@article {1108, title = {Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.}, journal = {JAMA}, volume = {302}, year = {2009}, month = {2009 Jul 08}, pages = {168-78}, abstract = {

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55\% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1\% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1\%-3\% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

}, keywords = {Adult, Aged, Aged, 80 and over, Aorta, Cardiovascular Diseases, Echocardiography, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Atria, Heart Ventricles, Humans, Male, Middle Aged, Organ Size, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1538-3598}, doi = {10.1001/jama.2009.978-a}, author = {Vasan, Ramachandran S and Glazer, Nicole L and Felix, Janine F and Lieb, Wolfgang and Wild, Philipp S and Felix, Stephan B and Watzinger, Norbert and Larson, Martin G and Smith, Nicholas L and Dehghan, Abbas and Grosshennig, Anika and Schillert, Arne and Teumer, Alexander and Schmidt, Reinhold and Kathiresan, Sekar and Lumley, Thomas and Aulchenko, Yurii S and K{\"o}nig, Inke R and Zeller, Tanja and Homuth, Georg and Struchalin, Maksim and Aragam, Jayashri and Bis, Joshua C and Rivadeneira, Fernando and Erdmann, Jeanette and Schnabel, Renate B and D{\"o}rr, Marcus and Zweiker, Robert and Lind, Lars and Rodeheffer, Richard J and Greiser, Karin Halina and Levy, Daniel and Haritunians, Talin and Deckers, Jaap W and Stritzke, Jan and Lackner, Karl J and V{\"o}lker, Uwe and Ingelsson, Erik and Kullo, Iftikhar and Haerting, Johannes and O{\textquoteright}Donnell, Christopher J and Heckbert, Susan R and Stricker, Bruno H and Ziegler, Andreas and Reffelmann, Thorsten and Redfield, Margaret M and Werdan, Karl and Mitchell, Gary F and Rice, Kenneth and Arnett, Donna K and Hofman, Albert and Gottdiener, John S and Uitterlinden, Andr{\'e} G and Meitinger, Thomas and Blettner, Maria and Friedrich, Nele and Wang, Thomas J and Psaty, Bruce M and van Duijn, Cornelia M and Wichmann, H-Erich and Munzel, Thomas F and Kroemer, Heyo K and Benjamin, Emelia J and Rotter, Jerome I and Witteman, Jacqueline C and Schunkert, Heribert and Schmidt, Helena and V{\"o}lzke, Henry and Blankenberg, Stefan} } @article {1244, title = {Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Dec}, pages = {1068-76}, abstract = {

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 {\texttimes} 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

}, keywords = {Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.716}, author = {Sotoodehnia, Nona and Isaacs, Aaron and de Bakker, Paul I W and D{\"o}rr, Marcus and Newton-Cheh, Christopher and Nolte, Ilja M and van der Harst, Pim and M{\"u}ller, Martina and Eijgelsheim, Mark and Alonso, Alvaro and Hicks, Andrew A and Padmanabhan, Sandosh and Hayward, Caroline and Smith, Albert Vernon and Polasek, Ozren and Giovannone, Steven and Fu, Jingyuan and Magnani, Jared W and Marciante, Kristin D and Pfeufer, Arne and Gharib, Sina A and Teumer, Alexander and Li, Man and Bis, Joshua C and Rivadeneira, Fernando and Aspelund, Thor and K{\"o}ttgen, Anna and Johnson, Toby and Rice, Kenneth and Sie, Mark P S and Wang, Ying A and Klopp, Norman and Fuchsberger, Christian and Wild, Sarah H and Mateo Leach, Irene and Estrada, Karol and V{\"o}lker, Uwe and Wright, Alan F and Asselbergs, Folkert W and Qu, Jiaxiang and Chakravarti, Aravinda and Sinner, Moritz F and Kors, Jan A and Petersmann, Astrid and Harris, Tamara B and Soliman, Elsayed Z and Munroe, Patricia B and Psaty, Bruce M and Oostra, Ben A and Cupples, L Adrienne and Perz, Siegfried and de Boer, Rudolf A and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Spector, Timothy D and Liu, Fang-Yu and Boerwinkle, Eric and Dominiczak, Anna F and Rotter, Jerome I and van Herpen, G{\'e} and Levy, Daniel and Wichmann, H-Erich and van Gilst, Wiek H and Witteman, Jacqueline C M and Kroemer, Heyo K and Kao, W H Linda and Heckbert, Susan R and Meitinger, Thomas and Hofman, Albert and Campbell, Harry and Folsom, Aaron R and van Veldhuisen, Dirk J and Schwienbacher, Christine and O{\textquoteright}Donnell, Christopher J and Volpato, Claudia Beu and Caulfield, Mark J and Connell, John M and Launer, Lenore and Lu, Xiaowen and Franke, Lude and Fehrmann, Rudolf S N and te Meerman, Gerard and Groen, Harry J M and Weersma, Rinse K and van den Berg, Leonard H and Wijmenga, Cisca and Ophoff, Roel A and Navis, Gerjan and Rudan, Igor and Snieder, Harold and Wilson, James F and Pramstaller, Peter P and Siscovick, David S and Wang, Thomas J and Gudnason, Vilmundur and van Duijn, Cornelia M and Felix, Stephan B and Fishman, Glenn I and Jamshidi, Yalda and Stricker, Bruno H Ch and Samani, Nilesh J and K{\"a}{\"a}b, Stefan and Arking, Dan E} } @article {1183, title = {New loci associated with kidney function and chronic kidney disease.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 May}, pages = {376-84}, abstract = {

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

}, keywords = {Cohort Studies, Creatinine, Cystatin C, Diet, Europe, Genetic Markers, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Models, Genetic, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.568}, author = {K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Glazer, Nicole L and Parsa, Afshin and Gao, Xiaoyi and Yang, Qiong and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Li, Man and Schmidt, Helena and Tanaka, Toshiko and Isaacs, Aaron and Ketkar, Shamika and Hwang, Shih-Jen and Johnson, Andrew D and Dehghan, Abbas and Teumer, Alexander and Par{\'e}, Guillaume and Atkinson, Elizabeth J and Zeller, Tanja and Lohman, Kurt and Cornelis, Marilyn C and Probst-Hensch, Nicole M and Kronenberg, Florian and T{\"o}njes, Anke and Hayward, Caroline and Aspelund, Thor and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Rampersaud, Evadnie and Mitchell, Braxton D and Arking, Dan E and Boerwinkle, Eric and Struchalin, Maksim and Cavalieri, Margherita and Singleton, Andrew and Giallauria, Francesco and Metter, Jeffrey and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Siscovick, David and Psaty, Bruce M and Zillikens, M Carola and Oostra, Ben A and Feitosa, Mary and Province, Michael and de Andrade, Mariza and Turner, Stephen T and Schillert, Arne and Ziegler, Andreas and Wild, Philipp S and Schnabel, Renate B and Wilde, Sandra and Munzel, Thomas F and Leak, Tennille S and Illig, Thomas and Klopp, Norman and Meisinger, Christa and Wichmann, H-Erich and Koenig, Wolfgang and Zgaga, Lina and Zemunik, Tatijana and Kolcic, Ivana and Minelli, Cosetta and Hu, Frank B and Johansson, Asa and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and Schreiber, Stefan and Aulchenko, Yurii S and Felix, Janine F and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Imboden, Medea and Nitsch, Dorothea and Brandst{\"a}tter, Anita and Kollerits, Barbara and Kedenko, Lyudmyla and M{\"a}gi, Reedik and Stumvoll, Michael and Kovacs, Peter and Boban, Mladen and Campbell, Susan and Endlich, Karlhans and V{\"o}lzke, Henry and Kroemer, Heyo K and Nauck, Matthias and V{\"o}lker, Uwe and Polasek, Ozren and Vitart, Veronique and Badola, Sunita and Parker, Alexander N and Ridker, Paul M and Kardia, Sharon L R and Blankenberg, Stefan and Liu, Yongmei and Curhan, Gary C and Franke, Andre and Rochat, Thierry and Paulweber, Bernhard and Prokopenko, Inga and Wang, Wei and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Shlipak, Michael G and van Duijn, Cornelia M and Borecki, Ingrid and Kr{\"a}mer, Bernhard K and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Witteman, Jacqueline C and Pramstaller, Peter P and Rettig, Rainer and Hastie, Nick and Chasman, Daniel I and Kao, W H and Heid, Iris M and Fox, Caroline S} } @article {1325, title = {Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.}, journal = {Nature}, volume = {478}, year = {2011}, month = {2011 Sep 11}, pages = {103-9}, abstract = {

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>=140 mm Hg systolic blood pressure or >=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

}, keywords = {Africa, Asia, Blood Pressure, Cardiovascular Diseases, Coronary Artery Disease, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Kidney Diseases, Polymorphism, Single Nucleotide, Stroke}, issn = {1476-4687}, doi = {10.1038/nature10405}, author = {Ehret, Georg B and Munroe, Patricia B and Rice, Kenneth M and Bochud, Murielle and Johnson, Andrew D and Chasman, Daniel I and Smith, Albert V and Tobin, Martin D and Verwoert, Germaine C and Hwang, Shih-Jen and Pihur, Vasyl and Vollenweider, Peter and O{\textquoteright}Reilly, Paul F and Amin, Najaf and Bragg-Gresham, Jennifer L and Teumer, Alexander and Glazer, Nicole L and Launer, Lenore and Zhao, Jing Hua and Aulchenko, Yurii and Heath, Simon and S{\~o}ber, Siim and Parsa, Afshin and Luan, Jian{\textquoteright}an and Arora, Pankaj and Dehghan, Abbas and Zhang, Feng and Lucas, Gavin and Hicks, Andrew A and Jackson, Anne U and Peden, John F and Tanaka, Toshiko and Wild, Sarah H and Rudan, Igor and Igl, Wilmar and Milaneschi, Yuri and Parker, Alex N and Fava, Cristiano and Chambers, John C and Fox, Ervin R and Kumari, Meena and Go, Min Jin and van der Harst, Pim and Kao, Wen Hong Linda and Sj{\"o}gren, Marketa and Vinay, D G and Alexander, Myriam and Tabara, Yasuharu and Shaw-Hawkins, Sue and Whincup, Peter H and Liu, Yongmei and Shi, Gang and Kuusisto, Johanna and Tayo, Bamidele and Seielstad, Mark and Sim, Xueling and Nguyen, Khanh-Dung Hoang and Lehtim{\"a}ki, Terho and Matullo, Giuseppe and Wu, Ying and Gaunt, Tom R and Onland-Moret, N Charlotte and Cooper, Matthew N and Platou, Carl G P and Org, Elin and Hardy, Rebecca and Dahgam, Santosh and Palmen, Jutta and Vitart, Veronique and Braund, Peter S and Kuznetsova, Tatiana and Uiterwaal, Cuno S P M and Adeyemo, Adebowale and Palmas, Walter and Campbell, Harry and Ludwig, Barbara and Tomaszewski, Maciej and Tzoulaki, Ioanna and Palmer, Nicholette D and Aspelund, Thor and Garcia, Melissa and Chang, Yen-Pei C and O{\textquoteright}Connell, Jeffrey R and Steinle, Nanette I and Grobbee, Diederick E and Arking, Dan E and Kardia, Sharon L and Morrison, Alanna C and Hernandez, Dena and Najjar, Samer and McArdle, Wendy L and Hadley, David and Brown, Morris J and Connell, John M and Hingorani, Aroon D and Day, Ian N M and Lawlor, Debbie A and Beilby, John P and Lawrence, Robert W and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Dreisbach, Albert W and Li, Yali and Young, J Hunter and Bis, Joshua C and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Adair, Linda S and Lee, Nanette R and Chen, Ming-Huei and Olden, Matthias and Pattaro, Cristian and Bolton, Judith A Hoffman and K{\"o}ttgen, Anna and Bergmann, Sven and Mooser, Vincent and Chaturvedi, Nish and Frayling, Timothy M and Islam, Muhammad and Jafar, Tazeen H and Erdmann, Jeanette and Kulkarni, Smita R and Bornstein, Stefan R and Gr{\"a}ssler, J{\"u}rgen and Groop, Leif and Voight, Benjamin F and Kettunen, Johannes and Howard, Philip and Taylor, Andrew and Guarrera, Simonetta and Ricceri, Fulvio and Emilsson, Valur and Plump, Andrew and Barroso, In{\^e}s and Khaw, Kay-Tee and Weder, Alan B and Hunt, Steven C and Sun, Yan V and Bergman, Richard N and Collins, Francis S and Bonnycastle, Lori L and Scott, Laura J and Stringham, Heather M and Peltonen, Leena and Perola, Markus and Vartiainen, Erkki and Brand, Stefan-Martin and Staessen, Jan A and Wang, Thomas J and Burton, Paul R and Soler Artigas, Maria and Dong, Yanbin and Snieder, Harold and Wang, Xiaoling and Zhu, Haidong and Lohman, Kurt K and Rudock, Megan E and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Doumatey, Ayo and Shriner, Daniel and Veldre, Gudrun and Viigimaa, Margus and Kinra, Sanjay and Prabhakaran, Dorairaj and Tripathy, Vikal and Langefeld, Carl D and Rosengren, Annika and Thelle, Dag S and Corsi, Anna Maria and Singleton, Andrew and Forrester, Terrence and Hilton, Gina and McKenzie, Colin A and Salako, Tunde and Iwai, Naoharu and Kita, Yoshikuni and Ogihara, Toshio and Ohkubo, Takayoshi and Okamura, Tomonori and Ueshima, Hirotsugu and Umemura, Satoshi and Eyheramendy, Susana and Meitinger, Thomas and Wichmann, H-Erich and Cho, Yoon Shin and Kim, Hyung-Lae and Lee, Jong-Young and Scott, James and Sehmi, Joban S and Zhang, Weihua and Hedblad, Bo and Nilsson, Peter and Smith, George Davey and Wong, Andrew and Narisu, Narisu and Stan{\v c}{\'a}kov{\'a}, Alena and Raffel, Leslie J and Yao, Jie and Kathiresan, Sekar and O{\textquoteright}Donnell, Christopher J and Schwartz, Stephen M and Ikram, M Arfan and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Shrine, Nick R G and Wain, Louise V and Morken, Mario A and Swift, Amy J and Laitinen, Jaana and Prokopenko, Inga and Zitting, Paavo and Cooper, Jackie A and Humphries, Steve E and Danesh, John and Rasheed, Asif and Goel, Anuj and Hamsten, Anders and Watkins, Hugh and Bakker, Stephan J L and van Gilst, Wiek H and Janipalli, Charles S and Mani, K Radha and Yajnik, Chittaranjan S and Hofman, Albert and Mattace-Raso, Francesco U S and Oostra, Ben A and Demirkan, Ayse and Isaacs, Aaron and Rivadeneira, Fernando and Lakatta, Edward G and Orr{\`u}, Marco and Scuteri, Angelo and Ala-Korpela, Mika and Kangas, Antti J and Lyytik{\"a}inen, Leo-Pekka and Soininen, Pasi and Tukiainen, Taru and W{\"u}rtz, Peter and Ong, Rick Twee-Hee and D{\"o}rr, Marcus and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Zelenika, Diana and Deloukas, Panos and Mangino, Massimo and Spector, Tim D and Zhai, Guangju and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Terzic, Janos and Kumar, M V Kranthi and Denniff, Matthew and Zukowska-Szczechowska, Ewa and Wagenknecht, Lynne E and Fowkes, F Gerald R and Charchar, Fadi J and Schwarz, Peter E H and Hayward, Caroline and Guo, Xiuqing and Rotimi, Charles and Bots, Michiel L and Brand, Eva and Samani, Nilesh J and Polasek, Ozren and Talmud, Philippa J and Nyberg, Fredrik and Kuh, Diana and Laan, Maris and Hveem, Kristian and Palmer, Lyle J and van der Schouw, Yvonne T and Casas, Juan P and Mohlke, Karen L and Vineis, Paolo and Raitakari, Olli and Ganesh, Santhi K and Wong, Tien Y and Tai, E Shyong and Cooper, Richard S and Laakso, Markku and Rao, Dabeeru C and Harris, Tamara B and Morris, Richard W and Dominiczak, Anna F and Kivimaki, Mika and Marmot, Michael G and Miki, Tetsuro and Saleheen, Danish and Chandak, Giriraj R and Coresh, Josef and Navis, Gerjan and Salomaa, Veikko and Han, Bok-Ghee and Zhu, Xiaofeng and Kooner, Jaspal S and Melander, Olle and Ridker, Paul M and Bandinelli, Stefania and Gyllensten, Ulf B and Wright, Alan F and Wilson, James F and Ferrucci, Luigi and Farrall, Martin and Tuomilehto, Jaakko and Pramstaller, Peter P and Elosua, Roberto and Soranzo, Nicole and Sijbrands, Eric J G and Altshuler, David and Loos, Ruth J F and Shuldiner, Alan R and Gieger, Christian and Meneton, Pierre and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Gudnason, Vilmundur and Rotter, Jerome I and Rettig, Rainer and Uda, Manuela and Strachan, David P and Witteman, Jacqueline C M and Hartikainen, Anna-Liisa and Beckmann, Jacques S and Boerwinkle, Eric and Vasan, Ramachandran S and Boehnke, Michael and Larson, Martin G and Jarvelin, Marjo-Riitta and Psaty, Bruce M and Abecasis, Goncalo R and Chakravarti, Aravinda and Elliott, Paul and van Duijn, Cornelia M and Newton-Cheh, Christopher and Levy, Daniel and Caulfield, Mark J and Johnson, Toby} } @article {1324, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orr{\`u}, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, Stephanie and DeStefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and Jarvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1307, title = {A genome-wide association study of aging.}, journal = {Neurobiol Aging}, volume = {32}, year = {2011}, month = {2011 Nov}, pages = {2109.e15-28}, abstract = {

Human longevity and healthy aging show moderate heritability (20\%-50\%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 {\texttimes} 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer{\textquoteright}s disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

}, keywords = {Aging, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Longevity}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2011.05.026}, author = {Walter, Stefan and Atzmon, Gil and Demerath, Ellen W and Garcia, Melissa E and Kaplan, Robert C and Kumari, Meena and Lunetta, Kathryn L and Milaneschi, Yuri and Tanaka, Toshiko and Tranah, Gregory J and V{\"o}lker, Uwe and Yu, Lei and Arnold, Alice and Benjamin, Emelia J and Biffar, Reiner and Buchman, Aron S and Boerwinkle, Eric and Couper, David and De Jager, Philip L and Evans, Denis A and Harris, Tamara B and Hoffmann, Wolfgang and Hofman, Albert and Karasik, David and Kiel, Douglas P and Kocher, Thomas and Kuningas, Maris and Launer, Lenore J and Lohman, Kurt K and Lutsey, Pamela L and Mackenbach, Johan and Marciante, Kristin and Psaty, Bruce M and Reiman, Eric M and Rotter, Jerome I and Seshadri, Sudha and Shardell, Michelle D and Smith, Albert V and van Duijn, Cornelia and Walston, Jeremy and Zillikens, M Carola and Bandinelli, Stefania and Baumeister, Sebastian E and Bennett, David A and Ferrucci, Luigi and Gudnason, Vilmundur and Kivimaki, Mika and Liu, Yongmei and Murabito, Joanne M and Newman, Anne B and Tiemeier, Henning and Franceschini, Nora} } @article {1355, title = {New gene functions in megakaryopoiesis and platelet formation.}, journal = {Nature}, volume = {480}, year = {2011}, month = {2011 Nov 30}, pages = {201-8}, abstract = {

