@article {7363, title = {Discovery of novel heart rate-associated loci using the Exome Chip.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9\% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx113}, author = {van den Berg, Marten E and Warren, Helen R and Cabrera, Claudia P and Verweij, Niek and Mifsud, Borbala and Haessler, Jeffrey and Bihlmeyer, Nathan A and Fu, Yi-Ping and Weiss, Stefan and Lin, Henry J and Grarup, Niels and Li-Gao, Ruifang and Pistis, Giorgio and Shah, Nabi and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Lin, Honghuang and Mei, Hao and Smith, Albert V and Lyytik{\"a}inen, Leo-Pekka and Hall, Leanne M and van Setten, Jessica and Trompet, Stella and Prins, Bram P and Isaacs, Aaron and Radmanesh, Farid and Marten, Jonathan and Entwistle, Aiman and Kors, Jan A and Silva, Claudia T and Alonso, Alvaro and Bis, Joshua C and de Boer, Rudolf and de Haan, Hugoline G and de Mutsert, Ren{\'e}e and Dedoussis, George and Dominiczak, Anna F and Doney, Alex S F and Ellinor, Patrick T and Eppinga, Ruben N and Felix, Stephan B and Guo, Xiuqing and Hagemeijer, Yanick and Hansen, Torben and Harris, Tamara B and Heckbert, Susan R and Huang, Paul L and Hwang, Shih-Jen and K{\"a}h{\"o}nen, Mika and Kanters, J{\o}rgen K and Kolcic, Ivana and Launer, Lenore J and Li, Man and Yao, Jie and Linneberg, Allan and Liu, Simin and Macfarlane, Peter W and Mangino, Massimo and Morris, Andrew D and Mulas, Antonella and Murray, Alison D and Nelson, Christopher P and Orr{\`u}, Marco and Padmanabhan, Sandosh and Peters, Annette and Porteous, David J and Poulter, Neil and Psaty, Bruce M and Qi, Lihong and Raitakari, Olli T and Rivadeneira, Fernando and Roselli, Carolina and Rudan, Igor and Sattar, Naveed and Sever, Peter and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Timothy D and Stanton, Alice V and Stirrups, Kathleen E and Taylor, Kent D and Tobin, Martin D and Uitterlinden, Andre and Vaartjes, Ilonca and Hoes, Arno W and van der Meer, Peter and V{\"o}lker, Uwe and Waldenberger, Melanie and Xie, Zhijun and Zoledziewska, Magdalena and Tinker, Andrew and Polasek, Ozren and Rosand, Jonathan and Jamshidi, Yalda and van Duijn, Cornelia M and Zeggini, Eleftheria and Wouter Jukema, J and Asselbergs, Folkert W and Samani, Nilesh J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Wilson, James and Lubitz, Steven A and K{\"a}{\"a}b, Stefan and Sotoodehnia, Nona and Caulfield, Mark J and Palmer, Colin N A and Sanna, Serena and Mook-Kanamori, Dennis O and Deloukas, Panos and Pedersen, Oluf and Rotter, Jerome I and D{\"o}rr, Marcus and O{\textquoteright}Donnell, Chris J and Hayward, Caroline and Arking, Dan E and Kooperberg, Charles and van der Harst, Pim and Eijgelsheim, Mark and Stricker, Bruno H and Munroe, Patricia B} } @article {7396, title = {Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {946-952}, abstract = {

