%0 Journal Article %J J Am Coll Cardiol %D 2016 %T 52 Genetic Loci Influencing Myocardial Mass. %A van der Harst, Pim %A van Setten, Jessica %A Verweij, Niek %A Vogler, Georg %A Franke, Lude %A Maurano, Matthew T %A Wang, Xinchen %A Mateo Leach, Irene %A Eijgelsheim, Mark %A Sotoodehnia, Nona %A Hayward, Caroline %A Sorice, Rossella %A Meirelles, Osorio %A Lyytikäinen, Leo-Pekka %A Polasek, Ozren %A Tanaka, Toshiko %A Arking, Dan E %A Ulivi, Sheila %A Trompet, Stella %A Müller-Nurasyid, Martina %A Smith, Albert V %A Dörr, Marcus %A Kerr, Kathleen F %A Magnani, Jared W %A del Greco M, Fabiola %A Zhang, Weihua %A Nolte, Ilja M %A Silva, Claudia T %A Padmanabhan, Sandosh %A Tragante, Vinicius %A Esko, Tõnu %A Abecasis, Goncalo R %A Adriaens, Michiel E %A Andersen, Karl %A Barnett, Phil %A Bis, Joshua C %A Bodmer, Rolf %A Buckley, Brendan M %A Campbell, Harry %A Cannon, Megan V %A Chakravarti, Aravinda %A Chen, Lin Y %A Delitala, Alessandro %A Devereux, Richard B %A Doevendans, Pieter A %A Dominiczak, Anna F %A Ferrucci, Luigi %A Ford, Ian %A Gieger, Christian %A Harris, Tamara B %A Haugen, Eric %A Heinig, Matthias %A Hernandez, Dena G %A Hillege, Hans L %A Hirschhorn, Joel N %A Hofman, Albert %A Hubner, Norbert %A Hwang, Shih-Jen %A Iorio, Annamaria %A Kähönen, Mika %A Kellis, Manolis %A Kolcic, Ivana %A Kooner, Ishminder K %A Kooner, Jaspal S %A Kors, Jan A %A Lakatta, Edward G %A Lage, Kasper %A Launer, Lenore J %A Levy, Daniel %A Lundby, Alicia %A Macfarlane, Peter W %A May, Dalit %A Meitinger, Thomas %A Metspalu, Andres %A Nappo, Stefania %A Naitza, Silvia %A Neph, Shane %A Nord, Alex S %A Nutile, Teresa %A Okin, Peter M %A Olsen, Jesper V %A Oostra, Ben A %A Penninger, Josef M %A Pennacchio, Len A %A Pers, Tune H %A Perz, Siegfried %A Peters, Annette %A Pinto, Yigal M %A Pfeufer, Arne %A Pilia, Maria Grazia %A Pramstaller, Peter P %A Prins, Bram P %A Raitakari, Olli T %A Raychaudhuri, Soumya %A Rice, Ken M %A Rossin, Elizabeth J %A Rotter, Jerome I %A Schafer, Sebastian %A Schlessinger, David %A Schmidt, Carsten O %A Sehmi, Jobanpreet %A Silljé, Herman H W %A Sinagra, Gianfranco %A Sinner, Moritz F %A Slowikowski, Kamil %A Soliman, Elsayed Z %A Spector, Timothy D %A Spiering, Wilko %A Stamatoyannopoulos, John A %A Stolk, Ronald P %A Strauch, Konstantin %A Tan, Sian-Tsung %A Tarasov, Kirill V %A Trinh, Bosco %A Uitterlinden, André G %A van den Boogaard, Malou %A van Duijn, Cornelia M %A van Gilst, Wiek H %A Viikari, Jorma S %A Visscher, Peter M %A Vitart, Veronique %A Völker, Uwe %A Waldenberger, Melanie %A Weichenberger, Christian X %A Westra, Harm-Jan %A Wijmenga, Cisca %A Wolffenbuttel, Bruce H %A Yang, Jian %A Bezzina, Connie R %A Munroe, Patricia B %A Snieder, Harold %A Wright, Alan F %A Rudan, Igor %A Boyer, Laurie A %A Asselbergs, Folkert W %A van Veldhuisen, Dirk J %A Stricker, Bruno H %A Psaty, Bruce M %A Ciullo, Marina %A Sanna, Serena %A Lehtimäki, Terho %A Wilson, James F %A Bandinelli, Stefania %A Alonso, Alvaro %A Gasparini, Paolo %A Jukema, J Wouter %A Kääb, Stefan %A Gudnason, Vilmundur %A Felix, Stephan B %A Heckbert, Susan R %A de Boer, Rudolf A %A Newton-Cheh, Christopher %A Hicks, Andrew A %A Chambers, John C %A Jamshidi, Yalda %A Visel, Axel %A Christoffels, Vincent M %A Isaacs, Aaron %A Samani, Nilesh J %A de Bakker, Paul I W %X

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.

OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.

METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.

RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.

CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

%B J Am Coll Cardiol %V 68 %P 1435-48 %8 2016 Sep 27 %G eng %N 13 %R 10.1016/j.jacc.2016.07.729 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. %A Natarajan, Pradeep %A Bis, Joshua C %A Bielak, Lawrence F %A Cox, Amanda J %A Dörr, Marcus %A Feitosa, Mary F %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A Isaacs, Aaron %A Jhun, Min A %A Kavousi, Maryam %A Li-Gao, Ruifang %A Lyytikäinen, Leo-Pekka %A Marioni, Riccardo E %A Schminke, Ulf %A Stitziel, Nathan O %A Tada, Hayato %A van Setten, Jessica %A Smith, Albert V %A Vojinovic, Dina %A Yanek, Lisa R %A Yao, Jie %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Baber, Usman %A Borecki, Ingrid B %A Carr, J Jeffrey %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A de Jong, Pim A %A de Koning, Harry %A de Vos, Bob D %A Demirkan, Ayse %A Fuster, Valentin %A Franco, Oscar H %A Goodarzi, Mark O %A Harris, Tamara B %A Heckbert, Susan R %A Heiss, Gerardo %A Hoffmann, Udo %A Hofman, Albert %A Išgum, Ivana %A Jukema, J Wouter %A Kähönen, Mika %A Kardia, Sharon L R %A Kral, Brian G %A Launer, Lenore J %A Massaro, Joseph %A Mehran, Roxana %A Mitchell, Braxton D %A Mosley, Thomas H %A de Mutsert, Renée %A Newman, Anne B %A Nguyen, Khanh-Dung %A North, Kari E %A O'Connell, Jeffrey R %A Oudkerk, Matthijs %A Pankow, James S %A Peloso, Gina M %A Post, Wendy %A Province, Michael A %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rivadeneira, Fernando %A Rosendaal, Frits %A Sartori, Samantha %A Taylor, Kent D %A Teumer, Alexander %A Trompet, Stella %A Turner, Stephen T %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Lugt, Aad %A Völker, Uwe %A Wardlaw, Joanna M %A Wassel, Christina L %A Weiss, Stefan %A Wojczynski, Mary K %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bowden, Donald W %A Deary, Ian J %A Dehghan, Abbas %A Felix, Stephan B %A Gudnason, Vilmundur %A Lehtimäki, Terho %A Mathias, Rasika %A Mook-Kanamori, Dennis O %A Psaty, Bruce M %A Rader, Daniel J %A Rotter, Jerome I %A Wilson, James G %A van Duijn, Cornelia M %A Völzke, Henry %A Kathiresan, Sekar %A Peyser, Patricia A %A O'Donnell, Christopher J %X