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

}, keywords = {Animals, Blood Platelets, Cell Size, Drosophila melanogaster, Drosophila Proteins, Europe, Gene Expression Profiling, Gene Silencing, Genome, Human, Genome-Wide Association Study, Hematopoiesis, Humans, Megakaryocytes, Platelet Count, Protein Interaction Maps, Transcription, Genetic, Zebrafish, Zebrafish Proteins}, issn = {1476-4687}, doi = {10.1038/nature10659}, author = {Gieger, Christian and Radhakrishnan, Aparna and Cvejic, Ana and Tang, Weihong and Porcu, Eleonora and Pistis, Giorgio and Serbanovic-Canic, Jovana and Elling, Ulrich and Goodall, Alison H and Labrune, Yann and Lopez, Lorna M and M{\"a}gi, Reedik and Meacham, Stuart and Okada, Yukinori and Pirastu, Nicola and Sorice, Rossella and Teumer, Alexander and Voss, Katrin and Zhang, Weihua and Ramirez-Solis, Ramiro and Bis, Joshua C and Ellinghaus, David and G{\"o}gele, Martin and Hottenga, Jouke-Jan and Langenberg, Claudia and Kovacs, Peter and O{\textquoteright}Reilly, Paul F and Shin, So-Youn and Esko, T{\~o}nu and Hartiala, Jaana and Kanoni, Stavroula and Murgia, Federico and Parsa, Afshin and Stephens, Jonathan and van der Harst, Pim and Ellen van der Schoot, C and Allayee, Hooman and Attwood, Antony and Balkau, Beverley and Bastardot, Fran{\c c}ois and Basu, Saonli and Baumeister, Sebastian E and Biino, Ginevra and Bomba, Lorenzo and Bonnefond, Am{\'e}lie and Cambien, Francois and Chambers, John C and Cucca, Francesco and D{\textquoteright}Adamo, Pio and Davies, Gail and de Boer, Rudolf A and de Geus, Eco J C and D{\"o}ring, Angela and Elliott, Paul and Erdmann, Jeanette and Evans, David M and Falchi, Mario and Feng, Wei and Folsom, Aaron R and Frazer, Ian H and Gibson, Quince D and Glazer, Nicole L and Hammond, Chris and Hartikainen, Anna-Liisa and Heckbert, Susan R and Hengstenberg, Christian and Hersch, Micha and Illig, Thomas and Loos, Ruth J F and Jolley, Jennifer and Khaw, Kay Tee and Kuhnel, Brigitte and Kyrtsonis, Marie-Christine and Lagou, Vasiliki and Lloyd-Jones, Heather and Lumley, Thomas and Mangino, Massimo and Maschio, Andrea and Mateo Leach, Irene and McKnight, Barbara and Memari, Yasin and Mitchell, Braxton D and Montgomery, Grant W and Nakamura, Yusuke and Nauck, Matthias and Navis, Gerjan and N{\"o}thlings, Ute and Nolte, Ilja M and Porteous, David J and Pouta, Anneli and Pramstaller, Peter P and Pullat, Janne and Ring, Susan M and Rotter, Jerome I and Ruggiero, Daniela and Ruokonen, Aimo and Sala, Cinzia and Samani, Nilesh J and Sambrook, Jennifer and Schlessinger, David and Schreiber, Stefan and Schunkert, Heribert and Scott, James and Smith, Nicholas L and Snieder, Harold and Starr, John M and Stumvoll, Michael and Takahashi, Atsushi and Tang, W H Wilson and Taylor, Kent and Tenesa, Albert and Lay Thein, Swee and T{\"o}njes, Anke and Uda, Manuela and Ulivi, Sheila and van Veldhuisen, Dirk J and Visscher, Peter M and V{\"o}lker, Uwe and Wichmann, H-Erich and Wiggins, Kerri L and Willemsen, Gonneke and Yang, Tsun-Po and Hua Zhao, Jing and Zitting, Paavo and Bradley, John R and Dedoussis, George V and Gasparini, Paolo and Hazen, Stanley L and Metspalu, Andres and Pirastu, Mario and Shuldiner, Alan R and Joost van Pelt, L and Zwaginga, Jaap-Jan and Boomsma, Dorret I and Deary, Ian J and Franke, Andre and Froguel, Philippe and Ganesh, Santhi K and Jarvelin, Marjo-Riitta and Martin, Nicholas G and Meisinger, Christa and Psaty, Bruce M and Spector, Timothy D and Wareham, Nicholas J and Akkerman, Jan-Willem N and Ciullo, Marina and Deloukas, Panos and Greinacher, Andreas and Jupe, Steve and Kamatani, Naoyuki and Khadake, Jyoti and Kooner, Jaspal S and Penninger, Josef and Prokopenko, Inga and Stemple, Derek and Toniolo, Daniela and Wernisch, Lorenz and Sanna, Serena and Hicks, Andrew A and Rendon, Augusto and Ferreira, Manuel A and Ouwehand, Willem H and Soranzo, Nicole} } @article {1359, title = {Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Feb 01}, pages = {100-12}, abstract = {

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI <=0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60\% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46{\texttimes}10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65{\texttimes}10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6{\texttimes}10(-5)), CYBA (rs3794624, P=6.3{\texttimes}10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Ankle Brachial Index, Chromosomes, Human, Pair 9, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15, Female, Genome-Wide Association Study, Genotype, HapMap Project, Humans, Logistic Models, Male, Middle Aged, Peripheral Vascular Diseases, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sex Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.961292}, author = {Murabito, Joanne M and White, Charles C and Kavousi, Maryam and Sun, Yan V and Feitosa, Mary F and Nambi, Vijay and Lamina, Claudia and Schillert, Arne and Coassin, Stefan and Bis, Joshua C and Broer, Linda and Crawford, Dana C and Franceschini, Nora and Frikke-Schmidt, Ruth and Haun, Margot and Holewijn, Suzanne and Huffman, Jennifer E and Hwang, Shih-Jen and Kiechl, Stefan and Kollerits, Barbara and Montasser, May E and Nolte, Ilja M and Rudock, Megan E and Senft, Andrea and Teumer, Alexander and van der Harst, Pim and Vitart, Veronique and Waite, Lindsay L and Wood, Andrew R and Wassel, Christina L and Absher, Devin M and Allison, Matthew A and Amin, Najaf and Arnold, Alice and Asselbergs, Folkert W and Aulchenko, Yurii and Bandinelli, Stefania and Barbalic, Maja and Boban, Mladen and Brown-Gentry, Kristin and Couper, David J and Criqui, Michael H and Dehghan, Abbas and den Heijer, Martin and Dieplinger, Benjamin and Ding, Jingzhong and D{\"o}rr, Marcus and Espinola-Klein, Christine and Felix, Stephan B and Ferrucci, Luigi and Folsom, Aaron R and Fraedrich, Gustav and Gibson, Quince and Goodloe, Robert and Gunjaca, Grgo and Haltmayer, Meinhard and Heiss, Gerardo and Hofman, Albert and Kieback, Arne and Kiemeney, Lambertus A and Kolcic, Ivana and Kullo, Iftikhar J and Kritchevsky, Stephen B and Lackner, Karl J and Li, Xiaohui and Lieb, Wolfgang and Lohman, Kurt and Meisinger, Christa and Melzer, David and Mohler, Emile R and Mudnic, Ivana and Mueller, Thomas and Navis, Gerjan and Oberhollenzer, Friedrich and Olin, Jeffrey W and O{\textquoteright}Connell, Jeff and O{\textquoteright}Donnell, Christopher J and Palmas, Walter and Penninx, Brenda W and Petersmann, Astrid and Polasek, Ozren and Psaty, Bruce M and Rantner, Barbara and Rice, Ken and Rivadeneira, Fernando and Rotter, Jerome I and Seldenrijk, Adrie and Stadler, Marietta and Summerer, Monika and Tanaka, Toshiko and Tybjaerg-Hansen, Anne and Uitterlinden, Andr{\'e} G and van Gilst, Wiek H and Vermeulen, Sita H and Wild, Sarah H and Wild, Philipp S and Willeit, Johann and Zeller, Tanja and Zemunik, Tatijana and Zgaga, Lina and Assimes, Themistocles L and Blankenberg, Stefan and Boerwinkle, Eric and Campbell, Harry and Cooke, John P and de Graaf, Jacqueline and Herrington, David and Kardia, Sharon L R and Mitchell, Braxton D and Murray, Anna and M{\"u}nzel, Thomas and Newman, Anne B and Oostra, Ben A and Rudan, Igor and Shuldiner, Alan R and Snieder, Harold and van Duijn, Cornelia M and V{\"o}lker, Uwe and Wright, Alan F and Wichmann, H-Erich and Wilson, James F and Witteman, Jacqueline C M and Liu, Yongmei and Hayward, Caroline and Borecki, Ingrid B and Ziegler, Andreas and North, Kari E and Cupples, L Adrienne and Kronenberg, Florian} } @article {1377, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {1383, title = {Meta-analysis identifies six new susceptibility loci for atrial fibrillation.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 29}, pages = {670-5}, abstract = {

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 {\texttimes} 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Child, Child, Preschool, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.2261}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Albert, Christine M and Glazer, Nicole L and Ritchie, Marylyn D and Smith, Albert V and Arking, Dan E and M{\"u}ller-Nurasyid, Martina and Krijthe, Bouwe P and Lubitz, Steven A and Bis, Joshua C and Chung, Mina K and D{\"o}rr, Marcus and Ozaki, Kouichi and Roberts, Jason D and Smith, J Gustav and Pfeufer, Arne and Sinner, Moritz F and Lohman, Kurt and Ding, Jingzhong and Smith, Nicholas L and Smith, Jonathan D and Rienstra, Michiel and Rice, Kenneth M and Van Wagoner, David R and Magnani, Jared W and Wakili, Reza and Clauss, Sebastian and Rotter, Jerome I and Steinbeck, Gerhard and Launer, Lenore J and Davies, Robert W and Borkovich, Matthew and Harris, Tamara B and Lin, Honghuang and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Milan, David J and Hofman, Albert and Boerwinkle, Eric and Chen, Lin Y and Soliman, Elsayed Z and Voight, Benjamin F and Li, Guo and Chakravarti, Aravinda and Kubo, Michiaki and Tedrow, Usha B and Rose, Lynda M and Ridker, Paul M and Conen, David and Tsunoda, Tatsuhiko and Furukawa, Tetsushi and Sotoodehnia, Nona and Xu, Siyan and Kamatani, Naoyuki and Levy, Daniel and Nakamura, Yusuke and Parvez, Babar and Mahida, Saagar and Furie, Karen L and Rosand, Jonathan and Muhammad, Raafia and Psaty, Bruce M and Meitinger, Thomas and Perz, Siegfried and Wichmann, H-Erich and Witteman, Jacqueline C M and Kao, W H Linda and Kathiresan, Sekar and Roden, Dan M and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and McKnight, Barbara and Sj{\"o}gren, Marketa and Newman, Anne B and Liu, Yongmei and Gollob, Michael H and Melander, Olle and Tanaka, Toshihiro and Stricker, Bruno H Ch and Felix, Stephan B and Alonso, Alvaro and Darbar, Dawood and Barnard, John and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Gudnason, Vilmundur and K{\"a}{\"a}b, Stefan} } @article {6288, title = {Common variants in Mendelian kidney disease genes and their association with renal function.}, journal = {J Am Soc Nephrol}, volume = {24}, year = {2013}, month = {2013 Dec}, pages = {2105-17}, abstract = {

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5\%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

}, keywords = {Databases, Genetic, European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Kidney, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2012100983}, author = {Parsa, Afshin and Fuchsberger, Christian and K{\"o}ttgen, Anna and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and de Andrade, Mariza and Chasman, Daniel I and Teumer, Alexander and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Kim, Young J and Taliun, Daniel and Li, Man and Feitosa, Mary and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and Glazer, Nicole and Isaacs, Aaron and Rao, Madhumathi and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Couraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Hofer, Edith and Hu, Frank and Demirkan, Ayse and Oostra, Ben A and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, B{\'e}n{\'e}dicte and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M and Bochud, Murielle and Heid, Iris M and Siscovick, David S and Fox, Caroline S and Kao, W Linda and B{\"o}ger, Carsten A} } @article {6291, title = {Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003796}, abstract = {

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

}, keywords = {Animals, Bone and Bones, Bone Density, Calcium, European Continental Ancestry Group, Gene Expression Regulation, Genome-Wide Association Study, Homeostasis, Humans, Kidney, Mice, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003796}, author = {O{\textquoteright}Seaghdha, Conall M and Wu, Hongsheng and Yang, Qiong and Kapur, Karen and Guessous, Idris and Zuber, Annie Mercier and K{\"o}ttgen, Anna and Stoudmann, Candice and Teumer, Alexander and Kutalik, Zolt{\'a}n and Mangino, Massimo and Dehghan, Abbas and Zhang, Weihua and Eiriksdottir, Gudny and Li, Guo and Tanaka, Toshiko and Portas, Laura and Lopez, Lorna M and Hayward, Caroline and Lohman, Kurt and Matsuda, Koichi and Padmanabhan, Sandosh and Firsov, Dmitri and Sorice, Rossella and Ulivi, Sheila and Brockhaus, A Catharina and Kleber, Marcus E and Mahajan, Anubha and Ernst, Florian D and Gudnason, Vilmundur and Launer, Lenore J and Mace, Aurelien and Boerwinckle, Eric and Arking, Dan E and Tanikawa, Chizu and Nakamura, Yusuke and Brown, Morris J and Gaspoz, Jean-Michel and Theler, Jean-Marc and Siscovick, David S and Psaty, Bruce M and Bergmann, Sven and Vollenweider, Peter and Vitart, Veronique and Wright, Alan F and Zemunik, Tatijana and Boban, Mladen and Kolcic, Ivana and Navarro, Pau and Brown, Edward M and Estrada, Karol and Ding, Jingzhong and Harris, Tamara B and Bandinelli, Stefania and Hernandez, Dena and Singleton, Andrew B and Girotto, Giorgia and Ruggiero, Daniela and d{\textquoteright}Adamo, Adamo Pio and Robino, Antonietta and Meitinger, Thomas and Meisinger, Christa and Davies, Gail and Starr, John M and Chambers, John C and Boehm, Bernhard O and Winkelmann, Bernhard R and Huang, Jie and Murgia, Federico and Wild, Sarah H and Campbell, Harry and Morris, Andrew P and Franco, Oscar H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and V{\"o}lker, Uwe and Hannemann, Anke and Biffar, Reiner and Hoffmann, Wolfgang and Shin, So-Youn and Lescuyer, Pierre and Henry, Hughes and Schurmann, Claudia and Munroe, Patricia B and Gasparini, Paolo and Pirastu, Nicola and Ciullo, Marina and Gieger, Christian and M{\"a}rz, Winfried and Lind, Lars and Spector, Tim D and Smith, Albert V and Rudan, Igor and Wilson, James F and Polasek, Ozren and Deary, Ian J and Pirastu, Mario and Ferrucci, Luigi and Liu, Yongmei and Kestenbaum, Bryan and Kooner, Jaspal S and Witteman, Jacqueline C M and Nauck, Matthias and Kao, W H Linda and Wallaschofski, Henri and Bonny, Olivier and Fox, Caroline S and Bochud, Murielle} } @article {6599, title = {Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {24-38}, abstract = {

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p <= 5 {\texttimes} 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 {\texttimes} 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

}, keywords = {Adolescent, Adult, Age Factors, Aged, Blood Pressure, Cohort Studies, Humans, Middle Aged, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.010}, author = {Simino, Jeannette and Shi, Gang and Bis, Joshua C and Chasman, Daniel I and Ehret, Georg B and Gu, Xiangjun and Guo, Xiuqing and Hwang, Shih-Jen and Sijbrands, Eric and Smith, Albert V and Verwoert, Germaine C and Bragg-Gresham, Jennifer L and Cadby, Gemma and Chen, Peng and Cheng, Ching-Yu and Corre, Tanguy and de Boer, Rudolf A and Goel, Anuj and Johnson, Toby and Khor, Chiea-Chuen and Llu{\'\i}s-Ganella, Carla and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Sim, Xueling and S{\~o}ber, Siim and van der Most, Peter J and Verweij, Niek and Zhao, Jing Hua and Amin, Najaf and Boerwinkle, Eric and Bouchard, Claude and Dehghan, Abbas and Eiriksdottir, Gudny and Elosua, Roberto and Franco, Oscar H and Gieger, Christian and Harris, Tamara B and Hercberg, Serge and Hofman, Albert and James, Alan L and Johnson, Andrew D and K{\"a}h{\"o}nen, Mika and Khaw, Kay-Tee and Kutalik, Zolt{\'a}n and Larson, Martin G and Launer, Lenore J and Li, Guo and Liu, Jianjun and Liu, Kiang and Morrison, Alanna C and Navis, Gerjan and Ong, Rick Twee-Hee and Papanicolau, George J and Penninx, Brenda W and Psaty, Bruce M and Raffel, Leslie J and Raitakari, Olli T and Rice, Kenneth and Rivadeneira, Fernando and Rose, Lynda M and Sanna, Serena and Scott, Robert A and Siscovick, David S and Stolk, Ronald P and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Klauw, Melanie M and Vasan, Ramachandran S and Vithana, Eranga Nishanthie and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Hugh and Young, Terri L and Aung, Tin and Bochud, Murielle and Farrall, Martin and Hartman, Catharina A and Laan, Maris and Lakatta, Edward G and Lehtim{\"a}ki, Terho and Loos, Ruth J F and Lucas, Gavin and Meneton, Pierre and Palmer, Lyle J and Rettig, Rainer and Snieder, Harold and Tai, E Shyong and Teo, Yik-Ying and van der Harst, Pim and Wareham, Nicholas J and Wijmenga, Cisca and Wong, Tien Yin and Fornage, Myriam and Gudnason, Vilmundur and Levy, Daniel and Palmas, Walter and Ridker, Paul M and Rotter, Jerome I and van Duijn, Cornelia M and Witteman, Jacqueline C M and Chakravarti, Aravinda and Rao, Dabeeru C} } @article {6544, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

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.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and D{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orr{\`u}, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {6294, title = {Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Feb}, pages = {e1004123}, abstract = {

Autoimmune thyroid diseases (AITD) are common, affecting 2-5\% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto{\textquoteright}s thyroiditis), as well as autoimmune hyperthyroidism (Graves{\textquoteright} disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5{\texttimes}10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95\% CI 1.68-2.81, P = 8.1{\texttimes}10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95\% CI 1.26-1.82, P = 2.9{\texttimes}10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95\% CI 0.66-0.89, P = 6.5{\texttimes}10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves{\textquoteright} disease (OR: 1.37, 95\% CI 1.22-1.54, P = 1.2{\texttimes}10(-7) and OR: 1.25, 95\% CI 1.12-1.39, P = 6.2{\texttimes}10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95\% CI 1.18-2.10, P = 1.9{\texttimes}10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

}, keywords = {Autoantibodies, Genetic Loci, Genome-Wide Association Study, Graves Disease, Hashimoto Disease, Humans, Iodide Peroxidase, Risk Factors, Thyroiditis, Autoimmune, Thyrotropin}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004123}, author = {Medici, Marco and Porcu, Eleonora and Pistis, Giorgio and Teumer, Alexander and Brown, Suzanne J and Jensen, Richard A and Rawal, Rajesh and Roef, Greet L and Plantinga, Theo S and Vermeulen, Sita H and Lahti, Jari and Simmonds, Matthew J and Husemoen, Lise Lotte N and Freathy, Rachel M and Shields, Beverley M and Pietzner, Diana and Nagy, Rebecca and Broer, Linda and Chaker, Layal and Korevaar, Tim I M and Plia, Maria Grazia and Sala, Cinzia and V{\"o}lker, Uwe and Richards, J Brent and Sweep, Fred C and Gieger, Christian and Corre, Tanguy and Kajantie, Eero and Thuesen, Betina and Taes, Youri E and Visser, W Edward and Hattersley, Andrew T and Kratzsch, J{\"u}rgen and Hamilton, Alexander and Li, Wei and Homuth, Georg and Lobina, Monia and Mariotti, Stefano and Soranzo, Nicole and Cocca, Massimiliano and Nauck, Matthias and Spielhagen, Christin and Ross, Alec and Arnold, Alice and van de Bunt, Martijn and Liyanarachchi, Sandya and Heier, Margit and Grabe, Hans J{\"o}rgen and Masciullo, Corrado and Galesloot, Tessel E and Lim, Ee M and Reischl, Eva and Leedman, Peter J and Lai, Sandra and Delitala, Alessandro and Bremner, Alexandra P and Philips, David I W and Beilby, John P and Mulas, Antonella and Vocale, Matteo and Abecasis, Goncalo and Forsen, Tom and James, Alan and Widen, Elisabeth and Hui, Jennie and Prokisch, Holger and Rietzschel, Ernst E and Palotie, Aarno and Feddema, Peter and Fletcher, Stephen J and Schramm, Katharina and Rotter, Jerome I and Kluttig, Alexander and Radke, D{\"o}rte and Traglia, Michela and Surdulescu, Gabriela L and He, Huiling and Franklyn, Jayne A and Tiller, Daniel and Vaidya, Bijay and De Meyer, Tim and J{\o}rgensen, Torben and Eriksson, Johan G and O{\textquoteright}Leary, Peter C and Wichmann, Eric and Hermus, Ad R and Psaty, Bruce M and Ittermann, Till and Hofman, Albert and Bosi, Emanuele and Schlessinger, David and Wallaschofski, Henri and Pirastu, Nicola and Aulchenko, Yurii S and de la Chapelle, Albert and Netea-Maier, Romana T and Gough, Stephen C L and Meyer Zu Schwabedissen, Henriette and Frayling, Timothy M and Kaufman, Jean-Marc and Linneberg, Allan and R{\"a}ikk{\"o}nen, Katri and Smit, Johannes W A and Kiemeney, Lambertus A and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Walsh, John P and Meisinger, Christa and den Heijer, Martin and Visser, Theo J and Spector, Timothy D and Wilson, Scott G and V{\"o}lzke, Henry and Cappola, Anne and Toniolo, Daniela and Sanna, Serena and Naitza, Silvia and Peeters, Robin P} } @article {6820, title = {Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.}, journal = {J Am Coll Cardiol}, volume = {63}, year = {2014}, month = {2014 Apr 1}, pages = {1200-10}, abstract = {

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

}, keywords = {Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.12.015}, author = {Lubitz, Steven A and Lunetta, Kathryn L and Lin, Honghuang and Arking, Dan E and Trompet, Stella and Li, Guo and Krijthe, Bouwe P and Chasman, Daniel I and Barnard, John and Kleber, Marcus E and D{\"o}rr, Marcus and Ozaki, Kouichi and Smith, Albert V and M{\"u}ller-Nurasyid, Martina and Walter, Stefan and Agarwal, Sunil K and Bis, Joshua C and Brody, Jennifer A and Chen, Lin Y and Everett, Brendan M and Ford, Ian and Franco, Oscar H and Harris, Tamara B and Hofman, Albert and K{\"a}{\"a}b, Stefan and Mahida, Saagar and Kathiresan, Sekar and Kubo, Michiaki and Launer, Lenore J and Macfarlane, Peter W and Magnani, Jared W and McKnight, Barbara and McManus, David D and Peters, Annette and Psaty, Bruce M and Rose, Lynda M and Rotter, Jerome I and Silbernagel, Guenther and Smith, Jonathan D and Sotoodehnia, Nona and Stott, David J and Taylor, Kent D and Tomaschitz, Andreas and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Murabito, Joanne M and Sinner, Moritz F and Gudnason, Vilmundur and Felix, Stephan B and M{\"a}rz, Winfried and Chung, Mina and Albert, Christine M and Stricker, Bruno H and Tanaka, Toshihiro and Heckbert, Susan R and Jukema, J Wouter and Alonso, Alvaro and Benjamin, Emelia J and Ellinor, Patrick T} } @article {6788, title = {Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.}, journal = {Blood}, volume = {126}, year = {2015}, month = {2015 Sep 10}, pages = {e19-29}, abstract = {

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.

