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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Wuttke, Matthias ; Li, Yong ; Li, Man ; Sieber, Karsten B. ; Feitosa, Mary F. ; Gorski, Mathias ; Tin, Adrienne ; Wang, Lihua ; Chu, Audrey Y. ; Hoppmann, Anselm ; Kirsten, Holger ; Giri, Ayush ; Chai, Jin-Fang ; Sveinbjornsson, Gardar ; Tayo, Bamidele O. ; Nutile, Teresa ; Fuchsberger, Christian ; Marten, Jonathan ; Cocca, Massimiliano ; Ghasemi, Sahar ; Xu, Yizhe ; Horn, Katrin ; Noce, Damia ; Van der Most, Peter J. ; Sedaghat, Sanaz ; Yu, Zhi ; Akiyama, Masato ; Afaq, Saima ; Ahluwalia, Tarunveer Singh ; Almgren, Peter ; Amin, Najaf ; Arnlov, Johan ; Bakker, Stephan J. L. ; Bansal, Nisha ; Baptista, Daniela ; Bergmann, Sven ; Biggs, Mary L. ; Biino, Ginevra ; Boehnke, Michael ; Boerwinkle, Eric ; Boissel, Mathilde ; Böttinger, Erwin ; Boutin, Thibaud S. ; Brenner, Hermann ; Brumat, Marco ; Burkhardt, Ralph ; Butterworth, Adam S. ; Campana, Eric ; Campbell, Archie ; Campbell, Harry ; Canouil, Mickael ; Carroll, Robert J. ; Catamo, Eulalia ; Chambers, John C. ; Chee, Miao-Ling ; Chee, Miao-Li ; Chen, Xu ; Cheng, Ching-Yu ; Cheng, Yurong ; Christensen, Kaare ; Cifkova, Renata ; Ciullo, Marina ; Concas, Maria Pina ; Cook, James P. ; Coresh, Josef ; Corre, Tanguy ; Sala, Cinzia Felicita ; Cusi, Daniele ; Danesh, John ; Daw, E. Warwick ; De Borst, Martin H. ; De Grandi, Alessandro ; De Mutsert, Renee ; De Vries, Aiko P. J. ; Degenhardt, Frauke ; Delgado, Graciela ; Demirkan, Ayse ; Di Angelantonio, Emanuele ; Dittrich, Katalin ; Divers, Jasmin ; Dorajoo, Rajkumar ; Eckardt, Kai-Uwe ; Ehret, Georg ; Elliott, Paul ; Endlich, Karlhans ; Evans, Michele K. ; Felix, Janine F. ; Foo, Valencia Hui Xian ; Franco, Oscar H. ; Franke, Andre ; Freedman, Barry I. ; Freitag-Wolf, Sandra ; Friedlander, Yechiel ; Froguel, Philippe ; Gansevoort, Ron T. ; Gao, He ; Gasparini, Paolo ; Gaziano, J. Michael ; Giedraitis, Vilmantas ; Gieger, Christian ; Girotto, Giorgia ; Giulianini, Franco ; Gogele, Martin ; Gordon, Scott D. ; Gudbjartsson, Daniel F. ; Gudnason, Vilmundur ; Haller, Toomas ; Hamet, Pavel ; Harris, Tamara B. ; Hartman, Catharina A. ; Hayward, Caroline ; Hellwege, Jacklyn N. ; Heng, Chew-Kiat ; Hicks, Andrew A. ; Hofer, Edith ; Huang, Wei ; Hutri-Kahonen, Nina ; Hwang, Shih-Jen ; Ikram, M. Arfan ; Indridason, Olafur S. ; Ingelsson, Erik ; Ising, Marcus ; Jaddoe, Vincent W. V. ; Jakobsdottir, Johanna ; Jonas, Jost B. ; Joshi, Peter K. ; Josyula, Navya Shilpa ; Jung, Bettina ; Kahonen, Mika ; Kamatani, Yoichiro ; Kammerer, Candace M. ; Kanai, Masahiro ; Kastarinen, Mika ; Kerr, Shona M. ; Khor, Chiea-Chuen ; Kiess, Wieland ; Kleber, Marcus E. ; Koenig, Wolfgang ; Kooner, Jaspal S. ; Korner, Antje ; Kovacs, Peter ; Kraja, Aldi T. ; Krajcoviechova, Alena ; Kramer, Holly ; Kramer, Bernhard K. ; Kronenberg, Florian ; Kubo, Michiaki ; Kuhnel, Brigitte ; Kuokkanen, Mikko ; Kuusisto, Johanna ; La Bianca, Martina ; Laakso, Markku ; Lange, Leslie A. ; Langefeld, Carl D. ; Lee, Jeannette Jen-Mai ; Lehne, Benjamin ; Lehtimaki, Terho ; Lieb, Wolfgang ; Lim, Su-Chi ; Lind, Lars ; Lindgren, Cecilia M. ; Liu, Jun ; Liu, Jianjun ; Loeffler, Markus ; Loos, Ruth J. F. ; Lucae, Susanne ; Lukas, Mary Ann ; Lyytikainen, Leo-Pekka ; Magi, Reedik ; Magnusson, Patrik K. E. ; Mahajan, Anubha ; Martin, Nicholas G. ; Martins, Jade ; Marz, Winfried ; Mascalzoni, Deborah ; Matsuda, Koichi ; Meisinger, Christa ; Meitinger, Thomas ; Melander, Olle ; Metspalu, Andres ; Mikaelsdottir, Evgenia K. ; Milaneschi, Yuri ; Miliku, Kozeta ; Mishra, Pashupati P. ; Program, V. A. Million Veteran ; Mohlke, Karen L. ; Mononen, Nina ; Montgomery, Grant W. ; Mook-Kanamori, Dennis O. ; Mychaleckyj, Josyf C. ; Nadkarni, Girish N. ; Nalls, Mike A. ; Nauck, Matthias ; Nikus, Kjell ; Ning, Boting ; Nolte, Ilja M. ; Noordam, Raymond ; Olafsson, Isleifur ; Oldehinkel, Albertine J. ; Orho-Melander, Marju ; Ouwehand, Willem H. ; Padmanabhan, Sandosh ; Palmer, Nicholette D. ; Palsson, Runolfur ; Penninx, Brenda W. J. H. ; Perls, Thomas ; Perola, Markus ; Pirastu, Mario ; Pirastu, Nicola ; Pistis, Giorgio ; Podgornaia, Anna I. ; Polasek, Ozren ; Ponte, Belen ; Porteous, David J. ; Poulain, Tanja ; Pramstaller, Peter P. ; Preuss, Michael H. ; Prins, Bram P. ; Province, Michael A. ; Rabelink, Ton J. ; Raffield, Laura M. ; Raitakari, Olli T. ; Reilly, Dermot F. ; Rettig, Rainer ; Rheinberger, Myriam ; Rice, Kenneth M. ; Ridker, Paul M. ; Rivadeneira, Fernando ; Rizzi, Federica ; Roberts, David J. ; Robino, Antonietta ; Rossing, Peter ; Rudan, Igor ; Rueedi, Rico ; Ruggiero, Daniela ; Ryan, Kathleen A. ; Saba, Yasaman ; Sabanayagam, Charumathi ; Salomaa, Veikko ; Salvi, Erika ; Saum, Kai-Uwe ; Schmidt, Helena ; Schmidt, Reinhold ; Ben Schottker ; Schulz, Christina-Alexandra ; Schupf, Nicole ; Shaffer, Christian M. ; Shi, Yuan ; Smith, Albert V. ; Smith, Blair H. ; Soranzo, Nicole ; Spracklen, Cassandra N. ; Strauch, Konstantin ; Stringham, Heather M. ; Stumvoll, Michael ; Svensson, Per O. ; Szymczak, Silke ; Tai, E-Shyong ; Tajuddin, Salman M. ; Tan, Nicholas Y. Q. ; Taylor, Kent D. ; Teren, Andrej ; Tham, Yih-Chung ; Thiery, Joachim ; Thio, Chris H. L. ; Thomsen, Hauke ; Thorleifsson, Gudmar ; Toniolo, Daniela ; Tonjes, Anke ; Tremblay, Johanne ; Tzoulaki, Ioanna ; Uitterlinden, Andre G. ; Vaccargiu, Simona ; Van Dam, Rob M. ; Van der Harst, Pim ; Van Duijn, Cornelia M. ; Edward, Digna R. Velez ; Verweij, Niek ; Vogelezang, Suzanne ; Volker, Uwe ; Vollenweider, Peter ; Waeber, Gerard ; Waldenberger, Melanie ; Wallentin, Lars ; Wang, Ya Xing ; Wang, Chaolong ; Waterworth, Dawn M. ; Bin Wei, Wen ; White, Harvey ; Whitfield, John B. ; Wild, Sarah H. ; Wilson, James F. ; Wojczynski, Mary K. ; Wong, Charlene ; Wong, Tien-Yin ; Xu, Liang ; Yang, Qiong ; Yasuda, Masayuki ; Yerges-Armstrong, Laura M. ; Zhang, Weihua ; Zonderman, Alan B. ; Rotter, Jerome I. ; Bochud, Murielle ; Psaty, Bruce M. ; Vitart, Veronique ; Wilson, James G. ; Dehghan, Abbas ; Parsa, Afshin ; Chasman, Daniel I. ; Ho, Kevin ; Morris, Andrew P. ; Devuyst, Olivier ; Akilesh, Shreeram ; Pendergrass, Sarah A. ; Sim, Xueling ; Boger, Carsten A. ; Okada, Yukinori ; Edwards, Todd L. ; Snieder, Harold ; Stefansson, Kari ; Hung, Adriana M. ; Heid, Iris M. ; Scholz, Markus ; Teumer, Alexander ; Kottgen, Anna ; Pattaro, Cristian
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry 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.
