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1. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author

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

Subjects
Biology (General), QH301-705.5
Abstract

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Published
2022
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2. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, and Anna Köttgen

Subjects
Science
Abstract

Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.

Published
2019
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3. Neptune: an environment for the delivery of genomic medicine

Author

Venner Eric, Victoria Yi, David Murdock, Sara E. Kalla, Tsung-Jung Wu, Aniko Sabo, Shoudong Li, Qingchang Meng, Xia Tian, Mullai Murugan, Michelle Cohen, Christie Kovar, Wei-Qi Wei, Wendy K. Chung, Chunhua Weng, Georgia L. Wiesner, Gail P. Jarvik, Donna Muzny, Richard A. Gibbs, Debra Abrams, Samuel E. Adunyah, Ladia Albertson-Junkans, Berta Almoguera, Darren C. Ames, Paul Appelbaum, Samuel Aronson, Sharon Aufox, Lawrence J. Babb, Adithya Balasubramanian, Hana Bangash, Melissa Basford, Lisa Bastarache, Samantha Baxter, Meckenzie Behr, Barbara Benoit, Elizabeth Bhoj, Suzette J. Bielinski, Sarah T. Bland, Carrie Blout, Kenneth Borthwick, Erwin P. Bottinger, Mark Bowser, Harrison Brand, Murray Brilliant, Wendy Brodeur, Pedro Caraballo, David Carrell, Andrew Carroll, Lisa Castillo, Victor Castro, Gauthami Chandanavelli, Theodore Chiang, Rex L. Chisholm, Kurt D. Christensen, Wendy Chung, Christopher G. Chute, Brittany City, Beth L. Cobb, John J. Connolly, Paul Crane, Katherine Crew, David R. Crosslin, Jyoti Dayal, Mariza De Andrade, Jessica De la Cruz, Josh C. Denny, Shawn Denson, Tim DeSmet, Ozan Dikilitas, Michael J. Dinsmore, Sheila Dodge, Phil Dunlea, Todd L. Edwards, Christine M. Eng, David Fasel, Alex Fedotov, Qiping Feng, Mark Fleharty, Andrea Foster, Robert Freimuth, Christopher Friedrich, Stephanie M. Fullerton, Birgit Funke, Stacey Gabriel, Vivian Gainer, Ali Gharavi, Andrew M. Glazer, Joseph T. Glessner, Jessica Goehringer, Adam S. Gordon, Chet Graham, Robert C. Green, Justin H. Gundelach, Heather S. Hain, Hakon Hakonarson, Maegan V. Harden, John Harley, Margaret Harr, Andrea Hartzler, M. Geoffrey Hayes, Scott Hebbring, Nora Henrikson, Andrew Hershey, Christin Hoell, Ingrid Holm, Kayla M. Howell, George Hripcsak, Jianhong Hu, Elizabeth Duffy Hynes, Joy C. Jayaseelan, Yunyun Jiang, Yoonjung Yoonie Joo, Sheethal Jose, Navya Shilpa Josyula, Anne E. Justice, Divya Kalra, Elizabeth W. Karlson, Brendan J. Keating, Melissa A. Kelly, Eimear E. Kenny, Dustin Key, Krzysztof Kiryluk, Terrie Kitchner, Barbara Klanderman, Eric Klee, David C. Kochan, Viktoriya Korchina, Leah Kottyan, Emily Kudalkar, Alanna Kulchak Rahm, Iftikhar J. Kullo, Philip Lammers, Eric B. Larson, Matthew S. Lebo, Magalie Leduc, Ming Ta (Michael) Lee, Niall J. Lennon, Kathleen A. Leppig, Nancy D. Leslie, Rongling Li, Wayne H. Liang, Chiao-Feng Lin, Jodell E. Linder, Noralane M. Lindor, Todd Lingren, James G. Linneman, Cong Liu, Wen Liu, Xiuping Liu, John Lynch, Hayley Lyon, Alyssa Macbeth, Harshad Mahadeshwar, Lisa Mahanta, Bradley Malin, Teri Manolio, Maddalena Marasa, Keith Marsolo, Michelle L. McGowan, Elizabeth McNally, Jim Meldrim, Frank Mentch, Hila Milo Rasouly, Jonathan Mosley, Shubhabrata Mukherjee, Thomas E. Mullen, Jesse Muniz, David R. Murdock, Shawn Murphy, Melanie F. Myers, Bahram Namjou, Yizhao Ni, Robert C. Onofrio, Aniwaa Owusu Obeng, Thomas N. Person, Josh F. Peterson, Lynn Petukhova, Cassandra J. Pisieczko, Siddharth Pratap, Cynthia A. Prows, Megan J. Puckelwartz, Ritika Raj, James D. Ralston, Arvind Ramaprasan, Andrea Ramirez, Luke Rasmussen, Laura Rasmussen-Torvik, Soumya Raychaudhuri, Heidi L. Rehm, Marylyn D. Ritchie, Catherine Rives, Beenish Riza, Dan M. Roden, Elisabeth A. Rosenthal, Avni Santani, Schaid Dan, Steven Scherer, Stuart Scott, Aaron Scrol, Soumitra Sengupta, Ning Shang, Himanshu Sharma, Richard R. Sharp, Rajbir Singh, Patrick M.A. Sleiman, Kara Slowik, Joshua C. Smith, Maureen E. Smith, Duane T. Smoot, Jordan W. Smoller, Sunghwan Sohn, Ian B. Stanaway, Justin Starren, Mary Stroud, Jessica Su, Casey Overby Taylor, Kasia Tolwinski, Sara L. Van Driest, Sean M. Vargas, Matthew Varugheese, David Veenstra, Eric Venner, Miguel Verbitsky, Gina Vicente, Michael Wagner, Kimberly Walker, Theresa Walunas, Liwen Wang, Qiaoyan Wang, Scott T. Weiss, Quinn S. Wells, Peter S. White, Ken L. Wiley, Janet L. Williams, Marc S. Williams, Michael W. Wilson, Leora Witkowski, Laura Allison Woods, Betty Woolf, Julia Wynn, Yaping Yang, Ge Zhang, Lan Zhang, and Hana Zouk

Subjects
Computer science, business.industry, Process (engineering), MEDLINE, High-Throughput Nucleotide Sequencing, Genomics, Data science, Article, Personalization, Variety (cybernetics), Workflow, Neptune, Pharmacogenomics, Health care, Electronic Health Records, Humans, business, Software, Genetics (clinical)
Abstract

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Published
2021

4. Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver

Author

Sudin Bhattacharya, Timothy R. Zacharewski, Norbert E. Kaminski, Edward Dere, Melvin E. Andersen, and Navya Shilpa Josyula

Subjects
0301 basic medicine, Polychlorinated Dibenzodioxins, Health, Toxicology and Mutagenesis, Gene regulatory network, Endogeny, 010501 environmental sciences, Biology, Toxicology, 01 natural sciences, 03 medical and health sciences, Cellular stress response, Gene expression, Basic Helix-Loop-Helix Transcription Factors, Animals, Gene Regulatory Networks, Gene, Transcription factor, 0105 earth and related environmental sciences, General Medicine, Aryl hydrocarbon receptor, Phenotype, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, Liver, Receptors, Aryl Hydrocarbon, Multigene Family, biology.protein, Chromatin Immunoprecipitation Sequencing, Female
Abstract

Four decades after its discovery, the aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor (TF) activated by the persistent environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), remains an enigmatic molecule with a controversial endogenous role. Here, we have assembled a global map of the AHR gene regulatory network in female C57BL/6 mice orally gavaged with 30 µg/kg of TCDD from a combination of previously published gene expression and genome-wide TF-binding data sets. Using Kohonen self-organizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Directly bound, indirectly bound, and non-genomic AHR target genes exhibit distinct expression patterns, with the directly bound targets associated with highest median expression. Interestingly, among the directly bound AHR target genes, the expression level increases with the number of AHR-binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes. Although the specific findings described here are restricted to hepatic effects under short-term TCDD exposure, this work describes a generalizable approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response, revealing network hierarchy and the nature of information flow from the initial signaling events to phenotypic outcomes. Such reconstructed networks can form the basis of a new generation of quantitative adverse outcome pathways.

Published
2019

5. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author

Ian B. Stanaway, Dan M. Roden, Divya Kalra, Dustin Key, Debra J. Abrams, David Fasel, Victor Castro, Brad Malin, Berta Almoguera, Beenish Riza, Meckenzie A. Behr, Eric Venner, Christine M. Eng, Joy Jayaseelan, Scott J. Hebbring, Michelle L. McGowan, Steven E. Scherer, Theresa L. Walunas, Mark Bowser, James D. Ralston, Wei-Qi Wei, Liwen Wang, David R. Murdock, Wayne H. Liang, Julia Wynn, Nancy D. Leslie, Laura J. Rasmussen-Torvik, Ming Ta (Michael) Lee, Frank D. Mentch, Lan Zhang, Alanna Kulchak Rahm, Josh F. Peterson, Jodell E. Linder, Joshua C. Smith, Soumitra Sengupta, Brendan J. Keating, Gina Vicente, Andrew Carroll, Nora B. Henrikson, Anne E. Justice, Heather S. Hain, Wen Liu, Andrea H. Ramirez, Matthew S. Lebo, Hana Zouk, Georgia L. Wiesner, Andrea L. Hartzler, Cassandra J. Pisieczko, Catherine M. Rives, Jessica Goehringer, Maegan V. Harden, John Lynch, Chiao-Feng Lin, Peter White, Phil Dunlea, Shawn N. Murphy, Mullai Murugan, Harshad Mahadeshwar, Mark Fleharty, Andrea Foster, Arvind Ramaprasan, Christopher A. Friedrich, Justin H. Gundelach, Hayley Lyon, Niall J. Lennon, Eric W. Klee, David R. Crosslin, Ge Zhang, Rongling Li, Ozan Dikilitas, Xiuping Liu, Christin Hoell, Aniwaa Owusu Obeng, Katherine D. Crew, Lisa M. Castillo, Justin Starren, Jonathan D. Mosley, Carrie L. Blout, Himanshu Sharma, Elizabeth M. McNally, Sarah T. Bland, Megan J. Puckelwartz, Matthew Varugheese, Keith Marsolo, Betty Woolf, Sharon Aufox, Janet L. Williams, Kimberly Walker, Murray H. Brilliant, Birgit Funke, Laura Allison Woods, Marylyn D. Ritchie, Brittany City, Todd Lingren, Hila Milo Rasouly, Lawrence J. Babb, Alex Fedotov, Robert C. Onofrio, Margaret Harr, Suzette J. Bielinski, Michael W. Wilson, Shubhabrata Mukherjee, Robert R. Freimuth, Chet Graham, Todd L. Edwards, Quinn S. Wells, Marc S. Williams, Jordan W. Smoller, Wendy K. Chung, Avni Santani, Paul K. Crane, George Hripcsak, QiPing Feng, Ali G. Gharavi, Yizhao Ni, Iftikhar J. Kullo, Michael Wagner, Philip E. Lammers, Michael J. Dinsmore, Thomas N. Person, Victoria Yi, Samuel E. Adunyah, Tim DeSmet, Eric B. Larson, Elizabeth Hynes, David C. Kochan, Eimear E. Kenny, Magalie S. Leduc, Lisa Mahanta, David Carrell, Paul S. Appelbaum, Viktoriya Korchina, Beth L. Cobb, Lynn Petukhova, Jessica De la Cruz, Patrick M. A. Sleiman, Stuart A. Scott, Tsung-Jung Wu, Gail P. Jarvik, Erwin P. Bottinger, Ken Wiley, Josh C. Denny, Melissa A. Basford, Samuel J. Aronson, David L. Veenstra, Yaping Yang, Kayla Marie Howell, John J. Connolly, Jessica Su, Yoonjung Yoonie Joo, Miguel Verbitsky, Sean M. Vargas, Cong Liu, Barbara Benoit, Andrew Hershey, Richard A. Gibbs, Cynthia A. Prows, Hana Bangash, Wendy Brodeur, Gauthami Chandanavelli, Sara L. Van Driest, Kurt D. Christensen, Elizabeth J. Bhoj, Vivian S. Gainer, Adam S. Gordon, Robert C. Green, Hakon Hakonarson, Krzysztof Kiryluk, Elisabeth A. Rosenthal, Rajbir Singh, James G. Linneman, Harrison Brand, Theodore Chiang, Sheila Dodge, Ingrid A. Holm, M. Geoffrey Hayes, Yunyun Jiang, Ning Shang, Samantha Baxter, Noralane M. Lindor, Kathleen A. Leppig, Teri A. Manolio, Sara E. Kalla, Pedro J. Caraballo, Ritika Raj, Aaron Scrol, Jyoti G. Dayal, Richard R. Sharp, Christie Kovar, Soumya Raychaudhuri, Sunghwan Sohn, Emily Kudalkar, Maddalena Marasa, Stacey Gabriel, Dan Schaid, Ladia Albertson-Junkans, Rex L. Chisholm, Maureen E. Smith, Donna M. Muzny, Casey Overby Taylor, Jianhong Hu, Elizabeth W. Karlson, Lisa Bastarache, Darren C. Ames, Joseph T. Glessner, Leora Witkowski, Siddharth Pratap, Qiaoyan Wang, Melissa A. Kelly, Adithya Balasubramanian, Kara Slowik, Terrie Kitchner, Barbara J. Klanderman, Shawn Denson, Mary Stroud, Alyssa Macbeth, Melanie F. Myers, Jesse Muniz, Kasia Tolwinski, Scott T. Weiss, Chunhua Weng, Stephanie M. Fullerton, John B. Harley, Christopher G. Chute, Heidi L. Rehm, Sheethal Jose, Andrew M. Glazer, Navya Shilpa Josyula, Kenneth M. Borthwick, Thomas E. Mullen, Mariza de Andrade, Leah C. Kottyan, Luke V. Rasmussen, James Meldrim, and Bahram Namjou

Subjects
0301 basic medicine, Standardization, Test data generation, business.industry, Computer science, Sequence Analysis, DNA, 030105 genetics & heredity, Precision medicine, Data science, Clinical decision support system, Biobank, Article, 3. Good health, Data sharing, 03 medical and health sciences, 030104 developmental biology, Genetics, Humans, Genetic Testing, Prospective Studies, Sample collection, Personalized medicine, Precision Medicine, business, Genetics (clinical)
Abstract

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Published
2019

6. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Published
2022

7. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Lukas Habegger, Charumathi Sabanayagam, Michael Preuss, Laura M. Raffield, Mary F. Feitosa, Bamidele O. Tayo, Kevin Ho, Leo-Pekka Lyytikäinen, Florian Kronenberg, Valencia Hui Xian Foo, Adrienne Tin, Michael Cantor, Nisha Bansal, Tarunveer S. Ahluwalia, Melanie Waldenberger, Sarah A. Pendergrass, Behrooz Z. Alizadeh, Wolfgang Koenig, Qiong Yang, Xiaodong Bai, Christoph Wanner, Ben Schöttker, Giovanni Coppola, A. R. Shuldiner, Leslie A. Lange, Piyush Gampawar, Markus Scholz, Tien Yin Wong, Mary L. Biggs, Morris Swertz, Alicia Hawes, Girish N. Nadkarni, Christina-Alexandra Schulz, Chiea Chuen Khor, Ricardo H. Ulloa, Jeffrey C. Staples, Miao-Li Chee, Laura M. Yerges-Armstrong, Andrew Blumenfeld, Karlhans Endlich, Bernhard Banas, Bruce H.R. Wolffenbuttel, Kai-Uwe Eckardt, Pavel Hamet, Carsten A. Böger, Harold Snieder, Marcus B. Jones, Judy Wang, Shih-Jen Hwang, Mathias Gorski, Anselm Hoppmann, Josyf C. Mychaleckyj, Bernd Holleczek, Pamela R. Matias-Garcia, Rainer Rettig, Karsten B. Sieber, Manasi Pradhan, Pashupati P. Mishra, Peter Rossing, Matthias Wuttke, Miao-Ling Chee, H. Marike Boezen, Yong Li, M. Arfan Ikram, Jeffrey G. Reid, Teresa Nutile, Maria Sotiropoulos Padilla, Lude Franke, Robert J. Carroll, Luca A. Lotta, Bernhard K. Krämer, Kjell Nikus, Jerome I. Rotter, Thomas Meitinger, Lars Wallentin, Cisca Wijmenga, Kent D. Taylor, Holly Kramer, Louis Widom, Olli T. Raitakari, Marcus E. Kleber, Man Li, Nina Hutri-Kähönen, Massimiliano Cocca, Reinhold Schmidt, John D. Overton, Cristian Pattaro, Michael Lattari, Sarah E. Wolf, Jin-Fang Chai, Karina Toledo, Brigitte Kühnel, Zhenhua Gu, Peter Almgren, Caitlin Forsythe, Yuri Milaneschi, Stephan J. L. Bakker, Layal Chaker, Dawn M. Waterworth, Silke Szymczak, James G. Wilson, Peter J. van der Most, Michelle L. O'Donoghue, William Salerno, Masayuki Yasuda, Sahar Ghasemi, Eric Boerwinkle, Josef Coresh, Ilja M. Nolte, Kia Manoochehri, Konstantin Strauch, Thomas D. Schleicher, Myriam Rheinberger, Audrey Y. Chu, Sanaz Sedaghat, Sandra Freitag-Wolf, Boting Ning, Matthias Nauck, Christina Beechert, Helena Schmidt, Harvey D. White, Nina Mononen, Johanne Tremblay, Navya Shilpa Josyula, Mika Kähönen, Katrin Horn, Andre Franke, Marianne Rots, Bettina Jung, Alexander R. Rosenkranz, Christian M. Shaffer, Mary Ann Lukas, Gerjan Navis, Christian Gieger, John Chalmers, Shareef Khalid, Uwe Völker, Marju Orho-Melander, Iris M. Heid, Brenda W.J.H. Penninx, A. Baras, Alexander Lopez, Evan Maxwell, Ruth J. F. Loos, Erin D. Fuller, Christa Meisinger, Gonçalo R. Abecasis, Suganthi Balasubramanian, Chris H. L. Thio, Martin H. de Borst, Stefan Coassin, Ching-Yu Cheng, Wolfgang Lieb, Kenneth Rice, Alexander Teumer, Mark Woodward, Gisu Eom, Hermann Brenner, Thomas W. Winkler, Anna Köttgen, Edith Hofer, Aris Economides, Ron T. Gansevoort, Pim van der Harst, Lyndon J. Mitnaul, Bruce M. Psaty, Erwin P. Bottinger, Olle Melander, Niek Verweij, Frauke Degenhardt, Yan Zhang, Mohsen Ghanbari, Veronika Wanner, Terho Lehtimäki, Leland Barnard, Tampere University, Primary Health Care, Department of Paediatrics, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Department of Marketing Management, Epidemiology, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
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(2)/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(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) 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., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

Published
2021

8. Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations

Author

Manuel A. R. Ferreira, Ali Naji, Todd L. Edwards, Anne E. Justice, Marylyn D. Ritchie, John D. Overton, Theodore G. Drivas, Nathan Katz, Ying H. Shen, Yanming Li, Renae Judy, Anastasia Lucas, Amanda Dobbyn, Anurag Verma, Scott M. Damrauer, Daniel J. Rader, Geetha Chittoor, Maria Fasolino, Xinyuan Zhang, Jinbo Chen, Scott A. LeMaire, Alexander H. Li, Joseph H. Breeyear, Rachel L. Kember, Kumardeep Chaudhary, Joseph Park, JoEllen Weaver, Shadi Ahmadmehrabi, Alan Daugherty, Hisashi Sawada, Yuki Bradford, Klaus H. Kaestner, Jeffrey G. Reid, Ron Do, Navya Shilpa Josyula, Golnaz Vahedi, Girish N. Nadkarni, Judy H. Cho, Chen Zhang, Aris Baras, and Venkata R M Chavali

Subjects
0301 basic medicine, Male, Genotype, Population, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Exome Sequencing, Electronic Health Records, Humans, Exome, education, Exome sequencing, Aged, Genetics, education.field_of_study, Computational Biology, General Medicine, Biobank, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Genome-Wide Association Study
Abstract

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P

Published
2021

9. A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

Author

Peter Kraft, Adriana Iglesias, Steffen Uebe, Alberta A H J Thiadens, Jessica N. Cooke Bailey, Paul Mitchell, Olusola Olawoye, Michele Ramsay, Caroline C.W. Klaver, Eranga N. Vithana, Ayub Qassim, Mark James Simcoe, Pirro G. Hysi, Xin Wang, Angela J. Cree, Juha Karjalainen, René Höhn, Cornelia van Duijn, Andrew J. Lotery, Veronique Vitart, Anthony P Khawaja, Terri L. Young, James E. Morgan, UK Biobank Eye, Yukihiro Shiga, Owen M. Siggs, Yukihide Momozawa, Stephen Akafo, Puya Gharahkhani, Robert P. Igo, Masato Akiama, Gen Tamiya, Sarah A. Pendergrass, Navya Shilpa Josyula, Chris Hammond, David A. Mackey, FinnGen study, Chiea Chuen Khor, Francesca Pasutto, Ewan Birney, Pieter W.M. Bonnemaijer, Aarno Palotie, Susan E. Williams, John Rouhana, Nishani Amersinghe, Peng T. Khaw, Stuart MacGregor, Ching-Yu Cheng, Yoichito Kamatani, Calvin Chi Pui Pang, Xikun Han, Alex W. Hewitt, Louis R. Pasquale, Jae Hee Kang, Eric Jorgenson, Ronald B. Melles, Michael Hauser, Li Jia Chen, Jonathan Haines, Masayuki Yamamoto, Alicia Poplawski, Ayellet V. Segrè, Jue-Sheng Ong, Kazuki Hashimoto, Hélène Choquet, Hannah Currant, Jamie E. Craig, Robert Luben, Adam Auton, Tin Aung, Paul J. Foster, Toru Nakazawa, Nicholas G. Strouthidis, Michiaki Kubo, K. Saidas Nair, Janey L. Wiggs, and Adeyinka O. Ashaye

Subjects
Genetics, 0303 health sciences, genetic structures, Open angle glaucoma, Glaucoma, Genome-wide association study, Disease, Biology, medicine.disease, eye diseases, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Meta-analysis, medicine, sense organs, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer’s disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.

Published
2020

10. A genome-wide association study of polycystic ovary syndrome identified from electronic health records

Author

Ky’Era Actkins, Kevin Ho, Gail P. Jarvik, Brody Holohan, Felix R. Day, Navya Shilpa Josyula, Yanfei Zhang, Hakon Hakonarson, Sarah A. Pendergrass, Digna R. Velez Edwards, Ming Ta Michael Lee, Jacob M. Keaton, Dustin N. Hartzel, David R. Crosslin, Patrick M. A. Sleiman, Lea K. Davis, Marc S. Williams, Anne E. Justice, Andrea H. Ramirez, and Ian B. Stanaway

Subjects
Adult, Infertility, Oncology, medicine.medical_specialty, Receptor, ErbB-4, Population, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Electronic Health Records, Humans, 030212 general & internal medicine, education, ERBB4, Adaptor Proteins, Signal Transducing, 030304 developmental biology, education.field_of_study, 0303 health sciences, 030219 obstetrics & reproductive medicine, Superoxide Dismutase, business.industry, Hyperandrogenism, Obstetrics and Gynecology, YAP-Signaling Proteins, Middle Aged, medicine.disease, Phenotype, Polycystic ovary, Biobank, 3. Good health, Oligomenorrhea, Ovarian Cysts, Case-Control Studies, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Trans-Activators, Etiology, Female, business, Infertility, Female, Genome-Wide Association Study, Polycystic Ovary Syndrome, Transcription Factors
Abstract

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. Previous studies have identified genetic variants associated with PCOS identified by different diagnostic criteria. The Rotterdam Criteria is the broadest and able to identify the most PCOS cases.ObjectivesTo identify novel associated genetic variants, we extracted PCOS cases and controls from the electronic health records (EHR) based on the Rotterdam Criteria and performed a genome-wide association study (GWAS).Study DesignWe developed a PCOS phenotyping algorithm based on the Rotterdam criteria and applied it to three EHR-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual GWAS using the Geisinger’s MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significantly association loci (P−6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analyses. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to identify protein-protein interaction network.ResultsWe identified 2,995 PCOS cases and 53,599 controls in total (2,742cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). GWAS identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8×10−8) located nearSOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10−8), an intronic variant ofERBB4that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45×10−7), a novel intronic variant inWWTR1. In the further association tests of the top 3 SNPs with each criterion in the PCOS algorithm, we found that rs17186366 was associated with polycystic and hyperandrogenism, while rs11316812 and rs144248326 were mainly associated with oligomenorrhea or infertility. Besides ERBB4, we also validated the association withDENND1A1.ConclusionThrough a discovery-validation GWAS on PCOS cases and controls identified from EHR using an algorithm based on Rotterdam criteria, we identified and validated a novel association with variants withinERBB4. We also identified novel associations nearbySOD2andWWTR1. These results suggest the eGFR and Hippo pathways in the disease etiology. With previously identified PCOS-associated lociYAP1, theERBB4-YAP1-WWTR1network implicates the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of PCOS.

Published
2019

11. PheWAS and Beyond: The Landscape of Associations with Medical Diagnoses and Clinical Measures across 38,662 Individuals from Geisinger

Author

Joseph B. Leader, Marylyn D. Ritchie, Sarah A. Pendergrass, Yu Zhang, Anastasia Lucas, Anqa Khan, Dustin N. Hartzel, Shefali S. Verma, Daniel R. Lavage, Anurag Verma, and Navya Shilpa Josyula

Subjects
0301 basic medicine, Context (language use), Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, Article, Open Reading Frames, 03 medical and health sciences, International Classification of Diseases, Genetics, Electronic Health Records, Humans, Medical diagnosis, Genetics (clinical), Genetic association, Clinical Laboratory Techniques, Genome, Human, Sequence Analysis, RNA, Reproducibility of Results, Molecular Sequence Annotation, Chromatin, Minor allele frequency, Phenotype, 030104 developmental biology, Gene Expression Regulation, Haplotypes, Genetic epidemiology, DNA, Intergenic, Genome-Wide Association Study, Demography
Abstract

Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We calculated associations between these diagnoses and traits with ∼630,000 common frequency SNPs with minor allele frequency > 0.01 for 38,662 individuals. In this landscape PheWAS, we explored results within diseases and traits, comparing results to those previously reported in genome-wide association studies (GWASs), as well as previously published PheWASs. We further leveraged the context of functional impact from protein-coding to regulatory regions, providing a deeper interpretation of these associations. The comprehensive nature of this PheWAS allows for novel hypothesis generation, the identification of phenotypes for further study for future phenotypic algorithm development, and identification of cross-phenotype associations.

Published
2018

12. Characterization of Genetic and Phenotypic Heterogeneity of Obstructive Sleep Apnea Using Electronic Health Records

Author

Diego R. Mazzotti, Allan I. Pack, Sarah A. Pendergrass, Navya Shilpa Josyula, Brendan T. Keenan, Christopher R. Bauer, Beth A. Malow, Janet D. Robishaw, Olivia J. Veatch, and Kanika Bagai

Subjects
Male, 0301 basic medicine, lcsh:Internal medicine, Candidate gene, lcsh:QH426-470, Genotype, Single-nucleotide polymorphism, Disease, Health records, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Ethnicity, Genetics, medicine, Humans, Electronic health records, SNP, Genetic Predisposition to Disease, lcsh:RC31-1245, Genetics (clinical), Genetic association, Pleiotropy, Sleep Apnea, Obstructive, Genetic heterogeneity, business.industry, Sleep disorders, Middle Aged, medicine.disease, Obstructive sleep apnea, Human genetics, nervous system diseases, 3. Good health, respiratory tract diseases, lcsh:Genetics, Phenotype, 030104 developmental biology, Systematic review, 030228 respiratory system, Case-Control Studies, Female, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Research Article
Abstract

Background Obstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete cessation of airflow during sleep and is linked to negative health outcomes. Understanding the genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic health records (EHRs) can be leveraged to both validate previously reported OSA-associated genomic variation and detect novel relationships between these variants and comorbidities. Methods We identified candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing research. Using datasets available at Geisinger (n = 39,407) and Vanderbilt University Medical Center (n = 24,084), we evaluated associations between 40 previously implicated SNPs and OSA diagnosis, defined using clinical codes. We also evaluated associations between these SNPs and OSA severity measures obtained from sleep reports at Geisinger (n = 6571). Finally, we used a phenome-wide association study approach to help reveal pleiotropic genetic effects between OSA candidate SNPs and other clinical codes and laboratory values available in the EHR. Results Most previously reported OSA candidate SNPs showed minimal to no evidence for associations with OSA diagnosis or severity in the EHR-derived datasets. Three SNPs in LEPR, MMP-9, and GABBR1 validated for an association with OSA diagnosis in European Americans; the SNP in GABBR1 was associated following meta-analysis of results from both clinical populations. The GABBR1 and LEPR SNPs, and one additional SNP, were associated with OSA severity measures in European Americans from Geisinger. Three additional candidate OSA SNPs were not associated with OSA-related traits but instead with hyperlipidemia and autoimmune diseases of the thyroid. Conclusions To our knowledge, this is one of the largest candidate gene studies and one of the first phenome-wide association studies of OSA genomic variation. Results validate genetic associates with OSA in the LEPR, MMP-9 and GABBR1 genes, but suggest that the majority of previously identified genetic associations with OSA may be false positives. Phenome-wide analyses provide evidence of mediated pleiotropy. Future well-powered genome-wide association analyses of OSA risk and severity across populations with diverse ancestral backgrounds are needed. The comprehensive nature of the analyses represents a platform for informing future work focused on understanding how genetic data can be useful to informing treatment of OSA and related comorbidities.

Published
2019
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13. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Tobias Hermle, Holger Kirsten, Karsten B. Sieber, Aiko P. J. de Vries, Su Chi Lim, Peter Kovacs, Charumathi Sabanayagam, Carl D. Langefeld, Bernhard K. Krämer, Kent D. Taylor, Janine F. Felix, Belen Ponte, Markus Loeffler, Mary F. Feitosa, Kai-Uwe Eckardt, Jianjun Liu, Katalin Dittrich, Charlene A. Wong, Uwe Völker, Adriana M. Hung, Thomas Meitinger, Anubha Mahajan, Anselm Hoppmann, Erik Ingelsson, Martin H. de Borst, Oscar H. Franco, Niek Verweij, Kai-Uwe Saum, Vilmundur Gudnason, Bram P. Prins, Carsten A. Böger, Terho Lehtimäki, Andrew A. Hicks, Todd L. Edwards, Olivier Devuyst, Peter P. Pramstaller, Katrin Horn, Leslie A. Lange, Johanne Tremblay, Jin-Fang Chai, Sahar Ghasemi, Kjell Nikus, Tanja Poulain, Massimiliano Cocca, Anna Köttgen, Eric Boerwinkle, Barry I. Freedman, Miao-Ling Chee, Man Li, Stephan J. L. Bakker, Tamara B. Harris, Albert V. Smith, Ton J. Rabelink, Dennis O. Mook-Kanamori, Iris M. Heid, Jasmin Divers, Chaolong Wang, Kathleen A. Ryan, Pavel Hamet, Silke Szymczak, Shih-Jen Hwang, Hauke Thomsen, Rainer Rettig, Ayush Giri, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Cristian Pattaro, Andrej Teren, Valencia Hui Xian Foo, Myriam Rheinberger, Audrey Y. Chu, Barbara McMullen, Franziska Grundner-Culemann, Masayuki Yasuda, Murielle Bochud, Martin Gögele, Anke Tönjes, Jeannette Lee, Adrienne Tin, Kevin Ho, Konstantin Strauch, Josef Coresh, Renée de Mutsert, Sandra Freitag-Wolf, Gardar Sveinbjornsson, Yizhe Xu, Katalin Susztak, Tien Yin Wong, Mary L. Biggs, Isleifur Olafsson, Qiong Yang, Antje Körner, Chengxiang Qiu, E-Shyong Tai, Martina Müller-Nurasyid, Ben Schöttker, Jeffrey O' Connell, Mengmeng Chen, Daniel F. Gudbjartsson, Dermot F. Reilly, Vincent W. V. Jaddoe, Damia Noce, Pim van der Harst, Sanaz Sedaghat, Chiea Chuen Khor, Adam S. Butterworth, Mathias Gorski, Robert J. Carroll, James G. Wilson, Johan Ärnlöv, Christa Meisinger, Kenneth Rice, Bettina Jung, Christian M. Shaffer, Unnur Thorsteinsdottir, Matthias Nauck, Shreeram Akilesh, Mika Kähönen, Johanna Jakobsdottir, Melanie Waldenberger, Ralph Burkhardt, Daniela Baptista, John Danesh, Benjamin B. Sun, Karlhans Endlich, Holly Kramer, Frauke Degenhardt, Wolfgang Lieb, Kari Stefansson, Joachim Thiery, Lars Lind, Nicholette D. Palmer, Sarah A. Pendergrass, Suzanne Vogelezang, Peter J. van der Most, Afshin Parsa, Markus Scholz, Florian Kronenberg, Joseph C. Maranville, Laura M. Raffield, Hermann Brenner, Wieland Kiess, Anna I. Podgornaia, Yuan Shi, Tanguy Corre, Miao-Li Chee, Deborah Mascalzoni, Bamidele O. Tayo, Navya Shilpa Josyula, Ching-Yu Cheng, Lea Gerstner, Nisha Bansal, Jerome I. Rotter, Alexander Teumer, Vilmantas Giedraitis, Raymond Noordam, Ron T. Gansevoort, Lihua Wang, Andrew P. Morris, Bruce M. Psaty, Boting Ning, Zhi Yu, Christian Fuchsberger, Matthias Wuttke, Heiko Runz, Annette Peters, Yih Chung Tham, James P. Cook, Yong Li, Chris H. L. Thio, Hilma Holm, Alessandro De Grandi, Jonathan Marten, André G. Uitterlinden, Andre Franke, Nicholas Y. Q. Tan, Otis D. Wilson, Georg Ehret, Cecilia M. Lindgren, Josyf C. Mychaleckyj, Wolfgang Koenig, Harold Snieder, Michael Stumvoll, Kozeta Miliku, M. Arfan Ikram, Teresa Nutile, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands, University of Iceland, Teumer, Alexander [0000-0002-8309-094X], Li, Yong [0000-0003-2651-8791], Wuttke, Matthias [0000-0003-3420-5082], Giri, Ayush [0000-0002-7786-4670], Qiu, Chengxiang [0000-0002-6346-8669], Kirsten, Holger [0000-0002-3126-7950], Tin, Adrienne [0000-0002-4207-5866], Feitosa, Mary F. [0000-0002-0933-2410], Chai, Jin-Fang [0000-0003-3770-1137], Cocca, Massimiliano [0000-0002-1127-7596], Gorski, Mathias [0000-0002-9103-5860], Horn, Katrin [0000-0002-5307-6936], Li, Man [0000-0002-3839-0281], Marten, Jonathan [0000-0001-6916-2014], van der Most, Peter J. [0000-0001-8450-3518], Burkhardt, Ralph [0000-0003-1924-1202], Coresh, Josef [0000-0002-4598-0669], de Borst, Martin H. [0000-0002-4127-8733], Ehret, Georg [0000-0002-5730-0675], Endlich, Karlhans [0000-0001-6052-6061], Felix, Janine F. [0000-0002-9801-5774], Franke, Andre [0000-0003-1530-5811], Freedman, Barry I. [0000-0003-0275-5530], Freitag-Wolf, Sandra [0000-0002-1069-7740], Giedraitis, Vilmantas [0000-0003-3423-2021], Grundner-Culemann, Franziska [0000-0001-9649-281X], Gudnason, Vilmundur [0000-0001-5696-0084], Hicks, Andrew A. [0000-0001-6320-0411], Ikram, M. Arfan [0000-0003-0372-8585], Ingelsson, Erik [0000-0003-2256-6972], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Josyula, Navya Shilpa [0000-0003-2782-8812], Khor, Chiea-Chuen [0000-0002-1128-4729], Koenig, Wolfgang [0000-0002-2064-9603], Kovacs, Peter [0000-0002-0290-5423], Kronenberg, Florian [0000-0003-2229-1120], Lindgren, Cecilia M. [0000-0002-4903-9374], Liu, Jianjun [0000-0002-3255-3019], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Mahajan, Anubha [0000-0001-5585-3420], Mascalzoni, Deborah [0000-0003-4156-1464], Miliku, Kozeta [0000-0002-9614-7191], Müller-Nurasyid, Martina [0000-0003-3793-5910], Mychaleckyj, Josyf C. [0000-0003-2595-0005], Palmer, Nicholette D. [0000-0001-8883-2511], Poulain, Tanja [0000-0003-3825-5829], Raffield, Laura M. [0000-0002-7892-193X], Rice, Kenneth M. [0000-0002-3071-7278], Rivadeneira, Fernando [0000-0001-9435-9441], Sabanayagam, Charumathi [0000-0002-4042-4719], Smith, Albert V. [0000-0003-1942-5845], Sun, Benjamin B. [0000-0001-6347-2281], Szymczak, Silke [0000-0002-8897-9035], Taylor, Kent D. [0000-0002-2756-4370], Thio, Chris H. L. [0000-0003-2623-7172], Uitterlinden, André G. [0000-0002-7276-3387], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Völker, Uwe [0000-0002-5689-3448], Wang, Chaolong [0000-0003-3945-1012], Yang, Qiong [0000-0002-3658-1375], Devuyst, Olivier [0000-0003-3744-4767], Edwards, Todd L. [0000-0003-4318-6119], Ho, Kevin [0000-0002-3054-8697], Morris, Andrew P. [0000-0002-6805-6014], Pendergrass, Sarah A. [0000-0002-0565-6522], Rotter, Jerome I. [0000-0001-7191-1723], Stefansson, Kari [0000-0003-1676-864X], Susztak, Katalin [0000-0002-1005-3726], Scholz, Markus [0000-0002-4059-1779], Butterworth, Adam S. [0000-0002-6915-9015], Hung, Adriana M. [0000-0002-3203-1608], Pattaro, Cristian [0000-0002-4119-0109], Köttgen, Anna [0000-0002-4671-3714], Apollo - University of Cambridge Repository, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Feitosa, Mary F [0000-0002-0933-2410], van der Most, Peter J [0000-0001-8450-3518], de Borst, Martin H [0000-0002-4127-8733], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jaddoe, Vincent WV [0000-0003-2939-0041], Lindgren, Cecilia M [0000-0002-4903-9374], Mychaleckyj, Josyf C [0000-0003-2595-0005], Palmer, Nicholette D [0000-0001-8883-2511], Raffield, Laura M [0000-0002-7892-193X], Rice, Kenneth M [0000-0002-3071-7278], Smith, Albert V [0000-0003-1942-5845], Sun, Benjamin B [0000-0001-6347-2281], Taylor, Kent D [0000-0002-2756-4370], Thio, Chris HL [0000-0003-2623-7172], Uitterlinden, André G [0000-0002-7276-3387], Edwards, Todd L [0000-0003-4318-6119], Morris, Andrew P [0000-0002-6805-6014], Pendergrass, Sarah A [0000-0002-0565-6522], Rotter, Jerome I [0000-0001-7191-1723], Butterworth, Adam S [0000-0002-6915-9015], and Hung, Adriana M [0000-0002-3203-1608]

Subjects
0301 basic medicine, Drosophila melanogaster/genetics, Diabetes Mellitus/genetics, LD SCORE REGRESSION, 030232 urology & nephrology, 45/43, General Physics and Astronomy, Genome-wide association study, BLOOD-PRESSURE, Bioinformatics, GLOMERULAR-FILTRATION-RATE, Genome-wide association studies, Diabetes mellitus genetics, 0302 clinical medicine, Creatinine/urine, Risk Factors, Genome-wide, Phenomics, lcsh:Science, ddc:616, Regulation of gene expression, RISK, Gene knockdown, Kidney diseases, Multidisciplinary, HERITABILITY, Albuminuria/genetics, article, Chromosome Mapping, Kidney disease, ddc, 3. Good health, Drosophila melanogaster, Creatinine, Nýrnasjúkdómar, 692/4022/1585, Slit diaphragm, Medical genetics, medicine.symptom, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, Science, 631/208/205/2138, 610 Medicine & health, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Meta-Analysis as Topic, 360 Social problems & social services, Diabetes Mellitus, medicine, Animals, Humans, Albuminuria, Genetic Predisposition to Disease, ddc:610, EXCRETION RATE, CARDIOVASCULAR EVENTS, Genetic association, Medicinsk genetik, TRANS-EQTLS, KIDNEY-DISEASE, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, COLLABORATIVE METAANALYSIS, lcsh:Q, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Published
2019
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14. Identifying Ligand Binding Sites of Proteins using Crystallographic Bfactors and Relative Pocket Sizes

Author

Constance J. Jeffery and Navya Shilpa Josyula

Subjects
chemistry.chemical_classification, Crystallography, Protein structure, chemistry, Biomolecule, Biophysics, A protein, Crystal structure, Ligand (biochemistry), Protein crystallization, Proteomics, Small molecule
Abstract

One of the goals of proteomics is to predict the functions of all proteins. Many protein functions involve interactions with other biological molecules. Some of the most important interactions are those of proteins with small molecule ligands. Several experimental and computational approaches have been proposed previously to predict the locations of ligand binding regions of proteins. The aim of this thesis is to test a new approach to identify the ligand binding regions on the surface of X-ray crystal structures of proteins with unknown functions. The hypothesis that was tested was that X-ray crystallographic B-factors, also known as temperature factors, of atoms located on the surface of a protein X-ray crystal structure, in combination with information about the relative sizes of surface pockets, can help in identifying the functional regions of proteins. We used as our test set of protein structures a non-redundant dataset of 328 proteins for which X-ray crystal structures have been solved for both ligand-bound and unbound forms. The main steps involved identifying the surface pocket that, out of the ten largest surface pockets, contains the largest number of atoms with low B-factor values, and then checking to see if that pocket corresponds to the known ligand-binding pocket. If so, the crystallographic B-factor values could be used as a parameter to aid in predicting the ligand-binding regions of many uncharacterized proteins. For the majority of proteins in our study, that is, for 66% of the proteins in our working dataset, the proposed methodology was able to identify correctly the ligand-binding pockets in the protein crystal structures of the unliganded forms of the proteins.

Published
2020

15. Healthcare Utilization and Patients’ Perspectives After Receiving a Positive Genetic Test for Familial Hypercholesterolemia

Author

Michael F. Murray, Sarah A. Pendergrass, Amanda L. Lazzeri, Navya Shilpa Josyula, Timothy Corcoran, Loren Butry, Amy C. Sturm, Kandamurugu Manickam, Alanna Kulchak Rahm, Laney K. Jones, and Daniel Komar

Subjects
medicine.medical_specialty, Pediatrics, business.industry, General Medicine, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, medicine.disease, Test (assessment), 03 medical and health sciences, 0302 clinical medicine, Healthcare utilization, Community health, Epidemiology, medicine, 030212 general & internal medicine, business, Exome sequencing
Abstract

Background: The MyCode Community Health Initiative (MyCode) is returning actionable results from whole exome sequencing. Familial hypercholesterolemia (FH) is an inherited condition characterized b...

Published
2018

16. Gene Coregulation and Coexpression in the Aryl Hydrocarbon Receptor-mediated Transcriptional Regulatory Network in the Mouse Liver

Author

Sudin Bhattacharya, Edward Dere, Timothy R. Zacharewski, Melvin E. Andersen, Norbert E. Kaminski, and Navya Shilpa Josyula

Subjects
0303 health sciences, biology, Gene regulatory network, Aryl hydrocarbon receptor, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cellular stress response, Gene expression, biology.protein, Binding site, Transcription factor, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Tissue-specific network models of chemical-induced gene perturbation can improve our mechanistic understanding of the intracellular events leading to adverse health effects resulting from chemical exposure. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor (TF) that activates a battery of genes and produces a variety of species-specific adverse effects in response to the potent and persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we assemble a global map of the AHR gene regulatory network in TCDD-treated mouse liver from a combination of previously published gene expression and genome-wide TF binding data sets. Using Kohonen selforganizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Specifically, directly-bound, indirectly-bound and non-genomic AHR target genes exhibit distinct patterns of gene expression, with the directly bound targets generally associated with highest median expression. Further, among the directly bound AHR target genes, the expression level increases with the number of AHR binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes, with AHR-bound target genes enriched for metabolic processes and enrichment of immune responses among AHR-unbound target genes, likely reflecting infiltration of immune cells into the mouse liver upon TCDD treatment. This work describes an approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response using bioinformatic and statistical tools.

Published
2018
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17. Rare variants in drug target genes contributing to complex diseases, phenome-wide

Author

Xinyuan Zhang, Frederick E. Dewey, Navya Shilpa Josyula, Dustin N. Hartzel, Shefali S. Verma, Daniel R. Lavage, Sarah A. Pendergrass, Joe Leader, Anurag Verma, Yogasudha Veturi, and Marylyn D. Ritchie

Subjects
0301 basic medicine, Genotype, Databases, Pharmaceutical, lcsh:Medicine, Computational biology, Phenome, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Humans, Disease, lcsh:Science, Author Correction, Gene, Exome sequencing, Loss function, Genetic Association Studies, Genetic association, Multidisciplinary, Genome, Human, lcsh:R, Computational Biology, Phenotype, 030104 developmental biology, Pharmaceutical Preparations, lcsh:Q, DrugBank, 030217 neurology & neurosurgery, Algorithms, Biomarkers, Genome-Wide Association Study
Abstract

The DrugBank database consists of ~800 genes that are well characterized drug targets. This list of genes is a useful resource for association testing. For example, loss of function (LOF) genetic variation has the potential to mimic the effect of drugs, and high impact variation in these genes can impact downstream traits. Identifying novel associations between genetic variation in these genes and a range of diseases can also uncover new uses for the drugs that target these genes. Phenome Wide Association Studies (PheWAS) have been successful in identifying genetic associations across hundreds of thousands of diseases. We have conducted a novel gene based PheWAS to test the effect of rare variants in DrugBank genes, evaluating associations between these genes and more than 500 quantitative and dichotomous phenotypes. We used whole exome sequencing data from 38,568 samples in Geisinger MyCode Community Health Initiative. We evaluated the results of this study when binning rare variants using various filters based on potential functional impact. We identified multiple novel associations, and the majority of the significant associations were driven by functionally annotated variation. Overall, this study provides a sweeping exploration of rare variant associations within functionally relevant genes across a wide range of diagnoses.

Published
2017

18. Author Correction: Rare variants in drug target genes contributing to complex diseases, phenome-wide

Author

Xinyuan Zhang, Daniel R. Lavage, Anurag Verma, Frederick E. Dewey, Marylyn D. Ritchie, Sarah A. Pendergrass, Shefali S. Verma, Yogasudha Veturi, Navya Shilpa Josyula, Joe Leader, and Dustin N. Hartzel

Subjects
0301 basic medicine, Multidisciplinary, Drug target, lcsh:R, lcsh:Medicine, Computational biology, Biology, Phenome, 03 medical and health sciences, 030104 developmental biology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lcsh:Q, lcsh:Science, Gene
Abstract

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Published
2018

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