}, keywords = {Cohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, von Willebrand Factor}, issn = {1528-0020}, doi = {10.1182/blood-2015-02-624551}, author = {Huffman, Jennifer E and de Vries, Paul S and Morrison, Alanna C and Sabater-Lleal, Maria and Kacprowski, Tim and Auer, Paul L and Brody, Jennifer A and Chasman, Daniel I and Chen, Ming-Huei and Guo, Xiuqing and Lin, Li-An and Marioni, Riccardo E and M{\"u}ller-Nurasyid, Martina and Yanek, Lisa R and Pankratz, Nathan and Grove, Megan L and de Maat, Moniek P M and Cushman, Mary and Wiggins, Kerri L and Qi, Lihong and Sennblad, Bengt and Harris, Sarah E and Polasek, Ozren and Riess, Helene and Rivadeneira, Fernando and Rose, Lynda M and Goel, Anuj and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and Yao, Jie and Tang, Weihong and Levy, Daniel and Waldenberger, Melanie and Becker, Diane M and Folsom, Aaron R and Giulianini, Franco and Greinacher, Andreas and Hofman, Albert and Huang, Chiang-Ching and Kooperberg, Charles and Silveira, Angela and Starr, John M and Strauch, Konstantin and Strawbridge, Rona J and Wright, Alan F and McKnight, Barbara and Franco, Oscar H and Zakai, Neil and Mathias, Rasika A and Psaty, Bruce M and Ridker, Paul M and Tofler, Geoffrey H and V{\"o}lker, Uwe and Watkins, Hugh and Fornage, Myriam and Hamsten, Anders and Deary, Ian J and Boerwinkle, Eric and Koenig, Wolfgang and Rotter, Jerome I and Hayward, Caroline and Dehghan, Abbas and Reiner, Alex P and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {7262, title = {52 Genetic Loci Influencing Myocardial~Mass.}, journal = {J Am Coll Cardiol}, volume = {68}, year = {2016}, month = {2016 Sep 27}, pages = {1435-48}, abstract = {

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~{\texttimes} 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.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.07.729}, author = {van der Harst, Pim and van Setten, Jessica and Verweij, Niek and Vogler, Georg and Franke, Lude and Maurano, Matthew T and Wang, Xinchen and Mateo Leach, Irene and Eijgelsheim, Mark and Sotoodehnia, Nona and Hayward, Caroline and Sorice, Rossella and Meirelles, Osorio and Lyytik{\"a}inen, Leo-Pekka and Polasek, Ozren and Tanaka, Toshiko and Arking, Dan E and Ulivi, Sheila and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Smith, Albert V and D{\"o}rr, Marcus and Kerr, Kathleen F and Magnani, Jared W and del Greco M, Fabiola and Zhang, Weihua and Nolte, Ilja M and Silva, Claudia T and Padmanabhan, Sandosh and Tragante, Vinicius and Esko, T{\~o}nu and Abecasis, Goncalo R and Adriaens, Michiel E and Andersen, Karl and Barnett, Phil and Bis, Joshua C and Bodmer, Rolf and Buckley, Brendan M and Campbell, Harry and Cannon, Megan V and Chakravarti, Aravinda and Chen, Lin Y and Delitala, Alessandro and Devereux, Richard B and Doevendans, Pieter A and Dominiczak, Anna F and Ferrucci, Luigi and Ford, Ian and Gieger, Christian and Harris, Tamara B and Haugen, Eric and Heinig, Matthias and Hernandez, Dena G and Hillege, Hans L and Hirschhorn, Joel N and Hofman, Albert and Hubner, Norbert and Hwang, Shih-Jen and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kellis, Manolis and Kolcic, Ivana and Kooner, Ishminder K and Kooner, Jaspal S and Kors, Jan A and Lakatta, Edward G and Lage, Kasper and Launer, Lenore J and Levy, Daniel and Lundby, Alicia and Macfarlane, Peter W and May, Dalit and Meitinger, Thomas and Metspalu, Andres and Nappo, Stefania and Naitza, Silvia and Neph, Shane and Nord, Alex S and Nutile, Teresa and Okin, Peter M and Olsen, Jesper V and Oostra, Ben A and Penninger, Josef M and Pennacchio, Len A and Pers, Tune H and Perz, Siegfried and Peters, Annette and Pinto, Yigal M and Pfeufer, Arne and Pilia, Maria Grazia and Pramstaller, Peter P and Prins, Bram P and Raitakari, Olli T and Raychaudhuri, Soumya and Rice, Ken M and Rossin, Elizabeth J and Rotter, Jerome I and Schafer, Sebastian and Schlessinger, David and Schmidt, Carsten O and Sehmi, Jobanpreet and Sillj{\'e}, Herman H W and Sinagra, Gianfranco and Sinner, Moritz F and Slowikowski, Kamil and Soliman, Elsayed Z and Spector, Timothy D and Spiering, Wilko and Stamatoyannopoulos, John A and Stolk, Ronald P and Strauch, Konstantin and Tan, Sian-Tsung and Tarasov, Kirill V and Trinh, Bosco and Uitterlinden, Andr{\'e} G and van den Boogaard, Malou and van Duijn, Cornelia M and van Gilst, Wiek H and Viikari, Jorma S and Visscher, Peter M and Vitart, Veronique and V{\"o}lker, Uwe and Waldenberger, Melanie and Weichenberger, Christian X and Westra, Harm-Jan and Wijmenga, Cisca and Wolffenbuttel, Bruce H and Yang, Jian and Bezzina, Connie R and Munroe, Patricia B and Snieder, Harold and Wright, Alan F and Rudan, Igor and Boyer, Laurie A and Asselbergs, Folkert W and van Veldhuisen, Dirk J and Stricker, Bruno H and Psaty, Bruce M and Ciullo, Marina and Sanna, Serena and Lehtim{\"a}ki, Terho and Wilson, James F and Bandinelli, Stefania and Alonso, Alvaro and Gasparini, Paolo and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Gudnason, Vilmundur and Felix, Stephan B and Heckbert, Susan R and de Boer, Rudolf A and Newton-Cheh, Christopher and Hicks, Andrew A and Chambers, John C and Jamshidi, Yalda and Visel, Axel and Christoffels, Vincent M and Isaacs, Aaron and Samani, Nilesh J and de Bakker, Paul I W} } @article {7254, title = {Genetic Variants Associated with Circulating Parathyroid Hormone.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 07}, abstract = {

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 {\texttimes} 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7\% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 {\texttimes} 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 {\texttimes} 10(-16)), rs4443100 near RTDR1 (P=8.7 {\texttimes} 10(-9)), and rs73186030 near CASR (P=4.8 {\texttimes} 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016010069}, author = {Robinson-Cohen, Cassianne and Lutsey, Pamela L and Kleber, Marcus E and Nielson, Carrie M and Mitchell, Braxton D and Bis, Joshua C and Eny, Karen M and Portas, Laura and Eriksson, Joel and Lorentzon, Mattias and Koller, Daniel L and Milaneschi, Yuri and Teumer, Alexander and Pilz, Stefan and Nethander, Maria and Selvin, Elizabeth and Tang, Weihong and Weng, Lu-Chen and Wong, Hoi Suen and Lai, Dongbing and Peacock, Munro and Hannemann, Anke and V{\"o}lker, Uwe and Homuth, Georg and Nauk, Matthias and Murgia, Federico and Pattee, Jack W and Orwoll, Eric and Zmuda, Joseph M and Riancho, Jose Antonio and Wolf, Myles and Williams, Frances and Penninx, Brenda and Econs, Michael J and Ryan, Kathleen A and Ohlsson, Claes and Paterson, Andrew D and Psaty, Bruce M and Siscovick, David S and Rotter, Jerome I and Pirastu, Mario and Streeten, Elizabeth and M{\"a}rz, Winfried and Fox, Caroline and Coresh, Josef and Wallaschofski, Henri and Pankow, James S and de Boer, Ian H and Kestenbaum, Bryan} } @article {7004, title = {Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0144997}, abstract = {

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5{\texttimes}10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5{\texttimes}10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8{\texttimes}10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2{\texttimes}10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2{\texttimes}10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

}, keywords = {Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0144997}, author = {Dehghan, Abbas and Bis, Joshua C and White, Charles C and Smith, Albert Vernon and Morrison, Alanna C and Cupples, L Adrienne and Trompet, Stella and Chasman, Daniel I and Lumley, Thomas and V{\"o}lker, Uwe and Buckley, Brendan M and Ding, Jingzhong and Jensen, Majken K and Folsom, Aaron R and Kritchevsky, Stephen B and Girman, Cynthia J and Ford, Ian and D{\"o}rr, Marcus and Salomaa, Veikko and Uitterlinden, Andr{\'e} G and Eiriksdottir, Gudny and Vasan, Ramachandran S and Franceschini, Nora and Carty, Cara L and Virtamo, Jarmo and Demissie, Serkalem and Amouyel, Philippe and Arveiler, Dominique and Heckbert, Susan R and Ferrieres, Jean and Ducimetiere, Pierre and Smith, Nicholas L and Wang, Ying A and Siscovick, David S and Rice, Kenneth M and Wiklund, Per-Gunnar and Taylor, Kent D and Evans, Alun and Kee, Frank and Rotter, Jerome I and Karvanen, Juha and Kuulasmaa, Kari and Heiss, Gerardo and Kraft, Peter and Launer, Lenore J and Hofman, Albert and Markus, Marcello R P and Rose, Lynda M and Silander, Kaisa and Wagner, Peter and Benjamin, Emelia J and Lohman, Kurt and Stott, David J and Rivadeneira, Fernando and Harris, Tamara B and Levy, Daniel and Liu, Yongmei and Rimm, Eric B and Jukema, J Wouter and V{\"o}lzke, Henry and Ridker, Paul M and Blankenberg, Stefan and Franco, Oscar H and Gudnason, Vilmundur and Psaty, Bruce M and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {7147, title = {Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 Oct}, pages = {811-24}, abstract = {

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30~884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90~years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

}, issn = {1474-9726}, doi = {10.1111/acel.12490}, author = {Teumer, Alexander and Qi, Qibin and Nethander, Maria and Aschard, Hugues and Bandinelli, Stefania and Beekman, Marian and Berndt, Sonja I and Bidlingmaier, Martin and Broer, Linda and Cappola, Anne and Ceda, Gian Paolo and Chanock, Stephen and Chen, Ming-Huei and Chen, Tai C and Chen, Yii-Der Ida and Chung, Jonathan and Del Greco Miglianico, Fabiola and Eriksson, Joel and Ferrucci, Luigi and Friedrich, Nele and Gnewuch, Carsten and Goodarzi, Mark O and Grarup, Niels and Guo, Tingwei and Hammer, Elke and Hayes, Richard B and Hicks, Andrew A and Hofman, Albert and Houwing-Duistermaat, Jeanine J and Hu, Frank and Hunter, David J and Husemoen, Lise L and Isaacs, Aaron and Jacobs, Kevin B and Janssen, Joop A M J L and Jansson, John-Olov and Jehmlich, Nico and Johnson, Simon and Juul, Anders and Karlsson, Magnus and Kilpel{\"a}inen, Tuomas O and Kovacs, Peter and Kraft, Peter and Li, Chao and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lorentzon, Mattias and Lu, Yingchang and Maggio, Marcello and M{\"a}gi, Reedik and Meigs, James and Mellstr{\"o}m, Dan and Nauck, Matthias and Newman, Anne B and Pollak, Michael N and Pramstaller, Peter P and Prokopenko, Inga and Psaty, Bruce M and Reincke, Martin and Rimm, Eric B and Rotter, Jerome I and Saint Pierre, Aude and Schurmann, Claudia and Seshadri, Sudha and Sj{\"o}gren, Klara and Slagboom, P Eline and Strickler, Howard D and Stumvoll, Michael and Suh, Yousin and Sun, Qi and Zhang, Cuilin and Svensson, Johan and Tanaka, Toshiko and Tare, Archana and T{\"o}njes, Anke and Uh, Hae-Won and van Duijn, Cornelia M and van Heemst, Diana and Vandenput, Liesbeth and Vasan, Ramachandran S and V{\"o}lker, Uwe and Willems, Sara M and Ohlsson, Claes and Wallaschofski, Henri and Kaplan, Robert C} } @article {7142, title = {GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 Oct}, pages = {792-800}, abstract = {

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27~581 individuals of European descent over 65~years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5~{\texttimes}~10(-8) ) and 39 suggestive (P-value< 5~{\texttimes}~10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β~=~0.47, SE~=~0.08, P-value~=~5.20~{\texttimes}~10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

}, issn = {1474-9726}, doi = {10.1111/acel.12468}, author = {Matteini, Amy M and Tanaka, Toshiko and Karasik, David and Atzmon, Gil and Chou, Wen-Chi and Eicher, John D and Johnson, Andrew D and Arnold, Alice M and Callisaya, Michele L and Davies, Gail and Evans, Daniel S and Holtfreter, Birte and Lohman, Kurt and Lunetta, Kathryn L and Mangino, Massimo and Smith, Albert V and Smith, Jennifer A and Teumer, Alexander and Yu, Lei and Arking, Dan E and Buchman, Aron S and Chibinik, Lori B and De Jager, Philip L and Evans, Denis A and Faul, Jessica D and Garcia, Melissa E and Gillham-Nasenya, Irina and Gudnason, Vilmundur and Hofman, Albert and Hsu, Yi-Hsiang and Ittermann, Till and Lahousse, Lies and Liewald, David C and Liu, Yongmei and Lopez, Lorna and Rivadeneira, Fernando and Rotter, Jerome I and Siggeirsdottir, Kristin and Starr, John M and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Weir, David R and Yaffe, Kristine and Zhao, Wei and Zhuang, Wei Vivian and Zmuda, Joseph M and Bennett, David A and Cummings, Steven R and Deary, Ian J and Ferrucci, Luigi and Harris, Tamara B and Kardia, Sharon L R and Kocher, Thomas and Kritchevsky, Stephen B and Psaty, Bruce M and Seshadri, Sudha and Spector, Timothy D and Srikanth, Velandai K and Windham, B Gwen and Zillikens, M Carola and Newman, Anne B and Walston, Jeremy D and Kiel, Douglas P and Murabito, Joanne M} } @article {7264, title = {Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Oct}, pages = {1162-70}, abstract = {

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

}, issn = {1546-1718}, doi = {10.1038/ng.3660}, author = {Liu, Chunyu and Kraja, Aldi T and Smith, Jennifer A and Brody, Jennifer A and Franceschini, Nora and Bis, Joshua C and Rice, Kenneth and Morrison, Alanna C and Lu, Yingchang and Weiss, Stefan and Guo, Xiuqing and Palmas, Walter and Martin, Lisa W and Chen, Yii-Der Ida and Surendran, Praveen and Drenos, Fotios and Cook, James P and Auer, Paul L and Chu, Audrey Y and Giri, Ayush and Zhao, Wei and Jakobsdottir, Johanna and Lin, Li-An and Stafford, Jeanette M and Amin, Najaf and Mei, Hao and Yao, Jie and Voorman, Arend and Larson, Martin G and Grove, Megan L and Smith, Albert V and Hwang, Shih-Jen and Chen, Han and Huan, Tianxiao and Kosova, Gulum and Stitziel, Nathan O and Kathiresan, Sekar and Samani, Nilesh and Schunkert, Heribert and Deloukas, Panos and Li, Man and Fuchsberger, Christian and Pattaro, Cristian and Gorski, Mathias and Kooperberg, Charles and Papanicolaou, George J and Rossouw, Jacques E and Faul, Jessica D and Kardia, Sharon L R and Bouchard, Claude and Raffel, Leslie J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Vasan, Ramachandran S and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Liu, Kiang and Bottinger, Erwin P and Gottesman, Omri and Daw, E Warwick and Giulianini, Franco and Ganesh, Santhi and Salfati, Elias and Harris, Tamara B and Launer, Lenore J and D{\"o}rr, Marcus and Felix, Stephan B and Rettig, Rainer and V{\"o}lzke, Henry and Kim, Eric and Lee, Wen-Jane and Lee, I-Te and Sheu, Wayne H-H and Tsosie, Krystal S and Edwards, Digna R Velez and Liu, Yongmei and Correa, Adolfo and Weir, David R and V{\"o}lker, Uwe and Ridker, Paul M and Boerwinkle, Eric and Gudnason, Vilmundur and Reiner, Alexander P and van Duijn, Cornelia M and Borecki, Ingrid B and Edwards, Todd L and Chakravarti, Aravinda and Rotter, Jerome I and Psaty, Bruce M and Loos, Ruth J F and Fornage, Myriam and Ehret, Georg B and Newton-Cheh, Christopher and Levy, Daniel and Chasman, Daniel I} } @article {6936, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {358-70}, abstract = {

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.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv454}, author = {de Vries, Paul S and Chasman, Daniel I and Sabater-Lleal, Maria and Chen, Ming-Huei and Huffman, Jennifer E and Steri, Maristella and Tang, Weihong and Teumer, Alexander and Marioni, Riccardo E and Grossmann, Vera and Hottenga, Jouke J and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Zhao, Jing Hua and Brody, Jennifer A and Kleber, Marcus E and Guo, Xiuqing and Wang, Jie Jin and Auer, Paul L and Attia, John R and Yanek, Lisa R and Ahluwalia, Tarunveer S and Lahti, Jari and Venturini, Cristina and Tanaka, Toshiko and Bielak, Lawrence F and Joshi, Peter K and Rocanin-Arjo, Ares and Kolcic, Ivana and Navarro, Pau and Rose, Lynda M and Oldmeadow, Christopher and Riess, Helene and Mazur, Johanna and Basu, Saonli and Goel, Anuj and Yang, Qiong and Ghanbari, Mohsen and Willemsen, Gonneke and Rumley, Ann and Fiorillo, Edoardo and de Craen, Anton J M and Grotevendt, Anne and Scott, Robert and Taylor, Kent D and Delgado, Graciela E and Yao, Jie and Kifley, Annette and Kooperberg, Charles and Qayyum, Rehan and Lopez, Lorna M and Berentzen, Tina L and R{\"a}ikk{\"o}nen, Katri and Mangino, Massimo and Bandinelli, Stefania and Peyser, Patricia A and Wild, Sarah and Tr{\'e}gou{\"e}t, David-Alexandre and Wright, Alan F and Marten, Jonathan and Zemunik, Tatijana and Morrison, Alanna C and Sennblad, Bengt and Tofler, Geoffrey and de Maat, Moniek P M and de Geus, Eco J C and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Binder, Harald and V{\"o}lker, Uwe and Waldenberger, Melanie and Khaw, Kay-Tee and McKnight, Barbara and Huang, Jie and Jenny, Nancy S and Holliday, Elizabeth G and Qi, Lihong and Mcevoy, Mark G and Becker, Diane M and Starr, John M and Sarin, Antti-Pekka and Hysi, Pirro G and Hernandez, Dena G and Jhun, Min A and Campbell, Harry and Hamsten, Anders and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Koenig, Wolfgang and Psaty, Bruce M and Haritunians, Talin and Liu, Jingmin and Palotie, Aarno and Uitterlinden, Andr{\'e} G and Stott, David J and Hofman, Albert and Franco, Oscar H and Polasek, Ozren and Rudan, Igor and Morange, Pierre-Emmanuel and Wilson, James F and Kardia, Sharon L R and Ferrucci, Luigi and Spector, Tim D and Eriksson, Johan G and Hansen, Torben and Deary, Ian J and Becker, Lewis C and Scott, Rodney J and Mitchell, Paul and M{\"a}rz, Winfried and Wareham, Nick J and Peters, Annette and Greinacher, Andreas and Wild, Philipp S and Jukema, J Wouter and Boomsma, Dorret I and Hayward, Caroline and Cucca, Francesco and Tracy, Russell and Watkins, Hugh and Reiner, Alex P and Folsom, Aaron R and Ridker, Paul M and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7257, title = {Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.}, journal = {Circ Cardiovasc Genet}, year = {2016}, month = {2016 Nov 21}, abstract = {

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

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

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

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001572}, author = {Natarajan, Pradeep and Bis, Joshua C and Bielak, Lawrence F and Cox, Amanda J and D{\"o}rr, Marcus and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and Isaacs, Aaron and Jhun, Min A and Kavousi, Maryam and Li-Gao, Ruifang and Lyytik{\"a}inen, Leo-Pekka and Marioni, Riccardo E and Schminke, Ulf and Stitziel, Nathan O and Tada, Hayato and van Setten, Jessica and Smith, Albert V and Vojinovic, Dina and Yanek, Lisa R and Yao, Jie and Yerges-Armstrong, Laura M and Amin, Najaf and Baber, Usman and Borecki, Ingrid B and Carr, J Jeffrey and Chen, Yii-Der Ida and Cupples, L Adrienne and de Jong, Pim A and de Koning, Harry and de Vos, Bob D and Demirkan, Ayse and Fuster, Valentin and Franco, Oscar H and Goodarzi, Mark O and Harris, Tamara B and Heckbert, Susan R and Heiss, Gerardo and Hoffmann, Udo and Hofman, Albert and I{\v s}gum, Ivana and Jukema, J Wouter and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Kral, Brian G and Launer, Lenore J and Massaro, Joseph and Mehran, Roxana and Mitchell, Braxton D and Mosley, Thomas H and de Mutsert, Ren{\'e}e and Newman, Anne B and Nguyen, Khanh-Dung and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Oudkerk, Matthijs and Pankow, James S and Peloso, Gina M and Post, Wendy and Province, Michael A and Raffield, Laura M and Raitakari, Olli T and Reilly, Dermot F and Rivadeneira, Fernando and Rosendaal, Frits and Sartori, Samantha and Taylor, Kent D and Teumer, Alexander and Trompet, Stella and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Lugt, Aad and V{\"o}lker, Uwe and Wardlaw, Joanna M and Wassel, Christina L and Weiss, Stefan and Wojczynski, Mary K and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Bowden, Donald W and Deary, Ian J and Dehghan, Abbas and Felix, Stephan B and Gudnason, Vilmundur and Lehtim{\"a}ki, Terho and Mathias, Rasika and Mook-Kanamori, Dennis O and Psaty, Bruce M and Rader, Daniel J and Rotter, Jerome I and Wilson, James G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Kathiresan, Sekar and Peyser, Patricia A and O{\textquoteright}Donnell, Christopher J} } @article {7139, title = {Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {40-55}, abstract = {