Warrington, Nicole ; Beaumont, Robin ; Horikoshi, Momoko ; Day, Felix R. ; Helgeland, Øyvind ; Laurin, Charles ; Bacelis, Jonas ; Peng, Shouneng ; Hao, Ke ; Feenstra, Bjarke ; Wood, Andrew R. ; Mahajan, Anubha ; Tyrrell, Jessica ; Robertson, Neil R. ; Rayner, N. William ; Qiao, Zhen ; Moen, Gunn-Helen ; Vaudel, Marc ; Marsit, Carmen ; Chen, Jia ; Nodzenski, Michael ; Schnurr, Theresia M. ; Zafarmand, Mohammad Hadi ; Bradfield, Jonathan P. ; Grarup, Niels ; Kooijman, Marjolein N. ; Li-Gao, Ruifang ; Geller, Frank ; Ahluwalia, Tarunveer Singh ; Paternoster, Lavinia ; Rueedi, Rico ; Huikari, Ville ; Hottenga, Jouke-Jan ; Lyytikäinen, Leo-Pekka ; Cavadino, Alana ; Metrustry, Sarah ; Cousminer, Diana L. ; Wu, Ying ; Thiering, Elisabeth Paula ; Wang, Carol A. ; Have, Christian Theil ; Vilor-Tejedor, Natalia ; Joshi, Peter K. ; Painter, Jodie N. ; Ntalla, Ioanna ; Myhre, Ronny ; Pitkänen, Niina ; van Leeuwen, Elisabeth M. ; Joro, Raimo ; Lagou, Vasiliki ; Richmond, Rebecca C. ; Espinosa, Ana ; Barton, Sheila J. ; Inskip, Hazel M. ; Holloway, John W. ; Santa-Marina, Loreto ; Estivill, Xavier ; Ang, Wei ; Marsh, Julie A. ; Reichetzeder, Christoph ; Marullo, Letizia ; Hocher, Berthold ; Lunetta, Kathryn L. ; Murabito, Joanne M. ; Relton, Caroline L. ; Kogevinas, Manolis ; Chatzi, Leda ; Allard, Catherine ; Bouchard, Luigi ; Hivert, Marie-France ; Zhang, Ge ; Muglia, Louis J. ; Heikkinen, Jani ; Morgen, Camilla S. ; van Kampen, Antoine H. C. ; van Schaik, Barbera D. C. ; Mentch, Frank D. ; Langenberg, Claudia ; Scott, Robert A. ; Zhao, Jing Hua ; Hemani, Gibran ; Ring, Susan M. ; Bennett, Amanda J. ; Gaulton, Kyle J. ; Fernandez-Tajes, Juan ; van Zuydam, Natalie R. ; Medina-Gomez, Carolina ; de Haan, Hugoline G. ; Rosendaal, Frits R. ; Kutalik, Zoltán ; Marques-Vidal, Pedro ; Das, Shikta ; Willemsen, Gonneke ; Mbarek, Hamdi ; Müller-Nurasyid, Martina ; Standl, Marie ; Appel, Emil V. R. ; Fonvig, Cilius Esmann ; Trier, Caecilie ; van Beijsterveldt, Catharina E. M. ; Murcia, Mario ; Bustamante, Mariona ; Bonàs-Guarch, Sílvia ; Hougaard, David M. ; Mercader, Josep M. ; Linneberg, Allan ; Schraut, Katharina E. ; Lind, Penelope A. ; Medland, Sarah Elizabeth ; Shields, Beverley M. ; Knight, Bridget A. ; Chai, Jin-Fang ; Panoutsopoulou, Kalliope ; Bartels, Meike ; Sánchez, Friman ; Stokholm, Jakob ; Torrents, David ; Vinding, Rebecca K. ; Willems, Sara M. ; Atalay, Mustafa ; Chawes, Bo L. ; Kovacs, Peter ; Prokopenko, Inga ; Tuke, Marcus A. ; Yaghootkar, Hanieh ; Ruth, Katherine S. ; Jones, Samuel E. ; Loh, Po-Ru ; Murray, Anna ; Weedon, Michael N. ; Tönjes, Anke ; Stumvoll, Michael ; Michaelsen, Kim Fleischer ; Eloranta, Aino-Maija ; Lakka, Timo A. ; van Duijn, Cornelia M. ; Kiess, Wieland ; Koerner, Antje ; Niinikoski, Harri ; Pahkala, Katja ; Raitakari, Olli T. ; Jacobsson, Bo ; Zeggini, Eleftheria ; Dedoussis, George V. ; Teo, Yik-Ying ; Saw, Seang-Mei ; Montgomery, Grant W. ; Campbell, Harry ; Wilson, James F. ; Vrijkotte, Tanja G. M. ; Vrijheid, Martine ; de Geus, Eco J. C. N. ; Hayes, M. Geoffrey ; Kadarmideen, Haja N. ; Holm, Jens-Christian ; Beilin, Lawrence J. ; Pennell, Craig E. ; Heinrich, Joachim ; Adair, Linda S. ; Borja, Judith B. ; Mohlke, Karen L. ; Eriksson, Johan G. ; Widen, Elisabeth E. ; Hattersley, Andrew T. ; Spector, Tim D. ; Kaehoenen, Mika ; Viikari, Jorma S. ; Lehtimaeki, Terho ; Boomsma, Dorret I. ; Sebert, Sylvain ; Vollenweider, Peter ; Sorensen, Thorkild I. A. ; Bisgaard, Hans ; Bonnelykke, Klaus ; Murray, Jeffrey C. ; Melbye, Mads ; Nohr, Ellen A. ; Mook-Kanamori, Dennis O. ; Rivadeneira, Fernando ; Hofman, Albert ; Felix, Janine F. ; Jaddoe, Vincent W. V. ; Hansen, Torben ; Pisinger, Charlotta ; Vaag, Allan A. ; Pedersen, Oluf ; Uitterlinden, Andre G. ; Jarvelin, Marjo-Riitta ; Power, Christine ; Hypponen, Elina ; Scholtens, Denise M. ; Lowe, William L. ; Smith, George Davey ; Timpson, Nicholas J. ; Morris, Andrew P. ; Wareham, Nicholas J. ; Hakonarson, Hakon ; Grant, Struan F. A. ; Frayling, Timothy M. ; Lawlor, Debbie A. ; Njolstad, Pal R. ; Johansson, Stefan ; Ong, Ken K. ; McCarthy, Mark I. ; Perry, John R. B. ; Evans, David M. ; Freathy, Rachel M.