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

%B Circ Cardiovasc Genet %8 2016 Nov 21 %G eng %R 10.1161/CIRCGENETICS.116.001572 %0 Journal Article %J Hum Mol Genet %D 2017 %T Discovery of novel heart rate-associated loci using the Exome Chip. %A van den Berg, Marten E %A Warren, Helen R %A Cabrera, Claudia P %A Verweij, Niek %A Mifsud, Borbala %A Haessler, Jeffrey %A Bihlmeyer, Nathan A %A Fu, Yi-Ping %A Weiss, Stefan %A Lin, Henry J %A Grarup, Niels %A Li-Gao, Ruifang %A Pistis, Giorgio %A Shah, Nabi %A Brody, Jennifer A %A Müller-Nurasyid, Martina %A Lin, Honghuang %A Mei, Hao %A Smith, Albert V %A Lyytikäinen, Leo-Pekka %A Hall, Leanne M %A van Setten, Jessica %A Trompet, Stella %A Prins, Bram P %A Isaacs, Aaron %A Radmanesh, Farid %A Marten, Jonathan %A Entwistle, Aiman %A Kors, Jan A %A Silva, Claudia T %A Alonso, Alvaro %A Bis, Joshua C %A de Boer, Rudolf %A de Haan, Hugoline G %A de Mutsert, Renée %A Dedoussis, George %A Dominiczak, Anna F %A Doney, Alex S F %A Ellinor, Patrick T %A Eppinga, Ruben N %A Felix, Stephan B %A Guo, Xiuqing %A Hagemeijer, Yanick %A Hansen, Torben %A Harris, Tamara B %A Heckbert, Susan R %A Huang, Paul L %A Hwang, Shih-Jen %A Kähönen, Mika %A Kanters, Jørgen K %A Kolcic, Ivana %A Launer, Lenore J %A Li, Man %A Yao, Jie %A Linneberg, Allan %A Liu, Simin %A Macfarlane, Peter W %A Mangino, Massimo %A Morris, Andrew D %A Mulas, Antonella %A Murray, Alison D %A Nelson, Christopher P %A Orrù, Marco %A Padmanabhan, Sandosh %A Peters, Annette %A Porteous, David J %A Poulter, Neil %A Psaty, Bruce M %A Qi, Lihong %A Raitakari, Olli T %A Rivadeneira, Fernando %A Roselli, Carolina %A Rudan, Igor %A Sattar, Naveed %A Sever, Peter %A Sinner, Moritz F %A Soliman, Elsayed Z %A Spector, Timothy D %A Stanton, Alice V %A Stirrups, Kathleen E %A Taylor, Kent D %A Tobin, Martin D %A Uitterlinden, Andre %A Vaartjes, Ilonca %A Hoes, Arno W %A van der Meer, Peter %A Völker, Uwe %A Waldenberger, Melanie %A Xie, Zhijun %A Zoledziewska, Magdalena %A Tinker, Andrew %A Polasek, Ozren %A Rosand, Jonathan %A Jamshidi, Yalda %A van Duijn, Cornelia M %A Zeggini, Eleftheria %A Wouter Jukema, J %A Asselbergs, Folkert W %A Samani, Nilesh J %A Lehtimäki, Terho %A Gudnason, Vilmundur %A Wilson, James %A Lubitz, Steven A %A Kääb, Stefan %A Sotoodehnia, Nona %A Caulfield, Mark J %A Palmer, Colin N A %A Sanna, Serena %A Mook-Kanamori, Dennis O %A Deloukas, Panos %A Pedersen, Oluf %A Rotter, Jerome I %A Dörr, Marcus %A O'Donnell, Chris J %A Hayward, Caroline %A Arking, Dan E %A Kooperberg, Charles %A van der Harst, Pim %A Eijgelsheim, Mark %A Stricker, Bruno H %A Munroe, Patricia B %X

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.

