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The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals
Ehret, Georg B; Ferreira, Teresa; Chasman, Daniel I; Jackson, Anne U; Schmidt, Ellen M; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Louise A; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J; Shungin, Dmitry; Hughes, Maria F; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E; Guo, Xiuqing; Lyytikainen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M; Magnusson, Patrik K; Salfati, Elias L; Rallidis, Loukianos S; Theusch, Elizabeth; Smith, Andrew J P; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H; Joehanes, Roby; Kim, Stuart K; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O; Bochud, Murielle; Absher, Devin; Adair, Linda S; Amin, Najaf; Arking, Dan E; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R; Barroso, Ines; Bevan, Stephen; Bis, Joshua C; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L; Boomsma, Dorret I; Bornstein, Stefan R; Brown, Morris J; Burnier, Michel; Cabrera, Claudia P; Chambers, John C; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S; Chung, Ren-Hua; Collins, Francis S; Connell, John M; Doring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F; Doney, Alex S F; Drenos, Fotios; Edkins, Sarah; Eicher, John D; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F; Ferrieres, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Franco, Oscar H; Franco-Cereceda, Anders; Fraser, Ross M; Ganesh, Santhi K; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H; Goodarzi, Mark O; Gorski, Mathias; Grassler, Jurgen; Groves, Christopher J; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Goran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A; Hingorani, Aroon D; Hirschhorn, Joel N; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A; Hunt, Steven C; Ikram, M Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A; Kahonen, Mika; Kang, Hyun Min; Kathiresan, Sekar; Keating, Brendan J; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S; Kosova, Gulum; Krauss, Ronald M; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaloy, Kirsti; Lakka, Timo A; Lee, Nanette R; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindstrom, Jaana; Lobbens, Stephane; Mannisto, Satu; Muller, Gabriele; Muller-Nurasyid, Martina; Mach, Francois; Markus, Hugh S; Marouli, Eirini; McCarthy, Mark I; McKenzie, Colin A; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E; Morris, Andrew D; Morrison, Alanna C; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J; O'Reilly, Paul F; Ong, Ken K; Paccaud, Fred; Palmer, Cameron D; Parsa, Afshin; Pedersen, Nancy L; Penninx, Brenda W; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rao, Dabeeru C; Rasheed, Asif; Rayner, N William; Renstrom, Frida; Rettig, Rainer; Rice, Kenneth M; Roberts, Robert; Rose, Lynda M; Rossouw, Jacques; Samani, Nilesh J; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H-H; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H; Smith, Albert V; Sosa, Maria X; Spector, Tim D; Stancakova, Alena; Stanton, Alice V; Stirrups, Kathleen E; Stringham, Heather M; Sundstrom, Johan; Swift, Amy J; Syvanen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D; Tremoli, Elena; Uitterlinden, Andre G; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M; van Iperen, Erik P A; Vasan, Ramachandran S; Verwoert, Germaine C; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F; Vollenweider, Peter; Wagner, Aline; Wain, Louise V; Wareham, Nicholas J; Watkins, Hugh; Weder, Alan B; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F; Wong, Tien Y; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S; Mohlke, Karen L; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J; Willer, Cristen J; Franke, Lude; Hovingh, G