Anders G. ; Svendsen, Jesper H. ; Hofman, Albert ; Uitterlinden, Andre G. ; Gudnason, Vilmundur ; Isobe, Mitsuaki ; Malik, Rainer ; Dichgans, Martin ; Rosand, Jonathan ; Van Wagoner, David R. ; Benjamin, Emelia J. ; Milan, David J. ; Melander, Olle ; Heckbert, Susan R. ; Ford, Ian ; Liu, Yongmei ; Barnard, John ; Olesen, Morten S. ; Stricker, Bruno H.C. ; Tanaka, Toshihiro ; Kääb, Stefan ; Ellinor, Patrick T. / Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. In: Circulation. 2014 ; Vol. 130, No. 15. pp. 1225-1235.
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title = "Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation",
abstract = "Background-Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results-To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95{\%} confidence interval [CI], 1.13-1.23; P=6.5×10-16), GJA1 (rs13216675; RR=1.10; 95{\%} CI, 1.06-1.14; P=2.2×10-8), TBX5 (rs10507248; RR=1.12; 95{\%} CI, 1.08-1.16; P=5.7×10-11), and CAND2 (rs4642101; RR=1.10; 95{\%} CI, 1.06-1.14; P=9.8×10-9). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95{\%} CI, 1.26-1.39; P=2.0×10-25) and CUX2 (rs6490029; RR=1.12; 95{\%} CI, 1.08-1.16; P=3.9×10-9). The top singlenucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10-19), GJA1 (P=2.66×10-6), and TBX5 (P=1.36×10-5). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17{\%} and 45{\%}, respectively). Conclusions-We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.",
author = "Sinner, {Moritz F.} and Tucker, {Nathan R.} and Lunetta, {Kathryn L.} and Kouichi Ozaki and Smith, {J. Gustav} and Stella Trompet and Bis, {Joshua C.} and Honghuang Lin and Chung, {Mina K.} and Nielsen, {Jonas B.} and Lubitz, {Steven A.} and Krijthe, {Bouwe P.} and Magnani, {Jared W.} and Jiangchuan Ye and Gollob, {Michael H.} and Tatsuhiko Tsunoda and Martina M{\"u}ller-Nurasyid and Peter Lichtner and Annette Peters and Elena Dolmatova and Michiaki Kubo and Smith, {Jonathan D.} and Psaty, {Bruce M.} and Smith, {Nicholas L.} and Jukema, {J. Wouter} and Chasman, {Daniel I.} and Albert, {Christine M.} and Yusuke Ebana and Tetsushi Furukawa and Macfarlane, {Peter W.} and Harris, {Tamara B.} and Dawood Darbar and Marcus D{\"o}rr and Holst, {Anders G.} and Svendsen, {Jesper H.} and Albert Hofman and Uitterlinden, {Andre G.} and Vilmundur Gudnason and Mitsuaki Isobe and Rainer Malik and Martin Dichgans and Jonathan Rosand and {Van Wagoner}, {David R.} and Benjamin, {Emelia J.} and Milan, {David J.} and Olle Melander and Heckbert, {Susan R.} and Ian Ford and Yongmei Liu and John Barnard and Olesen, {Morten S.} and Stricker, {Bruno H.C.} and Toshihiro Tanaka and Stefan K{\"a}{\"a}b and Ellinor, {Patrick T.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1161/CIRCULATIONAHA.114.009892",
language = "English",
volume = "130",
pages = "1225--1235",
journal = "Circulation",
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publisher = "Lippincott Williams and Wilkins",
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Sinner, MF, Tucker, NR, Lunetta, KL, Ozaki, K, Smith, JG, Trompet, S, Bis, JC, Lin, H, Chung, MK, Nielsen, JB, Lubitz, SA, Krijthe, BP, Magnani, JW, Ye, J, Gollob, MH, Tsunoda, T, Müller-Nurasyid, M, Lichtner, P, Peters, A, Dolmatova, E, Kubo, M, Smith, JD, Psaty, BM, Smith, NL, Jukema, JW, Chasman, DI, Albert, CM, Ebana, Y, Furukawa, T, Macfarlane, PW, Harris, TB, Darbar, D, Dörr, M, Holst, AG, Svendsen, JH, Hofman, A, Uitterlinden, AG, Gudnason, V, Isobe, M, Malik, R, Dichgans, M, Rosand, J, Van Wagoner, DR, Benjamin, EJ, Milan, DJ, Melander, O, Heckbert, SR, Ford, I, Liu, Y, Barnard, J, Olesen, MS, Stricker, BHC, Tanaka, T, Kääb, S & Ellinor, PT 2014, 'Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation', Circulation, vol. 130, no. 15, pp. 1225-1235. https://doi.org/10.1161/CIRCULATIONAHA.114.009892

Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. / Sinner, Moritz F.; Tucker, Nathan R.; Lunetta, Kathryn L.; Ozaki, Kouichi; Smith, J. Gustav; Trompet, Stella; Bis, Joshua C.; Lin, Honghuang; Chung, Mina K.; Nielsen, Jonas B.; Lubitz, Steven A.; Krijthe, Bouwe P.; Magnani, Jared W.; Ye, Jiangchuan; Gollob, Michael H.; Tsunoda, Tatsuhiko; Müller-Nurasyid, Martina; Lichtner, Peter; Peters, Annette; Dolmatova, Elena; Kubo, Michiaki; Smith, Jonathan D.; Psaty, Bruce M.; Smith, Nicholas L.; Jukema, J. Wouter; Chasman, Daniel I.; Albert, Christine M.; Ebana, Yusuke; Furukawa, Tetsushi; Macfarlane, Peter W.; Harris, Tamara B.; Darbar, Dawood; Dörr, Marcus; Holst, Anders G.; Svendsen, Jesper H.; Hofman, Albert; Uitterlinden, Andre G.; Gudnason, Vilmundur; Isobe, Mitsuaki; Malik, Rainer; Dichgans, Martin; Rosand, Jonathan; Van Wagoner, David R.; Benjamin, Emelia J.; Milan, David J.; Melander, Olle; Heckbert, Susan R.; Ford, Ian; Liu, Yongmei; Barnard, John; Olesen, Morten S.; Stricker, Bruno H.C.; Tanaka, Toshihiro; Kääb, Stefan; Ellinor, Patrick T.

In: Circulation, Vol. 130, No. 15, 01.01.2014, p. 1225-1235.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

AU - Sinner, Moritz F.

AU - Tucker, Nathan R.

AU - Lunetta, Kathryn L.

AU - Ozaki, Kouichi

AU - Smith, J. Gustav

AU - Trompet, Stella

AU - Bis, Joshua C.

AU - Lin, Honghuang

AU - Chung, Mina K.

AU - Nielsen, Jonas B.

AU - Lubitz, Steven A.

AU - Krijthe, Bouwe P.

AU - Magnani, Jared W.

AU - Ye, Jiangchuan

AU - Gollob, Michael H.

AU - Tsunoda, Tatsuhiko

AU - Müller-Nurasyid, Martina

AU - Lichtner, Peter

AU - Peters, Annette

AU - Dolmatova, Elena

AU - Kubo, Michiaki

AU - Smith, Jonathan D.

AU - Psaty, Bruce M.

AU - Smith, Nicholas L.

AU - Jukema, J. Wouter

AU - Chasman, Daniel I.

AU - Albert, Christine M.

AU - Ebana, Yusuke

AU - Furukawa, Tetsushi

AU - Macfarlane, Peter W.

AU - Harris, Tamara B.

AU - Darbar, Dawood

AU - Dörr, Marcus

AU - Holst, Anders G.

AU - Svendsen, Jesper H.

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Gudnason, Vilmundur

AU - Isobe, Mitsuaki

AU - Malik, Rainer

AU - Dichgans, Martin

AU - Rosand, Jonathan

AU - Van Wagoner, David R.

AU - Benjamin, Emelia J.

AU - Milan, David J.

AU - Melander, Olle

AU - Heckbert, Susan R.

AU - Ford, Ian

AU - Liu, Yongmei

AU - Barnard, John

AU - Olesen, Morten S.

AU - Stricker, Bruno H.C.

AU - Tanaka, Toshihiro

AU - Kääb, Stefan

AU - Ellinor, Patrick T.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background-Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results-To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10-16), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10-8), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10-11), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10-9). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10-25) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10-9). The top singlenucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10-19), GJA1 (P=2.66×10-6), and TBX5 (P=1.36×10-5). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions-We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

AB - Background-Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results-To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10-16), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10-8), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10-11), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10-9). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10-25) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10-9). The top singlenucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10-19), GJA1 (P=2.66×10-6), and TBX5 (P=1.36×10-5). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions-We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

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