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; 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; Morten S Olesen; METASTROKE Consortium

doi:10.1161/CIRCULATIONAHA.114.009892

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 DolmatovaMichiaki 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, Morten S Olesen, METASTROKE Consortium

122 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 single-nucleotide 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 language	English
Journal	Circulation
Volume	130
Issue number	15
Pages (from-to)	1225-1235
Number of pages	11
ISSN	0009-7322
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.114.009892
Publication status	Published - 2014

Keywords

Aged
Animals
Atrial Fibrillation
Chromosome Mapping
Connexin 43
Europe
Female
Gene Knockdown Techniques
Genetic Loci
Genetic Predisposition to Disease
Genotype
Homeodomain Proteins
Humans
Japan
Male
Middle Aged
Muscle Proteins
Nuclear Proteins
Quantitative Trait Loci
Repressor Proteins
T-Box Domain Proteins
Transcription Factors
Ubiquitin-Protein Ligases
Zebrafish
Zebrafish Proteins

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10.1161/CIRCULATIONAHA.114.009892

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Sinner, M. F., Tucker, N. R., Lunetta, K. L., Ozaki, K., Smith, J. G., Trompet, S., Bis, J. C., Lin, H., Chung, M. K., Nielsen, J. B., Lubitz, S. A., Krijthe, B. P., Magnani, J. W., Ye, J., Gollob, M. H., Tsunoda, T., Müller-Nurasyid, M., Lichtner, P., Peters, A., ... METASTROKE Consortium (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, 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, Olesen, MS & METASTROKE Consortium 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

@article{224c365e775d4179b0394a986861881f,

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 single-nucleotide 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.",

keywords = "Aged, Animals, Atrial Fibrillation, Chromosome Mapping, Connexin 43, Europe, Female, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Muscle Proteins, Nuclear Proteins, Quantitative Trait Loci, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins",

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 Olesen, {Morten S} and {METASTROKE Consortium}",

note = "{\textcopyright} 2014 American Heart Association, Inc.",

year = "2014",

doi = "10.1161/CIRCULATIONAHA.114.009892",

language = "English",

volume = "130",

pages = "1225--1235",

journal = "Circulation",

issn = "0009-7322",

publisher = "AHA/ASA",

number = "15",

}

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 - Olesen, Morten S

AU - METASTROKE Consortium

PY - 2014

Y1 - 2014

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 single-nucleotide 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 single-nucleotide 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.

KW - Aged

KW - Animals

KW - Atrial Fibrillation

KW - Chromosome Mapping

KW - Connexin 43

KW - Europe

KW - Female

KW - Gene Knockdown Techniques

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Homeodomain Proteins

KW - Humans

KW - Japan

KW - Male

KW - Middle Aged

KW - Muscle Proteins

KW - Nuclear Proteins

KW - Quantitative Trait Loci

KW - Repressor Proteins

KW - T-Box Domain Proteins

KW - Transcription Factors

KW - Ubiquitin-Protein Ligases

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1161/CIRCULATIONAHA.114.009892

DO - 10.1161/CIRCULATIONAHA.114.009892

M3 - Journal article

C2 - 25124494

SN - 0009-7322

VL - 130

SP - 1225

EP - 1235

JO - Circulation

JF - Circulation

IS - 15

ER -

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

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