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets{\textquoteright} important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.005}, author = {Eicher, John D and Chami, Nathalie and Kacprowski, Tim and Nomura, Akihiro and Chen, Ming-Huei and Yanek, Lisa R and Tajuddin, Salman M and Schick, Ursula M and Slater, Andrew J and Pankratz, Nathan and Polfus, Linda and Schurmann, Claudia and Giri, Ayush and Brody, Jennifer A and Lange, Leslie A and Manichaikul, Ani and Hill, W David and Pazoki, Raha and Elliot, Paul and Evangelou, Evangelos and Tzoulaki, Ioanna and Gao, He and Vergnaud, Anne-Claire and Mathias, Rasika A and Becker, Diane M and Becker, Lewis C and Burt, Amber and Crosslin, David R and Lyytik{\"a}inen, Leo-Pekka and Nikus, Kjell and Hernesniemi, Jussi and K{\"a}h{\"o}nen, Mika and Raitoharju, Emma and Mononen, Nina and Raitakari, Olli T and Lehtim{\"a}ki, Terho and Cushman, Mary and Zakai, Neil A and Nickerson, Deborah A and Raffield, Laura M and Quarells, Rakale and Willer, Cristen J and Peloso, Gina M and Abecasis, Goncalo R and Liu, Dajiang J and Deloukas, Panos and Samani, Nilesh J and Schunkert, Heribert and Erdmann, Jeanette and Fornage, Myriam and Richard, Melissa and Tardif, Jean-Claude and Rioux, John D and Dub{\'e}, Marie-Pierre and de Denus, Simon and Lu, Yingchang and Bottinger, Erwin P and Loos, Ruth J F and Smith, Albert Vernon and Harris, Tamara B and Launer, Lenore J and Gudnason, Vilmundur and Velez Edwards, Digna R and Torstenson, Eric S and Liu, Yongmei and Tracy, Russell P and Rotter, Jerome I and Rich, Stephen S and Highland, Heather M and Boerwinkle, Eric and Li, Jin and Lange, Ethan and Wilson, James G and Mihailov, Evelin and M{\"a}gi, Reedik and Hirschhorn, Joel and Metspalu, Andres and Esko, T{\~o}nu and Vacchi-Suzzi, Caterina and Nalls, Mike A and Zonderman, Alan B and Evans, Michele K and Engstr{\"o}m, Gunnar and Orho-Melander, Marju and Melander, Olle and O{\textquoteright}Donoghue, Michelle L and Waterworth, Dawn M and Wallentin, Lars and White, Harvey D and Floyd, James S and Bartz, Traci M and Rice, Kenneth M and Psaty, Bruce M and Starr, J M and Liewald, David C M and Hayward, Caroline and Deary, Ian J and Greinacher, Andreas and V{\"o}lker, Uwe and Thiele, Thomas and V{\"o}lzke, Henry and van Rooij, Frank J A and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Dehghan, Abbas and Edwards, Todd L and Ganesh, Santhi K and Kathiresan, Sekar and Faraday, Nauder and Auer, Paul L and Reiner, Alex P and Lettre, Guillaume and Johnson, Andrew D} } @article {8570, title = {A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 11 23}, pages = {13357}, abstract = {

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99\% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

}, keywords = {Anthropometry, Body Size, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Principal Component Analysis}, issn = {2041-1723}, doi = {10.1038/ncomms13357}, author = {Ried, Janina S and Jeff M, Janina and Chu, Audrey Y and Bragg-Gresham, Jennifer L and van Dongen, Jenny and Huffman, Jennifer E and Ahluwalia, Tarunveer S and Cadby, Gemma and Eklund, Niina and Eriksson, Joel and Esko, T{\~o}nu and Feitosa, Mary F and Goel, Anuj and Gorski, Mathias and Hayward, Caroline and Heard-Costa, Nancy L and Jackson, Anne U and Jokinen, Eero and Kanoni, Stavroula and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lahti, Jari and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mahajan, Anubha and Mangino, Massimo and Medina-G{\'o}mez, Carolina and Monda, Keri L and Nolte, Ilja M and Perusse, Louis and Prokopenko, Inga and Qi, Lu and Rose, Lynda M and Salvi, Erika and Smith, Megan T and Snieder, Harold and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tachmazidou, Ioanna and Teumer, Alexander and Thorleifsson, Gudmar and van der Harst, Pim and Walker, Ryan W and Wang, Sophie R and Wild, Sarah H and Willems, Sara M and Wong, Andrew and Zhang, Weihua and Albrecht, Eva and Couto Alves, Alexessander and Bakker, Stephan J L and Barlassina, Cristina and Bartz, Traci M and Beilby, John and Bellis, Claire and Bergman, Richard N and Bergmann, Sven and Blangero, John and Bl{\"u}her, Matthias and Boerwinkle, Eric and Bonnycastle, Lori L and Bornstein, Stefan R and Bruinenberg, Marcel and Campbell, Harry and Chen, Yii-Der Ida and Chiang, Charleston W K and Chines, Peter S and Collins, Francis S and Cucca, Fracensco and Cupples, L Adrienne and D{\textquoteright}Avila, Francesca and de Geus, Eco J C and Dedoussis, George and Dimitriou, Maria and D{\"o}ring, Angela and Eriksson, Johan G and Farmaki, Aliki-Eleni and Farrall, Martin and Ferreira, Teresa and Fischer, Krista and Forouhi, Nita G and Friedrich, Nele and Gjesing, Anette Prior and Glorioso, Nicola and Graff, Mariaelisa and Grallert, Harald and Grarup, Niels and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Hamsten, Anders and Harder, Marie Neergaard and Hartman, Catharina A and Hassinen, Maija and Hastie, Nicholas and Hattersley, Andrew Tym and Havulinna, Aki S and Heli{\"o}vaara, Markku and Hillege, Hans and Hofman, Albert and Holmen, Oddgeir and Homuth, Georg and Hottenga, Jouke-Jan and Hui, Jennie and Husemoen, Lise Lotte and Hysi, Pirro G and Isaacs, Aaron and Ittermann, Till and Jalilzadeh, Shapour and James, Alan L and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Marie Justesen, Johanne and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Karaleftheri, Maria and Tee Khaw, Kay and Keinanen-Kiukaanniemi, Sirkka M and Kinnunen, Leena and Knekt, Paul B and Koistinen, Heikki A and Kolcic, Ivana and Kooner, Ishminder K and Koskinen, Seppo and Kovacs, Peter and Kyriakou, Theodosios and Laitinen, Tomi and Langenberg, Claudia and Lewin, Alexandra M and Lichtner, Peter and Lindgren, Cecilia M and Lindstr{\"o}m, Jaana and Linneberg, Allan and Lorbeer, Roberto and Lorentzon, Mattias and Luben, Robert and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Manunta, Paolo and Leach, Irene Mateo and McArdle, Wendy L and McKnight, Barbara and Mohlke, Karen L and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Montasser, May E and Morris, Andrew P and M{\"u}ller, Gabriele and Musk, Arthur W and Narisu, Narisu and Ong, Ken K and Oostra, Ben A and Osmond, Clive and Palotie, Aarno and Pankow, James S and Paternoster, Lavinia and Penninx, Brenda W and Pichler, Irene and Pilia, Maria G and Polasek, Ozren and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rayner, Nigel W and Ribel-Madsen, Rasmus and Rice, Treva K and Richards, Marcus and Ridker, Paul M and Rivadeneira, Fernando and Ryan, Kathy A and Sanna, Serena and Sarzynski, Mark A and Scholtens, Salome and Scott, Robert A and Sebert, Sylvain and Southam, Lorraine and Spars{\o}, Thomas Hempel and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stolk, Ronald P and Strauch, Konstantin and Stringham, Heather M and Swertz, Morris A and Swift, Amy J and T{\"o}njes, Anke and Tsafantakis, Emmanouil and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Vartiainen, Erkki and Venturini, Cristina and Verweij, Niek and Viikari, Jorma S and Vitart, Veronique and Vohl, Marie-Claude and Vonk, Judith M and Waeber, G{\'e}rard and Widen, Elisabeth and Willemsen, Gonneke and Wilsgaard, Tom and Winkler, Thomas W and Wright, Alan F and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Zillikens, M Carola and Boomsma, Dorret I and Bouchard, Claude and Chambers, John C and Chasman, Daniel I and Cusi, Daniele and Gansevoort, Ron T and Gieger, Christian and Hansen, Torben and Hicks, Andrew A and Hu, Frank and Hveem, Kristian and Jarvelin, Marjo-Riitta and Kajantie, Eero and Kooner, Jaspal S and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Metspalu, Andres and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Palmer, Lyle J and Pedersen, Oluf and Perola, Markus and Peters, Annette and Psaty, Bruce M and Puolijoki, Hannu and Rauramaa, Rainer and Rudan, Igor and Salomaa, Veikko and Schwarz, Peter E H and Shudiner, Alan R and Smit, Jan H and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Tremblay, Angelo and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and V{\"o}lker, Uwe and Vollenweider, Peter and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Zeggini, Eleftheria and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and van Duijn, Cornelia M and Fox, Caroline and Groop, Leif C and Heid, Iris M and Hunter, David J and Kaplan, Robert C and McCarthy, Mark I and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Thorsteinsdottir, Unnur and Strachan, David P and Frayling, Timothy and Hirschhorn, Joel N and M{\"u}ller-Nurasyid, Martina and Loos, Ruth J F} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

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{\texttimes}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{\texttimes}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.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {7343, title = {Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0167742}, abstract = {

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5{\texttimes}10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5{\texttimes}10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20\% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0167742}, author = {de Vries, Paul S and Sabater-Lleal, Maria and Chasman, Daniel I and Trompet, Stella and Ahluwalia, Tarunveer S and Teumer, Alexander and Kleber, Marcus E and Chen, Ming-Huei and Wang, Jie Jin and Attia, John R and Marioni, Riccardo E and Steri, Maristella and Weng, Lu-Chen and Pool, Rene and Grossmann, Vera and Brody, Jennifer A and Venturini, Cristina and Tanaka, Toshiko and Rose, Lynda M and Oldmeadow, Christopher and Mazur, Johanna and Basu, Saonli and Fr{\r a}nberg, Mattias and Yang, Qiong and Ligthart, Symen and Hottenga, Jouke J and Rumley, Ann and Mulas, Antonella and de Craen, Anton J M and Grotevendt, Anne and Taylor, Kent D and Delgado, Graciela E and Kifley, Annette and Lopez, Lorna M and Berentzen, Tina L and Mangino, Massimo and Bandinelli, Stefania and Morrison, Alanna C and Hamsten, Anders and Tofler, Geoffrey and de Maat, Moniek P M and Draisma, Harmen H M and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Lackner, Karl J and V{\"o}lker, Uwe and McKnight, Barbara and Huang, Jie and Holliday, Elizabeth G and McEvoy, Mark A and Starr, John M and Hysi, Pirro G and Hernandez, Dena G and Guan, Weihua and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and de Geus, Eco J C and Stott, David J and Binder, Harald and Hofman, Albert and Franco, Oscar H and Rotter, Jerome I and Ferrucci, Luigi and Spector, Tim D and Deary, Ian J and M{\"a}rz, Winfried and Greinacher, Andreas and Wild, Philipp S and Cucca, Francesco and Boomsma, Dorret I and Watkins, Hugh and Tang, Weihong and Ridker, Paul M and Jukema, Jan W and Scott, Rodney J and Mitchell, Paul and Hansen, Torben and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7363, title = {Discovery of novel heart rate-associated loci using the Exome Chip.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

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

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx113}, author = {van den Berg, Marten E and Warren, Helen R and Cabrera, Claudia P and Verweij, Niek and Mifsud, Borbala and Haessler, Jeffrey and Bihlmeyer, Nathan A and Fu, Yi-Ping and Weiss, Stefan and Lin, Henry J and Grarup, Niels and Li-Gao, Ruifang and Pistis, Giorgio and Shah, Nabi and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Lin, Honghuang and Mei, Hao and Smith, Albert V and Lyytik{\"a}inen, Leo-Pekka and Hall, Leanne M and van Setten, Jessica and Trompet, Stella and Prins, Bram P and Isaacs, Aaron and Radmanesh, Farid and Marten, Jonathan and Entwistle, Aiman and Kors, Jan A and Silva, Claudia T and Alonso, Alvaro and Bis, Joshua C and de Boer, Rudolf and de Haan, Hugoline G and de Mutsert, Ren{\'e}e and Dedoussis, George and Dominiczak, Anna F and Doney, Alex S F and Ellinor, Patrick T and Eppinga, Ruben N and Felix, Stephan B and Guo, Xiuqing and Hagemeijer, Yanick and Hansen, Torben and Harris, Tamara B and Heckbert, Susan R and Huang, Paul L and Hwang, Shih-Jen and K{\"a}h{\"o}nen, Mika and Kanters, J{\o}rgen K and Kolcic, Ivana and Launer, Lenore J and Li, Man and Yao, Jie and Linneberg, Allan and Liu, Simin and Macfarlane, Peter W and Mangino, Massimo and Morris, Andrew D and Mulas, Antonella and Murray, Alison D and Nelson, Christopher P and Orr{\`u}, Marco and Padmanabhan, Sandosh and Peters, Annette and Porteous, David J and Poulter, Neil and Psaty, Bruce M and Qi, Lihong and Raitakari, Olli T and Rivadeneira, Fernando and Roselli, Carolina and Rudan, Igor and Sattar, Naveed and Sever, Peter and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Timothy D and Stanton, Alice V and Stirrups, Kathleen E and Taylor, Kent D and Tobin, Martin D and Uitterlinden, Andre and Vaartjes, Ilonca and Hoes, Arno W and van der Meer, Peter and V{\"o}lker, Uwe and Waldenberger, Melanie and Xie, Zhijun and Zoledziewska, Magdalena and Tinker, Andrew and Polasek, Ozren and Rosand, Jonathan and Jamshidi, Yalda and van Duijn, Cornelia M and Zeggini, Eleftheria and Wouter Jukema, J and Asselbergs, Folkert W and Samani, Nilesh J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Wilson, James and Lubitz, Steven A and K{\"a}{\"a}b, Stefan and Sotoodehnia, Nona and Caulfield, Mark J and Palmer, Colin N A and Sanna, Serena and Mook-Kanamori, Dennis O and Deloukas, Panos and Pedersen, Oluf and Rotter, Jerome I and D{\"o}rr, Marcus and O{\textquoteright}Donnell, Chris J and Hayward, Caroline and Arking, Dan E and Kooperberg, Charles and van der Harst, Pim and Eijgelsheim, Mark and Stricker, Bruno H and Munroe, Patricia B} } @article {7557, title = {Fifteen Genetic Loci Associated With the Electrocardiographic P Wave.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, abstract = {

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{\texttimes}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.

}, keywords = {Arrhythmias, Cardiac, Caveolin 1, Caveolin 2, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Genotype, Heart Atria, Humans, NAV1.5 Voltage-Gated Sodium Channel, NAV1.8 Voltage-Gated Sodium Channel, T-Box Domain Proteins}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001667}, author = {Christophersen, Ingrid E and Magnani, Jared W and Yin, Xiaoyan and Barnard, John and Weng, Lu-Chen and Arking, Dan E and Niemeijer, Maartje N and Lubitz, Steven A and Avery, Christy L and Duan, Qing and Felix, Stephan B and Bis, Joshua C and Kerr, Kathleen F and Isaacs, Aaron and M{\"u}ller-Nurasyid, Martina and M{\"u}ller, Christian and North, Kari E and Reiner, Alex P and Tinker, Lesley F and Kors, Jan A and Teumer, Alexander and Petersmann, Astrid and Sinner, Moritz F and B{\r u}zkov{\'a}, Petra and Smith, Jonathan D and Van Wagoner, David R and V{\"o}lker, Uwe and Waldenberger, Melanie and Peters, Annette and Meitinger, Thomas and Limacher, Marian C and Wilhelmsen, Kirk C and Psaty, Bruce M and Hofman, Albert and Uitterlinden, Andre and Krijthe, Bouwe P and Zhang, Zhu-Ming and Schnabel, Renate B and K{\"a}{\"a}b, Stefan and van Duijn, Cornelia and Rotter, Jerome I and Sotoodehnia, Nona and D{\"o}rr, Marcus and Li, Yun and Chung, Mina K and Soliman, Elsayed Z and Alonso, Alvaro and Whitsel, Eric A and Stricker, Bruno H and Benjamin, Emelia J and Heckbert, Susan R and Ellinor, Patrick T} } @article {7595, title = {Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 Sep 12}, pages = {11303}, abstract = {

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 {\texttimes} 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 {\texttimes} 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.

}, issn = {2045-2322}, doi = {10.1038/s41598-017-09396-7}, author = {Weng, Lu-Chen and Lunetta, Kathryn L and M{\"u}ller-Nurasyid, Martina and Smith, Albert Vernon and Th{\'e}riault, S{\'e}bastien and Weeke, Peter E and Barnard, John and Bis, Joshua C and Lyytik{\"a}inen, Leo-Pekka and Kleber, Marcus E and Martinsson, Andreas and Lin, Henry J and Rienstra, Michiel and Trompet, Stella and Krijthe, Bouwe P and D{\"o}rr, Marcus and Klarin, Derek and Chasman, Daniel I and Sinner, Moritz F and Waldenberger, Melanie and Launer, Lenore J and Harris, Tamara B and Soliman, Elsayed Z and Alonso, Alvaro and Par{\'e}, Guillaume and Teixeira, Pedro L and Denny, Joshua C and Shoemaker, M Benjamin and Van Wagoner, David R and Smith, Jonathan D and Psaty, Bruce M and Sotoodehnia, Nona and Taylor, Kent D and K{\"a}h{\"o}nen, Mika and Nikus, Kjell and Delgado, Graciela E and Melander, Olle and Engstr{\"o}m, Gunnar and Yao, Jie and Guo, Xiuqing and Christophersen, Ingrid E and Ellinor, Patrick T and Geelhoed, Bastiaan and Verweij, Niek and Macfarlane, Peter and Ford, Ian and Heeringa, Jan and Franco, Oscar H and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Teumer, Alexander and Rose, Lynda M and K{\"a}{\"a}b, Stefan and Gudnason, Vilmundur and Arking, Dan E and Conen, David and Roden, Dan M and Chung, Mina K and Heckbert, Susan R and Benjamin, Emelia J and Lehtim{\"a}ki, Terho and M{\"a}rz, Winfried and Smith, J Gustav and Rotter, Jerome I and van der Harst, Pim and Jukema, J Wouter and Stricker, Bruno H and Felix, Stephan B and Albert, Christine M and Lubitz, Steven A} } @article {7396, title = {Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {946-952}, abstract = {

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

}, issn = {1546-1718}, doi = {10.1038/ng.3843}, author = {Christophersen, Ingrid E and Rienstra, Michiel and Roselli, Carolina and Yin, Xiaoyan and Geelhoed, Bastiaan and Barnard, John and Lin, Honghuang and Arking, Dan E and Smith, Albert V and Albert, Christine M and Chaffin, Mark and Tucker, Nathan R and Li, Molong and Klarin, Derek and Bihlmeyer, Nathan A and Low, Siew-Kee and Weeke, Peter E and M{\"u}ller-Nurasyid, Martina and Smith, J Gustav and Brody, Jennifer A and Niemeijer, Maartje N and D{\"o}rr, Marcus and Trompet, Stella and Huffman, Jennifer and Gustafsson, Stefan and Schurmann, Claudia and Kleber, Marcus E and Lyytik{\"a}inen, Leo-Pekka and Sepp{\"a}l{\"a}, Ilkka and Malik, Rainer and Horimoto, Andrea R V R and Perez, Marco and Sinisalo, Juha and Aeschbacher, Stefanie and Th{\'e}riault, S{\'e}bastien and Yao, Jie and Radmanesh, Farid and Weiss, Stefan and Teumer, Alexander and Choi, Seung Hoan and Weng, Lu-Chen and Clauss, Sebastian and Deo, Rajat and Rader, Daniel J and Shah, Svati H and Sun, Albert and Hopewell, Jemma C and Debette, Stephanie and Chauhan, Ganesh and Yang, Qiong and Worrall, Bradford B and Par{\'e}, Guillaume and Kamatani, Yoichiro and Hagemeijer, Yanick P and Verweij, Niek and Siland, Joylene E and Kubo, Michiaki and Smith, Jonathan D and Van Wagoner, David R and Bis, Joshua C and Perz, Siegfried and Psaty, Bruce M and Ridker, Paul M and Magnani, Jared W and Harris, Tamara B and Launer, Lenore J and Shoemaker, M Benjamin and Padmanabhan, Sandosh and Haessler, Jeffrey and Bartz, Traci M and Waldenberger, Melanie and Lichtner, Peter and Arendt, Marina and Krieger, Jose E and K{\"a}h{\"o}nen, Mika and Risch, Lorenz and Mansur, Alfredo J and Peters, Annette and Smith, Blair H and Lind, Lars and Scott, Stuart A and Lu, Yingchang and Bottinger, Erwin B and Hernesniemi, Jussi and Lindgren, Cecilia M and Wong, Jorge A and Huang, Jie and Eskola, Markku and Morris, Andrew P and Ford, Ian and Reiner, Alex P and Delgado, Graciela and Chen, Lin Y and Chen, Yii-Der Ida and Sandhu, Roopinder K and Li, Man and Boerwinkle, Eric and Eisele, Lewin and Lannfelt, Lars and Rost, Natalia and Anderson, Christopher D and Taylor, Kent D and Campbell, Archie and Magnusson, Patrik K and Porteous, David and Hocking, Lynne J and Vlachopoulou, Efthymia and Pedersen, Nancy L and Nikus, Kjell and Orho-Melander, Marju and Hamsten, Anders and Heeringa, Jan and Denny, Joshua C and Kriebel, Jennifer and Darbar, Dawood and Newton-Cheh, Christopher and Shaffer, Christian and Macfarlane, Peter W and Heilmann-Heimbach, Stefanie and Almgren, Peter and Huang, Paul L and Sotoodehnia, Nona and Soliman, Elsayed Z and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and V{\"o}lker, Uwe and J{\"o}ckel, Karl-Heinz and Sinner, Moritz F and Lin, Henry J and Guo, Xiuqing and Dichgans, Martin and Ingelsson, Erik and Kooperberg, Charles and Melander, Olle and Loos, Ruth J F and Laurikka, Jari and Conen, David and Rosand, Jonathan and van der Harst, Pim and Lokki, Marja-Liisa and Kathiresan, Sekar and Pereira, Alexandre and Jukema, J Wouter and Hayward, Caroline and Rotter, Jerome I and M{\"a}rz, Winfried and Lehtim{\"a}ki, Terho and Stricker, Bruno H and Chung, Mina K and Felix, Stephan B and Gudnason, Vilmundur and Alonso, Alvaro and Roden, Dan M and K{\"a}{\"a}b, Stefan and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Tanaka, Toshihiro and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} } @article {7373, title = {Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 May 01}, pages = {1798-1812}, abstract = {

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

FUNDING: For detailed information per study, see Acknowledgments.