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Taal, H. Rob ; St Pourcain, Beate ; Thiering, Elisabeth ; Das, Shikta ; Mook-Kanamori, Dennis O. ; Warrington, Nicole M. ; Kaakinen, Marika ; Kreiner-Moller, Eskil ; Bradfield, Jonathan P. ; Freathy, Rachel M. ; Geller, Frank ; Guxens, Monica ; Cousminer, Diana L. ; Kerkhof, Marjan ; Timpson, Nicholas J. ; Ikram, M. Arfan ; Beilin, Lawrence J. ; Bonnelykke, Klaus ; Buxton, Jessica L. ; Charoen, Pimphen ; Chawes, Bo Lund Krogsgaard ; Eriksson, Johan ; Evans, David M. ; Hofman, Albert ; Kemp, John P. ; Kim, Cecilia E. ; Klopp, Norman ; Lahti, Jari ; Lye, Stephen J. ; McMahon, George ; Mentch, Frank D. ; Mueller-Nurasyid, Martina ; O'Reilly, Paul F. ; Prokopenko, Inga ; Rivadeneira, Fernando ; Steegers, Eric A. P. ; Sunyer, Jordi ; Tiesler, Carla ; Yaghootkar, Hanieh ; Breteler, Monique M. B. ; Debette, Stephanie ; Fornage, Myriam ; Gudnason, Vilmundur ; Launer, Lenore J. ; van der Lugt, Aad ; Mosley, Thomas H. ; Seshadri, Sudha ; Smith, Albert V. ; Vernooij, Meike W. ; Blakemore, Alexandra I. F. ; Chiavacci, Rosetta M. ; Feenstra, Bjarke ; Fernandez-Banet, Julio ; Grant, Struan F. A. ; Hartikainen, Anna-Liisa ; van der Heijden, Albert J. ; Iniguez, Carmen ; Lathrop, Mark ; McArdle, Wendy L. ; Molgaard, Anne ; Newnham, John P. ; Palmer, Lyle J. ; Palotie, Aarno ; Pouta, Annneli ; Ring, Susan M. ; Sovio, Ulla ; Standl, Marie ; Uitterlinden, Andre G. ; Wichmann, H-Erich ; Vissing, Nadja Hawwa ; DeCarli, Charles ; van Duijn, Cornelia M. ; McCarthy, Mark I. ; Koppelman, Gerard H. ; Estivill, Xavier ; Hattersley, Andrew T. ; Melbye, Mads ; Bisgaard, Hans ; Pennell, Craig E. ; Widen, Elisabeth ; Hakonarson, Hakon ; Smith, George Davey ; Heinrich, Joachim ; Jarvelin, Marjo-Riitta ; Jaddoe, Vincent W. V. ; Adair, Linda S. ; Ang, Wei ; Atalay, Mustafa ; van Beijsterveldt, Toos ; Bergen, Nienke ; Benke, Kelly ; Berry, Diane J. ; Bradfield, Jonathan P. ; Charoen, Pimphen ; Coin, Lachlan ; Cousminer, Diana L. ; Das, Shikta ; Davis, Oliver S. P. ; Elliott, Paul ; Evans, David M. ; Feenstra, Bjarke ; Flexeder, Claudia ; Frayling, Tim ; Freathy, Rachel M. ; Gaillard, Romy ; Geller, Frank ; Groen-Blokhuis, Maria ; Goh, Liang-Kee ; Guxens, Monica ; Haworth, Claire M. A. ; Hadley, Dexter ; Hebebrand, Johannes ; Hinney, Anke ; Hirschhorn, Joel N. ; Holloway, John W. ; Holst, Claus ; Hottenga, Jouke Jan ; Horikoshi, Momoko ; Huikari, Ville ; Hypponen, Elina ; Iniguez, Carmen ; Kaakinen, Marika ; Kilpelainen, Tuomas O. ; Kirin, Mirna ; Kowgier, Matthew ; Lakka, Hanna-Maaria ; Lange, Leslie A. ; Lawlor, Debbie A. ; Lehtimaki, Terho ; Lewin, Alex ; Lindgren, Cecilia ; Lindi, Virpi ; Maggi, Reedik ; Marsh, Julie ; Middeldorp, Christel ; Millwood, Iona ; Mook-Kanamori, Dennis O. ; Murray, Jeffrey C. ; Nivard, Michel ; Nohr, Ellen Aagaard ; Ntalla, Ioanna ; Oken, Emily ; O'Reilly, Paul F. ; Palmer, Lyle J. ; Panoutsopoulou, Kalliope ; Pararajasingham, Jennifer ; Prokopenko, Inga ; Rodriguez, Alina ; Salem, Rany M. ; Sebert, Sylvain ; Siitonen, Niina ; Sovio, Ulla ; St Pourcain, Beate ; Strachan, David P. ; Sunyer, Jordi ; Taal, H. Rob ; Teo, Yik-Ying ; Thiering, Elisabeth ; Tiesler, Carla ; Uitterlinden, Andre G. ; Valcarcel, Beatriz ; Warrington, Nicole M. ; White, Scott ; Willemsen, Gonneke ; Yaghootkar, Hanieh ; Zeggini, Eleftheria ; Boomsma, Dorret I. ; Cooper, Cyrus ; Estivill, Xavier ; Gillman, Matthew ; Grant, Struan F. A. ; Hakonarson, Hakon ; Hattersley, Andrew T. ; Heinrich, Joachim ; Hocher, Berthold ; Jaddoe, Vincent W. V. ; Jarvelin, Marjo-Riitta ; Lakka, Timo A. ; McCarthy, Mark I. ; Melbye, Mads ; Mohlke, Karen L. ; Dedoussis, George V. ; Ong, Ken K. ; Pearson, Ewan R. ; Pennell, Craig E. ; Price, Thomas S. ; Power, Chris ; Raitakari, Olli T. ; Saw, Seang-Mei ; Scherag, Andre ; Simell, Olli ; Sorensen, Thorkild I. A. ; Timpson, Nicholas J. ; Widen, Elisabeth ; Wilson, James F. ; Ang, Wei ; van Beijsterveldt, Toos ; Bergen, Nienke ; Benke, Kelly ; Berry, Diane J. ; Bradfield, Jonathan P. ; Charoen, Pimphen ; Coin, Lachlan ; Cousminer, Diana L. ; Das, Shikta ; Elliott, Paul ; Evans, David M. ; Frayling, Tim ; Freathy, Rachel M. ; Gaillard, Romy ; Groen-Blokhuis, Maria ; Guxens, Monica ; Hadley, Dexter ; Hottenga, Jouke Jan ; Huikari, Ville ; Hypponen, Elina ; Kaakinen, Marika ; Kowgier, Matthew ; Lawlor, Debbie A. ; Lewin, Alex ; Lindgren, Cecilia ; Marsh, Julie ; Middeldorp, Christel ; Millwood, Iona ; Mook-Kanamori, Dennis O. ; Nivard, Michel ; O'Reilly, Paul F. ; Palmer, Lyle J. ; Prokopenko, Inga ; Rodriguez, Alina ; Sebert, Sylvain ; Sovio, Ulla ; St Pourcain, Beate ; Standl, Marie ; Strachan, David P. ; Sunyer, Jordi ; Taal, H. Rob ; Thiering, Elisabeth ; Tiesler, Carla ; Uitterlinden, Andre G. ; Valcarcel, Beatriz ; Warrington, Nicole M. ; White, Scott ; Willemsen, Gonneke ; Yaghootkar, Hanieh ; Boomsma, Dorret I. ; Estivill, Xavier ; Grant, Struan F. A. ; Hakonarson, Hakon ; Hattersley, Andrew T. ; Heinrich, Joachim ; Jaddoe, Vincent W. V. ; Jarvelin, Marjo-Riitta ; McCarthy, Mark I. ; Pennell, Craig E. ; Power, Chris ; Timpson, Nicholas J. ; Widen, Elisabeth ; Ikram, M. Arfan ; Fornage, Myriam ; Smith, Albert V. ; Seshadri, Sudha ; Schmidt, Reinhold ; Debette, Stephanie ; Vrooman, Henri A. ; Sigurdsson, Sigurdur ; Ropele, Stefan ; Coker, Laura H. ; Longstreth, W. T. ; Niessen, Wiro J. ; DeStefano, Anita L. ; Beiser, Alexa ; Zijdenbos, Alex P. ; Struchalin, Maksim ; Jack, Clifford R. ; Nalls, Mike A. ; Au, Rhoda ; Hofman, Albert ; Gudnason, Haukur ; van der Lugt, Aad ; Harris, Tamara B. ; Meeks, William M. ; Vernooij, Meike W. ; van Buchem, Mark A. ; Catellier, Diane ; Gudnason, Vilmundur ; Windham, B. Gwen ; Wolf, Philip A. ; van Duijn, Cornelia M. ; Mosley, Thomas H. ; Schmidt, Helena ; Launer, Lenore J. ; Breteler, Monique M. B. ; DeCarli, Charles
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Arridge, Christopher S. ; Achilleos, N. ; Agarwal, Jessica ; Agnor, C. B. ; Ambrosi, R. ; Andre, N. ; Badman, S. V. ; Baines, K. ; Banfield, D. ; Barthelemy, M. ; Bisi, M. M. ; Blum, J. ; Bocanegra-Bahamon, T. ; Bonfond, B. ; Bracken, C. ; Brandt, P. ; Briand, C. ; Briois, C. ; Brooks, S. ; Castillo-Rogez, J. ; Cavalie, T. ; Christophe, B. ; Coates, Andrew J. ; Collinson, G. ; Cooper, John F. ; Costa-Sitja, M. ; Courtin, R. ; Daglis, I. A. ; De Pater, Imke ; Desai, M. ; Dirkx, D. ; Dougherty, M. K. ; Ebert, R. W. ; Filacchione, Gianrico ; Fletcher, Leigh N. ; Fortney, J. ; Gerth, I. ; Grassi, D. ; Grodent, D. ; Grün, Eberhard ; Gustin, J. ; Hedman, M. ; Helled, R. ; Henri, P. ; Hess, Sebastien ; Hillier, J. K. ; Hofstadter, M. H. ; Holme, R. ; Horanyi, M. ; Hospodarsky, George B. ; Hsu, S. ; Irwin, P. ; Jackman, C. M. ; Karatekin, O. ; Kempf, Sascha ; Khalisi, E. ; Konstantinidis, K. ; Kruger, H. ; Kurth, William S. ; Labrianidis, C. ; Lainey, V. ; Lamy, L. L. ; Laneuville, Matthieu ; Lucchesi, D. ; Luntzer, A. ; MacArthur, J. ; Maier, A. ; Masters, A. ; McKenna-Lawlor, S. ; Melin, H. ; Milillo, A. ; Moragas-Klostermeyer, Georg ; Morschhauser, Achim ; Moses, J. I. ; Mousis, O. ; Nettelmann, N. ; Neubauer, F. M. ; Nordheim, T. ; Noyelles, B. ; Orton, G. S. ; Owens, Mathew ; Peron, R. ; Plainaki, C. ; Postberg, F. ; Rambaux, N. ; Retherford, K. ; Reynaud, Serge ; Roussos, Elias ; Russell, C. T. ; Rymer, Am. ; Sallantin, R. ; Sanchez-Lavega, A. ; Santolik, O. ; Saur, J. ; Sayanagi, Km. ; Schenk, P. ; Schubert, J. ; Sergis, N. ; Sittler, E. C. ; Smith, A. ; Spahn, Frank ; Srama, Ralf ; Stallard, T. ; Sterken, V. ; Sternovsky, Zoltan ; Tiscareno, M. ; Tobie, G. ; Tosi, F. ; Trieloff, M. ; Turrini, D. ; Turtle, E. P. ; Vinatier, S. ; Wilson, R. ; Zarkat, P.