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

}, issn = {1546-1718}, doi = {10.1038/ng.3843}, author = {Christophersen, Ingrid E and Rienstra, Michiel and Roselli, Carolina and Yin, Xiaoyan and Geelhoed, Bastiaan and Barnard, John and Lin, Honghuang and Arking, Dan E and Smith, Albert V and Albert, Christine M and Chaffin, Mark and Tucker, Nathan R and Li, Molong and Klarin, Derek and Bihlmeyer, Nathan A and Low, Siew-Kee and Weeke, Peter E and M{\"u}ller-Nurasyid, Martina and Smith, J Gustav and Brody, Jennifer A and Niemeijer, Maartje N and D{\"o}rr, Marcus and Trompet, Stella and Huffman, Jennifer and Gustafsson, Stefan and Schurmann, Claudia and Kleber, Marcus E and Lyytik{\"a}inen, Leo-Pekka and Sepp{\"a}l{\"a}, Ilkka and Malik, Rainer and Horimoto, Andrea R V R and Perez, Marco and Sinisalo, Juha and Aeschbacher, Stefanie and Th{\'e}riault, S{\'e}bastien and Yao, Jie and Radmanesh, Farid and Weiss, Stefan and Teumer, Alexander and Choi, Seung Hoan and Weng, Lu-Chen and Clauss, Sebastian and Deo, Rajat and Rader, Daniel J and Shah, Svati H and Sun, Albert and Hopewell, Jemma C and Debette, Stephanie and Chauhan, Ganesh and Yang, Qiong and Worrall, Bradford B and Par{\'e}, Guillaume and Kamatani, Yoichiro and Hagemeijer, Yanick P and Verweij, Niek and Siland, Joylene E and Kubo, Michiaki and Smith, Jonathan D and Van Wagoner, David R and Bis, Joshua C and Perz, Siegfried and Psaty, Bruce M and Ridker, Paul M and Magnani, Jared W and Harris, Tamara B and Launer, Lenore J and Shoemaker, M Benjamin and Padmanabhan, Sandosh and Haessler, Jeffrey and Bartz, Traci M and Waldenberger, Melanie and Lichtner, Peter and Arendt, Marina and Krieger, Jose E and K{\"a}h{\"o}nen, Mika and Risch, Lorenz and Mansur, Alfredo J and Peters, Annette and Smith, Blair H and Lind, Lars and Scott, Stuart A and Lu, Yingchang and Bottinger, Erwin B and Hernesniemi, Jussi and Lindgren, Cecilia M and Wong, Jorge A and Huang, Jie and Eskola, Markku and Morris, Andrew P and Ford, Ian and Reiner, Alex P and Delgado, Graciela and Chen, Lin Y and Chen, Yii-Der Ida and Sandhu, Roopinder K and Li, Man and Boerwinkle, Eric and Eisele, Lewin and Lannfelt, Lars and Rost, Natalia and Anderson, Christopher D and Taylor, Kent D and Campbell, Archie and Magnusson, Patrik K and Porteous, David and Hocking, Lynne J and Vlachopoulou, Efthymia and Pedersen, Nancy L and Nikus, Kjell and Orho-Melander, Marju and Hamsten, Anders and Heeringa, Jan and Denny, Joshua C and Kriebel, Jennifer and Darbar, Dawood and Newton-Cheh, Christopher and Shaffer, Christian and Macfarlane, Peter W and Heilmann-Heimbach, Stefanie and Almgren, Peter and Huang, Paul L and Sotoodehnia, Nona and Soliman, Elsayed Z and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and V{\"o}lker, Uwe and J{\"o}ckel, Karl-Heinz and Sinner, Moritz F and Lin, Henry J and Guo, Xiuqing and Dichgans, Martin and Ingelsson, Erik and Kooperberg, Charles and Melander, Olle and Loos, Ruth J F and Laurikka, Jari and Conen, David and Rosand, Jonathan and van der Harst, Pim and Lokki, Marja-Liisa and Kathiresan, Sekar and Pereira, Alexandre and Jukema, J Wouter and Hayward, Caroline and Rotter, Jerome I and M{\"a}rz, Winfried and Lehtim{\"a}ki, Terho and Stricker, Bruno H and Chung, Mina K and Felix, Stephan B and Gudnason, Vilmundur and Alonso, Alvaro and Roden, Dan M and K{\"a}{\"a}b, Stefan and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Tanaka, Toshihiro and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} } @article {7801, title = {Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 May}, pages = {e002037}, abstract = {