}, issn = {1558-8238}, doi = {10.1172/JCI84840}, author = {Wild, Philipp S and Felix, Janine F and Schillert, Arne and Teumer, Alexander and Chen, Ming-Huei and Leening, Maarten J G and V{\"o}lker, Uwe and Gro{\ss}mann, Vera and Brody, Jennifer A and Irvin, Marguerite R and Shah, Sanjiv J and Pramana, Setia and Lieb, Wolfgang and Schmidt, Reinhold and Stanton, Alice V and Malzahn, D{\"o}rthe and Smith, Albert Vernon and Sundstr{\"o}m, Johan and Minelli, Cosetta and Ruggiero, Daniela and Lyytik{\"a}inen, Leo-Pekka and Tiller, Daniel and Smith, J Gustav and Monnereau, Claire and Di Tullio, Marco R and Musani, Solomon K and Morrison, Alanna C and Pers, Tune H and Morley, Michael and Kleber, Marcus E and Aragam, Jayashri and Benjamin, Emelia J and Bis, Joshua C and Bisping, Egbert and Broeckel, Ulrich and Cheng, Susan and Deckers, Jaap W and del Greco M, Fabiola and Edelmann, Frank and Fornage, Myriam and Franke, Lude and Friedrich, Nele and Harris, Tamara B and Hofer, Edith and Hofman, Albert and Huang, Jie and Hughes, Alun D and K{\"a}h{\"o}nen, Mika and Investigators, Knhi and Kruppa, Jochen and Lackner, Karl J and Lannfelt, Lars and Laskowski, Rafael and Launer, Lenore J and Leosdottir, Margr{\'e}t and Lin, Honghuang and Lindgren, Cecilia M and Loley, Christina and MacRae, Calum A and Mascalzoni, Deborah and Mayet, Jamil and Medenwald, Daniel and Morris, Andrew P and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nappo, Stefania and Nilsson, Peter M and Nuding, Sebastian and Nutile, Teresa and Peters, Annette and Pfeufer, Arne and Pietzner, Diana and Pramstaller, Peter P and Raitakari, Olli T and Rice, Kenneth M and Rivadeneira, Fernando and Rotter, Jerome I and Ruohonen, Saku T and Sacco, Ralph L and Samdarshi, Tandaw E and Schmidt, Helena and Sharp, Andrew S P and Shields, Denis C and Sorice, Rossella and Sotoodehnia, Nona and Stricker, Bruno H and Surendran, Praveen and Thom, Simon and T{\"o}glhofer, Anna M and Uitterlinden, Andr{\'e} G and Wachter, Rolf and V{\"o}lzke, Henry and Ziegler, Andreas and M{\"u}nzel, Thomas and M{\"a}rz, Winfried and Cappola, Thomas P and Hirschhorn, Joel N and Mitchell, Gary F and Smith, Nicholas L and Fox, Ervin R and Dueker, Nicole D and Jaddoe, Vincent W V and Melander, Olle and Russ, Martin and Lehtim{\"a}ki, Terho and Ciullo, Marina and Hicks, Andrew A and Lind, Lars and Gudnason, Vilmundur and Pieske, Burkert and Barron, Anthony J and Zweiker, Robert and Schunkert, Heribert and Ingelsson, Erik and Liu, Kiang and Arnett, Donna K and Psaty, Bruce M and Blankenberg, Stefan and Larson, Martin G and Felix, Stephan B and Franco, Oscar H and Zeller, Tanja and Vasan, Ramachandran S and D{\"o}rr, Marcus} } @article {7492, title = {Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.}, journal = {Hypertension}, year = {2017}, month = {2017 Jul 24}, abstract = {

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.09438}, author = {Wain, Louise V and Vaez, Ahmad and Jansen, Rick and Joehanes, Roby and van der Most, Peter J and Erzurumluoglu, A Mesut and O{\textquoteright}Reilly, Paul F and Cabrera, Claudia P and Warren, Helen R and Rose, Lynda M and Verwoert, Germaine C and Hottenga, Jouke-Jan and Strawbridge, Rona J and Esko, T{\~o}nu and Arking, Dan E and Hwang, Shih-Jen and Guo, Xiuqing and Kutalik, Zolt{\'a}n and Trompet, Stella and Shrine, Nick and Teumer, Alexander and Ried, Janina S and Bis, Joshua C and Smith, Albert V and Amin, Najaf and Nolte, Ilja M and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Wareham, Nicholas J and Hofer, Edith and Joshi, Peter K and Kristiansson, Kati and Traglia, Michela and Havulinna, Aki S and Goel, Anuj and Nalls, Mike A and S{\~o}ber, Siim and Vuckovic, Dragana and Luan, Jian{\textquoteright}an and del Greco M, Fabiola and Ayers, Kristin L and Marrugat, Jaume and Ruggiero, Daniela and Lopez, Lorna M and Niiranen, Teemu and Enroth, Stefan and Jackson, Anne U and Nelson, Christopher P and Huffman, Jennifer E and Zhang, Weihua and Marten, Jonathan and Gandin, Ilaria and Harris, Sarah E and Zemunik, Tatijana and Lu, Yingchang and Evangelou, Evangelos and Shah, Nabi and de Borst, Martin H and Mangino, Massimo and Prins, Bram P and Campbell, Archie and Li-Gao, Ruifang and Chauhan, Ganesh and Oldmeadow, Christopher and Abecasis, Goncalo and Abedi, Maryam and Barbieri, Caterina M and Barnes, Michael R and Batini, Chiara and Beilby, John and Blake, Tineka and Boehnke, Michael and Bottinger, Erwin P and Braund, Peter S and Brown, Morris and Brumat, Marco and Campbell, Harry and Chambers, John C and Cocca, Massimiliano and Collins, Francis and Connell, John and Cordell, Heather J and Damman, Jeffrey J and Davies, Gail and de Geus, Eco J and de Mutsert, Ren{\'e}e and Deelen, Joris and Demirkale, Yusuf and Doney, Alex S F and D{\"o}rr, Marcus and Farrall, Martin and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Gao, He and Giedraitis, Vilmantas and Gieger, Christian and Giulianini, Franco and Gow, Alan J and Hamsten, Anders and Harris, Tamara B and Hofman, Albert and Holliday, Elizabeth G and Hui, Jennie and Jarvelin, Marjo-Riitta and Johansson, Asa and Johnson, Andrew D and Jousilahti, Pekka and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Khaw, Kay-Tee and Kolcic, Ivana and Koskinen, Seppo and Langenberg, Claudia and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Liewald, David C M and Lin, Li and Lind, Lars and Mach, Fran{\c c}ois and Mamasoula, Chrysovalanto and Menni, Cristina and Mifsud, Borbala and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew D and Morrison, Alanna C and Munson, Peter J and Nandakumar, Priyanka and Nguyen, Quang Tri and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and Org, Elin and Padmanabhan, Sandosh and Palotie, Aarno and Par{\'e}, Guillaume and Pattie, Alison and Penninx, Brenda W J H and Poulter, Neil and Pramstaller, Peter P and Raitakari, Olli T and Ren, Meixia and Rice, Kenneth and Ridker, Paul M and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rotter, Jerome I and Rudan, Igor and Saba, Yasaman and Saint Pierre, Aude and Sala, Cinzia F and Sarin, Antti-Pekka and Schmidt, Reinhold and Scott, Rodney and Seelen, Marc A and Shields, Denis C and Siscovick, David and Sorice, Rossella and Stanton, Alice and Stott, David J and Sundstr{\"o}m, Johan and Swertz, Morris and Taylor, Kent D and Thom, Simon and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Vollenweider, Peter and Wild, Sarah and Willemsen, Gonneke and Wright, Alan F and Yao, Jie and Th{\'e}riault, S{\'e}bastien and Conen, David and Attia, John and Sever, Peter and Debette, Stephanie and Mook-Kanamori, Dennis O and Zeggini, Eleftheria and Spector, Tim D and van der Harst, Pim and Palmer, Colin N A and Vergnaud, Anne-Claire and Loos, Ruth J F and Polasek, Ozren and Starr, John M and Girotto, Giorgia and Hayward, Caroline and Kooner, Jaspal S and Lindgren, Cecila M and Vitart, Veronique and Samani, Nilesh J and Tuomilehto, Jaakko and Gyllensten, Ulf and Knekt, Paul and Deary, Ian J and Ciullo, Marina and Elosua, Roberto and Keavney, Bernard D and Hicks, Andrew A and Scott, Robert A and Gasparini, Paolo and Laan, Maris and Liu, Yongmei and Watkins, Hugh and Hartman, Catharina A and Salomaa, Veikko and Toniolo, Daniela and Perola, Markus and Wilson, James F and Schmidt, Helena and Zhao, Jing Hua and Lehtim{\"a}ki, Terho and van Duijn, Cornelia M and Gudnason, Vilmundur and Psaty, Bruce M and Peters, Annette and Rettig, Rainer and James, Alan and Jukema, J Wouter and Strachan, David P and Palmas, Walter and Metspalu, Andres and Ingelsson, Erik and Boomsma, Dorret I and Franco, Oscar H and Bochud, Murielle and Newton-Cheh, Christopher and Munroe, Patricia B and Elliott, Paul and Chasman, Daniel I and Chakravarti, Aravinda and Knight, Joanne and Morris, Andrew P and Levy, Daniel and Tobin, Martin D and Snieder, Harold and Caulfield, Mark J and Ehret, Georg B} } @article {7801, title = {Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 May}, pages = {e002037}, abstract = {

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

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

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

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

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

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

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

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

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

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

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

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

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.001758}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Warren, Helen R and Lin, Honghuang and Isaacs, Aaron and Liu, Ching-Ti and Marten, Jonathan and Radmanesh, Farid and Hall, Leanne M and Grarup, Niels and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Huffman, Jennifer E and Verweij, Niek and Guo, Xiuqing and Yao, Jie and Li-Gao, Ruifang and van den Berg, Marten and Weiss, Stefan and Prins, Bram P and van Setten, Jessica and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Bis, Joshua C and Austin, Tom and Chen, Yii-Der Ida and Psaty, Bruce M and Harrris, Tamara B and Launer, Lenore J and Padmanabhan, Sandosh and Dominiczak, Anna and Huang, Paul L and Xie, Zhijun and Ellinor, Patrick T and Kors, Jan A and Campbell, Archie and Murray, Alison D and Nelson, Christopher P and Tobin, Martin D and Bork-Jensen, Jette and Hansen, Torben and Pedersen, Oluf and Linneberg, Allan and Sinner, Moritz F and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Perz, Siegfried and Kolcic, Ivana and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Lin, Henry J and Taylor, Kent D and de Mutsert, Ren{\'e}e and Trompet, Stella and Jukema, J Wouter and Maan, Arie C and Stricker, Bruno H C and Rivadeneira, Fernando and Uitterlinden, Andre and V{\"o}lker, Uwe and Homuth, Georg and V{\"o}lzke, Henry and Felix, Stephan B and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Gudnason, Vilmundur and Munroe, Patricia B and Lubitz, Steven A and van Duijn, Cornelia M and Newton-Cheh, Christopher H and Hayward, Caroline and Rosand, Jonathan and Samani, Nilesh J and Kanters, J{\o}rgen K and Wilson, James G and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Rotter, Jerome I and Mook-Kanamori, Dennis O and Eijgelsheim, Mark and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Arking, Dan E and Sotoodehnia, Nona} } @article {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {7913, title = {GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 12 03}, pages = {5141}, abstract = {

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

}, keywords = {ADAMTS9 Protein, Amino Acid Oxidoreductases, Carotid Intima-Media Thickness, Coronary Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lod Score, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-018-07340-5}, author = {Franceschini, Nora and Giambartolomei, Claudia and de Vries, Paul S and Finan, Chris and Bis, Joshua C and Huntley, Rachael P and Lovering, Ruth C and Tajuddin, Salman M and Winkler, Thomas W and Graff, Misa and Kavousi, Maryam and Dale, Caroline and Smith, Albert V and Hofer, Edith and van Leeuwen, Elisabeth M and Nolte, Ilja M and Lu, Lingyi and Scholz, Markus and Sargurupremraj, Muralidharan and Pitk{\"a}nen, Niina and Franz{\'e}n, Oscar and Joshi, Peter K and Noordam, Raymond and Marioni, Riccardo E and Hwang, Shih-Jen and Musani, Solomon K and Schminke, Ulf and Palmas, Walter and Isaacs, Aaron and Correa, Adolfo and Zonderman, Alan B and Hofman, Albert and Teumer, Alexander and Cox, Amanda J and Uitterlinden, Andr{\'e} G and Wong, Andrew and Smit, Andries J and Newman, Anne B and Britton, Annie and Ruusalepp, Arno and Sennblad, Bengt and Hedblad, Bo and Pasaniuc, Bogdan and Penninx, Brenda W and Langefeld, Carl D and Wassel, Christina L and Tzourio, Christophe and Fava, Cristiano and Baldassarre, Damiano and O{\textquoteright}Leary, Daniel H and Teupser, Daniel and Kuh, Diana and Tremoli, Elena and Mannarino, Elmo and Grossi, Enzo and Boerwinkle, Eric and Schadt, Eric E and Ingelsson, Erik and Veglia, Fabrizio and Rivadeneira, Fernando and Beutner, Frank and Chauhan, Ganesh and Heiss, Gerardo and Snieder, Harold and Campbell, Harry and V{\"o}lzke, Henry and Markus, Hugh S and Deary, Ian J and Jukema, J Wouter and de Graaf, Jacqueline and Price, Jacqueline and Pott, Janne and Hopewell, Jemma C and Liang, Jingjing and Thiery, Joachim and Engmann, Jorgen and Gertow, Karl and Rice, Kenneth and Taylor, Kent D and Dhana, Klodian and Kiemeney, Lambertus A L M and Lind, Lars and Raffield, Laura M and Launer, Lenore J and Holdt, Lesca M and D{\"o}rr, Marcus and Dichgans, Martin and Traylor, Matthew and Sitzer, Matthias and Kumari, Meena and Kivimaki, Mika and Nalls, Mike A and Melander, Olle and Raitakari, Olli and Franco, Oscar H and Rueda-Ochoa, Oscar L and Roussos, Panos and Whincup, Peter H and Amouyel, Philippe and Giral, Philippe and Anugu, Pramod and Wong, Quenna and Malik, Rainer and Rauramaa, Rainer and Burkhardt, Ralph and Hardy, Rebecca and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Morris, Richard W and Strawbridge, Rona J and Wannamethee, S Goya and H{\"a}gg, Sara and Shah, Sonia and McLachlan, Stela and Trompet, Stella and Seshadri, Sudha and Kurl, Sudhir and Heckbert, Susan R and Ring, Susan and Harris, Tamara B and Lehtim{\"a}ki, Terho and Galesloot, Tessel E and Shah, Tina and de Faire, Ulf and Plagnol, Vincent and Rosamond, Wayne D and Post, Wendy and Zhu, Xiaofeng and Zhang, Xiaoling and Guo, Xiuqing and Saba, Yasaman and Dehghan, Abbas and Seldenrijk, Adrie and Morrison, Alanna C and Hamsten, Anders and Psaty, Bruce M and van Duijn, Cornelia M and Lawlor, Deborah A and Mook-Kanamori, Dennis O and Bowden, Donald W and Schmidt, Helena and Wilson, James F and Wilson, James G and Rotter, Jerome I and Wardlaw, Joanna M and Deanfield, John and Halcox, Julian and Lyytik{\"a}inen, Leo-Pekka and Loeffler, Markus and Evans, Michele K and Debette, Stephanie and Humphries, Steve E and V{\"o}lker, Uwe and Gudnason, Vilmundur and Hingorani, Aroon D and Bj{\"o}rkegren, Johan L M and Casas, Juan P and O{\textquoteright}Donnell, Christopher J} } @article {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

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

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @article {7815, title = {PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 25}, pages = {2904}, abstract = {

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.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04766-9}, author = {van Setten, Jessica and Brody, Jennifer A and Jamshidi, Yalda and Swenson, Brenton R and Butler, Anne M and Campbell, Harry and Del Greco, Fabiola M and Evans, Daniel S and Gibson, Quince and Gudbjartsson, Daniel F and Kerr, Kathleen F and Krijthe, Bouwe P and Lyytik{\"a}inen, Leo-Pekka and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and Padmanabhan, Sandosh and Ritchie, Marylyn D and Robino, Antonietta and Smith, Albert V and Steri, Maristella and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and Ulivi, Sheila and Verweij, Niek and Yin, Xiaoyan and Arnar, David O and Asselbergs, Folkert W and Bader, Joel S and Barnard, John and Bis, Josh and Blankenberg, Stefan and Boerwinkle, Eric and Bradford, Yuki and Buckley, Brendan M and Chung, Mina K and Crawford, Dana and den Hoed, Marcel and Denny, Josh C and Dominiczak, Anna F and Ehret, Georg B and Eijgelsheim, Mark and Ellinor, Patrick T and Felix, Stephan B and Franco, Oscar H and Franke, Lude and Harris, Tamara B and Holm, Hilma and Ilaria, Gandin and Iorio, Annamaria and K{\"a}h{\"o}nen, Mika and Kolcic, Ivana and Kors, Jan A and Lakatta, Edward G and Launer, Lenore J and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lubitz, Steven A and Macfarlane, Peter W and Magnani, Jared W and Leach, Irene Mateo and Meitinger, Thomas and Mitchell, Braxton D and M{\"u}nzel, Thomas and Papanicolaou, George J and Peters, Annette and Pfeufer, Arne and Pramstaller, Peter P and Raitakari, Olli T and Rotter, Jerome I and Rudan, Igor and Samani, Nilesh J and Schlessinger, David and Silva Aldana, Claudia T and Sinner, Moritz F and Smith, Jonathan D and Snieder, Harold and Soliman, Elsayed Z and Spector, Timothy D and Stott, David J and Strauch, Konstantin and Tarasov, Kirill V and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Jan Westra, Harm and Wild, Philipp S and Zeller, Tanja and Alonso, Alvaro and Avery, Christy L and Bandinelli, Stefania and Benjamin, Emelia J and Cucca, Francesco and D{\"o}rr, Marcus and Ferrucci, Luigi and Gasparini, Paolo and Gudnason, Vilmundur and Hayward, Caroline and Heckbert, Susan R and Hicks, Andrew A and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and Lehtim{\"a}ki, Terho and Liu, Yongmei and Munroe, Patricia B and Parsa, Afshin and Polasek, Ozren and Psaty, Bruce M and Roden, Dan M and Schnabel, Renate B and Sinagra, Gianfranco and Stefansson, Kari and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Wilson, James F and Gharib, Sina A and de Bakker, Paul I W and Isaacs, Aaron and Arking, Dan E and Sotoodehnia, Nona} } @article {8198, title = {Associations of autozygosity with a broad range of human phenotypes.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 31}, pages = {4957}, abstract = {