Giant planets helped to shape the conditions we see in the Solar System today and they account for more than 99% of the mass of the Sun's planetary system. They can be subdivided into the Ice Giants (Uranus and Neptune) and the Gas Giants (Jupiter and Saturn), which differ from each other in a number of fundamental ways. Uranus, in particular is the most challenging to our understanding of planetary formation and evolution, with its large obliquity, low self-luminosity, highly asymmetrical internal field, and puzzling internal structure. Uranus also has a rich planetary system consisting of a system of inner natural satellites and complex ring system, five major natural icy satellites, a system of irregular moons with varied dynamical histories, and a highly asymmetrical magnetosphere. Voyager 2 is the only spacecraft to have explored Uranus, with a flyby in 1986, and no mission is currently planned to this enigmatic system. However, a mission to the uranian system would open a new window on the origin and evolution of the Solar System and would provide crucial information on a wide variety of physicochemical processes in our Solar System. These have clear implications for understanding exoplanetary systems. In this paper we describe the science case for an orbital mission to Uranus with an atmospheric entry probe to sample the composition and atmospheric physics in Uranus' atmosphere. The characteristics of such an orbiter and a strawman scientific payload are described and we discuss the technical challenges for such a mission. This paper is based on a white paper submitted to the European Space Agency's call for science themes for its large-class mission programme in 2013.
Cohen, Andrew ; Campisano, C. ; Arrowsmith, J. Ramón ; Asrat, Asfawossen ; Behrensmeyer, A. K. ; Deino, A. ; Feibel, C. ; Hill, A. ; Johnson, R. ; Kingston, J. ; Lamb, Henry F. ; Lowenstein, T. ; Noren, A. ; Olago, D. ; Owen, R. B. ; Potts, R. ; Reed, Kate ; Renaut, R. ; Schäbitz, Frank ; Tiercelin, J. -J. ; Trauth, Martin H. ; Wynn, J. ; Ivory, S. ; Brady, K. ; Rodysill, J. ; Githiri, J. ; Russell, J. ; Förster, Verena ; Dommain, René ; Rucina, S. ; Deocampo, D. ; Russell, J. ; Billingsley, A. ; Beck, C. ; Dorenbeck, G. ; Dullo, L. ; Feary, D. ; Garello, D. ; Gromig, R. ; Johnson, T. ; Junginger, A. ; Karanja, M. ; Kimburi, E. ; Mbuthia, A. ; McCartney, T. ; McNulty, E. ; Muiruri, V. ; Nambiro, E. ; Negash, E. W. ; Njagi, D. ; Wilson, J. N. ; Rabideaux, N. ; Raub, T. ; Sier, M. J. ; Smith, P. ; Urban, J. ; Warren, M. ; Yadeta, M. ; Yost, C. ; Zinaye, B.
The role that climate and environmental history may have played in influencing human evolution has been the focus of considerable interest and controversy among paleoanthropologists for decades. Prior attempts to understand the environmental history side of this equation have centered around the study of outcrop sediments and fossils adjacent to where fossil hominins (ancestors or close relatives of modern humans) are found, or from the study of deep sea drill cores. However, outcrop sediments are often highly weathered and thus are unsuitable for some types of paleoclimatic records, and deep sea core records come from long distances away from the actual fossil and stone tool remains. The Hominin Sites and Paleolakes Drilling Project (HSPDP) was developed to address these issues. The project has focused its efforts on the eastern African Rift Valley, where much of the evidence for early hominins has been recovered. We have collected about 2 km of sediment drill core from six basins in Kenya and Ethiopia, in lake deposits immediately adjacent to important fossil hominin and archaeological sites. Collectively these cores cover in time many of the key transitions and critical intervals in human evolutionary history over the last 4 Ma, such as the earliest stone tools, the origin of our own genus Homo, and the earliest anatomically modern Homo sapiens. Here we document the initial field, physical property, and core description results of the 2012-2014 HSPDP coring campaign.