Kees; Taylor, Kent D; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L; Njolstad, Inger; Schwarz, Peter E H; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimaki, Terho; Hveem, Kristian; Palmas, Walter; Marz, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I; Rotter, Jerome I; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G; Kuulasmaa, Kari; Franks, Paul W; Hamsten, Anders; Wichmann, H-Erich; Palmer, Colin N A; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J F; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P; Newton-Cheh, Christopher; Munroe, Patricia B
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
PMCID:5042863
PMID: 27618452
ISSN: 1546-1718
CID: 2508002
Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci
Liu, Chunyu; Kraja, Aldi T; Smith, Jennifer A; Brody, Jennifer A; Franceschini, Nora; Bis, Joshua C; Rice, Kenneth; Morrison, Alanna C; Lu, Yingchang; Weiss, Stefan; Guo, Xiuqing; Palmas, Walter; Martin, Lisa W; Chen, Yii-Der Ida; Surendran, Praveen; Drenos, Fotios; Cook, James P; Auer, Paul L; Chu, Audrey Y; Giri, Ayush; Zhao, Wei; Jakobsdottir, Johanna; Lin, Li-An; Stafford, Jeanette M; Amin, Najaf; Mei, Hao; Yao, Jie; Voorman, Arend; Larson, Martin G; Grove, Megan L; Smith, Albert V; Hwang, Shih-Jen; Chen, Han; Huan, Tianxiao; Kosova, Gulum; Stitziel, Nathan O; Kathiresan, Sekar; Samani, Nilesh; Schunkert, Heribert; Deloukas, Panos; Li, Man; Fuchsberger, Christian; Pattaro, Cristian; Gorski, Mathias; Kooperberg, Charles; Papanicolaou, George J; Rossouw, Jacques E; Faul, Jessica D; Kardia, Sharon L R; Bouchard, Claude; Raffel, Leslie J; Uitterlinden, Andre G; Franco, Oscar H; Vasan, Ramachandran S; O'Donnell, Christopher J; Taylor, Kent D; Liu, Kiang; Bottinger, Erwin P; Gottesman, Omri; Daw, E Warwick; Giulianini, Franco; Ganesh, Santhi; Salfati, Elias; Harris, Tamara B; Launer, Lenore J; Dorr, Marcus; Felix, Stephan B; Rettig, Rainer; Volzke, Henry; Kim, Eric; Lee, Wen-Jane; Lee, I-Te; Sheu, Wayne H-H; Tsosie, Krystal S; Edwards, Digna R Velez; Liu, Yongmei; Correa, Adolfo; Weir, David R; Volker, Uwe; Ridker, Paul M; Boerwinkle, Eric; Gudnason, Vilmundur; Reiner, Alexander P; van Duijn, Cornelia M; Borecki, Ingrid B; Edwards, Todd L; Chakravarti, Aravinda; Rotter, Jerome I; Psaty, Bruce M; Loos, Ruth J F; Fornage, Myriam; Ehret, Georg B; Newton-Cheh, Christopher; Levy, Daniel; Chasman, Daniel I
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.
PMCID:5320952
PMID: 27618448
ISSN: 1546-1718
CID: 2746582
52 Genetic Loci Influencing Myocardial Mass
van der Harst, Pim; van Setten, Jessica; Verweij, Niek; Vogler, Georg; Franke, Lude; Maurano, Matthew T; Wang, Xinchen; Mateo Leach, Irene; Eijgelsheim, Mark; Sotoodehnia, Nona; Hayward, Caroline; Sorice, Rossella; Meirelles, Osorio; Lyytikainen, Leo-Pekka; Polasek, Ozren; Tanaka, Toshiko; Arking, Dan E; Ulivi, Sheila; Trompet, Stella; Muller-Nurasyid, Martina; Smith, Albert V; Dorr, Marcus; Kerr, Kathleen F; Magnani, Jared W; Del Greco M, Fabiola; Zhang, Weihua; Nolte, Ilja M; Silva, Claudia T; Padmanabhan, Sandosh; Tragante, Vinicius; Esko, Tonu; Abecasis, Goncalo R; Adriaens, Michiel E; Andersen, Karl; Barnett, Phil; Bis, Joshua C; Bodmer, Rolf; Buckley, Brendan M; Campbell, Harry; Cannon, Megan V; Chakravarti, Aravinda; Chen, Lin Y; Delitala, Alessandro; Devereux, Richard B; Doevendans, Pieter A; Dominiczak, Anna F; Ferrucci, Luigi; Ford, Ian; Gieger, Christian; Harris, Tamara B; Haugen, Eric; Heinig, Matthias; Hernandez, Dena G; Hillege, Hans L; Hirschhorn, Joel N; Hofman, Albert; Hubner, Norbert; Hwang, Shih-Jen; Iorio, Annamaria; Kahonen, Mika; Kellis, Manolis; Kolcic, Ivana; Kooner, Ishminder K; Kooner, Jaspal S; Kors, Jan A; Lakatta, Edward G; Lage, Kasper; Launer, Lenore J; Levy, Daniel; Lundby, Alicia; Macfarlane, Peter