%B Hum Mol Genet %8 2017 Apr 03 %G eng %R 10.1093/hmg/ddx113 %0 Journal Article %J Nat Commun %D 2017 %T Genetic loci associated with heart rate variability and their effects on cardiac disease risk. %A Nolte, Ilja M %A Munoz, M Loretto %A Tragante, Vinicius %A Amare, Azmeraw T %A Jansen, Rick %A Vaez, Ahmad %A von der Heyde, Benedikt %A Avery, Christy L %A Bis, Joshua C %A Dierckx, Bram %A van Dongen, Jenny %A Gogarten, Stephanie M %A Goyette, Philippe %A Hernesniemi, Jussi %A Huikari, Ville %A Hwang, Shih-Jen %A Jaju, Deepali %A Kerr, Kathleen F %A Kluttig, Alexander %A Krijthe, Bouwe P %A Kumar, Jitender %A van der Laan, Sander W %A Lyytikäinen, Leo-Pekka %A Maihofer, Adam X %A Minassian, Arpi %A van der Most, Peter J %A Müller-Nurasyid, Martina %A Nivard, Michel %A Salvi, Erika %A Stewart, James D %A Thayer, Julian F %A Verweij, Niek %A Wong, Andrew %A Zabaneh, Delilah %A Zafarmand, Mohammad H %A Abdellaoui, Abdel %A Albarwani, Sulayma %A Albert, Christine %A Alonso, Alvaro %A Ashar, Foram %A Auvinen, Juha %A Axelsson, Tomas %A Baker, Dewleen G %A de Bakker, Paul I W %A Barcella, Matteo %A Bayoumi, Riad %A Bieringa, Rob J %A Boomsma, Dorret %A Boucher, Gabrielle %A Britton, Annie R %A Christophersen, Ingrid %A Dietrich, Andrea %A Ehret, George B %A Ellinor, Patrick T %A Eskola, Markku %A Felix, Janine F %A Floras, John S %A Franco, Oscar H %A Friberg, Peter %A Gademan, Maaike G J %A Geyer, Mark A %A Giedraitis, Vilmantas %A Hartman, Catharina A %A Hemerich, Daiane %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huikuri, Heikki %A Hutri-Kähönen, Nina %A Jouven, Xavier %A Junttila, Juhani %A Juonala, Markus %A Kiviniemi, Antti M %A Kors, Jan A %A Kumari, Meena %A Kuznetsova, Tatiana %A Laurie, Cathy C %A Lefrandt, Joop D %A Li, Yong %A Li, Yun %A Liao, Duanping %A Limacher, Marian C %A Lin, Henry J %A Lindgren, Cecilia M %A Lubitz, Steven A %A Mahajan, Anubha %A McKnight, Barbara %A Zu Schwabedissen, Henriette Meyer %A Milaneschi, Yuri %A Mononen, Nina %A Morris, Andrew P %A Nalls, Mike A %A Navis, Gerjan %A Neijts, Melanie %A Nikus, Kjell %A North, Kari E %A O'Connor, Daniel T %A Ormel, Johan %A Perz, Siegfried %A Peters, Annette %A Psaty, Bruce M %A Raitakari, Olli T %A Risbrough, Victoria B %A Sinner, Moritz F %A Siscovick, David %A Smit, Johannes H %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Staessen, Jan A %A Stein, Phyllis K %A Stilp, Adrienne M %A Stolarz-Skrzypek, Katarzyna %A Strauch, Konstantin %A Sundström, Johan %A Swenne, Cees A %A Syvänen, Ann-Christine %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thornton, Timothy A %A Tinker, Lesley E %A Uitterlinden, André G %A van Setten, Jessica %A Voss, Andreas %A Waldenberger, Melanie %A Wilhelmsen, Kirk C %A Willemsen, Gonneke %A Wong, Quenna %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Cusi, Daniele %A Evans, Michele K %A Greiser, Halina K %A van der Harst, Pim %A Hassan, Mohammad %A Ingelsson, Erik %A Jarvelin, Marjo-Riitta %A Kääb, Stefan %A Kähönen, Mika %A Kivimaki, Mika %A Kooperberg, Charles %A Kuh, Diana %A Lehtimäki, Terho %A Lind, Lars %A Nievergelt, Caroline M %A O'Donnell, Chris J %A Oldehinkel, Albertine J %A Penninx, Brenda %A Reiner, Alexander P %A Riese, Harriëtte %A van Roon, Arie M %A Rioux, John D %A Rotter, Jerome I %A Sofer, Tamar %A Stricker, Bruno H %A Tiemeier, Henning %A Vrijkotte, Tanja G M %A Asselbergs, Folkert W %A Brundel, Bianca J J M %A Heckbert, Susan R %A Whitsel, Eric A %A den Hoed, Marcel %A Snieder, Harold %A de Geus, Eco J C %X

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 %B Nat Commun %V 8 %P 15805 %8 2017 Jun 14 %G eng %R 10.1038/ncomms15805 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. %A Lin, Honghuang %A van Setten, Jessica %A Smith, Albert V %A Bihlmeyer, Nathan A %A Warren, Helen R %A Brody, Jennifer A %A Radmanesh, Farid %A Hall, Leanne %A Grarup, Niels %A Müller-Nurasyid, Martina %A Boutin, Thibaud %A Verweij, Niek %A Lin, Henry J %A Li-Gao, Ruifang %A van den Berg, Marten E %A Marten, Jonathan %A Weiss, Stefan %A Prins, Bram P %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Mei, Hao %A Harris, Tamara B %A Launer, Lenore J %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Connell, John M %A Huang, Paul L %A Weng, Lu-Chen %A Jameson, Heather S %A Hucker, William %A Hanley, Alan %A Tucker, Nathan R %A Chen, Yii-Der Ida %A Bis, Joshua C %A Rice, Kenneth M %A Sitlani, Colleen M %A Kors, Jan A %A Xie, Zhijun %A Wen, Chengping %A Magnani, Jared W %A Nelson, Christopher P %A Kanters, Jørgen K %A Sinner, Moritz F %A Strauch, Konstantin %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Bork-Jensen, Jette %A Pedersen, Oluf %A Linneberg, Allan %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Yao, Jie %A Guo, Xiuqing %A Taylor, Kent D %A Sotoodehnia, Nona %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Eijgelsheim, Mark %A Padmanabhan, Sandosh %A Smith, Blair H %A Völzke, Henry %A Felix, Stephan B %A Homuth, Georg %A Völker, Uwe %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Kähönen, Mika %A Raitakari, Olli T %A Gudnason, Vilmundur %A Arking, Dan E %A Munroe, Patricia B %A Psaty, Bruce M %A van Duijn, Cornelia M %A Benjamin, Emelia J %A Rosand, Jonathan %A Samani, Nilesh J %A Hansen, Torben %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Jukema, J Wouter %A Stricker, Bruno H %A Hayward, Caroline %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Wilson, James G %A Ellinor, Patrick T %A Lubitz, Steven A %A Isaacs, Aaron %X