Patterson, Jenelle A. ; He, Hai ; Folz, Jacob S. ; Li, Qiang ; Wilson, Mark A. ; Fiehn, Oliver ; Bruner, Steven D. ; Bar-Even, Arren ; Hanson, Andrew D.
Formaldehyde (HCHO) is a reactive carbonyl compound that formylates and cross-links proteins, DNA, and small molecules. It is of specific concern as a toxic intermediate in the design of engineered pathways involving methanol oxidation or formate reduction. The interest in engineering these pathways is not, however, matched by engineering-relevant information on precisely why HCHO is toxic or on what damage-control mechanisms cells deploy to manage HCHO toxicity. The only well-defined mechanism for managing HCHO toxicity is formaldehyde dehydrogenase-mediated oxidation to formate, which is counterproductive if HCHO is a desired pathway intermediate. We therefore sought alternative HCHO damage-control mechanisms via comparative genomic analysis. This analysis associated homologs of the Escherichia coli pepP gene with HCHO-related one-carbon metabolism. Furthermore, deleting pepP increased the sensitivity of E. coli to supplied HCHO but not other carbonyl compounds. PepP is a proline aminopeptidase that cleaves peptides of the general formula X-Pro-Y, yielding X + Pro-Y. HCHO is known to react spontaneously with cysteine to form the close proline analog thioproline (thiazolidine-4-carboxylate), which is incorporated into proteins and hence into proteolytic peptides. We therefore hypothesized that certain thioproline-containing peptides are toxic and that PepP cleaves these aberrant peptides. Supporting this hypothesis, PepP cleaved the model peptide Ala-thioproline-Ala as efficiently as Ala-Pro-Ala in vitro and in vivo, and deleting pepP increased sensitivity to supplied thioproline. Our data thus (i) provide biochemical genetic evidence that thioproline formation contributes substantially to HCHO toxicity and (ii) make PepP a candidate damage-control enzyme for engineered pathways having HCHO as an intermediate.
Moving in the Anthropocene
(2018)
Tucker, Marlee A. ; Boehning-Gaese, Katrin ; Fagan, William F. ; Fryxell, John M. ; Van Moorter, Bram ; Alberts, Susan C. ; Ali, Abdullahi H. ; Allen, Andrew M. ; Attias, Nina ; Avgar, Tal ; Bartlam-Brooks, Hattie ; Bayarbaatar, Buuveibaatar ; Belant, Jerrold L. ; Bertassoni, Alessandra ; Beyer, Dean ; Bidner, Laura ; van Beest, Floris M. ; Blake, Stephen ; Blaum, Niels ; Bracis, Chloe ; Brown, Danielle ; de Bruyn, P. J. Nico ; Cagnacci, Francesca ; Calabrese, Justin M. ; Camilo-Alves, Constanca ; Chamaille-Jammes, Simon ; Chiaradia, Andre ; Davidson, Sarah C. ; Dennis, Todd ; DeStefano, Stephen ; Diefenbach, Duane ; Douglas-Hamilton, Iain ; Fennessy, Julian ; Fichtel, Claudia ; Fiedler, Wolfgang ; Fischer, Christina ; Fischhoff, Ilya ; Fleming, Christen H. ; Ford, Adam T. ; Fritz, Susanne A. ; Gehr, Benedikt ; Goheen, Jacob R. ; Gurarie, Eliezer ; Hebblewhite, Mark ; Heurich, Marco ; Hewison, A. J. Mark ; Hof, Christian ; Hurme, Edward ; Isbell, Lynne A. ; Janssen, Rene ; Jeltsch, Florian ; Kaczensky, Petra ; Kane, Adam ; Kappeler, Peter M. ; Kauffman, Matthew ; Kays, Roland ; Kimuyu, Duncan ; Koch, Flavia ; Kranstauber, Bart ; LaPoint, Scott ; Leimgruber, Peter ; Linnell, John D. C. ; Lopez-Lopez, Pascual ; Markham, A. Catherine ; Mattisson, Jenny ; Medici, Emilia Patricia ; Mellone, Ugo ; Merrill, Evelyn ; Mourao, Guilherme de Miranda ; Morato, Ronaldo G. ; Morellet, Nicolas ; Morrison, Thomas A. ; Diaz-Munoz, Samuel L. ; Mysterud, Atle ; Nandintsetseg, Dejid ; Nathan, Ran ; Niamir, Aidin ; Odden, John ; Oliveira-Santos, Luiz Gustavo R. ; Olson, Kirk A. ; Patterson, Bruce D. ; de Paula, Rogerio Cunha ; Pedrotti, Luca ; Reineking, Bjorn ; Rimmler, Martin ; Rogers, Tracey L. ; Rolandsen, Christer Moe ; Rosenberry, Christopher S. ; Rubenstein, Daniel I. ; Safi, Kamran ; Said, Sonia ; Sapir, Nir ; Sawyer, Hall ; Schmidt, Niels Martin ; Selva, Nuria ; Sergiel, Agnieszka ; Shiilegdamba, Enkhtuvshin ; Silva, Joao Paulo ; Singh, Navinder ; Solberg, Erling J. ; Spiegel, Orr ; Strand, Olav ; Sundaresan, Siva ; Ullmann, Wiebke ; Voigt, Ulrich ; Wall, Jake ; Wattles, David ; Wikelski, Martin ; Wilmers, Christopher C. ; Wilson, John W. ; Wittemyer, George ; Zieba, Filip ; Zwijacz-Kozica, Tomasz ; Mueller, Thomas
Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.