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2{\texttimes}10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9{\texttimes}10) and (=1.1{\texttimes}10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.002037}, author = {Lin, Honghuang and van Setten, Jessica and Smith, Albert V and Bihlmeyer, Nathan A and Warren, Helen R and Brody, Jennifer A and Radmanesh, Farid and Hall, Leanne and Grarup, Niels and M{\"u}ller-Nurasyid, Martina and Boutin, Thibaud and Verweij, Niek and Lin, Henry J and Li-Gao, Ruifang and van den Berg, Marten E and Marten, Jonathan and Weiss, Stefan and Prins, Bram P and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Mei, Hao and Harris, Tamara B and Launer, Lenore J and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Connell, John M and Huang, Paul L and Weng, Lu-Chen and Jameson, Heather S and Hucker, William and Hanley, Alan and Tucker, Nathan R and Chen, Yii-Der Ida and Bis, Joshua C and Rice, Kenneth M and Sitlani, Colleen M and Kors, Jan A and Xie, Zhijun and Wen, Chengping and Magnani, Jared W and Nelson, Christopher P and Kanters, J{\o}rgen K and Sinner, Moritz F and Strauch, Konstantin and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Bork-Jensen, Jette and Pedersen, Oluf and Linneberg, Allan and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Yao, Jie and Guo, Xiuqing and Taylor, Kent D and Sotoodehnia, Nona and Rotter, Jerome I and Mook-Kanamori, Dennis O and Trompet, Stella and Rivadeneira, Fernando and Uitterlinden, Andre and Eijgelsheim, Mark and Padmanabhan, Sandosh and Smith, Blair H and V{\"o}lzke, Henry and Felix, Stephan B and Homuth, Georg and V{\"o}lker, Uwe and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and K{\"a}h{\"o}nen, Mika and Raitakari, Olli T and Gudnason, Vilmundur and Arking, Dan E and Munroe, Patricia B and Psaty, Bruce M and van Duijn, Cornelia M and Benjamin, Emelia J and Rosand, Jonathan and Samani, Nilesh J and Hansen, Torben and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Jukema, J Wouter and Stricker, Bruno H and Hayward, Caroline and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Wilson, James G and Ellinor, Patrick T and Lubitz, Steven A and Isaacs, Aaron} } @article {7809, title = {Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.}, journal = {Genome Biol}, volume = {19}, year = {2018}, month = {2018 07 17}, pages = {87}, abstract = {

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874~individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

}, issn = {1474-760X}, doi = {10.1186/s13059-018-1457-6}, author = {Prins, Bram P and Mead, Timothy J and Brody, Jennifer A and Sveinbjornsson, Gardar and Ntalla, Ioanna and Bihlmeyer, Nathan A and van den Berg, Marten and Bork-Jensen, Jette and Cappellani, Stefania and Van Duijvenboden, Stefan and Klena, Nikolai T and Gabriel, George C and Liu, Xiaoqin and Gulec, Cagri and Grarup, Niels and Haessler, Jeffrey and Hall, Leanne M and Iorio, Annamaria and Isaacs, Aaron and Li-Gao, Ruifang and Lin, Honghuang and Liu, Ching-Ti and Lyytik{\"a}inen, Leo-Pekka and Marten, Jonathan and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Orini, Michele and Padmanabhan, Sandosh and Radmanesh, Farid and Ramirez, Julia and Robino, Antonietta and Schwartz, Molly and van Setten, Jessica and Smith, Albert V and Verweij, Niek and Warren, Helen R and Weiss, Stefan and Alonso, Alvaro and Arnar, David O and Bots, Michiel L and de Boer, Rudolf A and Dominiczak, Anna F and Eijgelsheim, Mark and Ellinor, Patrick T and Guo, Xiuqing and Felix, Stephan B and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Huang, Paul L and Jukema, J W and K{\"a}h{\"o}nen, Mika and Kors, Jan A and Lambiase, Pier D and Launer, Lenore J and Li, Man and Linneberg, Allan and Nelson, Christopher P and Pedersen, Oluf and Perez, Marco and Peters, Annette and Polasek, Ozren and Psaty, Bruce M and Raitakari, Olli T and Rice, Kenneth M and Rotter, Jerome I and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Tim D and Strauch, Konstantin and Thorsteinsdottir, Unnur and Tinker, Andrew and Trompet, Stella and Uitterlinden, Andre and Vaartjes, Ilonca and van der Meer, Peter and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wilson, James G and Xie, Zhijun and Asselbergs, Folkert W and D{\"o}rr, Marcus and van Duijn, Cornelia M and Gasparini, Paolo and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Hansen, Torben and K{\"a}{\"a}b, Stefan and Kanters, J{\o}rgen K and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Lin, Henry J and Lubitz, Steven A and Mook-Kanamori, Dennis O and Conti, Francesco J and Newton-Cheh, Christopher H and Rosand, Jonathan and Rudan, Igor and Samani, Nilesh J and Sinagra, Gianfranco and Smith, Blair H and Holm, Hilma and Stricker, Bruno H and Ulivi, Sheila and Sotoodehnia, Nona and Apte, Suneel S and van der Harst, Pim and Stefansson, Kari and Munroe, Patricia B and Arking, Dan E and Lo, Cecilia W and Jamshidi, Yalda} } @article {7784, title = {ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 Jan}, pages = {e001758}, abstract = {