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.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12283-6}, author = {Clark, David W and Okada, Yukinori and Moore, Kristjan H S and Mason, Dan and Pirastu, Nicola and Gandin, Ilaria and Mattsson, Hannele and Barnes, Catriona L K and Lin, Kuang and Zhao, Jing Hua and Deelen, Patrick and Rohde, Rebecca and Schurmann, Claudia and Guo, Xiuqing and Giulianini, Franco and Zhang, Weihua and Medina-G{\'o}mez, Carolina and Karlsson, Robert and Bao, Yanchun and Bartz, Traci M and Baumbach, Clemens and Biino, Ginevra and Bixley, Matthew J and Brumat, Marco and Chai, Jin-Fang and Corre, Tanguy and Cousminer, Diana L and Dekker, Annelot M and Eccles, David A and van Eijk, Kristel R and Fuchsberger, Christian and Gao, He and Germain, Marine and Gordon, Scott D and de Haan, Hugoline G and Harris, Sarah E and Hofer, Edith and Huerta-Chagoya, Alicia and Igartua, Catherine and Jansen, Iris E and Jia, Yucheng and Kacprowski, Tim and Karlsson, Torgny and Kleber, Marcus E and Li, Shengchao Alfred and Li-Gao, Ruifang and Mahajan, Anubha and Matsuda, Koichi and Meidtner, Karina and Meng, Weihua and Montasser, May E and van der Most, Peter J and Munz, Matthias and Nutile, Teresa and Palviainen, Teemu and Prasad, Gauri and Prasad, Rashmi B and Priyanka, Tallapragada Divya Sri and Rizzi, Federica and Salvi, Erika and Sapkota, Bishwa R and Shriner, Daniel and Skotte, Line and Smart, Melissa C and Smith, Albert Vernon and van der Spek, Ashley and Spracklen, Cassandra N and Strawbridge, Rona J and Tajuddin, Salman M and Trompet, Stella and Turman, Constance and Verweij, Niek and Viberti, Clara and Wang, Lihua and Warren, Helen R and Wootton, Robyn E and Yanek, Lisa R and Yao, Jie and Yousri, Noha A and Zhao, Wei and Adeyemo, Adebowale A and Afaq, Saima and Aguilar-Salinas, Carlos Alberto and Akiyama, Masato and Albert, Matthew L and Allison, Matthew A and Alver, Maris and Aung, Tin and Azizi, Fereidoun and Bentley, Amy R and Boeing, Heiner and Boerwinkle, Eric and Borja, Judith B and de Borst, Gert J and Bottinger, Erwin P and Broer, Linda and Campbell, Harry and Chanock, Stephen and Chee, Miao-Li and Chen, Guanjie and Chen, Yii-der I and Chen, Zhengming and Chiu, Yen-Feng and Cocca, Massimiliano and Collins, Francis S and Concas, Maria Pina and Corley, Janie and Cugliari, Giovanni and van Dam, Rob M and Damulina, Anna and Daneshpour, Maryam S and Day, Felix R and Delgado, Graciela E and Dhana, Klodian and Doney, Alexander S F and D{\"o}rr, Marcus and Doumatey, Ayo P and Dzimiri, Nduna and Ebenesersd{\'o}ttir, S Sunna and Elliott, Joshua and Elliott, Paul and Ewert, Ralf and Felix, Janine F and Fischer, Krista and Freedman, Barry I and Girotto, Giorgia and Goel, Anuj and G{\"o}gele, Martin and Goodarzi, Mark O and Graff, Mariaelisa and Granot-Hershkovitz, Einat and Grodstein, Francine and Guarrera, Simonetta and Gudbjartsson, Daniel F and Guity, Kamran and Gunnarsson, Bjarni and Guo, Yu and Hagenaars, Saskia P and Haiman, Christopher A and Halevy, Avner and Harris, Tamara B and Hedayati, Mehdi and van Heel, David A and Hirata, Makoto and H{\"o}fer, Imo and Hsiung, Chao Agnes and Huang, Jinyan and Hung, Yi-Jen and Ikram, M Arfan and Jagadeesan, Anuradha and Jousilahti, Pekka and Kamatani, Yoichiro and Kanai, Masahiro and Kerrison, Nicola D and Kessler, Thorsten and Khaw, Kay-Tee and Khor, Chiea Chuen and de Kleijn, Dominique P V and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter and Kr{\"a}mer, Bernhard K and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lawlor, Deborah A and Lee, I-Te and Lee, Wen-Jane and Lerch, Markus M and Li, Liming and Liu, Jianjun and Loh, Marie and London, Stephanie J and Loomis, Stephanie and Lu, Yingchang and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Manichaikul, Ani W and Manunta, Paolo and M{\'a}sson, G{\'\i}sli and Matoba, Nana and Mei, Xue W and Meisinger, Christa and Meitinger, Thomas and Mezzavilla, Massimo and Milani, Lili and Millwood, Iona Y and Momozawa, Yukihide and Moore, Amy and Morange, Pierre-Emmanuel and Moreno-Macias, Hortensia and Mori, Trevor A and Morrison, Alanna C and Muka, Taulant and Murakami, Yoshinori and Murray, Alison D and de Mutsert, Ren{\'e}e and Mychaleckyj, Josyf C and Nalls, Mike A and Nauck, Matthias and Neville, Matt J and Nolte, Ilja M and Ong, Ken K and Orozco, Lorena and Padmanabhan, Sandosh and P{\'a}lsson, Gunnar and Pankow, James S and Pattaro, Cristian and Pattie, Alison and Polasek, Ozren and Poulter, Neil and Pramstaller, Peter P and Quintana-Murci, Lluis and R{\"a}ikk{\"o}nen, Katri and Ralhan, Sarju and Rao, Dabeeru C and van Rheenen, Wouter and Rich, Stephen S and Ridker, Paul M and Rietveld, Cornelius A and Robino, Antonietta and van Rooij, Frank J A and Ruggiero, Daniela and Saba, Yasaman and Sabanayagam, Charumathi and Sabater-Lleal, Maria and Sala, Cinzia Felicita and Salomaa, Veikko and Sandow, Kevin and Schmidt, Helena and Scott, Laura J and Scott, William R and Sedaghati-Khayat, Bahareh and Sennblad, Bengt and van Setten, Jessica and Sever, Peter J and Sheu, Wayne H-H and Shi, Yuan and Shrestha, Smeeta and Shukla, Sharvari Rahul and Sigurdsson, Jon K and Sikka, Timo Tonis and Singh, Jai Rup and Smith, Blair H and Stan{\v c}{\'a}kov{\'a}, Alena and Stanton, Alice and Starr, John M and Stefansdottir, Lilja and Straker, Leon and Sulem, Patrick and Sveinbjornsson, Gardar and Swertz, Morris A and Taylor, Adele M and Taylor, Kent D and Terzikhan, Natalie and Tham, Yih-Chung and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tillander, Annika and Tracy, Russell P and Tusi{\'e}-Luna, Teresa and Tzoulaki, Ioanna and Vaccargiu, Simona and Vangipurapu, Jagadish and Veldink, Jan H and Vitart, Veronique and V{\"o}lker, Uwe and Vuoksimaa, Eero and Wakil, Salma M and Waldenberger, Melanie and Wander, Gurpreet S and Wang, Ya Xing and Wareham, Nicholas J and Wild, Sarah and Yajnik, Chittaranjan S and Yuan, Jian-Min and Zeng, Lingyao and Zhang, Liang and Zhou, Jie and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Becker, Diane M and Lehne, Benjamin and Bennett, David A and van den Berg, Leonard H and Berndt, Sonja I and Bharadwaj, Dwaipayan and Bielak, Lawrence F and Bochud, Murielle and Boehnke, Mike and Bouchard, Claude and Bradfield, Jonathan P and Brody, Jennifer A and Campbell, Archie and Carmi, Shai and Caulfield, Mark J and Cesarini, David and Chambers, John C and Chandak, Giriraj Ratan and Cheng, Ching-Yu and Ciullo, Marina and Cornelis, Marilyn and Cusi, Daniele and Smith, George Davey and Deary, Ian J and Dorajoo, Rajkumar and van Duijn, Cornelia M and Ellinghaus, David and Erdmann, Jeanette and Eriksson, Johan G and Evangelou, Evangelos and Evans, Michele K and Faul, Jessica D and Feenstra, Bjarke and Feitosa, Mary and Foisy, Sylvain and Franke, Andre and Friedlander, Yechiel and Gasparini, Paolo and Gieger, Christian and Gonzalez, Clicerio and Goyette, Philippe and Grant, Struan F A and Griffiths, Lyn R and Groop, Leif and Gudnason, Vilmundur and Gyllensten, Ulf and Hakonarson, Hakon and Hamsten, Anders and van der Harst, Pim and Heng, Chew-Kiat and Hicks, Andrew A and Hochner, Hagit and Huikuri, Heikki and Hunt, Steven C and Jaddoe, Vincent W V and De Jager, Philip L and Johannesson, Magnus and Johansson, Asa and Jonas, Jost B and Jukema, J Wouter and Junttila, Juhani and Kaprio, Jaakko and Kardia, Sharon L R and Karpe, Fredrik and Kumari, Meena and Laakso, Markku and van der Laan, Sander W and Lahti, Jari and Laudes, Matthias and Lea, Rodney A and Lieb, Wolfgang and Lumley, Thomas and Martin, Nicholas G and M{\"a}rz, Winfried and Matullo, Giuseppe and McCarthy, Mark I and Medland, Sarah E and Merriman, Tony R and Metspalu, Andres and Meyer, Brian F and Mohlke, Karen L and Montgomery, Grant W and Mook-Kanamori, Dennis and Munroe, Patricia B and North, Kari E and Nyholt, Dale R and O{\textquoteright}Connell, Jeffery R and Ober, Carole and Oldehinkel, Albertine J and Palmas, Walter and Palmer, Colin and Pasterkamp, Gerard G and Patin, Etienne and Pennell, Craig E and Perusse, Louis and Peyser, Patricia A and Pirastu, Mario and Polderman, Tinca J C and Porteous, David J and Posthuma, Danielle and Psaty, Bruce M and Rioux, John D and Rivadeneira, Fernando and Rotimi, Charles and Rotter, Jerome I and Rudan, Igor and den Ruijter, Hester M and Sanghera, Dharambir K and Sattar, Naveed and Schmidt, Reinhold and Schulze, Matthias B and Schunkert, Heribert and Scott, Robert A and Shuldiner, Alan R and Sim, Xueling and Small, Neil and Smith, Jennifer A and Sotoodehnia, Nona and Tai, E-Shyong and Teumer, Alexander and Timpson, Nicholas J and Toniolo, Daniela and Tr{\'e}gou{\"e}t, David-Alexandre and Tuomi, Tiinamaija and Vollenweider, Peter and Wang, Carol A and Weir, David R and Whitfield, John B and Wijmenga, Cisca and Wong, Tien-Yin and Wright, John and Yang, Jingyun and Yu, Lei and Zemel, Babette S and Zonderman, Alan B and Perola, Markus and Magnusson, Patrik K E and Uitterlinden, Andr{\'e} G and Kooner, Jaspal S and Chasman, Daniel I and Loos, Ruth J F and Franceschini, Nora and Franke, Lude and Haley, Chris S and Hayward, Caroline and Walters, Robin G and Perry, John R B and Esko, T{\~o}nu and Helgason, Agnar and Stefansson, Kari and Joshi, Peter K and Kubo, Michiaki and Wilson, James F} } @article {8109, title = {A catalog of genetic loci associated with kidney function from analyses of a million individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 06}, pages = {957-972}, abstract = {

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.

}, keywords = {Chromosome Mapping, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inheritance Patterns, Kidney Function Tests, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Renal Insufficiency, Chronic, Uromodulin}, issn = {1546-1718}, doi = {10.1038/s41588-019-0407-x}, author = {Wuttke, Matthias and Li, Yong and Li, Man and Sieber, Karsten B and Feitosa, Mary F and Gorski, Mathias and Tin, Adrienne and Wang, Lihua and Chu, Audrey Y and Hoppmann, Anselm and Kirsten, Holger and Giri, Ayush and Chai, Jin-Fang and Sveinbjornsson, Gardar and Tayo, Bamidele O and Nutile, Teresa and Fuchsberger, Christian and Marten, Jonathan and Cocca, Massimiliano and Ghasemi, Sahar and Xu, Yizhe and Horn, Katrin and Noce, Damia and van der Most, Peter J and Sedaghat, Sanaz and Yu, Zhi and Akiyama, Masato and Afaq, Saima and Ahluwalia, Tarunveer S and Almgren, Peter and Amin, Najaf and Arnl{\"o}v, Johan and Bakker, Stephan J L and Bansal, Nisha and Baptista, Daniela and Bergmann, Sven and Biggs, Mary L and Biino, Ginevra and Boehnke, Michael and Boerwinkle, Eric and Boissel, Mathilde and Bottinger, Erwin P and Boutin, Thibaud S and Brenner, Hermann and Brumat, Marco and Burkhardt, Ralph and Butterworth, Adam S and Campana, Eric and Campbell, Archie and Campbell, Harry and Canouil, Micka{\"e}l and Carroll, Robert J and Catamo, Eulalia and Chambers, John C and Chee, Miao-Ling and Chee, Miao-Li and Chen, Xu and Cheng, Ching-Yu and Cheng, Yurong and Christensen, Kaare and Cifkova, Renata and Ciullo, Marina and Concas, Maria Pina and Cook, James P and Coresh, Josef and Corre, Tanguy and Sala, Cinzia Felicita and Cusi, Daniele and Danesh, John and Daw, E Warwick and de Borst, Martin H and De Grandi, Alessandro and de Mutsert, Ren{\'e}e and de Vries, Aiko P J and Degenhardt, Frauke and Delgado, Graciela and Demirkan, Ayse and Di Angelantonio, Emanuele and Dittrich, Katalin and Divers, Jasmin and Dorajoo, Rajkumar and Eckardt, Kai-Uwe and Ehret, Georg and Elliott, Paul and Endlich, Karlhans and Evans, Michele K and Felix, Janine F and Foo, Valencia Hui Xian and Franco, Oscar H and Franke, Andre and Freedman, Barry I and Freitag-Wolf, Sandra and Friedlander, Yechiel and Froguel, Philippe and Gansevoort, Ron T and Gao, He and Gasparini, Paolo and Gaziano, J Michael and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Giulianini, Franco and G{\"o}gele, Martin and Gordon, Scott D and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Haller, Toomas and Hamet, Pavel and Harris, Tamara B and Hartman, Catharina A and Hayward, Caroline and Hellwege, Jacklyn N and Heng, Chew-Kiat and Hicks, Andrew A and Hofer, Edith and Huang, Wei and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Indridason, Olafur S and Ingelsson, Erik and Ising, Marcus and Jaddoe, Vincent W V and Jakobsdottir, Johanna and Jonas, Jost B and Joshi, Peter K and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kammerer, Candace M and Kanai, Masahiro and Kastarinen, Mika and Kerr, Shona M and Khor, Chiea-Chuen and Kiess, Wieland and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kraja, Aldi T and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kronenberg, Florian and Kubo, Michiaki and Kuhnel, Brigitte and Kuokkanen, Mikko and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lange, Leslie A and Langefeld, Carl D and Lee, Jeannette Jen-Mai and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Lim, Su-Chi and Lind, Lars and Lindgren, Cecilia M and Liu, Jun and Liu, Jianjun and Loeffler, Markus and Loos, Ruth J F and Lucae, Susanne and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mahajan, Anubha and Martin, Nicholas G and Martins, Jade and M{\"a}rz, Winfried and Mascalzoni, Deborah and Matsuda, Koichi and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mikaelsdottir, Evgenia K and Milaneschi, Yuri and Miliku, Kozeta and Mishra, Pashupati P and Mohlke, Karen L and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Noordam, Raymond and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donoghue, Michelle L and Olafsson, Isleifur and Oldehinkel, Albertine J and Orho-Melander, Marju and Ouwehand, Willem H and Padmanabhan, Sandosh and Palmer, Nicholette D and Palsson, Runolfur and Penninx, Brenda W J H and Perls, Thomas and Perola, Markus and Pirastu, Mario and Pirastu, Nicola and Pistis, Giorgio and Podgornaia, Anna I and Polasek, Ozren and Ponte, Belen and Porteous, David J and Poulain, Tanja and Pramstaller, Peter P and Preuss, Michael H and Prins, Bram P and Province, Michael A and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Reilly, Dermot F and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Ridker, Paul M and Rivadeneira, Fernando and Rizzi, Federica and Roberts, David J and Robino, Antonietta and Rossing, Peter and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Ryan, Kathleen A and Saba, Yasaman and Sabanayagam, Charumathi and Salomaa, Veikko and Salvi, Erika and Saum, Kai-Uwe and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Schupf, Nicole and Shaffer, Christian M and Shi, Yuan and Smith, Albert V and Smith, Blair H and Soranzo, Nicole and Spracklen, Cassandra N and Strauch, Konstantin and Stringham, Heather M and Stumvoll, Michael and Svensson, Per O and Szymczak, Silke and Tai, E-Shyong and Tajuddin, Salman M and Tan, Nicholas Y Q and Taylor, Kent D and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomsen, Hauke and Thorleifsson, Gudmar and Toniolo, Daniela and T{\"o}njes, Anke and Tremblay, Johanne and Tzoulaki, Ioanna and Uitterlinden, Andr{\'e} G and Vaccargiu, Simona and van Dam, Rob M and van der Harst, Pim and van Duijn, Cornelia M and Velez Edward, Digna R and Verweij, Niek and Vogelezang, Suzanne and V{\"o}lker, Uwe and Vollenweider, Peter and Waeber, G{\'e}rard and Waldenberger, Melanie and Wallentin, Lars and Wang, Ya Xing and Wang, Chaolong and Waterworth, Dawn M and Bin Wei, Wen and White, Harvey and Whitfield, John B and Wild, Sarah H and Wilson, James F and Wojczynski, Mary K and Wong, Charlene and Wong, Tien-Yin and Xu, Liang and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Weihua and Zonderman, Alan B and Rotter, Jerome I and Bochud, Murielle and Psaty, Bruce M and Vitart, Veronique and Wilson, James G and Dehghan, Abbas and Parsa, Afshin and Chasman, Daniel I and Ho, Kevin and Morris, Andrew P and Devuyst, Olivier and Akilesh, Shreeram and Pendergrass, Sarah A and Sim, Xueling and B{\"o}ger, Carsten A and Okada, Yukinori and Edwards, Todd L and Snieder, Harold and Stefansson, Kari and Hung, Adriana M and Heid, Iris M and Scholz, Markus and Teumer, Alexander and K{\"o}ttgen, Anna and Pattaro, Cristian} } @article {7972, title = {Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation.}, journal = {Circ Genom Precis Med}, volume = {12}, year = {2019}, month = {2019 Feb}, pages = {e002409}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.118.002409}, author = {D{\"o}rr, Marcus and Hamburg, Naomi M and M{\"u}ller, Christian and Smith, Nicholas L and Gustafsson, Stefan and Lehtim{\"a}ki, Terho and Teumer, Alexander and Zeller, Tanja and Li, Xiaohui and Lind, Lars and Raitakari, Olli T and V{\"o}lker, Uwe and Blankenberg, Stefan and McKnight, Barbara and Morris, Andrew P and K{\"a}h{\"o}nen, Mika and Lemaitre, Rozenn N and Wild, Philipp S and Nauck, Matthias and V{\"o}lzke, Henry and M{\"u}nzel, Thomas and Mitchell, Gary F and Psaty, Bruce M and Lindgren, Cecilia M and Larson, Martin G and Felix, Stephan B and Ingelsson, Erik and Lyytik{\"a}inen, Leo-Pekka and Herrington, David and Benjamin, Emelia J and Schnabel, Renate B} } @article {8207, title = {Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Oct}, pages = {1459-1474}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0504-x}, author = {Tin, Adrienne and Marten, Jonathan and Halperin Kuhns, Victoria L and Li, Yong and Wuttke, Matthias and Kirsten, Holger and Sieber, Karsten B and Qiu, Chengxiang and Gorski, Mathias and Yu, Zhi and Giri, Ayush and Sveinbjornsson, Gardar and Li, Man and Chu, Audrey Y and Hoppmann, Anselm and O{\textquoteright}Connor, Luke J and Prins, Bram and Nutile, Teresa and Noce, Damia and Akiyama, Masato and Cocca, Massimiliano and Ghasemi, Sahar and van der Most, Peter J and Horn, Katrin and Xu, Yizhe and Fuchsberger, Christian and Sedaghat, Sanaz and Afaq, Saima and Amin, Najaf and Arnl{\"o}v, Johan and Bakker, Stephan J L and Bansal, Nisha and Baptista, Daniela and Bergmann, Sven and Biggs, Mary L and Biino, Ginevra and Boerwinkle, Eric and Bottinger, Erwin P and Boutin, Thibaud S and Brumat, Marco and Burkhardt, Ralph and Campana, Eric and Campbell, Archie and Campbell, Harry and Carroll, Robert J and Catamo, Eulalia and Chambers, John C and Ciullo, Marina and Concas, Maria Pina and Coresh, Josef and Corre, Tanguy and Cusi, Daniele and Felicita, Sala Cinzia and de Borst, Martin H and De Grandi, Alessandro and de Mutsert, Ren{\'e}e and de Vries, Aiko P J and Delgado, Graciela and Demirkan, Ayse and Devuyst, Olivier and Dittrich, Katalin and Eckardt, Kai-Uwe and Ehret, Georg and Endlich, Karlhans and Evans, Michele K and Gansevoort, Ron T and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and G{\"o}gele, Martin and Gordon, Scott D and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Haller, Toomas and Hamet, Pavel and Harris, Tamara B and Hayward, Caroline and Hicks, Andrew A and Hofer, Edith and Holm, Hilma and Huang, Wei and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Lewis, Raychel M and Ingelsson, Erik and Jakobsdottir, Johanna and Jonsdottir, Ingileif and Jonsson, Helgi and Joshi, Peter K and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Kerr, Shona M and Kiess, Wieland and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kr{\"a}mer, Bernhard K and Kronenberg, Florian and Kubo, Michiaki and Kuhnel, Brigitte and La Bianca, Martina and Lange, Leslie A and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liu, Jun and Loeffler, Markus and Loos, Ruth J F and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Mahajan, Anubha and Martin, Nicholas G and M{\"a}rz, Winfried and Mascalzoni, Deborah and Matsuda, Koichi and Meisinger, Christa and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and O{\textquoteright}Donnell, Christopher J and Wilson, Otis D and Gaziano, J Michael and Mishra, Pashupati P and Mohlke, Karen L and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and M{\"u}ller-Nurasyid, Martina and Nadkarni, Girish N and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Noordam, Raymond and O{\textquoteright}Connell, Jeffrey R and Olafsson, Isleifur and Padmanabhan, Sandosh and Penninx, Brenda W J H and Perls, Thomas and Peters, Annette and Pirastu, Mario and Pirastu, Nicola and Pistis, Giorgio and Polasek, Ozren and Ponte, Belen and Porteous, David J and Poulain, Tanja and Preuss, Michael H and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Rizzi, Federica and Robino, Antonietta and Rudan, Igor and Krajcoviechova, Alena and Cifkova, Renata and Rueedi, Rico and Ruggiero, Daniela and Ryan, Kathleen A and Saba, Yasaman and Salvi, Erika and Schmidt, Helena and Schmidt, Reinhold and Shaffer, Christian M and Smith, Albert V and Smith, Blair H and Spracklen, Cassandra N and Strauch, Konstantin and Stumvoll, Michael and Sulem, Patrick and Tajuddin, Salman M and Teren, Andrej and Thiery, Joachim and Thio, Chris H L and Thorsteinsdottir, Unnur and Toniolo, Daniela and T{\"o}njes, Anke and Tremblay, Johanne and Uitterlinden, Andr{\'e} G and Vaccargiu, Simona and van der Harst, Pim and van Duijn, Cornelia M and Verweij, Niek and V{\"o}lker, Uwe and Vollenweider, Peter and Waeber, G{\'e}rard and Waldenberger, Melanie and Whitfield, John B and Wild, Sarah H and Wilson, James F and Yang, Qiong and Zhang, Weihua and Zonderman, Alan B and Bochud, Murielle and Wilson, James G and Pendergrass, Sarah A and Ho, Kevin and Parsa, Afshin and Pramstaller, Peter P and Psaty, Bruce M and B{\"o}ger, Carsten A and Snieder, Harold and Butterworth, Adam S and Okada, Yukinori and Edwards, Todd L and Stefansson, Kari and Susztak, Katalin and Scholz, Markus and Heid, Iris M and Hung, Adriana M and Teumer, Alexander and Pattaro, Cristian and Woodward, Owen M and Vitart, Veronique and K{\"o}ttgen, Anna} } @article {8625, title = {Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0230035}, abstract = {