Mise-Unseen
(2019)
Creating or arranging objects at runtime is needed in many virtual reality applications, but such changes are noticed when they occur inside the user's field of view. We present Mise-Unseen, a software system that applies such scene changes covertly inside the user's field of view. Mise-Unseen leverages gaze tracking to create models of user attention, intention, and spatial memory to determine if and when to inject a change. We present seven applications of Mise-Unseen to unnoticeably modify the scene within view (i) to hide that task difficulty is adapted to the user, (ii) to adapt the experience to the user's preferences, (iii) to time the use of low fidelity effects, (iv) to detect user choice for passive haptics even when lacking physical props, (v) to sustain physical locomotion despite a lack of physical space, (vi) to reduce motion sickness during virtual locomotion, and (vii) to verify user understanding during story progression. We evaluated Mise-Unseen and our applications in a user study with 15 participants and find that while gaze data indeed supports obfuscating changes inside the field of view, a change is rendered unnoticeably by using gaze in combination with common masking techniques.
Jones, Geraint H. ; Arridge, Christopher S. ; Coates, Andrew J. ; Lewis, Gethyn R. ; Kanani, Sheila ; Wellbrock, Anne ; Young, David T. ; Crary, Frank J. ; Tokar, Robert L. ; Wilson, R. J. ; Hill, Thomas W. ; Johnson, Robert E. ; Mitchell, Donald G. ; Schmidt, Jürgen ; Kempf, Sascha ; Beckmann, Uwe ; Russell, Christopher T. ; Jia, Y. D. ; Dougherty, Michele K. ; Waite, J. Hunter ; Magee, Brian A.
By traversing the plume erupting from high southern latitudes on Saturn's moon Enceladus, Cassini orbiter instruments can directly sample the material therein. Cassini Plasma Spectrometer, CAPS, data show that a major plume component comprises previously-undetected particles of nanometer scales and larger that bridge the mass gap between previously observed gaseous species and solid icy grains. This population is electrically charged both negative and positive, indicating that subsurface triboelectric charging, i.e., contact electrification of condensed plume material may occur through mutual collisions within vents. The electric field of Saturn's magnetosphere controls the jets' morphologies, separating particles according to mass and charge. Fine-scale structuring of these particles' spatial distribution correlates with discrete plume jets' sources, and reveals locations of other possible active regions. The observed plume population likely forms a major component of high velocity nanometer particle streams detected outside Saturn's magnetosphere.
Kubin, Markus ; Kern, Jan ; Gul, Sheraz ; Kroll, Thomas ; Chatterjee, Ruchira ; Loechel, Heike ; Fuller, Franklin D. ; Sierra, Raymond G. ; Quevedo, Wilson ; Weniger, Christian ; Rehanek, Jens ; Firsov, Anatoly ; Laksmono, Hartawan ; Weninger, Clemens ; Alonso-Mori, Roberto ; Nordlund, Dennis L. ; Lassalle-Kaiser, Benedikt ; Glownia, James M. ; Krzywinski, Jacek ; Moeller, Stefan ; Turner, Joshua J. ; Minitti, Michael P. ; Dakovski, Georgi L. ; Koroidov, Sergey ; Kawde, Anurag ; Kanady, Jacob S. ; Tsui, Emily Y. ; Suseno, Sandy ; Han, Zhiji ; Hill, Ethan ; Taguchi, Taketo ; Borovik, Andrew S. ; Agapie, Theodor ; Messinger, Johannes ; Erko, Alexei ; Föhlisch, Alexander ; Bergmann, Uwe ; Mitzner, Rolf ; Yachandra, Vittal K. ; Yano, Junko ; Wernet, Philippe
X-ray absorption spectroscopy at the L-edge of 3d transition metals provides unique information on the local metal charge and spin states by directly probing 3d-derived molecular orbitals through 2p-3d transitions. However, this soft x-ray technique has been rarely used at synchrotron facilities for mechanistic studies of metalloenzymes due to the difficulties of x-ray-induced sample damage and strong background signals from light elements that can dominate the low metal signal. Here, we combine femtosecond soft x-ray pulses from a free-electron laser with a novel x-ray fluorescence-yield spectrometer to overcome these difficulties. We present L-edge absorption spectra of inorganic high-valent Mn complexes (Mn similar to 6-15 mmol/l) with no visible effects of radiation damage. We also present the first L-edge absorption spectra of the oxygen evolving complex (Mn4CaO5) in Photosystem II (Mn < 1 mmol/l) at room temperature, measured under similar conditions. Our approach opens new ways to study metalloenzymes under functional conditions. (C) 2017 Author(s).
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