Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
Authors: Pattaro Cristian , Teumer Alexander , Gorski Mathias , Chu Audrey Y. , Li Man , Mijatovic Vladan , Garnaas Maija , Tin Adrienne , Sorice Rossella , Li Yong , Taliun Daniel , Olden Matthias , Foster Meredith , Yang Qiong , Chen Ming-Huei , Pers Tune H. , Johnson Andrew D. , Ko Yi-An , Fuchsberger Christian , Tayo Bamidele , Nalls Michael , Feitosa Mary F. , Isaacs Aaron , Dehghan Abbas , d’Adamo Pio , Adeyemo Adebowale , Dieffenbach Aida Karina , Zonderman Alan B. , Nolte Ilja M. , van der Most Peter J. , Wright Alan F. , Shuldiner Alan R. , Morrison Alanna C. , Hofman Albert , Smith Albert V. , Dreisbach Albert W. , Franke Andre , Uitterlinden Andre G. , Metspalu Andres , Tonjes Anke , Lupo Antonio , Robino Antonietta , Johansson Åsa , Demirkan Ayse , Kollerits Barbara , Freedman Barry I. , Ponte Belen , Oostra Ben A. , Paulweber Bernhard , Krämer Bernhard K. , Mitchell Braxton D. , Buckley Brendan M. , Peralta Carmen A. , Hayward Caroline , Helmer Catherine , Rotimi Charles N. , Shaffer Christian M. , Müller Christian , Sala Cinzia , van Duijn Cornelia M. , Saint-Pierre Aude , Ackermann Daniel , Shriner Daniel , Ruggiero Daniela , Toniolo Daniela , Lu Yingchang , Cusi Daniele , Czamara Darina , Ellinghaus David , Siscovick David S. , Ruderfer Douglas , Gieger Christian , Grallert Harald , Rochtchina Elena , Atkinson Elizabeth J. , Holliday Elizabeth G. , Boerwinkle Eric , Salvi Erika , Bottinger Erwin P. , Murgia Federico , Rivadeneira Fernando , Ernst Florian , Kronenberg Florian , Hu Frank B. , Navis Gerjan J. , Curhan Gary C. , Ehret George B. , Homuth Georg , Coassin Stefan , Thun Gian-Andri , Pistis Giorgio , Gambaro Giovanni , Malerba Giovanni , Montgomery Grant W. , Eiriksdottir Gudny , Jacobs Gunnar , Li Guo , Wichmann H-Erich , Campbell Harry , Schmidt Helena , Wallaschofski Henri , Völzke Henry , Brenner Hermann , Kroemer Heyo K. , Kramer Holly , Lin Honghuang , Leach I. Mateo , Ford Ian , Guessous Idris , Rudan Igor , Prokopenko Inga , Borecki Ingrid , Heid Iris M. , Kolcic Ivana , Persico Ivana , Jukema J. Wouter , Wilson James F. , Felix Janine F. , Divers Jasmin , Lambert Jean-Charles , Stafford Jeanette M. , Gaspoz Jean-Michel , Smith Jennifer A. , Faul Jessica D. , Wang Jie Jin , Ding Jingzhong , Hirschhorn Joel N. , Attia John , Whitfield John B. , Chalmers John , Viikari Jorma , Coresh Josef , Denny Joshua C. , Karjalainen Juha , Fernandes Jyotika K. , Endlich Karlhans , Butterbach Katja , Keene Keith L. , Lohman Kurt , Portas Laura , Launer Lenore J. , Lyytikäinen Leo-Pekka , Yengo Loic , Franke Lude , Ferrucci Luigi , Rose Lynda M. , Kedenko Lyudmyla , Rao Madhumathi , Struchalin Maksim , Kleber Marcus E. , Cavalieri Margherita , Haun Margot , Cornelis Marilyn C. , Ciullo Marina , Pirastu Mario , de Andrade Mariza , McEvoy Mark A. , Woodward Mark , Adam Martin , Cocca Massimiliano , Nauck Matthias , Imboden Medea , Waldenberger Melanie , Pruijm Menno , Metzger Marie , Stumvoll Michael , Evans Michele K. , Sale Michele M. , Kähönen Mika , Boban Mladen , Bochud Murielle , Rheinberger Myriam , Verweij Niek , Bouatia-Naji Nabila , Martin Nicholas