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95\% confidence interval: 1.43, 2.27; P = 7.12 {\texttimes} 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) >= 5 and variants with minor allele frequency (MAF) < 5\%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

}, keywords = {Aging, Coronary Artery Disease, Cross-Sectional Studies, Europe, European Continental Ancestry Group, Genetic Loci, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0230035}, author = {Hahn, Julie and Fu, Yi-Ping and Brown, Michael R and Bis, Joshua C and de Vries, Paul S and Feitosa, Mary F and Yanek, Lisa R and Weiss, Stefan and Giulianini, Franco and Smith, Albert Vernon and Guo, Xiuqing and Bartz, Traci M and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Brody, Jennifer A and Chen, Yii-Der Ida and Franco, Oscar H and Grove, Megan and Harris, Tamara B and Hofman, Albert and Hwang, Shih-Jen and Kral, Brian G and Launer, Lenore J and Markus, Marcello R P and Rice, Kenneth M and Rich, Stephen S and Ridker, Paul M and Rivadeneira, Fernando and Rotter, Jerome I and Sotoodehnia, Nona and Taylor, Kent D and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Yao, Jie and Chasman, Daniel I and D{\"o}rr, Marcus and Gudnason, Vilmundur and Mathias, Rasika A and Post, Wendy and Psaty, Bruce M and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C} } @article {8624, title = {Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.}, journal = {Kidney Int}, year = {2020}, month = {2020 Oct 30}, abstract = {

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.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2020.09.030}, author = {Gorski, Mathias and Jung, Bettina and Li, Yong and Matias-Garcia, Pamela R and Wuttke, Matthias and Coassin, Stefan and Thio, Chris H L and Kleber, Marcus E and Winkler, Thomas W and Wanner, Veronika and Chai, Jin-Fang and Chu, Audrey Y and Cocca, Massimiliano and Feitosa, Mary F and Ghasemi, Sahar and Hoppmann, Anselm and Horn, Katrin and Li, Man and Nutile, Teresa and Scholz, Markus and Sieber, Karsten B and Teumer, Alexander and Tin, Adrienne and Wang, Judy and Tayo, Bamidele O and Ahluwalia, Tarunveer S and Almgren, Peter and Bakker, Stephan J L and Banas, Bernhard and Bansal, Nisha and Biggs, Mary L and Boerwinkle, Eric and Bottinger, Erwin P and Brenner, Hermann and Carroll, Robert J and Chalmers, John and Chee, Miao-Li and Chee, Miao-Ling and Cheng, Ching-Yu and Coresh, Josef and de Borst, Martin H and Degenhardt, Frauke and Eckardt, Kai-Uwe and Endlich, Karlhans and Franke, Andre and Freitag-Wolf, Sandra and Gampawar, Piyush and Gansevoort, Ron T and Ghanbari, Mohsen and Gieger, Christian and Hamet, Pavel and Ho, Kevin and Hofer, Edith and Holleczek, Bernd and Xian Foo, Valencia Hui and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Josyula, Navya Shilpa and K{\"a}h{\"o}nen, Mika and Khor, Chiea-Chuen and Koenig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuhnel, Brigitte and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Loos, Ruth J F and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and O{\textquoteright}Donoghue, Michelle L and Orho-Melander, Marju and Pendergrass, Sarah A and Penninx, Brenda W J H and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Rosenkranz, Alexander R and Rossing, Peter and Rotter, Jerome I and Sabanayagam, Charumathi and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Sedaghat, Sanaz and Shaffer, Christian M and Strauch, Konstantin and Szymczak, Silke and Taylor, Kent D and Tremblay, Johanne and Chaker, Layal and van der Harst, Pim and van der Most, Peter J and Verweij, Niek and V{\"o}lker, Uwe and Waldenberger, Melanie and Wallentin, Lars and Waterworth, Dawn M and White, Harvey D and Wilson, James G and Wong, Tien-Yin and Woodward, Mark and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Yan and Snieder, Harold and Wanner, Christoph and B{\"o}ger, Carsten A and K{\"o}ttgen, Anna and Kronenberg, Florian and Pattaro, Cristian and Heid, Iris M} } @article {8368, title = {Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 May 21}, pages = {2542}, abstract = {

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

}, issn = {2041-1723}, doi = {10.1038/s41467-020-15706-x}, author = {Ntalla, Ioanna and Weng, Lu-Chen and Cartwright, James H and Hall, Amelia Weber and Sveinbjornsson, Gardar and Tucker, Nathan R and Choi, Seung Hoan and Chaffin, Mark D and Roselli, Carolina and Barnes, Michael R and Mifsud, Borbala and Warren, Helen R and Hayward, Caroline and Marten, Jonathan and Cranley, James J and Concas, Maria Pina and Gasparini, Paolo and Boutin, Thibaud and Kolcic, Ivana and Polasek, Ozren and Rudan, Igor and Araujo, Nathalia M and Lima-Costa, Maria Fernanda and Ribeiro, Antonio Luiz P and Souza, Renan P and Tarazona-Santos, Eduardo and Giedraitis, Vilmantas and Ingelsson, Erik and Mahajan, Anubha and Morris, Andrew P and del Greco M, Fabiola and Foco, Luisa and G{\"o}gele, Martin and Hicks, Andrew A and Cook, James P and Lind, Lars and Lindgren, Cecilia M and Sundstr{\"o}m, Johan and Nelson, Christopher P and Riaz, Muhammad B and Samani, Nilesh J and Sinagra, Gianfranco and Ulivi, Sheila and K{\"a}h{\"o}nen, Mika and Mishra, Pashupati P and Mononen, Nina and Nikus, Kjell and Caulfield, Mark J and Dominiczak, Anna and Padmanabhan, Sandosh and Montasser, May E and O{\textquoteright}Connell, Jeff R and Ryan, Kathleen and Shuldiner, Alan R and Aeschbacher, Stefanie and Conen, David and Risch, Lorenz and Th{\'e}riault, S{\'e}bastien and Hutri-K{\"a}h{\"o}nen, Nina and Lehtim{\"a}ki, Terho and Lyytik{\"a}inen, Leo-Pekka and Raitakari, Olli T and Barnes, Catriona L K and Campbell, Harry and Joshi, Peter K and Wilson, James F and Isaacs, Aaron and Kors, Jan A and van Duijn, Cornelia M and Huang, Paul L and Gudnason, Vilmundur and Harris, Tamara B and Launer, Lenore J and Smith, Albert V and Bottinger, Erwin P and Loos, Ruth J F and Nadkarni, Girish N and Preuss, Michael H and Correa, Adolfo and Mei, Hao and Wilson, James and Meitinger, Thomas and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Waldenberger, Melanie and Mangino, Massimo and Spector, Timothy D and Rienstra, Michiel and van de Vegte, Yordi J and van der Harst, Pim and Verweij, Niek and K{\"a}{\"a}b, Stefan and Schramm, Katharina and Sinner, Moritz F and Strauch, Konstantin and Cutler, Michael J and Fatkin, Diane and London, Barry and Olesen, Morten and Roden, Dan M and Benjamin Shoemaker, M and Gustav Smith, J and Biggs, Mary L and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Rice, Kenneth and Sotoodehnia, Nona and De Grandi, Alessandro and Fuchsberger, Christian and Pattaro, Cristian and Pramstaller, Peter P and Ford, Ian and Wouter Jukema, J and Macfarlane, Peter W and Trompet, Stella and D{\"o}rr, Marcus and Felix, Stephan B and V{\"o}lker, Uwe and Weiss, Stefan and Havulinna, Aki S and Jula, Antti and S{\"a}{\"a}ksj{\"a}rvi, Katri and Salomaa, Veikko and Guo, Xiuqing and Heckbert, Susan R and Lin, Henry J and Rotter, Jerome I and Taylor, Kent D and Yao, Jie and de Mutsert, Ren{\'e}e and Maan, Arie C and Mook-Kanamori, Dennis O and Noordam, Raymond and Cucca, Francesco and Ding, Jun and Lakatta, Edward G and Qian, Yong and Tarasov, Kirill V and Levy, Daniel and Lin, Honghuang and Newton-Cheh, Christopher H and Lunetta, Kathryn L and Murray, Alison D and Porteous, David J and Smith, Blair H and Stricker, Bruno H and Uitterlinden, Andre and van den Berg, Marten E and Haessler, Jeffrey and Jackson, Rebecca D and Kooperberg, Charles and Peters, Ulrike and Reiner, Alexander P and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Boerwinkle, Eric and Ehret, Georg B and Soliman, Elsayed Z and Avery, Christy L and Gogarten, Stephanie M and Kerr, Kathleen F and Laurie, Cathy C and Seyerle, Amanda A and Stilp, Adrienne and Assa, Solmaz and Abdullah Said, M and Yldau van der Ende, M and Lambiase, Pier D and Orini, Michele and Ramirez, Julia and Van Duijvenboden, Stefan and Arnar, David O and Gudbjartsson, Daniel F and Holm, Hilma and Sulem, Patrick and Thorleifsson, Gudmar and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Benjamin, Emelia J and Tinker, Andrew and Stefansson, Kari and Ellinor, Patrick T and Jamshidi, Yalda and Lubitz, Steven A and Munroe, Patricia B} } @article {8490, title = {The Polygenic and Monogenic Basis of Blood Traits and Diseases.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1214-1231.e11}, abstract = {

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.08.008}, author = {Vuckovic, Dragana and Bao, Erik L and Akbari, Parsa and Lareau, Caleb A and Mousas, Abdou and Jiang, Tao and Chen, Ming-Huei and Raffield, Laura M and Tardaguila, Manuel and Huffman, Jennifer E and Ritchie, Scott C and Megy, Karyn and Ponstingl, Hannes and Penkett, Christopher J and Albers, Patrick K and Wigdor, Emilie M and Sakaue, Saori and Moscati, Arden and Manansala, Regina and Lo, Ken Sin and Qian, Huijun and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamy N and Wilson, Peter W F and Choquet, Helene and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Felix, Stephan B and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Guo, Qi and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotios and Lange, Leslie A and Lehtim{\"a}ki, Terho and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nikus, Kjell and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Weiss, Stefan and Cai, Na and Kundu, Kousik and Watt, Stephen B and Walter, Klaudia and Zonderman, Alan B and Cho, Kelly and Li, Yun and Loos, Ruth J F and Knight, Julian C and Georges, Michel and Stegle, Oliver and Evangelou, Evangelos and Okada, Yukinori and Roberts, David J and Inouye, Michael and Johnson, Andrew D and Auer, Paul L and Astle, William J and Reiner, Alexander P and Butterworth, Adam S and Ouwehand, Willem H and Lettre, Guillaume and Sankaran, Vijay G and Soranzo, Nicole} } @article {8481, title = {Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1198-1213.e14}, abstract = {

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p~< 5~{\texttimes} 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in~vivo and IL-7 secretion levels in~vitro. Fine-mapping prioritized variants annotated as functional and generated 95\% credible sets that were 30\% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.06.045}, author = {Chen, Ming-Huei and Raffield, Laura M and Mousas, Abdou and Sakaue, Saori and Huffman, Jennifer E and Moscati, Arden and Trivedi, Bhavi and Jiang, Tao and Akbari, Parsa and Vuckovic, Dragana and Bao, Erik L and Zhong, Xue and Manansala, Regina and Laplante, V{\'e}ronique and Chen, Minhui and Lo, Ken Sin and Qian, Huijun and Lareau, Caleb A and Beaudoin, M{\'e}lissa and Hunt, Karen A and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamynaidu and Cho, Kelly and Choquet, Helene and Correa, Adolfo and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Qin Qin and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotis and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lerch, Markus M and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Martin, Hilary C and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ouwehand, Willem H and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Roberts, David J and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Trembath, Richard C and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Zonderman, Alan B and Wilson, Peter W F and Li, Yun and Butterworth, Adam S and Gauchat, Jean-Fran{\c c}ois and Chiang, Charleston W K and Li, Bingshan and Loos, Ruth J F and Astle, William J and Evangelou, Evangelos and van Heel, David A and Sankaran, Vijay G and Okada, Yukinori and Soranzo, Nicole and Johnson, Andrew D and Reiner, Alexander P and Auer, Paul L and Lettre, Guillaume} } @article {9006, title = {Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 12 09}, pages = {7173}, abstract = {

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.

}, keywords = {Amino Acid Transport System y+, Cohort Studies, CpG Islands, DNA Methylation, Epigenome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Transport Proteins, Facilitative, Gout, Humans, Male, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-021-27198-4}, author = {Tin, Adrienne and Schlosser, Pascal and Matias-Garcia, Pamela R and Thio, Chris H L and Joehanes, Roby and Liu, Hongbo and Yu, Zhi and Weihs, Antoine and Hoppmann, Anselm and Grundner-Culemann, Franziska and Min, Josine L and Kuhns, Victoria L Halperin and Adeyemo, Adebowale A and Agyemang, Charles and Arnl{\"o}v, Johan and Aziz, Nasir A and Baccarelli, Andrea and Bochud, Murielle and Brenner, Hermann and Bressler, Jan and Breteler, Monique M B and Carmeli, Cristian and Chaker, Layal and Coresh, Josef and Corre, Tanguy and Correa, Adolfo and Cox, Simon R and Delgado, Graciela E and Eckardt, Kai-Uwe and Ekici, Arif B and Endlich, Karlhans and Floyd, James S and Fraszczyk, Eliza and Gao, Xu and G{\`a}o, Xin and Gelber, Allan C and Ghanbari, Mohsen and Ghasemi, Sahar and Gieger, Christian and Greenland, Philip and Grove, Megan L and Harris, Sarah E and Hemani, Gibran and Henneman, Peter and Herder, Christian and Horvath, Steve and Hou, Lifang and Hurme, Mikko A and Hwang, Shih-Jen and Kardia, Sharon L R and Kasela, Silva and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and Kronenberg, Florian and Kuhnel, Brigitte and Ladd-Acosta, Christine and Lehtim{\"a}ki, Terho and Lind, Lars and Liu, Dan and Lloyd-Jones, Donald M and Lorkowski, Stefan and Lu, Ake T and Marioni, Riccardo E and M{\"a}rz, Winfried and McCartney, Daniel L and Meeks, Karlijn A C and Milani, Lili and Mishra, Pashupati P and Nauck, Matthias and Nowak, Christoph and Peters, Annette and Prokisch, Holger and Psaty, Bruce M and Raitakari, Olli T and Ratliff, Scott M and Reiner, Alex P and Sch{\"o}ttker, Ben and Schwartz, Joel and Sedaghat, Sanaz and Smith, Jennifer A and Sotoodehnia, Nona and Stocker, Hannah R and Stringhini, Silvia and Sundstr{\"o}m, Johan and Swenson, Brenton R and van Meurs, Joyce B J and van Vliet-Ostaptchouk, Jana V and Venema, Andrea and V{\"o}lker, Uwe and Winkelmann, Juliane and Wolffenbuttel, Bruce H R and Zhao, Wei and Zheng, Yinan and Loh, Marie and Snieder, Harold and Waldenberger, Melanie and Levy, Daniel and Akilesh, Shreeram and Woodward, Owen M and Susztak, Katalin and Teumer, Alexander and K{\"o}ttgen, Anna} } @article {8835, title = {Genetic insights into biological mechanisms governing human ovarian ageing.}, journal = {Nature}, volume = {596}, year = {2021}, month = {2021 Aug}, pages = {393-397}, abstract = {

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1\% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H{\r a}kansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Lo{\"\i}c and Li, Jingmei and Lindblom, Annika and Lindstr{\"o}m, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H{\r a}kan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chloe and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} } @article {8714, title = {Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.}, journal = {Mol Psychiatry}, year = {2021}, month = {2021 Apr 15}, abstract = {

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 {\texttimes} 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 {\texttimes} 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 {\texttimes} 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.

}, issn = {1476-5578}, doi = {10.1038/s41380-021-01087-0}, author = {Wang, Heming and Noordam, Raymond and Cade, Brian E and Schwander, Karen and Winkler, Thomas W and Lee, Jiwon and Sung, Yun Ju and Bentley, Amy R and Manning, Alisa K and Aschard, Hugues and Kilpel{\"a}inen, Tuomas O and Ilkov, Marjan and Brown, Michael R and Horimoto, Andrea R and Richard, Melissa and Bartz, Traci M and Vojinovic, Dina and Lim, Elise and Nierenberg, Jovia L and Liu, Yongmei and Chitrala, Kumaraswamynaidu and Rankinen, Tuomo and Musani, Solomon K and Franceschini, Nora and Rauramaa, Rainer and Alver, Maris and Zee, Phyllis C and Harris, Sarah E and van der Most, Peter J and Nolte, Ilja M and Munroe, Patricia B and Palmer, Nicholette D and Kuhnel, Brigitte and Weiss, Stefan and Wen, Wanqing and Hall, Kelly A and Lyytik{\"a}inen, Leo-Pekka and O{\textquoteright}Connell, Jeff and Eiriksdottir, Gudny and Launer, Lenore J and de Vries, Paul S and Arking, Dan E and Chen, Han and Boerwinkle, Eric and Krieger, Jose E and Schreiner, Pamela J and Sidney, Stephen and Shikany, James M and Rice, Kenneth and Chen, Yii-Der Ida and Gharib, Sina A and Bis, Joshua C and Luik, Annemarie I and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Amin, Najaf and Xu, Hanfei and Levy, Daniel and He, Jiang and Lohman, Kurt K and Zonderman, Alan B and Rice, Treva K and Sims, Mario and Wilson, Gregory and Sofer, Tamar and Rich, Stephen S and Palmas, Walter and Yao, Jie and Guo, Xiuqing and Rotter, Jerome I and Biermasz, Nienke R and Mook-Kanamori, Dennis O and Martin, Lisa W and Barac, Ana and Wallace, Robert B and Gottlieb, Daniel J and Komulainen, Pirjo and Heikkinen, Sami and M{\"a}gi, Reedik and Milani, Lili and Metspalu, Andres and Starr, John M and Milaneschi, Yuri and Waken, R J and Gao, Chuan and Waldenberger, Melanie and Peters, Annette and Strauch, Konstantin and Meitinger, Thomas and Roenneberg, Till and V{\"o}lker, Uwe and D{\"o}rr, Marcus and Shu, Xiao-Ou and Mukherjee, Sutapa and Hillman, David R and K{\"a}h{\"o}nen, Mika and Wagenknecht, Lynne E and Gieger, Christian and Grabe, Hans J and Zheng, Wei and Palmer, Lyle J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Morrison, Alanna C and Pereira, Alexandre C and Fornage, Myriam and Psaty, Bruce M and van Duijn, Cornelia M and Liu, Ching-Ti and Kelly, Tanika N and Evans, Michele K and Bouchard, Claude and Fox, Ervin R and Kooperberg, Charles and Zhu, Xiaofeng and Lakka, Timo A and Esko, T{\~o}nu and North, Kari E and Deary, Ian J and Snieder, Harold and Penninx, Brenda W J H and Gauderman, W James and Rao, Dabeeru C and Redline, Susan and van Heemst, Diana} } @article {9112, title = {Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 Jun 13}, pages = {580}, abstract = {

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.