W; May, Dalit; Meitinger, Thomas; Metspalu, Andres; Nappo, Stefania; Naitza, Silvia; Neph, Shane; Nord, Alex S; Nutile, Teresa; Okin, Peter M; Olsen, Jesper V; Oostra, Ben A; Penninger, Josef M; Pennacchio, Len A; Pers, Tune H; Perz, Siegfried; Peters, Annette; Pinto, Yigal M; Pfeufer, Arne; Pilia, Maria Grazia; Pramstaller, Peter P; Prins, Bram P; Raitakari, Olli T; Raychaudhuri, Soumya; Rice, Ken M; Rossin, Elizabeth J; Rotter, Jerome I; Schafer, Sebastian; Schlessinger, David; Schmidt, Carsten O; Sehmi, Jobanpreet; Sillje, Herman H W; Sinagra, Gianfranco; Sinner, Moritz F; Slowikowski, Kamil; Soliman, Elsayed Z; Spector, Timothy D; Spiering, Wilko; Stamatoyannopoulos, John A; Stolk, Ronald P; Strauch, Konstantin; Tan, Sian-Tsung; Tarasov, Kirill V; Trinh, Bosco; Uitterlinden, Andre G; van den Boogaard, Malou; van Duijn, Cornelia M; van Gilst, Wiek H; Viikari, Jorma S; Visscher, Peter M; Vitart, Veronique; Volker, Uwe; Waldenberger, Melanie; Weichenberger, Christian X; Westra, Harm-Jan; Wijmenga, Cisca; Wolffenbuttel, Bruce H; Yang, Jian; Bezzina, Connie R; Munroe, Patricia B; Snieder, Harold; Wright, Alan F; Rudan, Igor; Boyer, Laurie A; Asselbergs, Folkert W; van Veldhuisen, Dirk J; Stricker, Bruno H; Psaty, Bruce M; Ciullo, Marina; Sanna, Serena; Lehtimaki, Terho; Wilson, James F; Bandinelli, Stefania; Alonso, Alvaro; Gasparini, Paolo; Jukema, J Wouter; Kaab, Stefan; Gudnason, Vilmundur; Felix, Stephan B; Heckbert, Susan R; de Boer, Rudolf A; Newton-Cheh, Christopher; Hicks, Andrew A; Chambers, John C; Jamshidi, Yalda; Visel, Axel; Christoffels, Vincent M; Isaacs, Aaron; Samani, Nilesh J; de Bakker, Paul I W
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 x 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.
PMCID:5478167
PMID: 27659466
ISSN: 1558-3597
CID: 2254952
The Genome Project-Write
Boeke, Jef D; Church, George; Hessel, Andrew; Kelley, Nancy J; Arkin, Adam; Cai, Yizhi; Carlson, Rob; Chakravarti, Aravinda; Cornish, Virginia W; Holt, Liam; Isaacs, Farren J; Kuiken, Todd; Lajoie, Marc; Lessor, Tracy; Lunshof, Jeantine; Maurano, Matthew T; Mitchell, Leslie A; Rine, Jasper; Rosser, Susan; Sanjana, Neville E; Silver, Pamela A; Valle, David; Wang, Harris; Way, Jeffrey C; Yang, Luhan
PMID: 27256881
ISSN: 1095-9203
CID: 2126732
Rare coding TTN variants are associated with electrocardiographic QT interval in the general population
Kapoor, Ashish; Bakshy, Kiranmayee; Xu, Linda; Nandakumar, Priyanka; Lee, Dongwon; Boerwinkle, Eric; Grove, Megan L; Arking, Dan E; Chakravarti, Aravinda
We have shown previously that noncoding variants mapping around a specific set of 170 genes encoding cardiomyocyte intercalated disc (ID) proteins are more enriched for associations with QT interval than observed for genome-wide comparisons. At a false discovery rate (FDR) of 5%, we had identified 28 such ID protein-encoding genes. Here, we assessed whether coding variants at these 28 genes affect QT interval in the general population as well. We used exome sequencing in 4,469 European American (EA) and 1,880 African American (AA) ancestry individuals from the population-based ARIC (Atherosclerosis Risk In Communities) Study cohort to focus on rare (allele frequency <1%) potentially deleterious (nonsynonymous, stop-gain, splice) variants (n = 2,398 for EA; n = 1,693 for AA) and tested their effects on standardized QT interval residuals. We identified 27 nonsynonymous variants associated with QT interval (FDR 5%), 22 of which were in TTN. Taken together with the mapping of a QT interval GWAS locus near TTN, our observation of rare deleterious coding variants in TTN associated with QT interval show that TTN plays a role in regulation of cardiac electrical conductance and coupling, and is a risk factor for cardiac arrhythmias and sudden cardiac death.