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.

METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.

CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.001758}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Warren, Helen R and Lin, Honghuang and Isaacs, Aaron and Liu, Ching-Ti and Marten, Jonathan and Radmanesh, Farid and Hall, Leanne M and Grarup, Niels and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Huffman, Jennifer E and Verweij, Niek and Guo, Xiuqing and Yao, Jie and Li-Gao, Ruifang and van den Berg, Marten and Weiss, Stefan and Prins, Bram P and van Setten, Jessica and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Bis, Joshua C and Austin, Tom and Chen, Yii-Der Ida and Psaty, Bruce M and Harrris, Tamara B and Launer, Lenore J and Padmanabhan, Sandosh and Dominiczak, Anna and Huang, Paul L and Xie, Zhijun and Ellinor, Patrick T and Kors, Jan A and Campbell, Archie and Murray, Alison D and Nelson, Christopher P and Tobin, Martin D and Bork-Jensen, Jette and Hansen, Torben and Pedersen, Oluf and Linneberg, Allan and Sinner, Moritz F and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Perz, Siegfried and Kolcic, Ivana and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Lin, Henry J and Taylor, Kent D and de Mutsert, Ren{\'e}e and Trompet, Stella and Jukema, J Wouter and Maan, Arie C and Stricker, Bruno H C and Rivadeneira, Fernando and Uitterlinden, Andre and V{\"o}lker, Uwe and Homuth, Georg and V{\"o}lzke, Henry and Felix, Stephan B and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Gudnason, Vilmundur and Munroe, Patricia B and Lubitz, Steven A and van Duijn, Cornelia M and Newton-Cheh, Christopher H and Hayward, Caroline and Rosand, Jonathan and Samani, Nilesh J and Kanters, J{\o}rgen K and Wilson, James G and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Rotter, Jerome I and Mook-Kanamori, Dennis O and Eijgelsheim, Mark and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Arking, Dan E and Sotoodehnia, Nona} } @article {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @article {8368, title = {Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 May 21}, pages = {2542}, abstract = {

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5\% to 62.6\%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