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 (<1.2×10), 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 (=5.9×10) and (=1.1×10) 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.

%B Circ Genom Precis Med %V 11 %P e002037 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.117.002037 %0 Journal Article %J Genome Biol %D 2018 %T Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. %A Prins, Bram P %A Mead, Timothy J %A Brody, Jennifer A %A Sveinbjornsson, Gardar %A Ntalla, Ioanna %A Bihlmeyer, Nathan A %A van den Berg, Marten %A Bork-Jensen, Jette %A Cappellani, Stefania %A Van Duijvenboden, Stefan %A Klena, Nikolai T %A Gabriel, George C %A Liu, Xiaoqin %A Gulec, Cagri %A Grarup, Niels %A Haessler, Jeffrey %A Hall, Leanne M %A Iorio, Annamaria %A Isaacs, Aaron %A Li-Gao, Ruifang %A Lin, Honghuang %A Liu, Ching-Ti %A Lyytikäinen, Leo-Pekka %A Marten, Jonathan %A Mei, Hao %A Müller-Nurasyid, Martina %A Orini, Michele %A Padmanabhan, Sandosh %A Radmanesh, Farid %A Ramirez, Julia %A Robino, Antonietta %A Schwartz, Molly %A van Setten, Jessica %A Smith, Albert V %A Verweij, Niek %A Warren, Helen R %A Weiss, Stefan %A Alonso, Alvaro %A Arnar, David O %A Bots, Michiel L %A de Boer, Rudolf A %A Dominiczak, Anna F %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Guo, Xiuqing %A Felix, Stephan B %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Huang, Paul L %A Jukema, J W %A Kähönen, Mika %A Kors, Jan A %A Lambiase, Pier D %A Launer, Lenore J %A Li, Man %A Linneberg, Allan %A Nelson, Christopher P %A Pedersen, Oluf %A Perez, Marco %A Peters, Annette %A Polasek, Ozren %A Psaty, Bruce M %A Raitakari, Olli T %A Rice, Kenneth M %A Rotter, Jerome I %A Sinner, Moritz F %A Soliman, Elsayed Z %A Spector, Tim D %A Strauch, Konstantin %A Thorsteinsdottir, Unnur %A Tinker, Andrew %A Trompet, Stella %A Uitterlinden, Andre %A Vaartjes, Ilonca %A van der Meer, Peter %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wilson, James G %A Xie, Zhijun %A Asselbergs, Folkert W %A Dörr, Marcus %A van Duijn, Cornelia M %A Gasparini, Paolo %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Hansen, Torben %A Kääb, Stefan %A Kanters, Jørgen K %A Kooperberg, Charles %A Lehtimäki, Terho %A Lin, Henry J %A Lubitz, Steven A %A Mook-Kanamori, Dennis O %A Conti, Francesco J %A Newton-Cheh, Christopher H %A Rosand, Jonathan %A Rudan, Igor %A Samani, Nilesh J %A Sinagra, Gianfranco %A Smith, Blair H %A Holm, Hilma %A Stricker, Bruno H %A Ulivi, Sheila %A Sotoodehnia, Nona %A Apte, Suneel S %A van der Harst, Pim %A Stefansson, Kari %A Munroe, Patricia B %A Arking, Dan E %A Lo, Cecilia W %A Jamshidi, Yalda %X

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.