PMCID:4913250
PMID: 27321809
ISSN: 2045-2322
CID: 2746612
Commentary: The central questions of human genetics: Richard Lewontin's 1968 senior lecture in Victor McKusick's Bar Harbor short course
Chakravarti, Aravinda
PMID: 27582441
ISSN: 1464-3685
CID: 2746592
Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study [Correction]
Winkler, Thomas W; Justice, Anne E; Graff, Mariaelisa; Barata, Llilda; Feitosa, Mary F; Chu, Su; Czajkowski, Jacek; Esko, Tonu; Fall, Tove; Kilpelainen, Tuomas O; Lu, Yingchang; Magi, Reedik; Mihailov, Evelin; Pers, Tune H; Rueger, Sina; Teumer, Alexander; Ehret, Georg B; Ferreira, Teresa; Heard-Costa, Nancy L; Karjalainen, Juha; Lagou, Vasiliki; Mahajan, Anubha; Neinast, Michael D; Prokopenko, Inga; Simino, Jeannette; Teslovich, Tanya M; Jansen, Rick; Westra, Harm-Jan; White, Charles C; Absher, Devin; Ahluwalia, Tarunveer S; Ahmad, Shafqat; Albrecht, Eva; Alves, Alexessander Couto; Bragg-Gresham, Jennifer L; de Craen, Anton J M; Bis, Joshua C; Bonnefond, Amelie; Boucher, Gabrielle; Cadby, Gemma; Cheng, Yu-Ching; Chiang, Charleston W K; Delgado, Graciela; Demirkan, Ayse; Dueker, Nicole; Eklund, Niina; Eiriksdottir, Gudny; Eriksson, Joel; Feenstra, Bjarke; Fischer, Krista; Frau, Francesca; Galesloot, Tessel E; Geller, Frank; Goel, Anuj; Gorski, Mathias; Grammer, Tanja B; Gustafsson, Stefan; Haitjema, Saskia; Hottenga, Jouke-Jan; Huffman, Jennifer E; Jackson, Anne U; Jacobs, Kevin B; Johansson, Asa; Kaakinen, Marika; Kleber, Marcus E; Lahti, Jari; Mateo Leach, Irene; Lehne, Benjamin; Liu, Youfang; Lo, Ken Sin; Lorentzon, Mattias; Luan, Jian'an; Madden, Pamela A F; Mangino, Massimo; McKnight, Barbara; Medina-Gomez, Carolina; Monda, Keri L; Montasser, May E; Muller, Gabriele; Muller-Nurasyid, Martina; Nolte, Ilja M; Panoutsopoulou, Kalliope; Pascoe, Laura; Paternoster, Lavinia; Rayner, Nigel W; Renstrom, Frida; Rizzi, Federica; Rose, Lynda M; Ryan, Kathy A; Salo, Perttu; Sanna, Serena; Scharnagl, Hubert; Shi, Jianxin; Smith, Albert Vernon; Southam, Lorraine; Stancakova, Alena; Steinthorsdottir, Valgerdur; Strawbridge, Rona J; Sung, Yun Ju; Tachmazidou, Ioanna; Tanaka, Toshiko; Thorleifsson, Gudmar; Trompet, Stella; Pervjakova, Natalia; Tyrer, Jonathan P; Vandenput, Liesbeth; van der Laan, Sander W; van der Velde, Nathalie; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V; Verweij, Niek; Vlachopoulou, Efthymia; Waite, Lindsay L; Wang, Sophie R; Wang, Zhaoming; Wild, Sarah H; Willenborg, Christina; Wilson, James F; Wong, Andrew; Yang, Jian; Yengo, Loic; Yerges-Armstrong, Laura M; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Andersson, Ehm A; Bakker, Stephan J L; Baldassarre, Damiano; Banasik, Karina; Barcella, Matteo; Barlassina, Cristina; Bellis, Claire; Benaglio, Paola; Blangero, John; Bluher, Matthias; Bonnet, Fabrice; Bonnycastle, Lori L; Boyd, Heather A; Bruinenberg, Marcel; Buchman, Aron S; Campbell, Harry; Chen, Yii-Der Ida; Chines, Peter S; Claudi-Boehm, Simone; Cole, John; Collins, Francis S; de Geus, Eco J C; de Groot, Lisette C P G M; Dimitriou, Maria; Duan, Jubao; Enroth, Stefan; Eury, Elodie; Farmaki, Aliki-Eleni; Forouhi, Nita G; Friedrich, Nele; Gejman, Pablo V; Gigante, Bruna; Glorioso, Nicola; Go, Alan S; Gottesman, Omri; Grassler, Jurgen; Grallert, Harald; Grarup, Niels; Gu, Yu-Mei; Broer, Linda; Ham, Annelies C; Hansen, Torben; Harris, Tamara