Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation
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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; Olesen, Morten S; METASTROKE Consortium.
I: Circulation, Bind 130, Nr. 15, 2014, s. 1225-1235.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
N1 - © 2014 American Heart Association, Inc.
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
VL - 130
SP - 1225
EP - 1235
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 15
ER -
ID: 137625859