%B Genome Biol %V 19 %P 87 %8 2018 07 17 %G eng %N 1 %R 10.1186/s13059-018-1457-6 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Warren, Helen R %A Lin, Honghuang %A Isaacs, Aaron %A Liu, Ching-Ti %A Marten, Jonathan %A Radmanesh, Farid %A Hall, Leanne M %A Grarup, Niels %A Mei, Hao %A Müller-Nurasyid, Martina %A Huffman, Jennifer E %A Verweij, Niek %A Guo, Xiuqing %A Yao, Jie %A Li-Gao, Ruifang %A van den Berg, Marten %A Weiss, Stefan %A Prins, Bram P %A van Setten, Jessica %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Bis, Joshua C %A Austin, Tom %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Harrris, Tamara B %A Launer, Lenore J %A Padmanabhan, Sandosh %A Dominiczak, Anna %A Huang, Paul L %A Xie, Zhijun %A Ellinor, Patrick T %A Kors, Jan A %A Campbell, Archie %A Murray, Alison D %A Nelson, Christopher P %A Tobin, Martin D %A Bork-Jensen, Jette %A Hansen, Torben %A Pedersen, Oluf %A Linneberg, Allan %A Sinner, Moritz F %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Perz, Siegfried %A Kolcic, Ivana %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Lin, Henry J %A Taylor, Kent D %A de Mutsert, Renée %A Trompet, Stella %A Jukema, J Wouter %A Maan, Arie C %A Stricker, Bruno H C %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Völker, Uwe %A Homuth, Georg %A Völzke, Henry %A Felix, Stephan B %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Raitakari, Olli T %A Kähönen, Mika %A Mononen, Nina %A Gudnason, Vilmundur %A Munroe, Patricia B %A Lubitz, Steven A %A van Duijn, Cornelia M %A Newton-Cheh, Christopher H %A Hayward, Caroline %A Rosand, Jonathan %A Samani, Nilesh J %A Kanters, Jørgen K %A Wilson, James G %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Eijgelsheim, Mark %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Arking, Dan E %A Sotoodehnia, Nona %X

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.

%B Circ Genom Precis Med %V 11 %P e001758 %8 2018 Jan %G eng %N 1 %R 10.1161/CIRCGEN.117.001758 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J Nat Genet %D 2023 %T Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. %A Kavousi, Maryam %A Bos, Maxime M %A Barnes, Hanna J %A Lino Cardenas, Christian L %A Wong, Doris %A Lu, Haojie %A Hodonsky, Chani J %A Landsmeer, Lennart P L %A Turner, Adam W %A Kho, Minjung %A Hasbani, Natalie R %A de Vries, Paul S %A Bowden, Donald W %A Chopade, Sandesh %A Deelen, Joris %A Benavente, Ernest Diez %A Guo, Xiuqing %A Hofer, Edith %A Hwang, Shih-Jen %A Lutz, Sharon M %A Lyytikäinen, Leo-Pekka %A Slenders, Lotte %A Smith, Albert V %A Stanislawski, Maggie A %A van Setten, Jessica %A Wong, Quenna %A Yanek, Lisa R %A Becker, Diane M %A Beekman, Marian %A Budoff, Matthew J %A Feitosa, Mary F %A Finan, Chris %A Hilliard, Austin T %A Kardia, Sharon L R %A Kovacic, Jason C %A Kral, Brian G %A Langefeld, Carl D %A Launer, Lenore J %A Malik, Shaista %A Hoesein, Firdaus A A Mohamed %A Mokry, Michal %A Schmidt, Reinhold %A Smith, Jennifer A %A Taylor, Kent D %A Terry, James G %A van der Grond, Jeroen %A van Meurs, Joyce %A Vliegenthart, Rozemarijn %A Xu, Jianzhao %A Young, Kendra A %A Zilhão, Nuno R %A Zweiker, Robert %A Assimes, Themistocles L %A Becker, Lewis C %A Bos, Daniel %A Carr, J Jeffrey %A Cupples, L Adrienne %A de Kleijn, Dominique P V %A de Winther, Menno %A den Ruijter, Hester M %A Fornage, Myriam %A Freedman, Barry I %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Hokanson, John E %A Ikram, M Arfan %A Išgum, Ivana %A Jacobs, David R %A Kähönen, Mika %A Lange, Leslie A %A Lehtimäki, Terho %A Pasterkamp, Gerard %A Raitakari, Olli T %A Schmidt, Helena %A Slagboom, P Eline %A Uitterlinden, André G %A Vernooij, Meike W %A Bis, Joshua C %A Franceschini, Nora %A Psaty, Bruce M %A Post, Wendy S %A Rotter, Jerome I %A Björkegren, Johan L M %A O'Donnell, Christopher J %A Bielak, Lawrence F %A Peyser, Patricia A %A Malhotra, Rajeev %A van der Laan, Sander W %A Miller, Clint L %X

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

%B Nat Genet %V 55 %P 1651-1664 %8 2023 Oct %G eng %N 10 %R 10.1038/s41588-023-01518-4