B; Hartman, Catharina A; Hassinen, Maija; Hastie, Nicholas; Hattersley, Andrew T; Heath, Andrew C; Henders, Anjali K; Hernandez, Dena; Hillege, Hans; Holmen, Oddgeir; Hovingh, Kees G; Hui, Jennie; Husemoen, Lise L; Hutri-Kahonen, Nina; Hysi, Pirro G; Illig, Thomas; De Jager, Philip L; Jalilzadeh, Shapour; Jorgensen, Torben; Jukema, J Wouter; Juonala, Markus; Kanoni, Stavroula; Karaleftheri, Maria; Khaw, Kay Tee; Kinnunen, Leena; Kittner, Steven J; Koenig, Wolfgang; Kolcic, Ivana; Kovacs, Peter; Krarup, Nikolaj T; Kratzer, Wolfgang; Kruger, Janine; Kuh, Diana; Kumari, Meena; Kyriakou, Theodosios; Langenberg, Claudia; Lannfelt, Lars; Lanzani, Chiara; Lotay, Vaneet; Launer, Lenore J; Leander, Karin; Lindstrom, Jaana; Linneberg, Allan; Liu, Yan-Ping; Lobbens, Stephane; Luben, Robert; Lyssenko, Valeriya; Mannisto, Satu; Magnusson, Patrik K; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Milani, Lili; Montgomery, Grant W; Morris, Andrew P; Narisu, Narisu; Nelis, Mari; Ong, Ken K; Palotie, Aarno; Perusse, Louis; Pichler, Irene; Pilia, Maria G; Pouta, Anneli; Rheinberger, Myriam; Ribel-Madsen, Rasmus; Richards, Marcus; Rice, Kenneth M; Rice, Treva K; Rivolta, Carlo; Salomaa, Veikko; Sanders, Alan R; Sarzynski, Mark A; Scholtens, Salome; Scott, Robert A; Scott, William R; Sebert, Sylvain; Sengupta, Sebanti; Sennblad, Bengt; Seufferlein, Thomas; Silveira, Angela; Slagboom, P Eline; Smit, Jan H; Sparso, Thomas H; Stirrups, Kathleen; Stolk, Ronald P; Stringham, Heather M; Swertz, Morris A; Swift, Amy J; Syvanen, Ann-Christine; Tan, Sian-Tsung; Thorand, Barbara; Tonjes, Anke; Tremblay, Angelo; Tsafantakis, Emmanouil; van der Most, Peter J; Volker, Uwe; Vohl, Marie-Claude; Vonk, Judith M; Waldenberger, Melanie; Walker, Ryan W; Wennauer, Roman; Widen, Elisabeth; Willemsen, Gonneke; Wilsgaard, Tom; Wright, Alan F; Zillikens, M Carola; van Dijk, Suzanne C; van Schoor, Natasja M; Asselbergs, Folkert W; de Bakker, Paul I W; Beckmann, Jacques S; Beilby, John; Bennett, David A; Bergman, Richard N; Bergmann, Sven; Boger, Carsten A; Boehm, Bernhard O; Boerwinkle, Eric; Boomsma, Dorret I; Bornstein, Stefan R; Bottinger, Erwin P; Bouchard, Claude; Chambers, John C; Chanock, Stephen J; Chasman, Daniel I; Cucca, Francesco; Cusi, Daniele; Dedoussis, George; Erdmann, Jeanette; Eriksson, Johan G; Evans, Denis A; de Faire, Ulf; Farrall, Martin; Ferrucci, Luigi; Ford, Ian; Franke, Lude; Franks, Paul W; Froguel, Philippe; Gansevoort, Ron T; Gieger, Christian; Gronberg, Henrik; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Per; Hamsten, Anders; van der Harst, Pim; Hayward, Caroline; Heliovaara, Markku; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hofman, Albert; Hu, Frank; Huikuri, Heikki V; Hveem, Kristian; James, Alan L; Jordan, Joanne M; Jula, Antti; Kahonen, Mika; Kajantie, Eero; Kathiresan, Sekar; Kiemeney, Lambertus A L M; Kivimaki, Mika; Knekt, Paul B; Koistinen, Heikki A; Kooner, Jaspal S; Koskinen, Seppo; Kuusisto, Johanna; Maerz, Winfried; Martin, Nicholas G; Laakso, Markku; Lakka, Timo A; Lehtimaki, Terho; Lettre, Guillaume; Levinson, Douglas F; Lind, Lars; Lokki, Marja-Liisa; Mantyselka, Pekka; Melbye, Mads; Metspalu, Andres; Mitchell, Braxton D; Moll, Frans L; Murray, Jeffrey C; Musk, Arthur W; Nieminen, Markku S; Njolstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J; Oostra, Ben