%0 Journal Article %J Nat Genet %D 2013 %T Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. %A Köttgen, Anna %A Albrecht, Eva %A Teumer, Alexander %A Vitart, Veronique %A Krumsiek, Jan %A Hundertmark, Claudia %A Pistis, Giorgio %A Ruggiero, Daniela %A O'Seaghdha, Conall M %A Haller, Toomas %A Yang, Qiong %A Tanaka, Toshiko %A Johnson, Andrew D %A Kutalik, Zoltán %A Smith, Albert V %A Shi, Julia %A Struchalin, Maksim %A Middelberg, Rita P S %A Brown, Morris J %A Gaffo, Angelo L %A Pirastu, Nicola %A Li, Guo %A Hayward, Caroline %A Zemunik, Tatijana %A Huffman, Jennifer %A Yengo, Loic %A Zhao, Jing Hua %A Demirkan, Ayse %A Feitosa, Mary F %A Liu, Xuan %A Malerba, Giovanni %A Lopez, Lorna M %A van der Harst, Pim %A Li, Xinzhong %A Kleber, Marcus E %A Hicks, Andrew A %A Nolte, Ilja M %A Johansson, Asa %A Murgia, Federico %A Wild, Sarah H %A Bakker, Stephan J L %A Peden, John F %A Dehghan, Abbas %A Steri, Maristella %A Tenesa, Albert %A Lagou, Vasiliki %A Salo, Perttu %A Mangino, Massimo %A Rose, Lynda M %A Lehtimäki, Terho %A Woodward, Owen M %A Okada, Yukinori %A Tin, Adrienne %A Müller, Christian %A Oldmeadow, Christopher %A Putku, Margus %A Czamara, Darina %A Kraft, Peter %A Frogheri, Laura %A Thun, Gian Andri %A Grotevendt, Anne %A Gislason, Gauti Kjartan %A Harris, Tamara B %A Launer, Lenore J %A McArdle, Patrick %A Shuldiner, Alan R %A Boerwinkle, Eric %A Coresh, Josef %A Schmidt, Helena %A Schallert, Michael %A Martin, Nicholas G %A Montgomery, Grant W %A Kubo, Michiaki %A Nakamura, Yusuke %A Tanaka, Toshihiro %A Munroe, Patricia B %A Samani, Nilesh J %A Jacobs, David R %A Liu, Kiang %A D'Adamo, Pio %A Ulivi, Sheila %A Rotter, Jerome I %A Psaty, Bruce M %A Vollenweider, Peter %A Waeber, Gérard %A Campbell, Susan %A Devuyst, Olivier %A Navarro, Pau %A Kolcic, Ivana %A Hastie, Nicholas %A Balkau, Beverley %A Froguel, Philippe %A Esko, Tõnu %A Salumets, Andres %A Khaw, Kay Tee %A Langenberg, Claudia %A Wareham, Nicholas J %A Isaacs, Aaron %A Kraja, Aldi %A Zhang, Qunyuan %A Wild, Philipp S %A Scott, Rodney J %A Holliday, Elizabeth G %A Org, Elin %A Viigimaa, Margus %A Bandinelli, Stefania %A Metter, Jeffrey E %A Lupo, Antonio %A Trabetti, Elisabetta %A Sorice, Rossella %A Döring, Angela %A Lattka, Eva %A Strauch, Konstantin %A Theis, Fabian %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Bruinenberg, Marcel %A Stolk, Ronald P %A Kooner, Jaspal S %A Zhang, Weihua %A Winkelmann, Bernhard R %A Boehm, Bernhard O %A Lucae, Susanne %A Penninx, Brenda W %A Smit, Johannes H %A Curhan, Gary %A Mudgal, Poorva %A Plenge, Robert M %A Portas, Laura %A Persico, Ivana %A Kirin, Mirna %A Wilson, James F %A Mateo Leach, Irene %A van Gilst, Wiek H %A Goel, Anuj %A Ongen, Halit %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Imboden, Medea %A von Eckardstein, Arnold %A Cucca, Francesco %A Nagaraja, Ramaiah %A Piras, Maria Grazia %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Ernst, Florian %A Farrington, Susan M %A Theodoratou, Evropi %A Prokopenko, Inga %A Stumvoll, Michael %A Jula, Antti %A Perola, Markus %A Salomaa, Veikko %A Shin, So-Youn %A Spector, Tim D %A Sala, Cinzia %A Ridker, Paul M %A Kähönen, Mika %A Viikari, Jorma %A Hengstenberg, Christian %A Nelson, Christopher P %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Singleton, Andrew B %A Kamatani, Naoyuki %A Zeller, Tanja %A Burnier, Michel %A Attia, John %A Laan, Maris %A Klopp, Norman %A Hillege, Hans L %A Kloiber, Stefan %A Choi, Hyon %A Pirastu, Mario %A Tore, Silvia %A Probst-Hensch, Nicole M %A Völzke, Henry %A Gudnason, Vilmundur %A Parsa, Afshin %A Schmidt, Reinhold %A Whitfield, John B %A Fornage, Myriam %A Gasparini, Paolo %A Siscovick, David S %A Polasek, Ozren %A Campbell, Harry %A Rudan, Igor %A Bouatia-Naji, Nabila %A Metspalu, Andres %A Loos, Ruth J F %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Wolffenbuttel, Bruce H R %A Chambers, John C %A März, Winfried %A Pramstaller, Peter P %A Snieder, Harold %A Gyllensten, Ulf %A Wright, Alan F %A Navis, Gerjan %A Watkins, Hugh %A Witteman, Jacqueline C M %A Sanna, Serena %A Schipf, Sabine %A Dunlop, Malcolm G %A Tönjes, Anke %A Ripatti, Samuli %A Soranzo, Nicole %A Toniolo, Daniela %A Chasman, Daniel I %A Raitakari, Olli %A Kao, W H Linda %A Ciullo, Marina %A Fox, Caroline S %A Caulfield, Mark %A Bochud, Murielle %A Gieger, Christian %K Analysis of Variance %K European Continental Ancestry Group %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Glucose %K Gout %K Humans %K Inhibins %K Polymorphism, Single Nucleotide %K Signal Transduction %K Uric Acid %X

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

%B Nat Genet %V 45 %P 145-54 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract %R 10.1038/ng.2500 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A D'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orrù, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Boerwinkle, Eric %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J Blood %D 2015 %T Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. %A Huffman, Jennifer E %A de Vries, Paul S %A Morrison, Alanna C %A Sabater-Lleal, Maria %A Kacprowski, Tim %A Auer, Paul L %A Brody, Jennifer A %A Chasman, Daniel I %A Chen, Ming-Huei %A Guo, Xiuqing %A Lin, Li-An %A Marioni, Riccardo E %A Müller-Nurasyid, Martina %A Yanek, Lisa R %A Pankratz, Nathan %A Grove, Megan L %A de Maat, Moniek P M %A Cushman, Mary %A Wiggins, Kerri L %A Qi, Lihong %A Sennblad, Bengt %A Harris, Sarah E %A Polasek, Ozren %A Riess, Helene %A Rivadeneira, Fernando %A Rose, Lynda M %A Goel, Anuj %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Vaidya, Dhananjay %A Yao, Jie %A Tang, Weihong %A Levy, Daniel %A Waldenberger, Melanie %A Becker, Diane M %A Folsom, Aaron R %A Giulianini, Franco %A Greinacher, Andreas %A Hofman, Albert %A Huang, Chiang-Ching %A Kooperberg, Charles %A Silveira, Angela %A Starr, John M %A Strauch, Konstantin %A Strawbridge, Rona J %A Wright, Alan F %A McKnight, Barbara %A Franco, Oscar H %A Zakai, Neil %A Mathias, Rasika A %A Psaty, Bruce M %A Ridker, Paul M %A Tofler, Geoffrey H %A Völker, Uwe %A Watkins, Hugh %A Fornage, Myriam %A Hamsten, Anders %A Deary, Ian J %A Boerwinkle, Eric %A Koenig, Wolfgang %A Rotter, Jerome I %A Hayward, Caroline %A Dehghan, Abbas %A Reiner, Alex P %A O'Donnell, Christopher J %A Smith, Nicholas L %K Cohort Studies %K Factor VII %K Factor VIII %K Fibrinogen %K Gene Frequency %K Genetic Association Studies %K Genetic Variation %K Humans %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels %K von Willebrand Factor %X

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

%B Blood %V 126 %P e19-29 %8 2015 Sep 10 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract %R 10.1182/blood-2015-02-624551 %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 Genome Biol %D 2016 %T DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. %A Ligthart, Symen %A Marzi, Carola %A Aslibekyan, Stella %A Mendelson, Michael M %A Conneely, Karen N %A Tanaka, Toshiko %A Colicino, Elena %A Waite, Lindsay L %A Joehanes, Roby %A Guan, Weihua %A Brody, Jennifer A %A Elks, Cathy %A Marioni, Riccardo %A Jhun, Min A %A Agha, Golareh %A Bressler, Jan %A Ward-Caviness, Cavin K %A Chen, Brian H %A Huan, Tianxiao %A Bakulski, Kelly %A Salfati, Elias L %A Fiorito, Giovanni %A Wahl, Simone %A Schramm, Katharina %A Sha, Jin %A Hernandez, Dena G %A Just, Allan C %A Smith, Jennifer A %A Sotoodehnia, Nona %A Pilling, Luke C %A Pankow, James S %A Tsao, Phil S %A Liu, Chunyu %A Zhao, Wei %A Guarrera, Simonetta %A Michopoulos, Vasiliki J %A Smith, Alicia K %A Peters, Marjolein J %A Melzer, David %A Vokonas, Pantel %A Fornage, Myriam %A Prokisch, Holger %A Bis, Joshua C %A Chu, Audrey Y %A Herder, Christian %A Grallert, Harald %A Yao, Chen %A Shah, Sonia %A McRae, Allan F %A Lin, Honghuang %A Horvath, Steve %A Fallin, Daniele %A Hofman, Albert %A Wareham, Nicholas J %A Wiggins, Kerri L %A Feinberg, Andrew P %A Starr, John M %A Visscher, Peter M %A Murabito, Joanne M %A Kardia, Sharon L R %A Absher, Devin M %A Binder, Elisabeth B %A Singleton, Andrew B %A Bandinelli, Stefania %A Peters, Annette %A Waldenberger, Melanie %A Matullo, Giuseppe %A Schwartz, Joel D %A Demerath, Ellen W %A Uitterlinden, André G %A van Meurs, Joyce B J %A Franco, Oscar H %A Chen, Yii-Der Ida %A Levy, Daniel %A Turner, Stephen T %A Deary, Ian J %A Ressler, Kerry J %A Dupuis, Josée %A Ferrucci, Luigi %A Ong, Ken K %A Assimes, Themistocles L %A Boerwinkle, Eric %A Koenig, Wolfgang %A Arnett, Donna K %A Baccarelli, Andrea A %A Benjamin, Emelia J %A Dehghan, Abbas %X