G. , Hastie Nick , Probst-Hensch Nicole , Soranzo Nicole , Devuyst Olivier , Raitakari Olli , Gottesman Omri , Franco Oscar H. , Polasek Ozren , Gasparini Paolo , Munroe Patricia B. , Ridker Paul M. , Mitchell Paul , Muntner Paul , Meisinger Christa , Smit Johannes H. ,   ICBP Consortium, Abecasis Goncalo R. , Adair Linda S. , Alexander Myriam , Altshuler David , Amin Najaf , Arking Dan E. , Arora Pankaj , Aulchenko Yurii , Bakker Stephan J. L. , Bandinelli Stefania , Barroso Ines , Beckmann Jacques S. , Beilby John P. , Bergman Richard N. , Bergmann Sven , Bis Joshua C. , Boehnke Michael , Bonnycastle Lori L. , Bornstein Stefan R. , Bots Michiel L. , Bragg-Gresham Jennifer L. , Brand Stefan-Martin , Brand Eva , Braund Peter S. , Brown Morris J. , Burton Paul R. , Casas Juan P. , Caulfield Mark J. , Chakravarti Aravinda , Chambers John C. , Chandak Giriraj R. , Chang Yen-Pei C. , Charchar Fadi J. , Chaturvedi Nish , Shin Cho Yoon , Clarke Robert , Collins Francis S. , Collins Rory , Connell John M. , Cooper Jackie A. , Cooper Matthew N. , Cooper Richard S. , Corsi Anna Maria , Dörr Marcus , Dahgam Santosh , Danesh John , Smith George Davey , Day Ian N. M. , Deloukas Panos , Denniff Matthew , Dominiczak Anna F. , Dong Yanbin , Doumatey Ayo , Elliott Paul , Elosua Roberto , Erdmann Jeanette , Eyheramendy Susana , Farrall Martin , Fava Cristiano , Forrester Terrence , Fowkes F. Gerald R. , Fox Ervin R. , Frayling Timothy M. , Galan Pilar , Ganesh Santhi K. , Garcia Melissa , Gaunt Tom R. , Glazer Nicole L. , Go Min Jin , Goel Anuj , Grässler Jürgen , Grobbee Diederick E. , Groop Leif , Guarrera Simonetta , Guo Xiuqing , Hadley David , Hamsten Anders , Han Bok-Ghee , Hardy Rebecca , Hartikainen Anna-Liisa , Heath Simon , Heckbert Susan R. , Hedblad Bo , Hercberg Serge , Hernandez Dena , Hicks Andrew A. , Hilton Gina , Hingorani Aroon D. , Bolton Judith A Hoffman , Hopewell Jemma C. , Howard Philip , Humphries Steve E. , Hunt Steven C. , Hveem Kristian , Ikram M. Arfan , Islam Muhammad , Iwai Naoharu , Jarvelin Marjo-Riitta , Jackson Anne U. , Jafar Tazeen H. , Janipalli Charles S. , Johnson Toby , Kathiresan Sekar , Khaw Kay-Tee , Kim Hyung-Lae , Kinra Sanjay , Kita Yoshikuni , Kivimaki Mika , Kooner Jaspal S. , Kumar M. J. Kranthi , Kuh Diana , Kulkarni Smita R. , Kumari Meena , Kuusisto Johanna , Kuznetsova Tatiana , Laakso Markku , Laan Maris , Laitinen Jaana , Lakatta Edward G. , Langefeld Carl D. , Larson Martin G. , Lathrop Mark , Lawlor Debbie A. , Lawrence Robert W. , Lee Jong-Young , Lee Nanette R. , Levy Daniel , Li Yali , Longstreth Will T. , Luan Jian’an , Lucas Gavin , Ludwig Barbara , Mangino Massimo , Mani K. Radha , Marmot Michael G. , Mattace-Raso Francesco U. S. , Matullo Giuseppe , McArdle Wendy L. , McKenzie Colin A. , Meitinger Thomas , Melander Olle , Meneton Pierre , Meschia James F. , Miki Tetsuro , Milaneschi Yuri , Mohlke Karen L. , Mooser Vincent , Morken Mario A. , Morris Richard W. , Mosley Thomas H. , Najjar Samer , Narisu Narisu , Newton-Cheh Christopher , Nguyen Khanh-Dung Hoang , Nilsson Peter , Nyberg Fredrik , O’Donnell Christopher J. , Ogihara Toshio , Ohkubo Takayoshi , Okamura Tomonori , Ong