}, issn = {2041-1723}, doi = {10.1038/s41467-020-15706-x}, author = {Ntalla, Ioanna and Weng, Lu-Chen and Cartwright, James H and Hall, Amelia Weber and Sveinbjornsson, Gardar and Tucker, Nathan R and Choi, Seung Hoan and Chaffin, Mark D and Roselli, Carolina and Barnes, Michael R and Mifsud, Borbala and Warren, Helen R and Hayward, Caroline and Marten, Jonathan and Cranley, James J and Concas, Maria Pina and Gasparini, Paolo and Boutin, Thibaud and Kolcic, Ivana and Polasek, Ozren and Rudan, Igor and Araujo, Nathalia M and Lima-Costa, Maria Fernanda and Ribeiro, Antonio Luiz P and Souza, Renan P and Tarazona-Santos, Eduardo and Giedraitis, Vilmantas and Ingelsson, Erik and Mahajan, Anubha and Morris, Andrew P and del Greco M, Fabiola and Foco, Luisa and G{\"o}gele, Martin and Hicks, Andrew A and Cook, James P and Lind, Lars and Lindgren, Cecilia M and Sundstr{\"o}m, Johan and Nelson, Christopher P and Riaz, Muhammad B and Samani, Nilesh J and Sinagra, Gianfranco and Ulivi, Sheila and K{\"a}h{\"o}nen, Mika and Mishra, Pashupati P and Mononen, Nina and Nikus, Kjell and Caulfield, Mark J and Dominiczak, Anna and Padmanabhan, Sandosh and Montasser, May E and O{\textquoteright}Connell, Jeff R and Ryan, Kathleen and Shuldiner, Alan R and Aeschbacher, Stefanie and Conen, David and Risch, Lorenz and Th{\'e}riault, S{\'e}bastien and Hutri-K{\"a}h{\"o}nen, Nina and Lehtim{\"a}ki, Terho and Lyytik{\"a}inen, Leo-Pekka and Raitakari, Olli T and Barnes, Catriona L K and Campbell, Harry and Joshi, Peter K and Wilson, James F and Isaacs, Aaron and Kors, Jan A and van Duijn, Cornelia M and Huang, Paul L and Gudnason, Vilmundur and Harris, Tamara B and Launer, Lenore J and Smith, Albert V and Bottinger, Erwin P and Loos, Ruth J F and Nadkarni, Girish N and Preuss, Michael H and Correa, Adolfo and Mei, Hao and Wilson, James and Meitinger, Thomas and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Waldenberger, Melanie and Mangino, Massimo and Spector, Timothy D and Rienstra, Michiel and van de Vegte, Yordi J and van der Harst, Pim and Verweij, Niek and K{\"a}{\"a}b, Stefan and Schramm, Katharina and Sinner, Moritz F and Strauch, Konstantin and Cutler, Michael J and Fatkin, Diane and London, Barry and Olesen, Morten and Roden, Dan M and Benjamin Shoemaker, M and Gustav Smith, J and Biggs, Mary L and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Rice, Kenneth and Sotoodehnia, Nona and De Grandi, Alessandro and Fuchsberger, Christian and Pattaro, Cristian and Pramstaller, Peter P and Ford, Ian and Wouter Jukema, J and Macfarlane, Peter W and Trompet, Stella and D{\"o}rr, Marcus and Felix, Stephan B and V{\"o}lker, Uwe and Weiss, Stefan and Havulinna, Aki S and Jula, Antti and S{\"a}{\"a}ksj{\"a}rvi, Katri and Salomaa, Veikko and Guo, Xiuqing and Heckbert, Susan R and Lin, Henry J and Rotter, Jerome I and Taylor, Kent D and Yao, Jie and de Mutsert, Ren{\'e}e and Maan, Arie C and Mook-Kanamori, Dennis O and Noordam, Raymond and Cucca, Francesco and Ding, Jun and Lakatta, Edward G and Qian, Yong and Tarasov, Kirill V and Levy, Daniel and Lin, Honghuang and Newton-Cheh, Christopher H and Lunetta, Kathryn L and Murray, Alison D and Porteous, David J and Smith, Blair H and Stricker, Bruno H and Uitterlinden, Andre and van den Berg, Marten E and Haessler, Jeffrey and Jackson, Rebecca D and Kooperberg, Charles and Peters, Ulrike and Reiner, Alexander P and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Boerwinkle, Eric and Ehret, Georg B and Soliman, Elsayed Z and Avery, Christy L and Gogarten, Stephanie M and Kerr, Kathleen F and Laurie, Cathy C and Seyerle, Amanda A and Stilp, Adrienne and Assa, Solmaz and Abdullah Said, M and Yldau van der Ende, M and Lambiase, Pier D and Orini, Michele and Ramirez, Julia and Van Duijvenboden, Stefan and Arnar, David O and Gudbjartsson, Daniel F and Holm, Hilma and Sulem, Patrick and Thorleifsson, Gudmar and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Benjamin, Emelia J and Tinker, Andrew and Stefansson, Kari and Ellinor, Patrick T and Jamshidi, Yalda and Lubitz, Steven A and Munroe, Patricia B} }