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

%B Genome Biol %V 17 %P 255 %8 2016 Dec 12 %G eng %N 1 %R 10.1186/s13059-016-1119-5 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Epigenetic Signatures of Cigarette Smoking. %A Joehanes, Roby %A Just, Allan C %A Marioni, Riccardo E %A Pilling, Luke C %A Reynolds, Lindsay M %A Mandaviya, Pooja R %A Guan, Weihua %A Xu, Tao %A Elks, Cathy E %A Aslibekyan, Stella %A Moreno-Macias, Hortensia %A Smith, Jennifer A %A Brody, Jennifer A %A Dhingra, Radhika %A Yousefi, Paul %A Pankow, James S %A Kunze, Sonja %A Shah, Sonia H %A McRae, Allan F %A Lohman, Kurt %A Sha, Jin %A Absher, Devin M %A Ferrucci, Luigi %A Zhao, Wei %A Demerath, Ellen W %A Bressler, Jan %A Grove, Megan L %A Huan, Tianxiao %A Liu, Chunyu %A Mendelson, Michael M %A Yao, Chen %A Kiel, Douglas P %A Peters, Annette %A Wang-Sattler, Rui %A Visscher, Peter M %A Wray, Naomi R %A Starr, John M %A Ding, Jingzhong %A Rodriguez, Carlos J %A Wareham, Nicholas J %A Irvin, Marguerite R %A Zhi, Degui %A Barrdahl, Myrto %A Vineis, Paolo %A Ambatipudi, Srikant %A Uitterlinden, André G %A Hofman, Albert %A Schwartz, Joel %A Colicino, Elena %A Hou, Lifang %A Vokonas, Pantel S %A Hernandez, Dena G %A Singleton, Andrew B %A Bandinelli, Stefania %A Turner, Stephen T %A Ware, Erin B %A Smith, Alicia K %A Klengel, Torsten %A Binder, Elisabeth B %A Psaty, Bruce M %A Taylor, Kent D %A Gharib, Sina A %A Swenson, Brenton R %A Liang, Liming %A DeMeo, Dawn L %A O'Connor, George T %A Herceg, Zdenko %A Ressler, Kerry J %A Conneely, Karen N %A Sotoodehnia, Nona %A Kardia, Sharon L R %A Melzer, David %A Baccarelli, Andrea A %A van Meurs, Joyce B J %A Romieu, Isabelle %A Arnett, Donna K %A Ong, Ken K %A Liu, Yongmei %A Waldenberger, Melanie %A Deary, Ian J %A Fornage, Myriam %A Levy, Daniel %A London, Stephanie J %X

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

%B Circ Cardiovasc Genet %V 9 %P 436-447 %8 2016 Oct %G eng %N 5 %R 10.1161/CIRCGENETICS.116.001506 %0 Journal Article %J Stroke %D 2016 %T Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. %A Cheng, Yu-Ching %A Stanne, Tara M %A Giese, Anne-Katrin %A Ho, Weang Kee %A Traylor, Matthew %A Amouyel, Philippe %A Holliday, Elizabeth G %A Malik, Rainer %A Xu, Huichun %A Kittner, Steven J %A Cole, John W %A O'Connell, Jeffrey R %A Danesh, John %A Rasheed, Asif %A Zhao, Wei %A Engelter, Stefan %A Grond-Ginsbach, Caspar %A Kamatani, Yoichiro %A Lathrop, Mark %A Leys, Didier %A Thijs, Vincent %A Metso, Tiina M %A Tatlisumak, Turgut %A Pezzini, Alessandro %A Parati, Eugenio A %A Norrving, Bo %A Bevan, Steve %A Rothwell, Peter M %A Sudlow, Cathie %A Slowik, Agnieszka %A Lindgren, Arne %A Walters, Matthew R %A Jannes, Jim %A Shen, Jess %A Crosslin, David %A Doheny, Kimberly %A Laurie, Cathy C %A Kanse, Sandip M %A Bis, Joshua C %A Fornage, Myriam %A Mosley, Thomas H %A Hopewell, Jemma C %A Strauch, Konstantin %A Müller-Nurasyid, Martina %A Gieger, Christian %A Waldenberger, Melanie %A Peters, Annette %A Meisinger, Christine %A Ikram, M Arfan %A Longstreth, W T %A Meschia, James F %A Seshadri, Sudha %A Sharma, Pankaj %A Worrall, Bradford %A Jern, Christina %A Levi, Christopher %A Dichgans, Martin %A Boncoraglio, Giorgio B %A Markus, Hugh S %A Debette, Stephanie %A Rolfs, Arndt %A Saleheen, Danish %A Mitchell, Braxton D %K Adult %K African Continental Ancestry Group %K Age of Onset %K Aged %K Asian Continental Ancestry Group %K Brain Ischemia %K Chromosomes, Human, Pair 10 %K Computer Simulation %K DNA, Intergenic %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Stroke %X

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.

RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

%B Stroke %V 47 %P 307-16 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract %R 10.1161/STROKEAHA.115.011328 %0 Journal Article %J Hum Mol Genet %D 2016 %T A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. %A de Vries, Paul S %A Chasman, Daniel I %A Sabater-Lleal, Maria %A Chen, Ming-Huei %A Huffman, Jennifer E %A Steri, Maristella %A Tang, Weihong %A Teumer, Alexander %A Marioni, Riccardo E %A Grossmann, Vera %A Hottenga, Jouke J %A Trompet, Stella %A Müller-Nurasyid, Martina %A Zhao, Jing Hua %A Brody, Jennifer A %A Kleber, Marcus E %A Guo, Xiuqing %A Wang, Jie Jin %A Auer, Paul L %A Attia, John R %A Yanek, Lisa R %A Ahluwalia, Tarunveer S %A Lahti, Jari %A Venturini, Cristina %A Tanaka, Toshiko %A Bielak, Lawrence F %A Joshi, Peter K %A Rocanin-Arjo, Ares %A Kolcic, Ivana %A Navarro, Pau %A Rose, Lynda M %A Oldmeadow, Christopher %A Riess, Helene %A Mazur, Johanna %A Basu, Saonli %A Goel, Anuj %A Yang, Qiong %A Ghanbari, Mohsen %A Willemsen, Gonneke %A Rumley, Ann %A Fiorillo, Edoardo %A de Craen, Anton J M %A Grotevendt, Anne %A Scott, Robert %A Taylor, Kent D %A Delgado, Graciela E %A Yao, Jie %A Kifley, Annette %A Kooperberg, Charles %A Qayyum, Rehan %A Lopez, Lorna M %A Berentzen, Tina L %A Räikkönen, Katri %A Mangino, Massimo %A Bandinelli, Stefania %A Peyser, Patricia A %A Wild, Sarah %A Trégouët, David-Alexandre %A Wright, Alan F %A Marten, Jonathan %A Zemunik, Tatijana %A Morrison, Alanna C %A Sennblad, Bengt %A Tofler, Geoffrey %A de Maat, Moniek P M %A de Geus, Eco J C %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Binder, Harald %A Völker, Uwe %A Waldenberger, Melanie %A Khaw, Kay-Tee %A McKnight, Barbara %A Huang, Jie %A Jenny, Nancy S %A Holliday, Elizabeth G %A Qi, Lihong %A Mcevoy, Mark G %A Becker, Diane M %A Starr, John M %A Sarin, Antti-Pekka %A Hysi, Pirro G %A Hernandez, Dena G %A Jhun, Min A %A Campbell, Harry %A Hamsten, Anders %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Koenig, Wolfgang %A Psaty, Bruce M %A Haritunians, Talin %A Liu, Jingmin %A Palotie, Aarno %A Uitterlinden, André G %A Stott, David J %A Hofman, Albert %A Franco, Oscar H %A Polasek, Ozren %A Rudan, Igor %A Morange, Pierre-Emmanuel %A Wilson, James F %A Kardia, Sharon L R %A Ferrucci, Luigi %A Spector, Tim D %A Eriksson, Johan G %A Hansen, Torben %A Deary, Ian J %A Becker, Lewis C %A Scott, Rodney J %A Mitchell, Paul %A März, Winfried %A Wareham, Nick J %A Peters, Annette %A Greinacher, Andreas %A Wild, Philipp S %A Jukema, J Wouter %A Boomsma, Dorret I %A Hayward, Caroline %A Cucca, Francesco %A Tracy, Russell %A Watkins, Hugh %A Reiner, Alex P %A Folsom, Aaron R %A Ridker, Paul M %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