RickTwee-Hee , Ongen Halit , Onland-Moret N. Charlotte , O’Reilly Paul F. , Org Elin , Orru Marco , Palmas Walter , Palmen Jutta , Palmer Lyle J. , Palmer Nicholette D. , Parker Alex N. , Peden John F. , Peltonen Leena , Perola Markus , Pihur Vasyl , Platou Carl G. P. , Plump Andrew , Prabhakaran Dorairajan , Psaty Bruce M. , Raffel Leslie J. , Rao Dabeeru C. , Rasheed Asif , Ricceri Fulvio , Rice Kenneth M. , Rosengren Annika , Rotter Jerome I. , Rudock Megan E. , Sõber Siim , Salako Tunde , Saleheen Danish , Salomaa Veikko , Samani Nilesh J. , Schwartz Steven M. , Schwarz Peter E. H. , Scott Laura J. , Scott James , Scuteri Angelo , Sehmi Joban S. , Seielstad Mark , Seshadri Sudha , Sharma Pankaj , Shaw-Hawkins Sue , Shi Gang , Shrine Nick R. G. , Sijbrands Eric J. G. , Sim Xueling , Singleton Andrew , Sjögren Marketa , Smith Nicholas L. , Artigas Maria Soler , Spector Tim D. , Staessen Jan A. , Stancakova Alena , Steinle Nanette I. , Strachan David P. , Stringham Heather M. , Sun Yan V. , Swift Amy J. , Tabara Yasuharu , Tai E-Shyong , Talmud Philippa J. , Taylor Andrew , Terzic Janos , Thelle Dag S. , Tobin Martin D. , Tomaszewski Maciej , Tripathy Vikal , Tuomilehto Jaakko , Tzoulaki Ioanna , Uda Manuela , Ueshima Hirotsugu , Uiterwaal Cuno S. P. M. , Umemura Satoshi , van der Harst Pim , van der Schouw Yvonne T. , van Gilst Wiek H. , Vartiainen Erkki , Vasan Ramachandran S. , Veldre Gudrun , Verwoert Germaine C. , Viigimaa Margus , Vinay D. G. , Vineis Paolo , Voight Benjamin F. , Vollenweider Peter , Wagenknecht Lynne E. , Wain Louise V. , Wang Xiaoling , Wang Thomas J. , Wareham Nicholas J. , Watkins Hugh , Weder Alan B. , Whincup Peter H. , Wiggins Kerri L. , Witteman Jacqueline C. M. , Wong Andrew , Wu Ying , Yajnik Chittaranjan S. , Yao Jie , Young J. H. , Zelenika Diana , Zhai Guangju , Zhang Weihua , Zhang Feng , Zhao Jing Hua , Zhu Haidong , Zhu Xiaofeng , Zitting Paavo , Zukowska-Szczechowska Ewa ,   AGEN Consortium, Okada Yukinori , Wu Jer-Yuarn , Gu Dongfeng , Takeuchi Fumihiko , Takahashi Atsushi , Maeda Shiro , Tsunoda Tatsuhiko , Chen Peng , Lim Su-Chi , Wong Tien-Yin , Liu Jianjun , Young Terri L. , Aung Tin , Teo Yik-Ying , Kim Young Jin , Kang Daehee , Chen Chien-Hsiun , Tsai Fuu-Jen , Chang Li-Ching , Fann S. -J. Cathy , Mei Hao , Hixson James E. , Chen Shufeng , Katsuya Tomohiro , Isono Masato , Albrecht Eva , Yamamoto Kazuhiko , Kubo Michiaki , Nakamura Yusuke , Kamatani Naoyuki , Kato Norihiro , He Jiang , Chen Yuan-Tsong , Tanaka Toshihiro ,   CARDIOGRAM, Reilly Muredach P , Schunkert Heribert , Assimes Themistocles L. , Hall Alistair , Hengstenberg Christian , König Inke R. , Laaksonen Reijo , McPherson Ruth , Thompson John R. , Thorsteinsdottir Unnur , Ziegler Andreas , Absher Devin , Chen Li , Cupples L. Adrienne , Halperin Eran , Li Mingyao , Musunuru Kiran , Preuss Michael , Schillert Arne , Thorleifsson Gudmar , Wells George A. , Holm Hilma , Roberts Robert , Stewart Alexandre F. R. , Fortmann Stephen , Go Alan , Hlatky Mark , Iribarren Carlos , Knowles Joshua , Myers Richard , Quertermous Thomas , Sidney Steven , Risch Neil , Tang Hua , Blankenberg Stefan , Schnabel Renate , Sinning Christoph , Lackner