A; Palmer, Lyle J; Pankow, James S; Pasterkamp, Gerard; Pedersen, Nancy L; Pedersen, Oluf; Penninx, Brenda W; Perola, Markus; Peters, Annette; Polasek, Ozren; Pramstaller, Peter P; Psaty, Bruce M; Qi, Lu; Quertermous, Thomas; Raitakari, Olli T; Rankinen, Tuomo; Rauramaa, Rainer; Ridker, Paul M; Rioux, John D; Rivadeneira, Fernando; Rotter, Jerome I; Rudan, Igor; den Ruijter, Hester M; Saltevo, Juha; Sattar, Naveed; Schunkert, Heribert; Schwarz, Peter E H; Shuldiner, Alan R; Sinisalo, Juha; Snieder, Harold; Sorensen, Thorkild I A; Spector, Tim D; Staessen, Jan A; Stefania, Bandinelli; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tardif, Jean-Claude; Tremoli, Elena; Tuomilehto, Jaakko; Uitterlinden, Andre G; Uusitupa, Matti; Verbeek, Andre L M; Vermeulen, Sita H; Viikari, Jorma S; Vitart, Veronique; Volzke, Henry; Vollenweider, Peter; Waeber, Gerard; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Zeggini, Eleftheria; Chakravarti, Aravinda; Clegg, Deborah J; Cupples, L Adrienne; Gordon-Larsen, Penny; Jaquish, Cashell E; Rao, D C; Abecasis, Goncalo R; Assimes, Themistocles L; Barroso, Ines; Berndt, Sonja I; Boehnke, Michael; Deloukas, Panos; Fox, Caroline S; Groop, Leif C; Hunter, David J; Ingelsson, Erik; Kaplan, Robert C; McCarthy, Mark I; Mohlke, Karen L; O'Connell, Jeffrey R; Schlessinger, David; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Hirschhorn, Joel N; Lindgren, Cecilia M; Heid, Iris M; North, Kari E; Borecki, Ingrid B; Kutalik, Zoltan; Loos, Ruth J F
[This corrects the article DOI: 10.1371/journal.pgen.1005378.].
PMCID:4927064
PMID: 27355579
ISSN: 1553-7404
CID: 2746602
Revealing rate-limiting steps in complex disease biology: The crucial importance of studying rare, extreme-phenotype families
Chakravarti, Aravinda; Turner, Tychele N
The major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate-limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the details of each GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate-limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders.
PMID: 27062178
ISSN: 1521-1878
CID: 2746622
Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk
Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen; Brody, Jennifer A; Amin, Najaf; Auer, Paul L; Bis, Joshua C; Boerwinkle, Eric; Burke, Gregory L; Chakravarti, Aravinda; Correa, Adolfo; Dreisbach, Albert W; Franco, Oscar H; Ehret, Georg B; Franceschini, Nora; Hofman, Albert; Lin, Dan-Yu; Metcalf, Ginger A; Musani, Solomon K; Muzny, Donna; Palmas, Walter; Raffel, Leslie; Reiner, Alex; Rice, Ken; Rotter, Jerome I; Veeraraghavan, Narayanan; Fox, Ervin; Guo, Xiuqing; North, Kari E; Gibbs, Richard A; van Duijn, Cornelia M; Psaty, Bruce M; Levy, Daniel; Newton-Cheh, Christopher; Morrison, Alanna C
BACKGROUND: Rare genetic variants influence blood pressure (BP). METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of approximately 170 000 common variants (minor allele frequency, >/=1%; statistical significance, P
PMCID:4771070
PMID: 26658788
ISSN: 1942-3268
CID: 2746652
Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa
Rose, Anna M; Shah, Amna Z; Venturini, Giulia; Krishna, Abhay; Chakravarti, Aravinda; Rivolta, Carlo; Bhattacharya, Shomi S
PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation.
PMCID:4725990
PMID: 26781568
ISSN: 2045-2322
CID: 2746632