%B Hum Mol Genet %V 25 %P 358-70 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract %R 10.1093/hmg/ddv454 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B J Am Soc Nephrol %8 2016 Dec 05 %G eng %R 10.1681/ASN.2016020131 %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 Genet %D 2017 %T Exome-wide association study of plasma lipids in >300,000 individuals. %A Liu, Dajiang J %A Peloso, Gina M %A Yu, Haojie %A Butterworth, Adam S %A Wang, Xiao %A Mahajan, Anubha %A Saleheen, Danish %A Emdin, Connor %A Alam, Dewan %A Alves, Alexessander Couto %A Amouyel, Philippe %A Di Angelantonio, Emanuele %A Arveiler, Dominique %A Assimes, Themistocles L %A Auer, Paul L %A Baber, Usman %A Ballantyne, Christie M %A Bang, Lia E %A Benn, Marianne %A Bis, Joshua C %A Boehnke, Michael %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brandslund, Ivan %A Brown, Morris %A Busonero, Fabio %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Y Eugene %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Connell, John M %A Cucca, Francesco %A Cupples, L Adrienne %A Damrauer, Scott M %A Davies, Gail %A Deary, Ian J %A Dedoussis, George %A Denny, Joshua C %A Dominiczak, Anna %A Dubé, Marie-Pierre %A Ebeling, Tapani %A Eiriksdottir, Gudny %A Esko, Tõnu %A Farmaki, Aliki-Eleni %A Feitosa, Mary F %A Ferrario, Marco %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frayling, Timothy M %A Frikke-Schmidt, Ruth %A Fritsche, Lars G %A Frossard, Philippe %A Fuster, Valentin %A Ganesh, Santhi K %A Gao, Wei %A Garcia, Melissa E %A Gieger, Christian %A Giulianini, Franco %A Goodarzi, Mark O %A Grallert, Harald %A Grarup, Niels %A Groop, Leif %A Grove, Megan L %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hirschhorn, Joel N %A Holmen, Oddgeir L %A Huffman, Jennifer %A Huo, Yong %A Hveem, Kristian %A Jabeen, Sehrish %A Jackson, Anne U %A Jakobsdottir, Johanna %A Jarvelin, Marjo-Riitta %A Jensen, Gorm B %A Jørgensen, Marit E %A Jukema, J Wouter %A Justesen, Johanne M %A Kamstrup, Pia R %A Kanoni, Stavroula %A Karpe, Fredrik %A Kee, Frank %A Khera, Amit V %A Klarin, Derek %A Koistinen, Heikki A %A Kooner, Jaspal S %A Kooperberg, Charles %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo %A Langenberg, Claudia %A Langsted, Anne %A Launer, Lenore J %A Lauritzen, Torsten %A Liewald, David C M %A Lin, Li An %A Linneberg, Allan %A Loos, Ruth J F %A Lu, Yingchang %A Lu, Xiangfeng %A Mägi, Reedik %A Mälarstig, Anders %A Manichaikul, Ani %A Manning, Alisa K %A Mäntyselkä, Pekka %A Marouli, Eirini %A Masca, Nicholas G D %A Maschio, Andrea %A Meigs, James B %A Melander, Olle %A Metspalu, Andres %A Morris, Andrew P %A Morrison, Alanna C %A Mulas, Antonella %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Neville, Matt J %A Nielsen, Jonas B %A Nielsen, Sune F %A Nordestgaard, Børge G %A Ordovas, Jose M %A Mehran, Roxana %A O'Donnell, Christoper J %A Orho-Melander, Marju %A Molony, Cliona M %A Muntendam, Pieter %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasko, Dorota %A Patel, Aniruddh P %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Pisinger, Charlotta %A Pistis, Giorgio %A Polasek, Ozren %A Poulter, Neil %A Psaty, Bruce M %A Rader, Daniel J %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Rich, Stephen S %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil R %A Roden, Dan M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sanna, Serena %A Sattar, Naveed %A Schmidt, Ellen M %A Scott, Robert A %A Sever, Peter %A Sevilla, Raquel S %A Shaffer, Christian M %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert V %A Smith, Blair H %A Somayajula, Sangeetha %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stirrups, Kathleen E %A Stitziel, Nathan %A Strauch, Konstantin %A Stringham, Heather M %A Surendran, Praveen %A Tada, Hayato %A Tall, Alan R %A Tang, Hua %A Tardif, Jean-Claude %A Taylor, Kent D %A Trompet, Stella %A Tsao, Philip S %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A van Zuydam, Natalie R %A Varbo, Anette %A Varga, Tibor V %A Virtamo, Jarmo %A Waldenberger, Melanie %A Wang, Nan %A Wareham, Nick J %A Warren, Helen R %A Weeke, Peter E %A Weinstock, Joshua %A Wessel, Jennifer %A Wilson, James G %A Wilson, Peter W F %A Xu, Ming %A Yaghootkar, Hanieh %A Young, Robin %A Zeggini, Eleftheria %A Zhang, He %A Zheng, Neil S %A Zhang, Weihua %A Zhang, Yan %A Zhou, Wei %A Zhou, Yanhua %A Zoledziewska, Magdalena %A Howson, Joanna M M %A Danesh, John %A McCarthy, Mark I %A Cowan, Chad A %A Abecasis, Goncalo %A Deloukas, Panos %A Musunuru, Kiran %A Willer, Cristen J %A Kathiresan, Sekar %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Lipids %K Macular Degeneration %K Phenotype %K Risk Factors %X

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

%B Nat Genet %V 49 %P 1758-1766 %8 2017 Dec %G eng %N 12 %R 10.1038/ng.3977 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. %A Christophersen, Ingrid E %A Magnani, Jared W %A Yin, Xiaoyan %A Barnard, John %A Weng, Lu-Chen %A Arking, Dan E %A Niemeijer, Maartje N %A Lubitz, Steven A %A Avery, Christy L %A Duan, Qing %A Felix, Stephan B %A Bis, Joshua C %A Kerr, Kathleen F %A Isaacs, Aaron %A Müller-Nurasyid, Martina %A Müller, Christian %A North, Kari E %A Reiner, Alex P %A Tinker, Lesley F %A Kors, Jan A %A Teumer, Alexander %A Petersmann, Astrid %A Sinner, Moritz F %A Bůzková, Petra %A Smith, Jonathan D %A Van Wagoner, David R %A Völker, Uwe %A Waldenberger, Melanie %A Peters, Annette %A Meitinger, Thomas %A Limacher, Marian C %A Wilhelmsen, Kirk C %A Psaty, Bruce M %A Hofman, Albert %A Uitterlinden, Andre %A Krijthe, Bouwe P %A Zhang, Zhu-Ming %A Schnabel, Renate B %A Kääb, Stefan %A van Duijn, Cornelia %A Rotter, Jerome I %A Sotoodehnia, Nona %A Dörr, Marcus %A Li, Yun %A Chung, Mina K %A Soliman, Elsayed Z %A Alonso, Alvaro %A Whitsel, Eric A %A Stricker, Bruno H %A Benjamin, Emelia J %A Heckbert, Susan R %A Ellinor, Patrick T %K Arrhythmias, Cardiac %K Caveolin 1 %K Caveolin 2 %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Humans %K NAV1.5 Voltage-Gated Sodium Channel %K NAV1.8 Voltage-Gated Sodium Channel %K T-Box Domain Proteins %X

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

%B Circ Cardiovasc Genet %V 10 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001667 %0 Journal Article %J Sci Rep %D 2017 %T Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. %A Weng, Lu-Chen %A Lunetta, Kathryn L %A Müller-Nurasyid, Martina %A Smith, Albert Vernon %A Thériault, Sébastien %A Weeke, Peter E %A Barnard, John %A Bis, Joshua C %A Lyytikäinen, Leo-Pekka %A Kleber, Marcus E %A Martinsson, Andreas %A Lin, Henry J %A Rienstra, Michiel %A Trompet, Stella %A Krijthe, Bouwe P %A Dörr, Marcus %A Klarin, Derek %A Chasman, Daniel I %A Sinner, Moritz F %A Waldenberger, Melanie %A Launer, Lenore J %A Harris, Tamara B %A Soliman, Elsayed Z %A Alonso, Alvaro %A Paré, Guillaume %A Teixeira, Pedro L %A Denny, Joshua C %A Shoemaker, M Benjamin %A Van Wagoner, David R %A Smith, Jonathan D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Taylor, Kent D %A Kähönen, Mika %A Nikus, Kjell %A Delgado, Graciela E %A Melander, Olle %A Engström, Gunnar %A Yao, Jie %A Guo, Xiuqing %A Christophersen, Ingrid E %A Ellinor, Patrick T %A Geelhoed, Bastiaan %A Verweij, Niek %A Macfarlane, Peter %A Ford, Ian %A Heeringa, Jan %A Franco, Oscar H %A Uitterlinden, André G %A Völker, Uwe %A Teumer, Alexander %A Rose, Lynda M %A Kääb, Stefan %A Gudnason, Vilmundur %A Arking, Dan E %A Conen, David %A Roden, Dan M %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Lehtimäki, Terho %A März, Winfried %A Smith, J Gustav %A Rotter, Jerome I %A van der Harst, Pim %A Jukema, J Wouter %A Stricker, Bruno H %A Felix, Stephan B %A Albert, Christine M %A Lubitz, Steven A %X

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

%B Sci Rep %V 7 %P 11303 %8 2017 Sep 12 %G eng %N 1 %R 10.1038/s41598-017-09396-7 %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 Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A März, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %X

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.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %R 10.1038/ng.3843 %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 Blood %D 2018 %T DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis. %A Ward-Caviness, Cavin K %A Huffman, Jennifer E %A Evertt, Karl %A Germain, Marine %A van Dongen, Jenny %A Hill, W David %A Jhun, Min A %A Brody, Jennifer A %A Ghanbari, Mohsen %A Du, Lei %A Roetker, Nicholas S %A de Vries, Paul S %A Waldenberger, Melanie %A Gieger, Christian %A Wolf, Petra %A Prokisch, Holger %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Levy, Daniel %A Liu, Chunyu %A Truong, Vinh %A Wells, Philip S %A Trégouët, David-Alexandre %A Tang, Weihong %A Morrison, Alanna C %A Boerwinkle, Eric %A Wiggins, Kerri L %A McKnight, Barbara %A Guo, Xiuqing %A Psaty, Bruce M %A Sotoodenia, Nona %A Boomsa, Dorret I %A Willemsen, Gonneke %A Ligthart, Lannie %A Deary, Ian J %A Zhao, Wei %A Ware, Erin B %A Kardia, Sharon L R %A van Meurs, Joyce B J %A Uitterlinden, André G %A Franco, Oscar H %A Eriksson, Per %A Franco-Cereceda, Anders %A Pankow, James S %A Johnson, Andrew D %A Gagnon, France %A Morange, Pierre-Emmanuel %A de Geus, Eco J C %A Starr, John M %A Smith, Jennifer A %A Dehghan, Abbas %A Björck, Hanna M %A Smith, Nicholas L %A Peters, Annette %X

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

%B Blood %8 2018 Jul 24 %G eng %R 10.1182/blood-2018-02-831347 %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 Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Boerwinkle, Eric %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Göran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %X

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %R 10.1371/journal.pone.0198166 %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 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J PLoS One %D 2019 %T Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. %A Ward-Caviness, Cavin K %A de Vries, Paul S %A Wiggins, Kerri L %A Huffman, Jennifer E %A Yanek, Lisa R %A Bielak, Lawrence F %A Giulianini, Franco %A Guo, Xiuqing %A Kleber, Marcus E %A Kacprowski, Tim %A Groß, Stefan %A Petersman, Astrid %A Davey Smith, George %A Hartwig, Fernando P %A Bowden, Jack %A Hemani, Gibran %A Müller-Nuraysid, Martina %A Strauch, Konstantin %A Koenig, Wolfgang %A Waldenberger, Melanie %A Meitinger, Thomas %A Pankratz, Nathan %A Boerwinkle, Eric %A Tang, Weihong %A Fu, Yi-Ping %A Johnson, Andrew D %A Song, Ci %A de Maat, Moniek P M %A Uitterlinden, André G %A Franco, Oscar H %A Brody, Jennifer A %A McKnight, Barbara %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Mathias, Rasika A %A Becker, Diane M %A Peyser, Patricia A %A Smith, Jennifer A %A Bielinski, Suzette J %A Ridker, Paul M %A Taylor, Kent D %A Yao, Jie %A Tracy, Russell %A Delgado, Graciela %A Trompet, Stella %A Sattar, Naveed %A Jukema, J Wouter %A Becker, Lewis C %A Kardia, Sharon L R %A Rotter, Jerome I %A März, Winfried %A Dörr, Marcus %A Chasman, Daniel I %A Dehghan, Abbas %A O'Donnell, Christopher J %A Smith, Nicholas L %A Peters, Annette %A Morrison, Alanna C %X

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

%B PLoS One %V 14 %P e0216222 %8 2019 %G eng %N 5 %R 10.1371/journal.pone.0216222 %0 Journal Article %J Am J Epidemiol %D 2019 %T Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. %A de Vries, Paul S %A Brown, Michael R %A Bentley, Amy R %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Schwander, Karen %A Kraja, Aldi T %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Deng, Xuan %A Dorajoo, Rajkumar %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Evangelou, Evangelos %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lee, Joseph H %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Riaz, Muhammad %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Ballantyne, Christie %A Boerwinkle, Eric %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Connell, John M %A de Faire, Ulf %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Ding, Jingzhong %A Dominiczak, Anna F %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Ghanbari, Mohsen %A Giulianini, Franco %A Grabe, Hans J %A Grove, Megan L %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Howard, Barbara V %A Ikram, M Arfan %A Jacobs, David R %A Johnson, Craig %A Jonas, Jost Bruno %A Kammerer, Candace M %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Steve B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lemaitre, Rozenn N %A Li, Yize %A Liang, Jingjing %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Mosley, Thomas H %A Mukamal, Kenneth J %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Sotoodehnia, Nona %A O'Connell, Jeff R %A Palmer, Nicholette D %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Reiner, Alex P %A Rice, Treva K %A Rich, Stephen S %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Blair H %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tan, Nicholas %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A van Heemst, Diana %A Vuckovic, Dragana %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Yujie %A Wang, Zhe %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Penninx, Brenda %A Pereira, Alexandre C %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Zheng, Wei %A Elliott, Paul %A North, Kari E %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Liu, Ching-Ti %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Kardia, Sharon L R %A Zhu, Xiaofeng %A Rotimi, Charles N %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Liu, Jingmin %A Rotter, Jerome I %A Gauderman, W James %A Province, Michael A %A Munroe, Patricia B %A Rice, Kenneth %A Chasman, Daniel I %A Cupples, L Adrienne %A Rao, Dabeeru C %A Morrison, Alanna C %X

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

%B Am J Epidemiol %8 2019 Jan 29 %G eng %R 10.1093/aje/kwz005 %0 Journal Article %J Nat Genet %D 2019 %T Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. %A Bentley, Amy R %A Sung, Yun J %A Brown, Michael R %A Winkler, Thomas W %A Kraja, Aldi T %A Ntalla, Ioanna %A Schwander, Karen %A Chasman, Daniel I %A Lim, Elise %A Deng, Xuan %A Guo, Xiuqing %A Liu, Jingmin %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Baker, Jenna %A Chen, Guanjie %A Aschard, Hugues %A Bartz, Traci M %A Ding, Jingzhong %A Dorajoo, Rajkumar %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Zhao, Wei %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Hung, Yi-Jen %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Leander, Karin %A Lin, Keng-Hung %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Prins, Bram %A Riaz, Muhammad %A Robino, Antonietta %A Said, M Abdullah %A Schupf, Nicole %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Tzung-Dau %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Xiang, Yong-Bing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Adeyemo, Adebowale %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Arzumanyan, Zorayr %A Aung, Tin %A Ballantyne, Christie %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Broeckel, Ulrich %A Brown, Morris %A Cade, Brian E %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Christensen, Kaare %A Concas, Maria Pina %A Connell, John M %A de Las Fuentes, Lisa %A de Silva, H Janaka %A de Vries, Paul S %A Doumatey, Ayo %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Floyd, James S %A Forouhi, Nita G %A Forrester, Terrence %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gharib, Sina A %A Gigante, Bruna %A Giulianini, Franco %A Grabe, Hans J %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Ikram, M Arfan %A Jia, Yucheng %A Joehanes, Roby %A Johnson, Craig %A Jonas, Jost Bruno %A Justice, Anne E %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Liang, Jingjing %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Lohman, Kurt K %A Louie, Tin %A Luzzi, Anna %A Mägi, Reedik %A Mahajan, Anubha %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Morris, Andrew P %A Murray, Alison D %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Papanicolau, George J %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raitakari, Olli T %A Reiner, Alex P %A Renstrom, Frida %A Rice, Treva K %A Rich, Stephen S %A Robinson, Jennifer G %A Rose, Lynda M %A Rosendaal, Frits R %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Tiemeier, Henning %A Turner, Stephen T %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Heming %A Wang, Lan %A Wang, Lihua %A Wei, Wen Bin %A Williams, Christine A %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Young, Kristin %A Yu, Caizheng %A Yuan, Jian-Min %A Zhou, Jie %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Cooper, Richard S %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Juang, Jyh-Ming Jimmy %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Laurie, Cathy C %A Lee, I-Te %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Pereira, Alexandre C %A Rauramaa, Rainer %A Redline, Susan %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Jun-Sing %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zeggini, Eleftheria %A Zheng, Wei %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Province, Michael A %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Franceschini, Nora %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Rao, Dabeeru C %A Rotimi, Charles N %A Cupples, L Adrienne %X

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

%B Nat Genet %V 51 %P 636-648 %8 2019 Apr %G eng %N 4 %R 10.1038/s41588-019-0378-y %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. %A Noordam, Raymond %A Bos, Maxime M %A Wang, Heming %A Winkler, Thomas W %A Bentley, Amy R %A Kilpeläinen, Tuomas O %A de Vries, Paul S %A Sung, Yun Ju %A Schwander, Karen %A Cade, Brian E %A Manning, Alisa %A Aschard, Hugues %A Brown, Michael R %A Chen, Han %A Franceschini, Nora %A Musani, Solomon K %A Richard, Melissa %A Vojinovic, Dina %A Aslibekyan, Stella %A Bartz, Traci M %A de Las Fuentes, Lisa %A Feitosa, Mary %A Horimoto, Andrea R %A Ilkov, Marjan %A Kho, Minjung %A Kraja, Aldi %A Li, Changwei %A Lim, Elise %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Rankinen, Tuomo %A Tajuddin, Salman M %A van der Spek, Ashley %A Wang, Zhe %A Marten, Jonathan %A Laville, Vincent %A Alver, Maris %A Evangelou, Evangelos %A Graff, Maria E %A He, Meian %A Kuhnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Marques-Vidal, Pedro %A Nolte, Ilja M %A Palmer, Nicholette D %A Rauramaa, Rainer %A Shu, Xiao-Ou %A Snieder, Harold %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Adolfo, Correa %A Ballantyne, Christie %A Bielak, Larry %A Biermasz, Nienke R %A Boerwinkle, Eric %A Dimou, Niki %A Eiriksdottir, Gudny %A Gao, Chuan %A Gharib, Sina A %A Gottlieb, Daniel J %A Haba-Rubio, José %A Harris, Tamara B %A Heikkinen, Sami %A Heinzer, Raphael %A Hixson, James E %A Homuth, Georg %A Ikram, M Arfan %A Komulainen, Pirjo %A Krieger, Jose E %A Lee, Jiwon %A Liu, Jingmin %A Lohman, Kurt K %A Luik, Annemarie I %A Mägi, Reedik %A Martin, Lisa W %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Nalls, Mike A %A O'Connell, Jeff %A Peters, Annette %A Peyser, Patricia %A Raitakari, Olli T %A Reiner, Alex P %A Rensen, Patrick C N %A Rice, Treva K %A Rich, Stephen S %A Roenneberg, Till %A Rotter, Jerome I %A Schreiner, Pamela J %A Shikany, James %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Sofer, Tamar %A Strauch, Konstantin %A Swertz, Morris A %A Taylor, Kent D %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Waldenberger, Melanie %A Wallance, Robert B %A van Dijk, Ko Willems %A Yu, Caizheng %A Zonderman, Alan B %A Becker, Diane M %A Elliott, Paul %A Esko, Tõnu %A Gieger, Christian %A Grabe, Hans J %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Penninx, Brenda W J H %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wu, Tangchun %A Xiang, Yong-Bing %A Zheng, Wei %A Arnett, Donna K %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Loos, Ruth J F %A Pereira, Alexandre C %A Province, Mike %A Psaty, Bruce M %A Rotimi, Charles %A Zhu, Xiaofeng %A Amin, Najaf %A Cupples, L Adrienne %A Fornage, Myriam %A Fox, Ervin F %A Guo, Xiuqing %A Gauderman, W James %A Rice, Kenneth %A Kooperberg, Charles %A Munroe, Patricia B %A Liu, Ching-Ti %A Morrison, Alanna C %A Rao, Dabeeru C %A van Heemst, Diana %A Redline, Susan %X

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

%B Nat Commun %V 10 %P 5121 %8 2019 Nov 12 %G eng %N 1 %R 10.1038/s41467-019-12958-0 %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Sung, Yun Ju %A Schwander, Karen %A Winkler, Thomas W %A Jakupović, Hermina %A Chasman, Daniel I %A Manning, Alisa %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Richard, Melissa %A Wang, Heming %A Wang, Zhe %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Lohman, Kurt K %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Zhao, Jing Hua %A Kraja, Aldi T %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Stringham, Heather M %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Ware, Erin B %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Arnett, Donna K %A Boerwinkle, Eric %A Brumat, Marco %A Cade, Brian %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Eaton, Charles B %A Faul, Jessica D %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jonas, Jost B %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Mohlke, Karen L %A Mosley, Thomas H %A Murray, Alison D %A Nalls, Mike A %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A O'Connell, Jeff %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Poveda, Alaitz %A Raitakari, Olli T %A Rich, Stephen S %A Risch, Neil %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Sidney, Stephen S %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A Starr, John M %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Tsai, Michael Y %A Tuomilehto, Jaakko %A Uitterlinden, André G %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Samani, Nilesh J %A Shu, Xiao-Ou %A van der Harst, Pim %A van Vliet-Ostaptchouk, Jana V %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A Weir, David R %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Evans, Michele K %A Franks, Paul W %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Liu, Yongmei %A North, Kari E %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Kardia, Sharon L R %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Redline, Susan %A van Duijn, Cornelia M %A Rotter, Jerome I %A Kooperberg, Charles B %A Gauderman, W James %A Psaty, Bruce M %A Rice, Kenneth %A Munroe, Patricia B %A Fornage, Myriam %A Cupples, L Adrienne %A Rotimi, Charles N %A Morrison, Alanna C %A Rao, Dabeeru C %A Loos, Ruth J F %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic Americans %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Young Adult %X

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

%B Nat Commun %V 10 %P 376 %8 2019 01 22 %G eng %N 1 %R 10.1038/s41467-018-08008-w %0 Journal Article %J Nat Genet %D 2019 %T Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. %A Tin, Adrienne %A Marten, Jonathan %A Halperin Kuhns, Victoria L %A Li, Yong %A Wuttke, Matthias %A Kirsten, Holger %A Sieber, Karsten B %A Qiu, Chengxiang %A Gorski, Mathias %A Yu, Zhi %A Giri, Ayush %A Sveinbjornsson, Gardar %A Li, Man %A Chu, Audrey Y %A Hoppmann, Anselm %A O'Connor, Luke J %A Prins, Bram %A Nutile, Teresa %A Noce, Damia %A Akiyama, Masato %A Cocca, Massimiliano %A Ghasemi, Sahar %A van der Most, Peter J %A Horn, Katrin %A Xu, Yizhe %A Fuchsberger, Christian %A Sedaghat, Sanaz %A Afaq, Saima %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boerwinkle, Eric %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brumat, Marco %A Burkhardt, Ralph %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Ciullo, Marina %A Concas, Maria Pina %A Coresh, Josef %A Corre, Tanguy %A Cusi, Daniele %A Felicita, Sala Cinzia %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Delgado, Graciela %A Demirkan, Ayse %A Devuyst, Olivier %A Dittrich, Katalin %A Eckardt, Kai-Uwe %A Ehret, Georg %A Endlich, Karlhans %A Evans, Michele K %A Gansevoort, Ron T %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hayward, Caroline %A Hicks, Andrew A %A Hofer, Edith %A Holm, Hilma %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Lewis, Raychel M %A Ingelsson, Erik %A Jakobsdottir, Johanna %A Jonsdottir, Ingileif %A Jonsson, Helgi %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerr, Shona M %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A La Bianca, Martina %A Lange, Leslie A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liu, Jun %A Loeffler, Markus %A Loos, Ruth J F %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mahajan, Anubha %A Martin, Nicholas G %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A O'Donnell, Christopher J %A Wilson, Otis D %A Gaziano, J Michael %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Müller-Nurasyid, Martina %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey R %A Olafsson, Isleifur %A Padmanabhan, Sandosh %A Penninx, Brenda W J H %A Perls, Thomas %A Peters, Annette %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Preuss, Michael H %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Robino, Antonietta %A Rudan, Igor %A Krajcoviechova, Alena %A Cifkova, Renata %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Shaffer, Christian M %A Smith, Albert V %A Smith, Blair H %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stumvoll, Michael %A Sulem, Patrick %A Tajuddin, Salman M %A Teren, Andrej %A Thiery, Joachim %A Thio, Chris H L %A Thorsteinsdottir, Unnur %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Uitterlinden, André G %A Vaccargiu, Simona %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Yang, Qiong %A Zhang, Weihua %A Zonderman, Alan B %A Bochud, Murielle %A Wilson, James G %A Pendergrass, Sarah A %A Ho, Kevin %A Parsa, Afshin %A Pramstaller, Peter P %A Psaty, Bruce M %A Böger, Carsten A %A Snieder, Harold %A Butterworth, Adam S %A Okada, Yukinori %A Edwards, Todd L %A Stefansson, Kari %A Susztak, Katalin %A Scholz, Markus %A Heid, Iris M %A Hung, Adriana M %A Teumer, Alexander %A Pattaro, Cristian %A Woodward, Owen M %A Vitart, Veronique %A Köttgen, Anna %X

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

%B Nat Genet %V 51 %P 1459-1474 %8 2019 Oct %G eng %N 10 %R 10.1038/s41588-019-0504-x %0 Journal Article %J Mol Psychiatry %D 2020 %T Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. %A de Las Fuentes, Lisa %A Sung, Yun Ju %A Noordam, Raymond %A Winkler, Thomas %A Feitosa, Mary F %A Schwander, Karen %A Bentley, Amy R %A Brown, Michael R %A Guo, Xiuqing %A Manning, Alisa %A Chasman, Daniel I %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Hartwig, Fernando P %A Horimoto, A R V R %A Li, Changwei %A Li-Gao, Ruifang %A Liu, Yongmei %A Marten, Jonathan %A Musani, Solomon K %A Ntalla, Ioanna %A Rankinen, Tuomo %A Richard, Melissa %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Tayo, Bamidele O %A Vojinovic, Dina %A Warren, Helen R %A Xuan, Deng %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin-Fang %A Chen, Xu %A Christensen, Kaare %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Girotto, Giorgia %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kuhnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Rueedi, Rico %A Shu, Xiao-Ou %A Snieder, Harold %A Sofer, Tamar %A Takeuchi, Fumihiko %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Yanek, Lisa R %A Amin, Najaf %A Arking, Dan E %A Arnett, Donna K %A Bergmann, Sven %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Brumat, Marco %A Burke, Gregory %A Cabrera, Claudia P %A Canouil, Mickaël %A Chee, Miao Li %A Chen, Yii-Der Ida %A Cocca, Massimiliano %A Connell, John %A de Silva, H Janaka %A de Vries, Paul S %A Eiriksdottir, Gudny %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Fox, Ervin F %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven %A Ikram, M Arfan %A Irvin, Marguerite R %A Kähönen, Mika %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Kraja, Aldi T %A Krieger, J E %A Langefeld, Carl D %A Li, Yize %A Liang, Jingjing %A Liewald, David C M %A Liu, Ching-Ti %A Liu, Jianjun %A Lohman, Kurt K %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mook-Kanamori, Dennis O %A Nalls, Mike A %A Nelson, Christopher P %A Norris, Jill M %A O'Connell, Jeff %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Pedersen, Nancy L %A Perls, Thomas %A Peters, Annette %A Petersmann, Astrid %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Raffel, Leslie J %A Rice, Treva K %A Rotter, Jerome I %A Rudan, Igor %A Rueda-Ochoa, Oscar-Leonel %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Schreiner, Pamela J %A Shikany, James M %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Swertz, Morris A %A Teumer, Alexander %A Tham, Yih Chung %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Ende, M Yldau %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya-Xing %A Wei, Wen-Bin %A Weir, David R %A Wen, Wanqing %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Bowden, Donald W %A Deary, Ian J %A Dörr, Marcus %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kammerer, Candace M %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Marques-Vidal, Pedro %A Penninx, Brenda W J H %A Samani, Nilesh J %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Cooper, Richard S %A Correa, Adolfo %A Evans, Michele K %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Levy, Daniel %A Palmas, Walter R %A Pereira, A C %A Province, Michael M %A Psaty, Bruce M %A Ridker, Paul M %A Rotimi, Charles N %A Tai, E Shyong %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Rice, Kenneth %A Gauderman, W James %A Morrison, Alanna C %A North, Kari E %A Kardia, Sharon L R %A Caulfield, Mark J %A Elliott, Paul %A Munroe, Patricia B %A Franks, Paul W %A Rao, Dabeeru C %A Fornage, Myriam %X

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

%B Mol Psychiatry %8 2020 May 05 %G eng %R 10.1038/s41380-020-0719-3 %0 Journal Article %J Kidney Int %D 2020 %T Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. %A Gorski, Mathias %A Jung, Bettina %A Li, Yong %A Matias-Garcia, Pamela R %A Wuttke, Matthias %A Coassin, Stefan %A Thio, Chris H L %A Kleber, Marcus E %A Winkler, Thomas W %A Wanner, Veronika %A Chai, Jin-Fang %A Chu, Audrey Y %A Cocca, Massimiliano %A Feitosa, Mary F %A Ghasemi, Sahar %A Hoppmann, Anselm %A Horn, Katrin %A Li, Man %A Nutile, Teresa %A Scholz, Markus %A Sieber, Karsten B %A Teumer, Alexander %A Tin, Adrienne %A Wang, Judy %A Tayo, Bamidele O %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Carroll, Robert J %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Coresh, Josef %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Franke, Andre %A Freitag-Wolf, Sandra %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Gieger, Christian %A Hamet, Pavel %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Xian Foo, Valencia Hui %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Kähönen, Mika %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Lange, Leslie A %A Lehtimäki, Terho %A Lieb, Wolfgang %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A O'Donoghue, Michelle L %A Orho-Melander, Marju %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Sabanayagam, Charumathi %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Strauch, Konstantin %A Szymczak, Silke %A Taylor, Kent D %A Tremblay, Johanne %A Chaker, Layal %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Waldenberger, Melanie %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Yan %A Snieder, Harold %A Wanner, Christoph %A Böger, Carsten A %A Köttgen, Anna %A Kronenberg, Florian %A Pattaro, Cristian %A Heid, Iris M %X

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

%B Kidney Int %8 2020 Oct 30 %G eng %R 10.1016/j.kint.2020.09.030 %0 Journal Article %J Nat Commun %D 2020 %T Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. %A Ntalla, Ioanna %A Weng, Lu-Chen %A Cartwright, James H %A Hall, Amelia Weber %A Sveinbjornsson, Gardar %A Tucker, Nathan R %A Choi, Seung Hoan %A Chaffin, Mark D %A Roselli, Carolina %A Barnes, Michael R %A Mifsud, Borbala %A Warren, Helen R %A Hayward, Caroline %A Marten, Jonathan %A Cranley, James J %A Concas, Maria Pina %A Gasparini, Paolo %A Boutin, Thibaud %A Kolcic, Ivana %A Polasek, Ozren %A Rudan, Igor %A Araujo, Nathalia M %A Lima-Costa, Maria Fernanda %A Ribeiro, Antonio Luiz P %A Souza, Renan P %A Tarazona-Santos, Eduardo %A Giedraitis, Vilmantas %A Ingelsson, Erik %A Mahajan, Anubha %A Morris, Andrew P %A del Greco M, Fabiola %A Foco, Luisa %A Gögele, Martin %A Hicks, Andrew A %A Cook, James P %A Lind, Lars %A Lindgren, Cecilia M %A Sundström, Johan %A Nelson, Christopher P %A Riaz, Muhammad B %A Samani, Nilesh J %A Sinagra, Gianfranco %A Ulivi, Sheila %A Kähönen, Mika %A Mishra, Pashupati P %A Mononen, Nina %A Nikus, Kjell %A Caulfield, Mark J %A Dominiczak, Anna %A Padmanabhan, Sandosh %A Montasser, May E %A O'Connell, Jeff R %A Ryan, Kathleen %A Shuldiner, Alan R %A Aeschbacher, Stefanie %A Conen, David %A Risch, Lorenz %A Thériault, Sébastien %A Hutri-Kähönen, Nina %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Raitakari, Olli T %A Barnes, Catriona L K %A Campbell, Harry %A Joshi, Peter K %A Wilson, James F %A Isaacs, Aaron %A Kors, Jan A %A van Duijn, Cornelia M %A Huang, Paul L %A Gudnason, Vilmundur %A Harris, Tamara B %A Launer, Lenore J %A Smith, Albert V %A Bottinger, Erwin P %A Loos, Ruth J F %A Nadkarni, Girish N %A Preuss, Michael H %A Correa, Adolfo %A Mei, Hao %A Wilson, James %A Meitinger, Thomas %A Müller-Nurasyid, Martina %A Peters, Annette %A Waldenberger, Melanie %A Mangino, Massimo %A Spector, Timothy D %A Rienstra, Michiel %A van de Vegte, Yordi J %A van der Harst, Pim %A Verweij, Niek %A Kääb, Stefan %A Schramm, Katharina %A Sinner, Moritz F %A Strauch, Konstantin %A Cutler, Michael J %A Fatkin, Diane %A London, Barry %A Olesen, Morten %A Roden, Dan M %A Benjamin Shoemaker, M %A Gustav Smith, J %A Biggs, Mary L %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Rice, Kenneth %A Sotoodehnia, Nona %A De Grandi, Alessandro %A Fuchsberger, Christian %A Pattaro, Cristian %A Pramstaller, Peter P %A Ford, Ian %A Wouter Jukema, J %A Macfarlane, Peter W %A Trompet, Stella %A Dörr, Marcus %A Felix, Stephan B %A Völker, Uwe %A Weiss, Stefan %A Havulinna, Aki S %A Jula, Antti %A Sääksjärvi, Katri %A Salomaa, Veikko %A Guo, Xiuqing %A Heckbert, Susan R %A Lin, Henry J %A Rotter, Jerome I %A Taylor, Kent D %A Yao, Jie %A de Mutsert, Renée %A Maan, Arie C %A Mook-Kanamori, Dennis O %A Noordam, Raymond %A Cucca, Francesco %A Ding, Jun %A Lakatta, Edward G %A Qian, Yong %A Tarasov, Kirill V %A Levy, Daniel %A Lin, Honghuang %A Newton-Cheh, Christopher H %A Lunetta, Kathryn L %A Murray, Alison D %A Porteous, David J %A Smith, Blair H %A Stricker, Bruno H %A Uitterlinden, Andre %A van den Berg, Marten E %A Haessler, Jeffrey %A Jackson, Rebecca D %A Kooperberg, Charles %A Peters, Ulrike %A Reiner, Alexander P %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Boerwinkle, Eric %A Ehret, Georg B %A Soliman, Elsayed Z %A Avery, Christy L %A Gogarten, Stephanie M %A Kerr, Kathleen F %A Laurie, Cathy C %A Seyerle, Amanda A %A Stilp, Adrienne %A Assa, Solmaz %A Abdullah Said, M %A Yldau van der Ende, M %A Lambiase, Pier D %A Orini, Michele %A Ramirez, Julia %A Van Duijvenboden, Stefan %A Arnar, David O %A Gudbjartsson, Daniel F %A Holm, Hilma %A Sulem, Patrick %A Thorleifsson, Gudmar %A Thorolfsdottir, Rosa B %A Thorsteinsdottir, Unnur %A Benjamin, Emelia J %A Tinker, Andrew %A Stefansson, Kari %A Ellinor, Patrick T %A Jamshidi, Yalda %A Lubitz, Steven A %A Munroe, Patricia B %X

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.

%B Nat Commun %V 11 %P 2542 %8 2020 May 21 %G eng %N 1 %R 10.1038/s41467-020-15706-x %0 Journal Article %J Circ Genom Precis Med %D 2020 %T Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. %A Ma, Jiantao %A Rebholz, Casey M %A Braun, Kim V E %A Reynolds, Lindsay M %A Aslibekyan, Stella %A Xia, Rui %A Biligowda, Niranjan G %A Huan, Tianxiao %A Liu, Chunyu %A Mendelson, Michael M %A Joehanes, Roby %A Hu, Emily A %A Vitolins, Mara Z %A Wood, Alexis C %A Lohman, Kurt %A Ochoa-Rosales, Carolina %A van Meurs, Joyce %A Uitterlinden, Andre %A Liu, Yongmei %A Elhadad, Mohamed A %A Heier, Margit %A Waldenberger, Melanie %A Peters, Annette %A Colicino, Elena %A Whitsel, Eric A %A Baldassari, Antoine %A Gharib, Sina A %A Sotoodehnia, Nona %A Brody, Jennifer A %A Sitlani, Colleen M %A Tanaka, Toshiko %A Hill, W David %A Corley, Janie %A Deary, Ian J %A Zhang, Yan %A Schöttker, Ben %A Brenner, Hermann %A Walker, Maura E %A Ye, Shumao %A Nguyen, Steve %A Pankow, Jim %A Demerath, Ellen W %A Zheng, Yinan %A Hou, Lifang %A Liang, Liming %A Lichtenstein, Alice H %A Hu, Frank B %A Fornage, Myriam %A Voortman, Trudy %A Levy, Daniel %X

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.

METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).

CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

%B Circ Genom Precis Med %V 13 %P e002766 %8 2020 Aug %G eng %N 4 %R 10.1161/CIRCGEN.119.002766 %0 Journal Article %J Nat Commun %D 2021 %T Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. %A Tin, Adrienne %A Schlosser, Pascal %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Yu, Zhi %A Weihs, Antoine %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Kuhns, Victoria L Halperin %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Bressler, Jan %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A Delgado, Graciela E %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Floyd, James S %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Gelber, Allan C %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kronenberg, Florian %A Kuhnel, Brigitte %A Ladd-Acosta, Christine %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Lloyd-Jones, Donald M %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Völker, Uwe %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Waldenberger, Melanie %A Levy, Daniel %A Akilesh, Shreeram %A Woodward, Owen M %A Susztak, Katalin %A Teumer, Alexander %A Köttgen, Anna %K Amino Acid Transport System y+ %K Cohort Studies %K CpG Islands %K DNA Methylation %K Epigenome %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Transport Proteins, Facilitative %K Gout %K Humans %K Male %K Uric Acid %X

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

%B Nat Commun %V 12 %P 7173 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27198-4 %0 Journal Article %J Nat Commun %D 2021 %T Meta-analyses identify DNA methylation associated with kidney function and damage. %A Schlosser, Pascal %A Tin, Adrienne %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Weihs, Antoine %A Yu, Zhi %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Chambers, John C %A Cole, Shelley A %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A de Klein, Niek %A Delgado, Graciela E %A Domingo-Relloso, Arce %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Evans, Kathryn L %A Floyd, James S %A Fornage, Myriam %A Franke, Lude %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Jarvelin, Marjo-Riitta %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kramer, Holly %A Kronenberg, Florian %A Kuhnel, Brigitte %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Liu, Yongmei %A Lloyd-Jones, Donald M %A Lohman, Kurt %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Navas-Acien, Ana %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Rosas, Sylvia E %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A Tellez-Plaza, Maria %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Verweij, Niek %A Walker, Rosie M %A Wielscher, Matthias %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Levy, Daniel %A Waldenberger, Melanie %A Susztak, Katalin %A Köttgen, Anna %A Teumer, Alexander %K Adult %K Aged %K CpG Islands %K DNA Methylation %K Female %K Glomerular Filtration Rate %K Humans %K Interferon Regulatory Factors %K Kidney %K Kidney Function Tests %K LIM Domain Proteins %K Male %K Membrane Proteins %K Middle Aged %K Renal Insufficiency, Chronic %K Transcription Factors %X

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

%B Nat Commun %V 12 %P 7174 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27234-3 %0 Journal Article %J Eur J Epidemiol %D 2021 %T Meta-analysis of epigenome-wide association studies of carotid intima-media thickness. %A Portilla-Fernández, Eliana %A Hwang, Shih-Jen %A Wilson, Rory %A Maddock, Jane %A Hill, W David %A Teumer, Alexander %A Mishra, Pashupati P %A Brody, Jennifer A %A Joehanes, Roby %A Ligthart, Symen %A Ghanbari, Mohsen %A Kavousi, Maryam %A Roks, Anton J M %A Danser, A H Jan %A Levy, Daniel %A Peters, Annette %A Ghasemi, Sahar %A Schminke, Ulf %A Dörr, Marcus %A Grabe, Hans J %A Lehtimäki, Terho %A Kähönen, Mika %A Hurme, Mikko A %A Bartz, Traci M %A Sotoodehnia, Nona %A Bis, Joshua C %A Thiery, Joachim %A Koenig, Wolfgang %A Ong, Ken K %A Bell, Jordana T %A Meisinger, Christine %A Wardlaw, Joanna M %A Starr, John M %A Seissler, Jochen %A Then, Cornelia %A Rathmann, Wolfgang %A Ikram, M Arfan %A Psaty, Bruce M %A Raitakari, Olli T %A Völzke, Henry %A Deary, Ian J %A Wong, Andrew %A Waldenberger, Melanie %A O'Donnell, Christopher J %A Dehghan, Abbas %X

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

%B Eur J Epidemiol %8 2021 Jun 06 %G eng %R 10.1007/s10654-021-00759-z %0 Journal Article %J HGG Adv %D 2021 %T Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. %A Sun, Daokun %A Richard, Melissa %A Musani, Solomon K %A Sung, Yun Ju %A Winkler, Thomas W %A Schwander, Karen %A Chai, Jin Fang %A Guo, Xiuqing %A Kilpeläinen, Tuomas O %A Vojinovic, Dina %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Brown, Michael R %A Chitrala, Kumaraswamy %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Liu, Yongmei %A Manning, Alisa K %A Noordam, Raymond %A Smith, Albert V %A Harris, Sarah E %A Kuhnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A van der Most, Peter J %A Wang, Rujia %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Arking, Dan E %A Arnett, Donna K %A Barac, Ana %A Boerwinkle, Eric %A Broeckel, Ulrich %A Chakravarti, Aravinda %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A Davigulus, Martha L %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Vries, Paul S %A Delaney, Joseph A C %A Roux, Ana V Diez %A Dörr, Marcus %A Faul, Jessica D %A Fretts, Amanda M %A Gallo, Linda C %A Grabe, Hans Jörgen %A Gu, C Charles %A Harris, Tamara B %A Hartman, Catharina C A %A Heikkinen, Sami %A Ikram, M Arfan %A Isasi, Carmen %A Johnson, W Craig %A Jonas, Jost Bruno %A Kaplan, Robert C %A Komulainen, Pirjo %A Krieger, Jose E %A Levy, Daniel %A Liu, Jianjun %A Lohman, Kurt %A Luik, Annemarie I %A Martin, Lisa W %A Meitinger, Thomas %A Milaneschi, Yuri %A O'Connell, Jeff R %A Palmas, Walter R %A Peters, Annette %A Peyser, Patricia A %A Pulkki-Råback, Laura %A Raffel, Leslie J %A Reiner, Alex P %A Rice, Kenneth %A Robinson, Jennifer G %A Rosendaal, Frits R %A Schmidt, Carsten Oliver %A Schreiner, Pamela J %A Schwettmann, Lars %A Shikany, James M %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Sotoodehnia, Nona %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent %A Uitterlinden, André G %A van Duijn, Cornelia M %A Waldenberger, Melanie %A Wee, Hwee-Lin %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Zeng, Donglin %A Zhao, Wei %A Zhu, Xiaofeng %A Zonderman, Alan B %A Becker, Diane M %A Deary, Ian J %A Gieger, Christian %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Snieder, Harold %A Wang, Ya-Xing %A Weir, David R %A Zheng, Wei %A Evans, Michele K %A Gauderman, W James %A Gudnason, Vilmundur %A Horta, Bernardo L %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Morrison, Alanna C %A Pereira, Alexandre C %A Psaty, Bruce M %A Amin, Najaf %A Fox, Ervin R %A Kooperberg, Charles %A Sim, Xueling %A Bierut, Laura %A Rotter, Jerome I %A Kardia, Sharon L R %A Franceschini, Nora %A Rao, Dabeeru C %A Fornage, Myriam %X

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

%B HGG Adv %V 2 %8 2021 Jan 14 %G eng %N 1 %R 10.1016/j.xhgg.2020.100013 %0 Journal Article %J Mol Psychiatry %D 2021 %T Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. %A Wang, Heming %A Noordam, Raymond %A Cade, Brian E %A Schwander, Karen %A Winkler, Thomas W %A Lee, Jiwon %A Sung, Yun Ju %A Bentley, Amy R %A Manning, Alisa K %A Aschard, Hugues %A Kilpeläinen, Tuomas O %A Ilkov, Marjan %A Brown, Michael R %A Horimoto, Andrea R %A Richard, Melissa %A Bartz, Traci M %A Vojinovic, Dina %A Lim, Elise %A Nierenberg, Jovia L %A Liu, Yongmei %A Chitrala, Kumaraswamynaidu %A Rankinen, Tuomo %A Musani, Solomon K %A Franceschini, Nora %A Rauramaa, Rainer %A Alver, Maris %A Zee, Phyllis C %A Harris, Sarah E %A van der Most, Peter J %A Nolte, Ilja M %A Munroe, Patricia B %A Palmer, Nicholette D %A Kuhnel, Brigitte %A Weiss, Stefan %A Wen, Wanqing %A Hall, Kelly A %A Lyytikäinen, Leo-Pekka %A O'Connell, Jeff %A Eiriksdottir, Gudny %A Launer, Lenore J %A de Vries, Paul S %A Arking, Dan E %A Chen, Han %A Boerwinkle, Eric %A Krieger, Jose E %A Schreiner, Pamela J %A Sidney, Stephen %A Shikany, James M %A Rice, Kenneth %A Chen, Yii-Der Ida %A Gharib, Sina A %A Bis, Joshua C %A Luik, Annemarie I %A Ikram, M Arfan %A Uitterlinden, André G %A Amin, Najaf %A Xu, Hanfei %A Levy, Daniel %A He, Jiang %A Lohman, Kurt K %A Zonderman, Alan B %A Rice, Treva K %A Sims, Mario %A Wilson, Gregory %A Sofer, Tamar %A Rich, Stephen S %A Palmas, Walter %A Yao, Jie %A Guo, Xiuqing %A Rotter, Jerome I %A Biermasz, Nienke R %A Mook-Kanamori, Dennis O %A Martin, Lisa W %A Barac, Ana %A Wallace, Robert B %A Gottlieb, Daniel J %A Komulainen, Pirjo %A Heikkinen, Sami %A Mägi, Reedik %A Milani, Lili %A Metspalu, Andres %A Starr, John M %A Milaneschi, Yuri %A Waken, R J %A Gao, Chuan %A Waldenberger, Melanie %A Peters, Annette %A Strauch, Konstantin %A Meitinger, Thomas %A Roenneberg, Till %A Völker, Uwe %A Dörr, Marcus %A Shu, Xiao-Ou %A Mukherjee, Sutapa %A Hillman, David R %A Kähönen, Mika %A Wagenknecht, Lynne E %A Gieger, Christian %A Grabe, Hans J %A Zheng, Wei %A Palmer, Lyle J %A Lehtimäki, Terho %A Gudnason, Vilmundur %A Morrison, Alanna C %A Pereira, Alexandre C %A Fornage, Myriam %A Psaty, Bruce M %A van Duijn, Cornelia M %A Liu, Ching-Ti %A Kelly, Tanika N %A Evans, Michele K %A Bouchard, Claude %A Fox, Ervin R %A Kooperberg, Charles %A Zhu, Xiaofeng %A Lakka, Timo A %A Esko, Tõnu %A North, Kari E %A Deary, Ian J %A Snieder, Harold %A Penninx, Brenda W J H %A Gauderman, W James %A Rao, Dabeeru C %A Redline, Susan %A van Heemst, Diana %X

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

%B Mol Psychiatry %8 2021 Apr 15 %G eng %R 10.1038/s41380-021-01087-0 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z %0 Journal Article %J Kidney Int %D 2022 %T Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. %A Gorski, Mathias %A Rasheed, Humaira %A Teumer, Alexander %A Thomas, Laurent F %A Graham, Sarah E %A Sveinbjornsson, Gardar %A Winkler, Thomas W %A Günther, Felix %A Stark, Klaus J %A Chai, Jin-Fang %A Tayo, Bamidele O %A Wuttke, Matthias %A Li, Yong %A Tin, Adrienne %A Ahluwalia, Tarunveer S %A Arnlöv, Johan %A Åsvold, Bjørn Olav %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Biino, Ginevra %A Böhnke, Michael %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Brumpton, Ben %A Carroll, Robert J %A Chaker, Layal %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Chu, Audrey Y %A Ciullo, Marina %A Cocca, Massimiliano %A Cook, James P %A Coresh, Josef %A Cusi, Daniele %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Evans, Michele K %A Feitosa, Mary F %A Franke, Andre %A Freitag-Wolf, Sandra %A Fuchsberger, Christian %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Giedraitis, Vilmantas %A Gieger, Christian %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hishida, Asahi %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Holm, Hilma %A Hoppmann, Anselm %A Horn, Katrin %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Karabegović, Irma %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Laakso, Markku %A Lange, Leslie A %A Lehtimäki, Terho %A Li, Man %A Lieb, Wolfgang %A Lind, Lars %A Lindgren, Cecilia M %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Matias-Garcia, Pamela R %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Morris, Andrew P %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Naito, Mariko %A Nakatochi, Masahiro %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Nutile, Teresa %A O'Donoghue, Michelle L %A O'Connell, Jeffrey %A Olafsson, Isleifur %A Orho-Melander, Marju %A Parsa, Afshin %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Pirastu, Mario %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Ruggiero, Daniela %A Ryan, Kathleen A %A Sabanayagam, Charumathi %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Scholz, Markus %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Sieber, Karsten B %A Sim, Xueling %A Sims, Mario %A Snieder, Harold %A Stanzick, Kira J %A Thorsteinsdottir, Unnur %A Stocker, Hannah %A Strauch, Konstantin %A Stringham, Heather M %A Sulem, Patrick %A Szymczak, Silke %A Taylor, Kent D %A Thio, Chris H L %A Tremblay, Johanne %A Vaccargiu, Simona %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Wakai, Kenji %A Waldenberger, Melanie %A Wallentin, Lars %A Wallner, Stefan %A Wang, Judy %A Waterworth, Dawn M %A White, Harvey D %A Willer, Cristen J %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yerges-Armstrong, Laura M %A Zimmermann, Martina %A Zonderman, Alan B %A Bergler, Tobias %A Stefansson, Kari %A Böger, Carsten A %A Pattaro, Cristian %A Köttgen, Anna %A Kronenberg, Florian %A Heid, Iris M %X

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

%B Kidney Int %8 2022 Jun 16 %G eng %R 10.1016/j.kint.2022.05.021 %0 Journal Article %J Aging Cell %D 2022 %T Integrative analysis of clinical and epigenetic biomarkers of mortality. %A Huan, Tianxiao %A Nguyen, Steve %A Colicino, Elena %A Ochoa-Rosales, Carolina %A Hill, W David %A Brody, Jennifer A %A Soerensen, Mette %A Zhang, Yan %A Baldassari, Antoine %A Elhadad, Mohamed Ahmed %A Toshiko, Tanaka %A Zheng, Yinan %A Domingo-Relloso, Arce %A Lee, Dong Heon %A Ma, Jiantao %A Yao, Chen %A Liu, Chunyu %A Hwang, Shih-Jen %A Joehanes, Roby %A Fornage, Myriam %A Bressler, Jan %A van Meurs, Joyce B J %A Debrabant, Birgit %A Mengel-From, Jonas %A Hjelmborg, Jacob %A Christensen, Kaare %A Vokonas, Pantel %A Schwartz, Joel %A Gahrib, Sina A %A Sotoodehnia, Nona %A Sitlani, Colleen M %A Kunze, Sonja %A Gieger, Christian %A Peters, Annette %A Waldenberger, Melanie %A Deary, Ian J %A Ferrucci, Luigi %A Qu, Yishu %A Greenland, Philip %A Lloyd-Jones, Donald M %A Hou, Lifang %A Bandinelli, Stefania %A Voortman, Trudy %A Hermann, Brenner %A Baccarelli, Andrea %A Whitsel, Eric %A Pankow, James S %A Levy, Daniel %K Biomarkers %K Cardiovascular Diseases %K DNA Methylation %K Epigenesis, Genetic %K Epigenomics %K Humans %K Male %K Neoplasms %X

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P  = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

%B Aging Cell %V 21 %P e13608 %8 2022 Jun %G eng %N 6 %R 10.1111/acel.13608 %0 Journal Article %J Front Genet %D 2023 %T Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. %A de Las Fuentes, Lisa %A Schwander, Karen L %A Brown, Michael R %A Bentley, Amy R %A Winkler, Thomas W %A Sung, Yun Ju %A Munroe, Patricia B %A Miller, Clint L %A Aschard, Hugo %A Aslibekyan, Stella %A Bartz, Traci M %A Bielak, Lawrence F %A Chai, Jin Fang %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Feitosa, Mary F %A Guo, Xiuqing %A Hartwig, Fernando P %A Horimoto, Andrea %A Kolcic, Ivana %A Lim, Elise %A Liu, Yongmei %A Manning, Alisa K %A Marten, Jonathan %A Musani, Solomon K %A Noordam, Raymond %A Padmanabhan, Sandosh %A Rankinen, Tuomo %A Richard, Melissa A %A Ridker, Paul M %A Smith, Albert V %A Vojinovic, Dina %A Zonderman, Alan B %A Alver, Maris %A Boissel, Mathilde %A Christensen, Kaare %A Freedman, Barry I %A Gao, Chuan %A Giulianini, Franco %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kuhnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Sofer, Tamar %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhan, Yiqiang %A Amin, Najaf %A Arking, Dan E %A Ballantyne, Christie %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Chai, Xiaoran %A Chen, Yii-Der Ida %A Chen, Xu %A Chitrala, Kumaraswamy Naidu %A Concas, Maria Pina %A de Faire, Ulf %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Do, Ahn %A Faul, Jessica D %A Fisher, Virginia %A Floyd, James S %A Forrester, Terrence %A Friedlander, Yechiel %A Girotto, Giorgia %A Gu, C Charles %A Hallmans, Göran %A Heikkinen, Sami %A Heng, Chew-Kiat %A Homuth, Georg %A Hunt, Steven %A Ikram, M Arfan %A Jacobs, David R %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Langefeld, Carl D %A Liang, Jingjing %A Liu, Kiang %A Liu, Jianjun %A Lohman, Kurt %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Milaneschi, Yuri %A Nauck, Matthias %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pereira, Alexandre C %A Perls, Thomas %A Peters, Annette %A Polasek, Ozren %A Raitakari, Olli T %A Rice, Kenneth %A Rice, Treva K %A Rich, Stephen S %A Sabanayagam, Charumathi %A Schreiner, Pamela J %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent D %A Tsai, Michael Y %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Ya-Xing %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Becker, Diane M %A Bonnefond, Amélie %A Bowden, Donald W %A Cooper, Richard S %A Deary, Ian J %A Divers, Jasmin %A Esko, Tõnu %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Jonas, Jost B %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A North, Kari E %A Ntalla, Ioanna %A Penninx, Brenda %A Samani, Nilesh J %A Snieder, Harold %A Spedicati, Beatrice %A van der Harst, Pim %A Völzke, Henry %A Wagenknecht, Lynne E %A Weir, David R %A Wojczynski, Mary K %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Chasman, Daniel I %A Evans, Michele K %A Fox, Ervin R %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kardia, Sharon L R %A Krieger, Jose Eduardo %A Mook-Kanamori, Dennis O %A Peyser, Patricia A %A Province, Michael M %A Psaty, Bruce M %A Rudan, Igor %A Sim, Xueling %A Smith, Blair H %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Arnett, Donna K %A Rao, Dabeeru C %A Gauderman, James %A Liu, Ching-Ti %A Morrison, Alanna C %A Rotter, Jerome I %A Fornage, Myriam %X

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

%B Front Genet %V 14 %P 1235337 %8 2023 %G eng %R 10.3389/fgene.2023.1235337