Karl J. , Tiret Laurence , Nicaud Viviane , Cambien Francois , Bickel Christoph , Rupprecht Hans J. , Perret Claire , Proust Carole , Münzel Thomas F. , Barbalic Maja , Chen Ida Yii-Der , Demissie-Banjaw Serkalem , Folsom Aaron , Lumley Thomas , Marciante Kristin , Taylor Kent D. , Volcik Kelly , Gretarsdottir Solveig , Gulcher Jeffrey R. , Kong Augustine , Stefansson Kari , Thorgeirsson Gudmundur , Andersen Karl , Fischer Marcus , Grosshennig Anika , Linsel-Nitschke Patrick , Stark Klaus , Schreiber Stefan , Aherrahrou Zouhair , Bruse Petra , Doering Angela , Klopp Norman , Diemert Patrick , Loley Christina , Medack Anja , Nahrstedt Janja , Peters Annette , Wagner Arnika K. , Willenborg Christina , Böhm Bernhard O. , Dobnig Harald , Grammer Tanja B. , Hoffmann Michael M. , Meinitzer Andreas , Winkelmann Bernhard R. , Pilz Stefan , Renner Wilfried , Scharnagl Hubert , Stojakovic Tatjana , Tomaschitz Andreas , Winkler Karl , Guiducci Candace , Burtt Noel , Gabriel Stacey B. , Dandona Sonny , Jarinova Olga , Qu Liming , Wilensky Robert , Matthai William , Hakonarson Hakon H. , Devaney Joe , Burnett Mary Susan , Pichard Augusto D. , Kent Kenneth M. , Satler Lowell , Lindsay Joseph M. , Waksman Ron , Knouff Christopher W. , Waterworth Dawn M. , Walker Max C. , Epstein Stephen E. , Rader Daniel J. , Nelson Christopher P. , Wright Benjamin J. , Balmforth Anthony J. , Ball Stephen G. ,   CHARGe-Heart Failure Group, Loehr Laura R. , Rosamond Wayne D. , Benjamin Emelia , Haritunians Talin , Couper David , Murabito Joanne , Wang Ying A. , Stricker Bruno H. , Chang Patricia P. , Willerson James T. ,   ECHOGen Consortium, Felix Stephan B. , Watzinger Norbert , Aragam Jayashri , Zweiker Robert , Lind Lars , Rodeheffer Richard J. , Greiser Karin Halina , Deckers Jaap W. , Stritzke Jan , Ingelsson Erik , Kullo Iftikhar , Haerting Johannes , Reffelmann Thorsten , Redfield Margaret M. , Werdan Karl , Mitchell Gary F. , Arnett Donna K. , Gottdiener John S. , Blettner Maria , Friedrich Nele , Kovacs Peter , Wild Philipp S. , Froguel Philippe , Rettig Rainer , Mägi Reedik , Biffar Reiner , Schmidt Reinhold , Middelberg Rita P. S. , Carroll Robert J. , Penninx Brenda W. , Scott Rodney J. , Katz Ronit , Sedaghat Sanaz , Wild Sarah H. , Kardia Sharon L. R. , Ulivi Sheila , Hwang Shih-Jen , Enroth Stefan , Kloiber Stefan , Trompet Stella , Stengel Benedicte , Hancock Stephen J. , Turner Stephen T. , Rosas Sylvia E. , Stracke Sylvia , Harris Tamara B. , Zeller Tanja , Zemunik Tatijana , Lehtimäki Terho , Illig Thomas , Aspelund Thor , Nikopensius Tiit , Esko Tonu , Tanaka Toshiko , Gyllensten Ulf , Völker Uwe , Emilsson Valur , Vitart Veronique , Aalto Ville , Gudnason Vilmundur , Chouraki Vincent , Chen Wei-Min , Igl Wilmar , März Winfried , Koenig Wolfgang , Lieb Wolfgang , Loos Ruth J. F. , Liu Yongmei , Snieder Harold , Pramstaller Peter P. , Parsa Afshin , O’Connell Jeffrey R. , Susztak Katalin , Hamet Pavel , Tremblay Johanne , de Boer Ian H. , Böger Carsten A. , Goessling Wolfram , Chasman Daniel I. , Köttgen Anna , Kao W. H. Linda , Fox Caroline S. 
Published: February 2016

AbstractReduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.