}, keywords = {Creatinine, Diabetes Mellitus, Diabetic Nephropathies, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney}, issn = {2399-3642}, doi = {10.1038/s42003-022-03448-z}, author = {Winkler, Thomas W and Rasheed, Humaira and Teumer, Alexander and Gorski, Mathias and Rowan, Bryce X and Stanzick, Kira J and Thomas, Laurent F and Tin, Adrienne and Hoppmann, Anselm and Chu, Audrey Y and Tayo, Bamidele and Thio, Chris H L and Cusi, Daniele and Chai, Jin-Fang and Sieber, Karsten B and Horn, Katrin and Li, Man and Scholz, Markus and Cocca, Massimiliano and Wuttke, Matthias and van der Most, Peter J and Yang, Qiong and Ghasemi, Sahar and Nutile, Teresa and Li, Yong and Pontali, Giulia and G{\"u}nther, Felix and Dehghan, Abbas and Correa, Adolfo and Parsa, Afshin and Feresin, Agnese and de Vries, Aiko P J and Zonderman, Alan B and Smith, Albert V and Oldehinkel, Albertine J and De Grandi, Alessandro and Rosenkranz, Alexander R and Franke, Andre and Teren, Andrej and Metspalu, Andres and Hicks, Andrew A and Morris, Andrew P and T{\"o}njes, Anke and Morgan, Anna and Podgornaia, Anna I and Peters, Annette and K{\"o}rner, Antje and Mahajan, Anubha and Campbell, Archie and Freedman, Barry I and Spedicati, Beatrice and Ponte, Belen and Sch{\"o}ttker, Ben and Brumpton, Ben and Banas, Bernhard and Kr{\"a}mer, Bernhard K and Jung, Bettina and {\r A}svold, Bj{\o}rn Olav and Smith, Blair H and Ning, Boting and Penninx, Brenda W J H and Vanderwerff, Brett R and Psaty, Bruce M and Kammerer, Candace M and Langefeld, Carl D and Hayward, Caroline and Spracklen, Cassandra N and Robinson-Cohen, Cassianne and Hartman, Catharina A and Lindgren, Cecilia M and Wang, Chaolong and Sabanayagam, Charumathi and Heng, Chew-Kiat and Lanzani, Chiara and Khor, Chiea-Chuen and Cheng, Ching-Yu and Fuchsberger, Christian and Gieger, Christian and Shaffer, Christian M and Schulz, Christina-Alexandra and Willer, Cristen J and Chasman, Daniel I and Gudbjartsson, Daniel F and Ruggiero, Daniela and Toniolo, Daniela and Czamara, Darina and Porteous, David J and Waterworth, Dawn M and Mascalzoni, Deborah and Mook-Kanamori, Dennis O and Reilly, Dermot F and Daw, E Warwick and Hofer, Edith and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Tai, E-Shyong and Catamo, Eulalia and Rizzi, Federica and Guo, Feng and Rivadeneira, Fernando and Guilianini, Franco and Sveinbjornsson, Gardar and Ehret, Georg and Waeber, G{\'e}rard and Biino, Ginevra and Girotto, Giorgia and Pistis, Giorgio and Nadkarni, Girish N and Delgado, Graciela E and Montgomery, Grant W and Snieder, Harold and Campbell, Harry and White, Harvey D and Gao, He and Stringham, Heather M and Schmidt, Helena and Li, Hengtong and Brenner, Hermann and Holm, Hilma and Kirsten, Holgen and Kramer, Holly and Rudan, Igor and Nolte, Ilja M and Tzoulaki, Ioanna and Olafsson, Isleifur and Martins, Jade and Cook, James P and Wilson, James F and Halbritter, Jan and Felix, Janine F and Divers, Jasmin and Kooner, Jaspal S and Lee, Jeannette Jen-Mai and O{\textquoteright}Connell, Jeffrey and Rotter, Jerome I and Liu, Jianjun and Xu, Jie and Thiery, Joachim and Arnl{\"o}v, Johan and Kuusisto, Johanna and Jakobsdottir, Johanna and Tremblay, Johanne and Chambers, John C and Whitfield, John B and Gaziano, John M and Marten, Jonathan and Coresh, Josef and Jonas, Jost B and Mychaleckyj, Josyf C and Christensen, Kaare and Eckardt, Kai-Uwe and Mohlke, Karen L and Endlich, Karlhans and Dittrich, Katalin and Ryan, Kathleen A and Rice, Kenneth M and Taylor, Kent D and Ho, Kevin and Nikus, Kjell and Matsuda, Koichi and Strauch, Konstantin and Miliku, Kozeta and Hveem, Kristian and Lind, Lars and Wallentin, Lars and Yerges-Armstrong, Laura M and Raffield, Laura M and Phillips, Lawrence S and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Lange, Leslie A and Citterio, Lorena and Klaric, Lucija and Ikram, M Arfan and Ising, Marcus and Kleber, Marcus E and Francescatto, Margherita and Concas, Maria Pina and Ciullo, Marina and Piratsu, Mario and Orho-Melander, Marju and Laakso, Markku and Loeffler, Markus and Perola, Markus and de Borst, Martin H and G{\"o}gele, Martin and Bianca, Martina La and Lukas, Mary Ann and Feitosa, Mary F and Biggs, Mary L and Wojczynski, Mary K and Kavousi, Maryam and Kanai, Masahiro and Akiyama, Masato and Yasuda, Masayuki and Nauck, Matthias and Waldenberger, Melanie and Chee, Miao-Li and Chee, Miao-Ling and Boehnke, Michael and Preuss, Michael H and Stumvoll, Michael and Province, Michael A and Evans, Michele K and O{\textquoteright}Donoghue, Michelle L and Kubo, Michiaki and K{\"a}h{\"o}nen, Mika and Kastarinen, Mika and Nalls, Mike A and Kuokkanen, Mikko and Ghanbari, Mohsen and Bochud, Murielle and Josyula, Navya Shilpa and Martin, Nicholas G and Tan, Nicholas Y Q and Palmer, Nicholette D and Pirastu, Nicola and Schupf, Nicole and Verweij, Niek and Hutri-K{\"a}h{\"o}nen, Nina and Mononen, Nina and Bansal, Nisha and Devuyst, Olivier and Melander, Olle and Raitakari, Olli T and Polasek, Ozren and Manunta, Paolo and Gasparini, Paolo and Mishra, Pashupati P and Sulem, Patrick and Magnusson, Patrik K E and Elliott, Paul and Ridker, Paul M and Hamet, Pavel and Svensson, Per O and Joshi, Peter K and Kovacs, Peter and Pramstaller, Peter P and Rossing, Peter and Vollenweider, Peter and van der Harst, Pim and Dorajoo, Rajkumar and Sim, Ralene Z H and Burkhardt, Ralph and Tao, Ran and Noordam, Raymond and M{\"a}gi, Reedik and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Rueedi, Rico and van Dam, Rob M and Carroll, Robert J and Gansevoort, Ron T and Loos, Ruth J F and Felicita, Sala Cinzia and Sedaghat, Sanaz and Padmanabhan, Sandosh and Freitag-Wolf, Sandra and Pendergrass, Sarah A and Graham, Sarah E and Gordon, Scott D and Hwang, Shih-Jen and Kerr, Shona M and Vaccargiu, Simona and Patil, Snehal B and Hallan, Stein and Bakker, Stephan J L and Lim, Su-Chi and Lucae, Susanne and Vogelezang, Suzanne and Bergmann, Sven and Corre, Tanguy and Ahluwalia, Tarunveer S and Lehtim{\"a}ki, Terho and Boutin, Thibaud S and Meitinger, Thomas and Wong, Tien-Yin and Bergler, Tobias and Rabelink, Ton J and Esko, T{\~o}nu and Haller, Toomas and Thorsteinsdottir, Unnur and V{\"o}lker, Uwe and Foo, Valencia Hui Xian and Salomaa, Veikko and Vitart, Veronique and Giedraitis, Vilmantas and Gudnason, Vilmundur and Jaddoe, Vincent W V and Huang, Wei and Zhang, Weihua and Wei, Wen Bin and Kiess, Wieland and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and G{\`a}o, Xin and Sim, Xueling and Wang, Ya Xing and Friedlander, Yechiel and Tham, Yih-Chung and Kamatani, Yoichiro and Okada, Yukinori and Milaneschi, Yuri and Yu, Zhi and Stark, Klaus J and Stefansson, Kari and B{\"o}ger, Carsten A and Hung, Adriana M and Kronenberg, Florian and K{\"o}ttgen, Anna and Pattaro, Cristian and Heid, Iris M} } @article {9093, title = {Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.}, journal = {Kidney Int}, year = {2022}, month = {2022 Jun 16}, abstract = {

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.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2022.05.021}, author = {Gorski, Mathias and Rasheed, Humaira and Teumer, Alexander and Thomas, Laurent F and Graham, Sarah E and Sveinbjornsson, Gardar and Winkler, Thomas W and G{\"u}nther, Felix and Stark, Klaus J and Chai, Jin-Fang and Tayo, Bamidele O and Wuttke, Matthias and Li, Yong and Tin, Adrienne and Ahluwalia, Tarunveer S and Arnl{\"o}v, Johan and {\r A}svold, Bj{\o}rn Olav and Bakker, Stephan J L and Banas, Bernhard and Bansal, Nisha and Biggs, Mary L and Biino, Ginevra and B{\"o}hnke, Michael and Boerwinkle, Eric and Bottinger, Erwin P and Brenner, Hermann and Brumpton, Ben and Carroll, Robert J and Chaker, Layal and Chalmers, John and Chee, Miao-Li and Chee, Miao-Ling and Cheng, Ching-Yu and Chu, Audrey Y and Ciullo, Marina and Cocca, Massimiliano and Cook, James P and Coresh, Josef and Cusi, Daniele and de Borst, Martin H and Degenhardt, Frauke and Eckardt, Kai-Uwe and Endlich, Karlhans and Evans, Michele K and Feitosa, Mary F and Franke, Andre and Freitag-Wolf, Sandra and Fuchsberger, Christian and Gampawar, Piyush and Gansevoort, Ron T and Ghanbari, Mohsen and Ghasemi, Sahar and Giedraitis, Vilmantas and Gieger, Christian and Gudbjartsson, Daniel F and Hallan, Stein and Hamet, Pavel and Hishida, Asahi and Ho, Kevin and Hofer, Edith and Holleczek, Bernd and Holm, Hilma and Hoppmann, Anselm and Horn, Katrin and Hutri-K{\"a}h{\"o}nen, Nina and Hveem, Kristian and Hwang, Shih-Jen and Ikram, M Arfan and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Karabegovi{\'c}, Irma and Khor, Chiea-Chuen and Koenig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuhnel, Brigitte and Kuusisto, Johanna and Laakso, Markku and Lange, Leslie A and Lehtim{\"a}ki, Terho and Li, Man and Lieb, Wolfgang and Lind, Lars and Lindgren, Cecilia M and Loos, Ruth J F and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Matias-Garcia, Pamela R and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Morris, Andrew P and Mychaleckyj, Josyf C and Nadkarni, Girish N and Naito, Mariko and Nakatochi, Masahiro and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Nutile, Teresa and O{\textquoteright}Donoghue, Michelle L and O{\textquoteright}Connell, Jeffrey and Olafsson, Isleifur and Orho-Melander, Marju and Parsa, Afshin and Pendergrass, Sarah A and Penninx, Brenda W J H and Pirastu, Mario and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rheinberger, Myriam and Rice, Kenneth M and Rizzi, Federica and Rosenkranz, Alexander R and Rossing, Peter and Rotter, Jerome I and Ruggiero, Daniela and Ryan, Kathleen A and Sabanayagam, Charumathi and Salvi, Erika and Schmidt, Helena and Schmidt, Reinhold and Scholz, Markus and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Sedaghat, Sanaz and Shaffer, Christian M and Sieber, Karsten B and Sim, Xueling and Sims, Mario and Snieder, Harold and Stanzick, Kira J and Thorsteinsdottir, Unnur and Stocker, Hannah and Strauch, Konstantin and Stringham, Heather M and Sulem, Patrick and Szymczak, Silke and Taylor, Kent D and Thio, Chris H L and Tremblay, Johanne and Vaccargiu, Simona and van der Harst, Pim and van der Most, Peter J and Verweij, Niek and V{\"o}lker, Uwe and Wakai, Kenji and Waldenberger, Melanie and Wallentin, Lars and Wallner, Stefan and Wang, Judy and Waterworth, Dawn M and White, Harvey D and Willer, Cristen J and Wong, Tien-Yin and Woodward, Mark and Yang, Qiong and Yerges-Armstrong, Laura M and Zimmermann, Martina and Zonderman, Alan B and Bergler, Tobias and Stefansson, Kari and B{\"o}ger, Carsten A and Pattaro, Cristian and K{\"o}ttgen, Anna and Kronenberg, Florian and Heid, Iris M} } @article {9169, title = {Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.}, journal = {Mol Psychiatry}, year = {2022}, month = {2022 Aug 16}, abstract = {

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

}, issn = {1476-5578}, doi = {10.1038/s41380-022-01710-8}, author = {Lahti, Jari and Tuominen, Samuli and Yang, Qiong and Pergola, Giulio and Ahmad, Shahzad and Amin, Najaf and Armstrong, Nicola J and Beiser, Alexa and Bey, Katharina and Bis, Joshua C and Boerwinkle, Eric and Bressler, Jan and Campbell, Archie and Campbell, Harry and Chen, Qiang and Corley, Janie and Cox, Simon R and Davies, Gail and De Jager, Philip L and Derks, Eske M and Faul, Jessica D and Fitzpatrick, Annette L and Fohner, Alison E and Ford, Ian and Fornage, Myriam and Gerring, Zachary and Grabe, Hans J and Grodstein, Francine and Gudnason, Vilmundur and Simonsick, Eleanor and Holliday, Elizabeth G and Joshi, Peter K and Kajantie, Eero and Kaprio, Jaakko and Karell, Pauliina and Kleineidam, Luca and Knol, Maria J and Kochan, Nicole A and Kwok, John B and Leber, Markus and Lam, Max and Lee, Teresa and Li, Shuo and Loukola, Anu and Luck, Tobias and Marioni, Riccardo E and Mather, Karen A and Medland, Sarah and Mirza, Saira S and Nalls, Mike A and Nho, Kwangsik and O{\textquoteright}Donnell, Adrienne and Oldmeadow, Christopher and Painter, Jodie and Pattie, Alison and Reppermund, Simone and Risacher, Shannon L and Rose, Richard J and Sadashivaiah, Vijay and Scholz, Markus and Satizabal, Claudia L and Schofield, Peter W and Schraut, Katharina E and Scott, Rodney J and Simino, Jeannette and Smith, Albert V and Smith, Jennifer A and Stott, David J and Surakka, Ida and Teumer, Alexander and Thalamuthu, Anbupalam and Trompet, Stella and Turner, Stephen T and van der Lee, Sven J and Villringer, Arno and V{\"o}lker, Uwe and Wilson, Robert S and Wittfeld, Katharina and Vuoksimaa, Eero and Xia, Rui and Yaffe, Kristine and Yu, Lei and Zare, Habil and Zhao, Wei and Ames, David and Attia, John and Bennett, David A and Brodaty, Henry and Chasman, Daniel I and Goldman, Aaron L and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon L R and Lencz, Todd and Loeffler, Markus and Mattay, Venkata S and Palotie, Aarno and Psaty, Bruce M and Ramirez, Alfredo and Ridker, Paul M and Riedel-Heller, Steffi G and Sachdev, Perminder S and Saykin, Andrew J and Scherer, Martin and Schofield, Peter R and Sidney, Stephen and Starr, John M and Trollor, Julian and Ulrich, William and Wagner, Michael and Weir, David R and Wilson, James F and Wright, Margaret J and Weinberger, Daniel R and Debette, Stephanie and Eriksson, Johan G and Mosley, Thomas H and Launer, Lenore J and van Duijn, Cornelia M and Deary, Ian J and Seshadri, Sudha and R{\"a}ikk{\"o}nen, Katri} } @article {9449, title = {Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 12}, abstract = {

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10\% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

}, doi = {10.1101/2023.06.07.23291095}, author = {Huffman, Jennifer E and Nicolas, Jayna and Hahn, Julie and Heath, Adam S and Raffield, Laura M and Yanek, Lisa R and Brody, Jennifer A and Thibord, Florian and Almasy, Laura and Bartz, Traci M and Bielak, Lawrence F and Bowler, Russell P and Carrasquilla, Germ{\'a}n D and Chasman, Daniel I and Chen, Ming-Huei and Emmert, David B and Ghanbari, Mohsen and Haessle, Jeffery and Hottenga, Jouke-Jan and Kleber, Marcus E and Le, Ngoc-Quynh and Lee, Jiwon and Lewis, Joshua P and Li-Gao, Ruifang and Luan, Jian{\textquoteright}an and Malmberg, Anni and Mangino, Massimo and Marioni, Riccardo E and Martinez-Perez, Angel and Pankratz, Nathan and Polasek, Ozren and Richmond, Anne and Rodriguez, Benjamin At and Rotter, Jerome I and Steri, Maristella and Suchon, Pierre and Trompet, Stella and Weiss, Stefan and Zare, Marjan and Auer, Paul and Cho, Michael H and Christofidou, Paraskevi and Davies, Gail and de Geus, Eco and Deleuze, Jean-Francois and Delgado, Graciela E and Ekunwe, Lynette and Faraday, Nauder and G{\"o}gele, Martin and Greinacher, Andreas and He, Gao and Howard, Tom and Joshi, Peter K and Kilpel{\"a}inen, Tuomas O and Lahti, Jari and Linneberg, Allan and Naitza, Silvia and Noordam, Raymond and Pa{\"u}ls-Verg{\'e}s, Ferran and Rich, Stephen S and Rosendaal, Frits R and Rudan, Igor and Ryan, Kathleen A and Souto, Juan Carlos and van Rooij, Frank Ja and Wang, Heming and Zhao, Wei and Becker, Lewis C and Beswick, Andrew and Brown, Michael R and Cade, Brian E and Campbell, Harry and Cho, Kelly and Crapo, James D and Curran, Joanne E and de Maat, Moniek Pm and Doyle, Margaret and Elliott, Paul and Floyd, James S and Fuchsberger, Christian and Grarup, Niels and Guo, Xiuqing and Harris, Sarah E and Hou, Lifang and Kolcic, Ivana and Kooperberg, Charles and Menni, Cristina and Nauck, Matthias and O{\textquoteright}Connell, Jeffrey R and Orr{\`u}, Valeria and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Smith, Jennifer A and Soria, Jos{\'e} Manuel and Stott, David J and van Hylckama Vlieg, Astrid and Watkins, Hugh and Willemsen, Gonneke and Wilson, Peter and Ben-Shlomo, Yoav and Blangero, John and Boomsma, Dorret and Cox, Simon R and Dehghan, Abbas and Eriksson, Johan G and Fiorillo, Edoardo and Fornage, Myriam and Hansen, Torben and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon Lr and Lange, Leslie A and M{\"a}rz, Winfried and Mathias, Rasika A and Mitchell, Braxton D and Mook-Kanamori, Dennis O and Morange, Pierre-Emmanuel and Pedersen, Oluf and Pramstaller, Peter P and Redline, Susan and Reiner, Alexander and Ridker, Paul M and Silverman, Edwin K and Spector, Tim D and V{\"o}lker, Uwe and Wareham, Nick and Wilson, James F and Yao, Jie and Tr{\'e}gou{\"e}t, David-Alexandre and Johnson, Andrew D and Wolberg, Alisa S and de Vries, Paul S and Sabater-Lleal, Maria and Morrison, Alanna C and Smith, Nicholas L} } @article {9579, title = {X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Jan 18}, pages = {586}, abstract = {

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

}, keywords = {Androgens, Chromosomes, Human, X, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney, Male, Polymorphism, Single Nucleotide, Response Elements, Tetraspanins}, issn = {2041-1723}, doi = {10.1038/s41467-024-44709-1}, author = {Scholz, Markus and Horn, Katrin and Pott, Janne and Wuttke, Matthias and K{\"u}hnapfel, Andreas and Nasr, M Kamal and Kirsten, Holger and Li, Yong and Hoppmann, Anselm and Gorski, Mathias and Ghasemi, Sahar and Li, Man and Tin, Adrienne and Chai, Jin-Fang and Cocca, Massimiliano and Wang, Judy and Nutile, Teresa and Akiyama, Masato and {\r A}svold, Bj{\o}rn Olav and Bansal, Nisha and Biggs, Mary L and Boutin, Thibaud and Brenner, Hermann and Brumpton, Ben and Burkhardt, Ralph and Cai, Jianwen and Campbell, Archie and Campbell, Harry and Chalmers, John and Chasman, Daniel I and Chee, Miao Ling and Chee, Miao Li and Chen, Xu and Cheng, Ching-Yu and Cifkova, Renata and Daviglus, Martha and Delgado, Graciela and Dittrich, Katalin and Edwards, Todd L and Endlich, Karlhans and Michael Gaziano, J and Giri, Ayush and Giulianini, Franco and Gordon, Scott D and Gudbjartsson, Daniel F and Hallan, Stein and Hamet, Pavel and Hartman, Catharina A and Hayward, Caroline and Heid, Iris M and Hellwege, Jacklyn N and Holleczek, Bernd and Holm, Hilma and Hutri-K{\"a}h{\"o}nen, Nina and Hveem, Kristian and Isermann, Berend and Jonas, Jost B and Joshi, Peter K and Kamatani, Yoichiro and Kanai, Masahiro and Kastarinen, Mika and Khor, Chiea Chuen and Kiess, Wieland and Kleber, Marcus E and K{\"o}rner, Antje and Kovacs, Peter and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuokkanen, Mikko and K{\"a}h{\"o}nen, Mika and Lange, Leslie A and Lash, James P and Lehtim{\"a}ki, Terho and Li, Hengtong and Lin, Bridget M and Liu, Jianjun and Loeffler, Markus and Lyytik{\"a}inen, Leo-Pekka and Magnusson, Patrik K E and Martin, Nicholas G and Matsuda, Koichi and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and M{\"a}rz, Winfried and Nauck, Matthias and Nikus, Kjell and Nolte, Ilja M and Noordam, Raymond and Okada, Yukinori and Olafsson, Isleifur and Oldehinkel, Albertine J and Penninx, Brenda W J H and Perola, Markus and Pirastu, Nicola and Polasek, Ozren and Porteous, David J and Poulain, Tanja and Psaty, Bruce M and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Rasheed, Humaira and Reilly, Dermot F and Rice, Kenneth M and Richmond, Anne and Ridker, Paul M and Rotter, Jerome I and Rudan, Igor and Sabanayagam, Charumathi and Salomaa, Veikko and Schneiderman, Neil and Sch{\"o}ttker, Ben and Sims, Mario and Snieder, Harold and Stark, Klaus J and Stefansson, Kari and Stocker, Hannah and Stumvoll, Michael and Sulem, Patrick and Sveinbjornsson, Gardar and Svensson, Per O and Tai, E-Shyong and Taylor, Kent D and Tayo, Bamidele O and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomas, Laurent F and Tremblay, Johanne and T{\"o}njes, Anke and van der Most, Peter J and Vitart, Veronique and V{\"o}lker, Uwe and Wang, Ya Xing and Wang, Chaolong and Wei, Wen Bin and Whitfield, John B and Wild, Sarah H and Wilson, James F and Winkler, Thomas W and Wong, Tien-Yin and Woodward, Mark and Sim, Xueling and Chu, Audrey Y and Feitosa, Mary F and Thorsteinsdottir, Unnur and Hung, Adriana M and Teumer, Alexander and Franceschini, Nora and Parsa, Afshin and K{\"o}ttgen, Anna and Schlosser, Pascal and Pattaro, Cristian} }