PUBLICATION
Integrating Genetic, Transcriptional, and Functional Analyses to Identify Five Novel Genes for Atrial Fibrillation
- Authors
- 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., Dolmatova, E., Kubo, M., Smith, J.D., Psaty, B.M., Smith, N.L., Jukema, J.W., Chasman, D.I., Albert, C.M., Ebana, Y., Furukawa, T., MacFarlane, P., Harris, T.B., Darbar, D., Dörr, M., Holst, A.G., Svendsen, J.H., Hofman, A., Uitterlinden, A., Gudnason, V., Isobe, M., Malik, R., Dichgans, M., Rosand, J., Van Wagoner, D.R., METASTROKE Consortium, AFGen Consortium, Benjamin, E.J., Milan, D.J., Melander, O., Heckbert, S., Ford, I., Liu, Y., Barnard, J., Olesen, M.S., Stricker, B.H., Tanaka, T., Kääb, S., Ellinor, P.T.
- ID
- ZDB-PUB-140816-14
- Date
- 2014
- Source
- Circulation 130(15): 1225-35 (Journal)
- Registered Authors
- Ellinor, Patrick
- Keywords
- Genome Wide Association Study, atrial fibrillation, expression experiments, genetics, association studies, genetics, knockout models, zebrafish
- MeSH Terms
-
- Repressor Proteins/genetics*
- Repressor Proteins/physiology
- Nuclear Proteins/genetics*
- Nuclear Proteins/physiology
- Atrial Fibrillation/ethnology
- Atrial Fibrillation/genetics*
- Atrial Fibrillation/physiopathology
- Muscle Proteins
- Middle Aged
- Male
- Chromosome Mapping
- Quantitative Trait Loci
- Genotype
- Ubiquitin-Protein Ligases/genetics*
- Ubiquitin-Protein Ligases/physiology
- Genetic Predisposition to Disease/ethnology
- Zebrafish
- Humans
- Europe
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology
- Japan
- Connexin 43/genetics*
- Connexin 43/physiology
- Female
- Gene Knockdown Techniques
- Transcription Factors/genetics
- Transcription Factors/physiology
- Aged
- Homeodomain Proteins/genetics*
- Homeodomain Proteins/physiology
- T-Box Domain Proteins/genetics*
- T-Box Domain Proteins/physiology
- Genetic Loci/physiology
- Animals
- PubMed
- 25124494 Full text @ Circulation
Citation
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., Dolmatova, E., Kubo, M., Smith, J.D., Psaty, B.M., Smith, N.L., Jukema, J.W., Chasman, D.I., Albert, C.M., Ebana, Y., Furukawa, T., MacFarlane, P., Harris, T.B., Darbar, D., Dörr, M., Holst, A.G., Svendsen, J.H., Hofman, A., Uitterlinden, A., Gudnason, V., Isobe, M., Malik, R., Dichgans, M., Rosand, J., Van Wagoner, D.R., METASTROKE Consortium, AFGen Consortium, Benjamin, E.J., Milan, D.J., Melander, O., Heckbert, S., Ford, I., Liu, Y., Barnard, J., Olesen, M.S., Stricker, B.H., Tanaka, T., Kääb, S., Ellinor, P.T. (2014) Integrating Genetic, Transcriptional, and Functional Analyses to Identify Five Novel Genes for Atrial Fibrillation. Circulation. 130(15):1225-35.
Abstract
Background -Atrial fibrillation (AF) affects over 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 utilized a multifaceted approach, combining large-scale genotyping in two ethnically distinct populations, cis-eQTL mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501, RR=1.18, 95%CI 1.13 - 1.23, p=6.5x10(-16)), GJA1 (rs13216675, RR=1.10, 95%CI 1.06 - 1.14, p=2.2x10(-8)), TBX5 (rs10507248, RR=1.12, 95%CI 1.08 - 1.16, p=5.7x10(-11)), and CAND2 (rs4642101, RR=1.10, 95%CI 1.06 - 1.14, p=9.8x10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555, RR=1.32, 95%CI 1.26-1.39, p=2.0x10(-25)) and CUX2 (rs6490029, RR=1.12, 95%CI 1.08-1.16, p=3.9x10(-9)). The top SNPs or their proxies were identified as cis-eQTLs for the genes CAND2 (p=2.6x10(-19)), GJA1 (p=2.66x10(-6)), and TBX5 (p=1.36x10(-05)). 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 five novel loci for AF. Our results further expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping