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1. A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans

Author

Marta R. Moksnes, Ailin F. Hansen, Brooke N. Wolford, Laurent F. Thomas, Humaira Rasheed, Anica Simić, Laxmi Bhatta, Anne Lise Brantsæter, Ida Surakka, Wei Zhou, Per Magnus, Pål R. Njølstad, Ole A. Andreassen, Tore Syversen, Jie Zheng, Lars G. Fritsche, David M. Evans, Nicole M. Warrington, Therese H. Nøst, Bjørn Olav Åsvold, Trond Peder Flaten, Cristen J. Willer, Kristian Hveem, and Ben M. Brumpton

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.

Published
2024
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2. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Rosalie B. T. M. Sterenborg, Inga Steinbrenner, Yong Li, Melissa N. Bujnis, Tatsuhiko Naito, Eirini Marouli, Tessel E. Galesloot, Oladapo Babajide, Laura Andreasen, Arne Astrup, Bjørn Olav Åsvold, Stefania Bandinelli, Marian Beekman, John P. Beilby, Jette Bork-Jensen, Thibaud Boutin, Jennifer A. Brody, Suzanne J. Brown, Ben Brumpton, Purdey J. Campbell, Anne R. Cappola, Graziano Ceresini, Layal Chaker, Daniel I. Chasman, Maria Pina Concas, Rodrigo Coutinho de Almeida, Simone M. Cross, Francesco Cucca, Ian J. Deary, Alisa Devedzic Kjaergaard, Justin B. Echouffo Tcheugui, Christina Ellervik, Johan G. Eriksson, Luigi Ferrucci, Jan Freudenberg, GHS DiscovEHR, Regeneron Genetics Center, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E. Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N. Harding, Sarah E. Harris, Stig Haunsø, Caroline Hayward, Jennie Hui, Till Ittermann, J. Wouter Jukema, Eero Kajantie, Jørgen K. Kanters, Line L. Kårhus, Lambertus A. L. M. Kiemeney, Margreet Kloppenburg, Brigitte Kühnel, Jari Lahti, Claudia Langenberg, Bruno Lapauw, Graham Leese, Shuo Li, David C. M. Liewald, Allan Linneberg, Jesus V. T. Lominchar, Jian’an Luan, Nicholas G. Martin, Antonela Matana, Marcel E. Meima, Thomas Meitinger, Ingrid Meulenbelt, Braxton D. Mitchell, Line T. Møllehave, Samia Mora, Silvia Naitza, Matthias Nauck, Romana T. Netea-Maier, Raymond Noordam, Casia Nursyifa, Yukinori Okada, Stefano Onano, Areti Papadopoulou, Colin N. A. Palmer, Cristian Pattaro, Oluf Pedersen, Annette Peters, Maik Pietzner, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Ante Punda, Debashree Ray, Paul Redmond, J. Brent Richards, Paul M. Ridker, Tom C. Russ, Kathleen A. Ryan, Morten Salling Olesen, Ulla T. Schultheiss, Elizabeth Selvin, Moneeza K. Siddiqui, Carlo Sidore, P. Eline Slagboom, Thorkild I. A. Sørensen, Enrique Soto-Pedre, Tim D. Spector, Beatrice Spedicati, Sundararajan Srinivasan, John M. Starr, David J. Stott, Toshiko Tanaka, Vesela Torlak, Stella Trompet, Johanna Tuhkanen, André G. Uitterlinden, Erik B. van den Akker, Tibbert van den Eynde, Melanie M. van der Klauw, Diana van Heemst, Charlotte Verroken, W. Edward Visser, Dina Vojinovic, Henry Völzke, Melanie Waldenberger, John P. Walsh, Nicholas J. Wareham, Stefan Weiss, Cristen J. Willer, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Hanneke J. C. M. Wouters, Margaret J. Wright, Qiong Yang, Tatijana Zemunik, Wei Zhou, Gu Zhu, Sebastian Zöllner, Johannes W. A. Smit, Robin P. Peeters, Anna Köttgen, Alexander Teumer, and Marco Medici

Subjects
Science
Abstract

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Published
2024
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3. COL11A1 is associated with developmental dysplasia of the hip and secondary osteoarthritis in the HUNT study

Author

Kaya Kvarme Jacobsen, Sigrid Børte, Lene Bjerke Laborie, Hege Kristiansen, Annette Schäfer, Trude Gundersen, Tetyana Zayats, Bendik Kristoffer Slagsvold Winsvold, Karen Rosendahl, Amy E. Martinsen, Anne Heidi Skogholt, Ben M. Brumpton, Cristen J. Willer, Egil A. Fors, Espen S. Kristoffersen, Ingrid Heuch, Ingunn Mundal, John-Anker Zwart, Jonas B. Nielsen, Kjersti Storheim, Knut Hagen, Kristian Bernhard Nilsen, Kristian Hveem, Lars G. Fritsche, Laurent F. Thomas, Linda M. Pedersen, Maiken E. Gabrielsen, Marie U. Lie, Synne Ø. Stensland, and Wei Zhou

Subjects
Developmental dysplasia of the hip, Genetic, Hip dysplasia, COL11A1, HUNT, Diseases of the musculoskeletal system, RC925-935
Abstract

Objective: Developmental dysplasia of the hip (DDH) is a congenital condition affecting 2–3% of all infants. DDH increases the risk of osteoarthritis, is the cause of 30 ​% of all total hip arthroplasties (THAs) in adults

Published
2024
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4. Unravelling the genetic architecture of human complex traits through whole genome sequencing

Author

Ozvan Bocher, Cristen J. Willer, and Eleftheria Zeggini

Subjects
Science
Abstract

Whole genome sequencing has enabled new insights into the genetic architecture of complex traits, especially through access to low-frequency and rare variation. This Comment highlights the key contributions from this technology and discusses considerations for its use and future perspectives.

Published
2023
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5. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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6. 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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7. Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Author

Marta R. Moksnes, Sarah E. Graham, Kuan-Han Wu, Ailin Falkmo Hansen, Sarah A. Gagliano Taliun, Wei Zhou, Ketil Thorstensen, Lars G. Fritsche, Dipender Gill, Amy Mason, Francesco Cucca, David Schlessinger, Gonçalo R. Abecasis, Stephen Burgess, Bjørn Olav Åsvold, Jonas B. Nielsen, Kristian Hveem, Cristen J. Willer, and Ben M. Brumpton

Subjects
Biology (General), QH301-705.5
Abstract

A GWAS on the four major iron-related biomarkers is conducted using data from the Trøndelag Health Study (HUNT), Michigan Genomics Initiative (MGI), and SardiNIA study, to identify 123 loci associated with iron homeostasis and effect on all-cause mortality.

Published
2022
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8. Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits

Author

Ananyo Choudhury, Jean-Tristan Brandenburg, Tinashe Chikowore, Dhriti Sengupta, Palwende Romuald Boua, Nigel J. Crowther, Godfred Agongo, Gershim Asiki, F. Xavier Gómez-Olivé, Isaac Kisiangani, Eric Maimela, Matshane Masemola-Maphutha, Lisa K. Micklesfield, Engelbert A. Nonterah, Shane A. Norris, Hermann Sorgho, Halidou Tinto, Stephen Tollman, Sarah E. Graham, Cristen J. Willer, AWI-Gen study, H3Africa Consortium, Scott Hazelhurst, and Michèle Ramsay

Subjects
Science
Abstract

Genetic associations and polygenic scores for lipid traits have low transferability to African individuals. Here, the authors perform a large sub-Sarahan African lipid GWAS and find that larger datasets and better global representation in discovery GWAS help to bridge this gap.

Published
2022
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9. The Michigan Genomics Initiative: A biobank linking genotypes and electronic clinical records in Michigan Medicine patients

Author

Matthew Zawistowski, Lars G. Fritsche, Anita Pandit, Brett Vanderwerff, Snehal Patil, Ellen M. Schmidt, Peter VandeHaar, Cristen J. Willer, Chad M. Brummett, Sachin Kheterpal, Xiang Zhou, Michael Boehnke, Gonçalo R. Abecasis, and Sebastian Zöllner

Subjects
Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Biobanks of linked clinical patient histories and biological samples are an efficient strategy to generate large cohorts for modern genetics research. Biobank recruitment varies by factors such as geographic catchment and sampling strategy, which affect biobank demographics and research utility. Here, we describe the Michigan Genomics Initiative (MGI), a single-health-system biobank currently consisting of >91,000 participants recruited primarily during surgical encounters at Michigan Medicine. The surgical enrollment results in a biobank enriched for many diseases and ideally suited for a disease genetics cohort. Compared with the much larger population-based UK Biobank, MGI has higher prevalence for nearly all diagnosis-code-based phenotypes and larger absolute case counts for many phenotypes. Genome-wide association study (GWAS) results replicate known findings, thereby validating the genetic and clinical data. Our results illustrate that opportunistic biobank sampling within single health systems provides a unique and complementary resource for exploring the genetics of complex diseases.

Published
2023
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10. Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Author

Ying Wang, Shinichi Namba, Esteban Lopera, Sini Kerminen, Kristin Tsuo, Kristi Läll, Masahiro Kanai, Wei Zhou, Kuan-Han Wu, Marie-Julie Favé, Laxmi Bhatta, Philip Awadalla, Ben Brumpton, Patrick Deelen, Kristian Hveem, Valeria Lo Faro, Reedik Mägi, Yoshinori Murakami, Serena Sanna, Jordan W. Smoller, Jasmina Uzunovic, Brooke N. Wolford, Cristen Willer, Eric R. Gamazon, Nancy J. Cox, Ida Surakka, Yukinori Okada, Alicia R. Martin, Jibril Hirbo, Kuan-Han H. Wu, Humaira Rasheed, Jibril B. Hirbo, Arjun Bhattacharya, Huiling Zhao, Esteban A. Lopera-Maya, Sinéad B. Chapman, Juha Karjalainen, Mitja Kurki, Maasha Mutaamba, Juulia J. Partanen, Ben M. Brumpton, Sameer Chavan, Tzu-Ting Chen, Michelle Daya, Yi Ding, Yen-Chen A. Feng, Christopher R. Gignoux, Sarah E. Graham, Whitney E. Hornsby, Nathan Ingold, Ruth Johnson, Triin Laisk, Kuang Lin, Jun Lv, Iona Y. Millwood, Priit Palta, Anita Pandit, Michael H. Preuss, Unnur Thorsteinsdottir, Matthew Zawistowski, Xue Zhong, Archie Campbell, Kristy Crooks, Geertruida H. de Bock, Nicholas J. Douville, Sarah Finer, Lars G. Fritsche, Christopher J. Griffiths, Yu Guo, Karen A. Hunt, Takahiro Konuma, Riccardo E. Marioni, Jansonius Nomdo, Snehal Patil, Nicholas Rafaels, Anne Richmond, Jonathan A. Shortt, Peter Straub, Ran Tao, Brett Vanderwerff, Kathleen C. Barnes, Marike Boezen, Zhengming Chen, Chia-Yen Chen, Judy Cho, George Davey Smith, Hilary K. Finucane, Lude Franke, Andrea Ganna, Tom R. Gaunt, Tian Ge, Hailiang Huang, Jennifer Huffman, Jukka T. Koskela, Clara Lajonchere, Matthew H. Law, Liming Li, Cecilia M. Lindgren, Ruth J.F. Loos, Stuart MacGregor, Koichi Matsuda, Catherine M. Olsen, David J. Porteous, Jordan A. Shavit, Harold Snieder, Richard C. Trembath, Judith M. Vonk, David Whiteman, Stephen J. Wicks, Cisca Wijmenga, John Wright, Jie Zheng, Xiang Zhou, Michael Boehnke, Daniel H. Geschwind, Caroline Hayward, Eimear E. Kenny, Yen-Feng Lin, Hilary C. Martin, Sarah E. Medland, Aarno V. Palotie, Bogdan Pasaniuc, Kari Stefansson, David A. van Heel, Robin G. Walters, Sebastian Zöllner, Cristen J. Willer, Mark J. Daly, and Benjamin M. Neale

Subjects
Global-Biobank Meta-analysis Initiative, polygenic risk scores, multi-ancestry genetic prediction, accuracy heterogeneity, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Published
2023
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11. Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

Author

George Hindy, Daniel J. Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope Blakely, Ayse Bilge Ozel, Sarah Graham, Grace H. Holton, Joseph Dowsett, Akl C. Fahed, Kingsley-Michael Amadi, Grace K. Erne, Annika Tekmulla, Anis Ismail, Christopher Launius, Nona Sotoodehnia, James S. Pankow, Lise Wegner Thørner, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, on behalf of the DBDS Consortium, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, on behalf of the Regeneron Genetics Center, Gunnar Engström, Olle Melander, Marju Orho-Melander, Lili Zhao, Venkatesh L. Murthy, David J. Pinsky, Cristen J. Willer, Susan R. Heckbert, Jochen Reiser, Daniel R. Goldstein, Karl C. Desch, and Salim S. Hayek

Subjects
Cardiology, Medicine
Abstract

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Published
2022
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12. Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Author

Kira J. Stanzick, Yong Li, Pascal Schlosser, Mathias Gorski, Matthias Wuttke, Laurent F. Thomas, Humaira Rasheed, Bryce X. Rowan, Sarah E. Graham, Brett R. Vanderweff, Snehal B. Patil, VA Million Veteran Program, Cassiane Robinson-Cohen, John M. Gaziano, Christopher J. O’Donnell, Cristen J. Willer, Stein Hallan, Bjørn Olav Åsvold, Andre Gessner, Adriana M. Hung, Cristian Pattaro, Anna Köttgen, Klaus J. Stark, Iris M. Heid, and Thomas W. Winkler

Subjects
Science
Abstract

Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

Published
2021
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13. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Author

Jonas B. Nielsen, Oren Rom, Ida Surakka, Sarah E. Graham, Wei Zhou, Tanmoy Roychowdhury, Lars G. Fritsche, Sarah A. Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E. Hornsby, Akua Acheampong, Austen Grooms, Amanda Schaefer, Gregory J. M. Zajac, Luis Villacorta, Jifeng Zhang, Ben Brumpton, Mari Løset, Vivek Rai, Pia R. Lundegaard, Morten S. Olesen, Kent D. Taylor, Nicholette D. Palmer, Yii-Der Chen, Seung H. Choi, Steven A. Lubitz, Patrick T. Ellinor, Kathleen C. Barnes, Michelle Daya, Nicholas Rafaels, Scott T. Weiss, Jessica Lasky-Su, Russell P. Tracy, Ramachandran S. Vasan, L. Adrienne Cupples, Rasika A. Mathias, Lisa R. Yanek, Lewis C. Becker, Patricia A. Peyser, Lawrence F. Bielak, Jennifer A. Smith, Stella Aslibekyan, Bertha A. Hidalgo, Donna K. Arnett, Marguerite R. Irvin, James G. Wilson, Solomon K. Musani, Adolfo Correa, Stephen S. Rich, Xiuqing Guo, Jerome I. Rotter, Barbara A. Konkle, Jill M. Johnsen, Allison E. Ashley-Koch, Marilyn J. Telen, Vivien A. Sheehan, John Blangero, Joanne E. Curran, Juan M. Peralta, Courtney Montgomery, Wayne H-H Sheu, Ren-Hua Chung, Karen Schwander, Seyed M. Nouraie, Victor R. Gordeuk, Yingze Zhang, Charles Kooperberg, Alexander P. Reiner, Rebecca D. Jackson, Eugene R. Bleecker, Deborah A. Meyers, Xingnan Li, Sayantan Das, Ketian Yu, Jonathon LeFaive, Albert Smith, Tom Blackwell, Daniel Taliun, Sebastian Zollner, Lukas Forer, Sebastian Schoenherr, Christian Fuchsberger, Anita Pandit, Matthew Zawistowski, Sachin Kheterpal, Chad M. Brummett, Pradeep Natarajan, David Schlessinger, Seunggeun Lee, Hyun Min Kang, Francesco Cucca, Oddgeir L. Holmen, Bjørn O. Åsvold, Michael Boehnke, Sekar Kathiresan, Goncalo R. Abecasis, Y. Eugene Chen, Cristen J. Willer, and Kristian Hveem

Subjects
Science
Abstract

Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Published
2020
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14. Identification of cell type specific ACE2 modifiers by CRISPR screening.

Author

Emily J Sherman, Carmen Mirabelli, Vi T Tang, Taslima G Khan, Kyle Leix, Andrew A Kennedy, Sarah E Graham, Cristen J Willer, Andrew W Tai, Jonathan Z Sexton, Christiane E Wobus, and Brian T Emmer

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

SARS-CoV-2 infection is initiated by binding of the viral spike protein to its receptor, ACE2, on the surface of host cells. ACE2 expression is heterogeneous both in vivo and in immortalized cell lines, but the molecular pathways that govern ACE2 expression remain unclear. We now report high-throughput CRISPR screens for functional modifiers of ACE2 surface abundance. In liver-derived HuH7 cells, we identified 35 genes whose disruption was associated with a change in the surface abundance of ACE2. Enriched among these ACE2 regulators were established transcription factors, epigenetic regulators, and functional networks. We further characterized individual HuH7 cell lines with disruption of SMAD4, EP300, PIAS1, or BAMBI and found these genes to regulate ACE2 at the mRNA level and to influence cellular susceptibility to SARS-CoV-2 infection. Orthogonal screening of lung-derived Calu-3 cells revealed a distinct set of ACE2 modifiers comprised of ACE2, KDM6A, MOGS, GPAA1, and UGP2. Collectively, our findings clarify the host factors involved in SARS-CoV-2 entry, highlight the cell type specificity of ACE2 regulatory networks, and suggest potential targets for therapeutic development.

Published
2022
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15. MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk

Author

Ida Surakka, Lars G. Fritsche, Wei Zhou, Joshua Backman, Jack A. Kosmicki, Haocheng Lu, Ben Brumpton, Jonas B. Nielsen, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, Sarah E. Graham, Y. Eugene Chen, Seunggeun Lee, Hyun Min Kang, Arnulf Langhammer, Siri Forsmo, Bjørn O. Åsvold, Unnur Styrkarsdottir, Hilma Holm, Daniel Gudbjartsson, Kari Stefansson, Aris Baras, Regeneron Genetics Center, Goncalo R. Abecasis, Kristian Hveem, and Cristen J. Willer

Subjects
Science
Abstract

Bone mineral density (BMD) is associated with fracture risk and many genetic loci with small effect sizes have been discovered by genome-wide association studies (GWAS). Here, the authors discover a large-effect rare loss-of-function genetic variant for BMD in the MEPE gene in the Norwegian HUNT study which replicates in the UK Biobank.

Published
2020
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16. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Author

Wei Zhou, Ben Brumpton, Omer Kabil, Julius Gudmundsson, Gudmar Thorleifsson, Josh Weinstock, Matthew Zawistowski, Jonas B. Nielsen, Layal Chaker, Marco Medici, Alexander Teumer, Silvia Naitza, Serena Sanna, Ulla T. Schultheiss, Anne Cappola, Juha Karjalainen, Mitja Kurki, Morgan Oneka, Peter Taylor, Lars G. Fritsche, Sarah E. Graham, Brooke N. Wolford, William Overton, Humaira Rasheed, Eirin B. Haug, Maiken E. Gabrielsen, Anne Heidi Skogholt, Ida Surakka, George Davey Smith, Anita Pandit, Tanmoy Roychowdhury, Whitney E. Hornsby, Jon G. Jonasson, Leigha Senter, Sandya Liyanarachchi, Matthew D. Ringel, Li Xu, Lambertus A. Kiemeney, Huiling He, Romana T. Netea-Maier, Jose I. Mayordomo, Theo S. Plantinga, Jon Hrafnkelsson, Hannes Hjartarson, Erich M. Sturgis, Aarno Palotie, Mark Daly, Cintia E. Citterio, Peter Arvan, Chad M. Brummett, Michael Boehnke, Albert de la Chapelle, Kari Stefansson, Kristian Hveem, Cristen J. Willer, and Bjørn Olav Åsvold

Subjects
Science
Abstract

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre.

Published
2020
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17. A Novel Variant in APOB Gene Causes Extremely Low LDL-C Without Known Adverse Effects

Author

Ida Surakka, PhD, Whitney E. Hornsby, PhD, Linda Farhat, MS, Melvyn Rubenfire, MD, Lars G. Fritsche, PhD, Kristian Hveem, MD, PhD, Y. Eugene Chen, MD, PhD, Robert D. Brook, MD, Cristen J. Willer, PhD, and Richard L. Weinberg, MD, PhD

Subjects
apolipoprotein B loss-of-function, hypobetalipoproteinemia, low-density lipoprotein cholesterol, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

A novel frameshift variant was identified in APOB that segregates in a dominant manner with low levels of low-density lipoprotein cholesterol. Affected family members show no apparent clinical complications. There is no consensus regarding clinical management, and the long-term consequences of low levels of low-density lipoprotein cholesterol remain unknown. (Level of Difficulty: Advanced.)

Published
2020
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18. Author Correction: Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits

Author

Ananyo Choudhury, Jean-Tristan Brandenburg, Tinashe Chikowore, Dhriti Sengupta, Palwende Romuald Boua, Nigel J. Crowther, Godfred Agongo, Gershim Asiki, F. Xavier Gómez-Olivé, Isaac Kisiangani, Eric Maimela, Matshane Masemola-Maphutha, Lisa K. Micklesfield, Engelbert A. Nonterah, Shane A. Norris, Hermann Sorgho, Halidou Tinto, Stephen Tollman, Sarah E. Graham, Cristen J. Willer, AWI-Gen study, H3Africa Consortium, Scott Hazelhurst, and Michèle Ramsay

Subjects
Science
Published
2022
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19. Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2

Author

Yanbo Fan, Brooke N. Wolford, Haocheng Lu, Wenying Liang, Jinjian Sun, Wei Zhou, Oren Rom, Anubha Mahajan, Ida Surakka, Sarah E. Graham, Zhipeng Liu, Hyunbae Kim, Shweta Ramdas, Lars G. Fritsche, Jonas B. Nielsen, Maiken Elvestad Gabrielsen, Kristian Hveem, Dongshan Yang, Jun Song, Minerva T. Garcia-Barrio, Jifeng Zhang, Wanqing Liu, Kezhong Zhang, Cristen J. Willer, and Y. Eugene Chen

Subjects
Physiology, Molecular physiology, Diabetology, Genomics, Science
Abstract

Summary: The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice.

Published
2021
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20. Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

Author

Heming Wang, Jacqueline M. Lane, Samuel E. Jones, Hassan S. Dashti, Hanna M. Ollila, Andrew R. Wood, Vincent T. van Hees, Ben Brumpton, Bendik S. Winsvold, Katri Kantojärvi, Teemu Palviainen, Brian E. Cade, Tamar Sofer, Yanwei Song, Krunal Patel, Simon G. Anderson, David A. Bechtold, Jack Bowden, Richard Emsley, Simon D. Kyle, Max A. Little, Andrew S. Loudon, Frank A. J. L. Scheer, Shaun M. Purcell, Rebecca C. Richmond, Kai Spiegelhalder, Jessica Tyrrell, Xiaofeng Zhu, Christer Hublin, Jaakko A. Kaprio, Kati Kristiansson, Sonja Sulkava, Tiina Paunio, Kristian Hveem, Jonas B. Nielsen, Cristen J. Willer, John-Anker Zwart, Linn B. Strand, Timothy M. Frayling, David Ray, Deborah A. Lawlor, Martin K. Rutter, Michael N. Weedon, Susan Redline, and Richa Saxena

Subjects
Science
Abstract

A main symptom of chronic insufficient sleep is excessive daytime sleepiness. Here, Wang et al. report 42 genome-wide significant loci for self-reported daytime sleepiness in 452,071 individuals from the UK Biobank that cluster into two biological subtypes of either sleep propensity or sleep fragmentation.

Published
2019
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21. Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

Author

Sarah E. Graham, Jonas B. Nielsen, Matthew Zawistowski, Wei Zhou, Lars G. Fritsche, Maiken E. Gabrielsen, Anne Heidi Skogholt, Ida Surakka, Whitney E. Hornsby, Damian Fermin, Daniel B. Larach, Sachin Kheterpal, Chad M. Brummett, Seunggeun Lee, Hyun Min Kang, Goncalo R. Abecasis, Solfrid Romundstad, Stein Hallan, Matthew G. Sampson, Kristian Hveem, and Cristen J. Willer

Subjects
Science
Abstract

Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.

Published
2019
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22. Author Correction: GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer

Author

Wei Zhou, Ben Brumpton, Omer Kabil, Julius Gudmundsson, Gudmar Thorleifsson, Josh Weinstock, Matthew Zawistowski, Jonas B. Nielsen, Layal Chaker, Marco Medici, Alexander Teumer, Silvia Naitza, Serena Sanna, Ulla T. Schultheiss, Anne Cappola, Juha Karjalainen, Mitja Kurki, Morgan Oneka, Peter Taylor, Lars G. Fritsche, Sarah E. Graham, Brooke N. Wolford, William Overton, Humaira Rasheed, Eirin B. Haug, Maiken E. Gabrielsen, Anne Heidi Skogholt, Ida Surakka, George Davey Smith, Anita Pandit, Tanmoy Roychowdhury, Whitney E. Hornsby, Jon G. Jonasson, Leigha Senter, Sandya Liyanarachchi, Matthew D. Ringel, Li Xu, Lambertus A. Kiemeney, Huiling He, Romana T. Netea-Maier, Jose I. Mayordomo, Theo S. Plantinga, Jon Hrafnkelsson, Hannes Hjartarson, Erich M. Sturgis, Aarno Palotie, Mark Daly, Cintia E. Citterio, Peter Arvan, Chad M. Brummett, Michael Boehnke, Albert de la Chapelle, Kari Stefansson, Kristian Hveem, Cristen J. Willer, and Bjørn Olav Åsvold

Subjects
Science
Published
2021
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23. Genome-scale CRISPR screening for modifiers of cellular LDL uptake.

Author

Brian T Emmer, Emily J Sherman, Paul J Lascuna, Sarah E Graham, Cristen J Willer, and David Ginsburg

Subjects
Genetics, QH426-470
Abstract

Hypercholesterolemia is a causal and modifiable risk factor for atherosclerotic cardiovascular disease. A critical pathway regulating cholesterol homeostasis involves the receptor-mediated endocytosis of low-density lipoproteins into hepatocytes, mediated by the LDL receptor. We applied genome-scale CRISPR screening to query the genetic determinants of cellular LDL uptake in HuH7 cells cultured under either lipoprotein-rich or lipoprotein-starved conditions. Candidate LDL uptake regulators were validated through the synthesis and secondary screening of a customized library of gRNA at greater depth of coverage. This secondary screen yielded significantly improved performance relative to the primary genome-wide screen, with better discrimination of internal positive controls, no identification of negative controls, and improved concordance between screen hits at both the gene and gRNA level. We then applied our customized gRNA library to orthogonal screens that tested for the specificity of each candidate regulator for LDL versus transferrin endocytosis, the presence or absence of genetic epistasis with LDLR deletion, the impact of each perturbation on LDLR expression and trafficking, and the generalizability of LDL uptake modifiers across multiple cell types. These findings identified several previously unrecognized genes with putative roles in LDL uptake and suggest mechanisms for their functional interaction with LDLR.

Published
2021
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24. Exposure and risk factors for COVID-19 and the impact of staying home on Michigan residents.

Author

Kuan-Han H Wu, Whitney E Hornsby, Bethany Klunder, Amelia Krause, Anisa Driscoll, John Kulka, Ryan Bickett-Hickok, Austin Fellows, Sarah Graham, Erin O Kaleba, Salim S Hayek, Xu Shi, Nadia R Sutton, Nicholas Douville, Bhramar Mukherjee, Kenneth Jamerson, Chad M Brummett, and Cristen J Willer

Subjects
Medicine, Science
Abstract

COVID-19 has had a substantial impact on clinical care and lifestyles globally. The State of Michigan reports over 80,000 positive COVID-19 tests between March 1, 2020 and July 29, 2020. We surveyed 8,041 Michigan Medicine biorepository participants in late June 2020. We found that 55% of COVID-19 cases reported no known exposure to family members or to someone outside the house diagnosed with COVID-19. A significantly higher rate of COVID-19 cases were employed as essential workers (45% vs 19%, p = 9x10-12). COVID-19 cases reporting a fever were more likely to require hospitalization (categorized as severe; OR = 4.4 [95% CI: 1.6-12.5, p = 0.005]) whereas respondents reporting rhinorrhea was less likely to require hospitalization (categorized as mild-to-moderate; OR = 0.16 [95% CI: 0.04-0.73, p = 0.018]). African-Americans reported higher rates of being diagnosed with COVID-19 (OR = 4.0 [95% CI: 2.2-7.2, p = 5x10-6]), as well as higher rates of exposure to family or someone outside the household diagnosed with COVID-19, an annual household income < $40,000, living in rental housing, and chronic diseases. During the Executive Order in Michigan, African Americans, women, and the lowest income group reported worsening health behaviors and higher overall concern for the potential detrimental effects of the pandemic. The higher risk of contracting COVID-19 observed among African Americans may be due to the increased rates of working as essential employees, lower socioeconomic status, and exposure to known positive cases. Continued efforts should focus on COVID-19 prevention and mitigation strategies, as well as address the inequality gaps that result in higher risks for both short-term and long-term health outcomes.

Published
2021
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25. Genetic associations with temporal shifts in obesity and severe obesity during the obesity epidemic in Norway: A longitudinal population-based cohort (the HUNT Study).

Author

Maria Brandkvist, Johan Håkon Bjørngaard, Rønnaug Astri Ødegård, Ben Brumpton, George Davey Smith, Bjørn Olav Åsvold, Erik R Sund, Kirsti Kvaløy, Cristen J Willer, and Gunnhild Åberge Vie

Subjects
Medicine
Abstract

BackgroundObesity has tripled worldwide since 1975 as environments are becoming more obesogenic. Our study investigates how changes in population weight and obesity over time are associated with genetic predisposition in the context of an obesogenic environment over 6 decades and examines the robustness of the findings using sibling design.Methods and findingsA total of 67,110 individuals aged 13-80 years in the Nord-Trøndelag region of Norway participated with repeated standardized body mass index (BMI) measurements from 1966 to 2019 and were genotyped in a longitudinal population-based health study, the Trøndelag Health Study (the HUNT Study). Genotyping required survival to and participation in the HUNT Study in the 1990s or 2000s. Linear mixed models with observations nested within individuals were used to model the association between a genome-wide polygenic score (GPS) for BMI and BMI, while generalized estimating equations were used for obesity (BMI ≥ 30 kg/m2) and severe obesity (BMI ≥ 35 kg/m2). The increase in the average BMI and prevalence of obesity was steeper among the genetically predisposed. Among 35-year-old men, the prevalence of obesity for the least predisposed tenth increased from 0.9% (95% confidence interval [CI] 0.6% to 1.2%) to 6.5% (95% CI 5.0% to 8.0%), while the most predisposed tenth increased from 14.2% (95% CI 12.6% to 15.7%) to 39.6% (95% CI 36.1% to 43.0%). Equivalently for women of the same age, the prevalence of obesity for the least predisposed tenth increased from 1.1% (95% CI 0.7% to1.5%) to 7.6% (95% CI 6.0% to 9.2%), while the most predisposed tenth increased from 15.4% (95% CI 13.7% to 17.2%) to 42.0% (95% CI 38.7% to 45.4%). Thus, for 35-year-old men and women, respectively, the absolute change in the prevalence of obesity from 1966 to 2019 was 19.8 percentage points (95% CI 16.2 to 23.5, p < 0.0001) and 20.0 percentage points (95% CI 16.4 to 23.7, p < 0.0001) greater for the most predisposed tenth compared with the least predisposed tenth, defined using the GPS for BMI. The corresponding absolute changes in the prevalence of severe obesity for men and women, respectively, were 8.5 percentage points (95% CI 6.3 to 10.7, p < 0.0001) and 12.6 percentage points (95% CI 9.6 to 15.6, p < 0.0001) greater for the most predisposed tenth. The greater increase in BMI in genetically predisposed individuals over time was apparent after adjustment for family-level confounding using a sibling design. Key limitations include a slightly lower survival to date of genetic testing for the older cohorts and that we apply a contemporary genetic score to past time periods. Future research should validate our findings using a polygenic risk score constructed from historical data.ConclusionsIn the context of increasingly obesogenic changes in our environment over 6 decades, our findings reveal a growing inequality in the risk for obesity and severe obesity across GPS tenths. Our results suggest that while obesity is a partially heritable trait, it is still modifiable by environmental factors. While it may be possible to identify those most susceptible to environmental change, who thus have the most to gain from preventive measures, efforts to reverse the obesogenic environment will benefit the whole population and help resolve the obesity epidemic.

Published
2020
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26. A fast linkage method for population GWAS cohorts with related individuals

Author

Gregory J. M. Zajac, Sarah A. Gagliano Taliun, Carlo Sidore, Sarah E. Graham, Bjørn O. Åsvold, Ben Brumpton, Jonas B. Nielsen, Wei Zhou, Maiken Gabrielsen, Anne H. Skogholt, Lars G. Fritsche, David Schlessinger, Francesco Cucca, Kristian Hveem, Cristen J. Willer, and Gonçalo R. Abecasis

Subjects
Epidemiology, Genetics (clinical)
Published
2023
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27. Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Author

Manuel A R Ferreira, Judith M Vonk, Hansjörg Baurecht, Ingo Marenholz, Chao Tian, Joshua D Hoffman, Quinta Helmer, Annika Tillander, Vilhelmina Ullemar, Yi Lu, Sarah Grosche, Franz Rüschendorf, Raquel Granell, Ben M Brumpton, Lars G Fritsche, Laxmi Bhatta, Maiken E Gabrielsen, Jonas B Nielsen, Wei Zhou, Kristian Hveem, Arnulf Langhammer, Oddgeir L Holmen, Mari Løset, Gonçalo R Abecasis, Cristen J Willer, Nima C Emami, Taylor B Cavazos, John S Witte, Agnieszka Szwajda, andMe Research Team, collaborators of the SHARE study, David A Hinds, Norbert Hübner, Stephan Weidinger, Patrik Ke Magnusson, Eric Jorgenson, Robert Karlsson, Lavinia Paternoster, Dorret I Boomsma, Catarina Almqvist, Young-Ae Lee, and Gerard H Koppelman

Subjects
Genetics, QH426-470
Abstract

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P

Published
2020
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28. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Author

Pradeep Natarajan, Gina M. Peloso, Seyedeh Maryam Zekavat, May Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, Wei Zhou, Jonathan M. Bloom, Jesse M. Engreitz, Jason Ernst, Jeffrey R. O’Connell, Sanni E. Ruotsalainen, Maris Alver, Ani Manichaikul, W. Craig Johnson, James A. Perry, Timothy Poterba, Cotton Seed, Ida L. Surakka, Tonu Esko, Samuli Ripatti, Veikko Salomaa, Adolfo Correa, Ramachandran S. Vasan, Manolis Kellis, Benjamin M. Neale, Eric S. Lander, Goncalo Abecasis, Braxton Mitchell, Stephen S. Rich, James G. Wilson, L. Adrienne Cupples, Jerome I. Rotter, Cristen J. Willer, Sekar Kathiresan, and NHLBI TOPMed Lipids Working Group

Subjects
Science
Abstract

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

Published
2018
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29. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

Viktoria Gusarova, Colm O’Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, Michael F. Murray, Anubha Mahajan, Jonas B. Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F. Gudbjartsson, Marketa Sjögren, Connor A. Emdin, Robert A. Scott, Wen-Jane Lee, Aeron Small, Lydia C. Kwee, Om Prakash Dwivedi, Rashmi B. Prasad, Shannon Bruse, Alexander E. Lopez, John Penn, Anthony Marcketta, Joseph B. Leader, Christopher D. Still, H. Lester Kirchner, Uyenlinh L. Mirshahi, Amr H. Wardeh, Cassandra M. Hartle, Lukas Habegger, Samantha N. Fetterolf, Teresa Tusie-Luna, Andrew P. Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I. Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M. Brummett, Amit V. Khera, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A. Lotta, Cristen J. Willer, Oddgeir L. Holmen, Marylyn D. Ritchie, David H. Ledbetter, Andrew J. Murphy, Ingrid B. Borecki, Jeffrey G. Reid, John D. Overton, Ola Hansson, Leif Groop, Svati H. Shah, William E. Kraus, Daniel J. Rader, Yii-Der I. Chen, Kristian Hveem, Nicholas J. Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Goncalo R. Abecasis, David Altshuler, Jose C. Florez, Michael Boehnke, Mark I. McCarthy, George D. Yancopoulos, David J. Carey, Alan R. Shuldiner, Aris Baras, Frederick E. Dewey, and Jesper Gromada

Subjects
Science
Abstract

Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4 −/− mice on a high-fat diet show improved insulin sensitivity.

Published
2018
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30. Genome-wide analysis yields new loci associating with aortic valve stenosis

Author

Anna Helgadottir, Gudmar Thorleifsson, Solveig Gretarsdottir, Olafur A. Stefansson, Vinicius Tragante, Rosa B. Thorolfsdottir, Ingileif Jonsdottir, Thorsteinn Bjornsson, Valgerdur Steinthorsdottir, Niek Verweij, Jonas B. Nielsen, Wei Zhou, Lasse Folkersen, Andreas Martinsson, Mahyar Heydarpour, Siddharth Prakash, Gylfi Oskarsson, Tomas Gudbjartsson, Arnar Geirsson, Isleifur Olafsson, Emil L. Sigurdsson, Peter Almgren, Olle Melander, Anders Franco-Cereceda, Anders Hamsten, Lars Fritsche, Maoxuan Lin, Bo Yang, Whitney Hornsby, Dongchuan Guo, Chad M. Brummett, Gonçalo Abecasis, Michael Mathis, Dianna Milewicz, Simon C. Body, Per Eriksson, Cristen J. Willer, Kristian Hveem, Christopher Newton-Cheh, J. Gustav Smith, Ragnar Danielsen, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hilma Holm, and Kari Stefansson

Subjects
Science
Abstract

Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.

Published
2018
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31. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Author

Florian, Thibord, Derek, Klarin, Jennifer A, Brody, Ming-Huei, Chen, Michael G, Levin, Daniel I, Chasman, Ellen L, Goode, Kristian, Hveem, Maris, Teder-Laving, Angel, Martinez-Perez, Dylan, Aïssi, Delphine, Daian-Bacq, Kaoru, Ito, Pradeep, Natarajan, Pamela L, Lutsey, Girish N, Nadkarni, Paul S, de Vries, Gabriel, Cuellar-Partida, Brooke N, Wolford, Jack W, Pattee, Charles, Kooperberg, Sigrid K, Braekkan, Ruifang, Li-Gao, Noemie, Saut, Corriene, Sept, Marine, Germain, Renae L, Judy, Kerri L, Wiggins, Darae, Ko, Christopher J, O'Donnell, Kent D, Taylor, Franco, Giulianini, Mariza, De Andrade, Therese H, Nøst, Anne, Boland, Jean-Philippe, Empana, Satoshi, Koyama, Thomas, Gilliland, Ron, Do, Jennifer E, Huffman, Xin, Wang, Wei, Zhou, Jose, Manuel Soria, Juan, Carlos Souto, Nathan, Pankratz, Jeffery, Haessler, Kristian, Hindberg, Frits R, Rosendaal, Constance, Turman, Robert, Olaso, Rachel L, Kember, Traci M, Bartz, Julie A, Lynch, Susan R, Heckbert, Sebastian M, Armasu, Ben, Brumpton, David M, Smadja, Xavier, Jouven, Issei, Komuro, Katharine R, Clapham, Ruth J F, Loos, Cristen J, Willer, Maria, Sabater-Lleal, James S, Pankow, Alexander P, Reiner, Vania M, Morelli, Paul M, Ridker, Astrid van Hylckama, Vlieg, Jean-François, Deleuze, Peter, Kraft, Daniel J, Rader, Kyung, Min Lee, Bruce M, Psaty, Anne, Heidi Skogholt, Joseph, Emmerich, Pierre, Suchon, Stephen S, Rich, Ha My T, Vy, Weihong, Tang, Rebecca D, Jackson, John-Bjarne, Hansen, Pierre-Emmanuel, Morange, Christopher, Kabrhel, David-Alexandre, Trégouët, Scott M, Damrauer, Andrew D, Johnson, Nicholas L, Smith, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
genome-wide association study, venous thromboembolism, Quantitative Trait Loci, Thrombosis, Genomics, Venous Thromboembolism, Polymorphism, Single Nucleotide, meta-analysis, Meta-analysis, Physiology (medical), Venous thrombosis, Genetics, Humans, genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic Predisposition to Disease, venous thrombosis, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022
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32. Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Author

Bo Yang, Wei Zhou, Jiao Jiao, Jonas B. Nielsen, Michael R. Mathis, Mahyar Heydarpour, Guillaume Lettre, Lasse Folkersen, Siddharth Prakash, Claudia Schurmann, Lars Fritsche, Gregory A. Farnum, Maoxuan Lin, Mohammad Othman, Whitney Hornsby, Anisa Driscoll, Alexandra Levasseur, Marc Thomas, Linda Farhat, Marie-Pierre Dubé, Eric M. Isselbacher, Anders Franco-Cereceda, Dong-chuan Guo, Erwin P. Bottinger, G. Michael Deeb, Anna Booher, Sachin Kheterpal, Y. Eugene Chen, Hyun Min Kang, Jacob Kitzman, Heather J. Cordell, Bernard D. Keavney, Judith A. Goodship, Santhi K. Ganesh, Gonçalo Abecasis, Kim A. Eagle, Alan P. Boyle, Ruth J. F. Loos, Per Eriksson, Jean-Claude Tardif, Chad M. Brummett, Dianna M. Milewicz, Simon C. Body, and Cristen J. Willer

Subjects
Science
Abstract

Bicuspid aortic valve (BAV) is the most common human congenital cardiovascular malformation. Here, the authors perform a genome-wide association study for BAV and identify risk variants in the gene region of cardiac-specific transcription factor GATA4 and implicate GATA4 in heart valve development.

Published
2017
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33. Incorporating family disease history and controlling case–control imbalance for population-based genetic association studies

Author

Yongwen Zhuang, Brooke N Wolford, Kisung Nam, Wenjian Bi, Wei Zhou, Cristen J Willer, Bhramar Mukherjee, and Seunggeun Lee

Subjects
Statistics and Probability, Computational Mathematics, Phenotype, Computational Theory and Mathematics, Case-Control Studies, Computer Simulation, Polymorphism, Single Nucleotide, Molecular Biology, Biochemistry, Genome-Wide Association Study, Computer Science Applications
Abstract

Motivation In the genome-wide association analysis of population-based biobanks, most diseases have low prevalence, which results in low detection power. One approach to tackle the problem is using family disease history, yet existing methods are unable to address type I error inflation induced by increased correlation of phenotypes among closely related samples, as well as unbalanced phenotypic distribution. Results We propose a new method for genetic association test with family disease history, mixed-model-based Test with Adjusted Phenotype and Empirical saddlepoint approximation, which controls for increased phenotype correlation by adopting a two-variance-component mixed model, accounts for case–control imbalance by using empirical saddlepoint approximation, and is flexible to incorporate any existing adjusted phenotypes, such as phenotypes from the LT-FH method. We show through simulation studies and analysis of UK Biobank data of white British samples and the Korean Genome and Epidemiology Study of Korean samples that the proposed method is robust and yields better calibration compared to existing methods while gaining power for detection of variant–phenotype associations. Availability and implementation The summary statistics and code generated in this study are available at https://github.com/styvon/TAPE. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2022
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34. Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility

Author

Andrea M, Murad, Hannah L, Hill, Yu, Wang, Michael, Ghannam, Min-Lee, Yang, Norma L, Pugh, Federico M, Asch, Whitney, Hornsby, Anisa, Driscoll, Jennifer, McNamara, Cristen J, Willer, Ellen S, Regalado, Dianna M, Milewicz, Kim A, Eagle, Santhi K, Ganesh, Cardiology, and ACS - Heart failure & arrhythmias

Subjects
Loeys-Dietz Syndrome, Coronary Vessel Anomalies, arterial disease, Article, Risk Factors, spontaneous coronary artery dissection, Genetics, Humans, familial thoracic aortic aneurysm and dissection, Ehlers-Danlos Syndrome, Genetic Predisposition to Disease, Vascular Diseases, Genetics (clinical), genetic susceptibility
Abstract

Spontaneous coronary artery dissection (SCAD) is a potential precipitant of myocardial infarction and sudden death for which the etiology is poorly understood. Mendelian vascular and connective tissue disorders underlying thoracic aortic disease (TAD), have been reported in ~5% of individuals with SCAD. We therefore hypothesized that patients with TAD are at elevated risk for SCAD. We queried registries enrolling patients with TAD to define the incidence of SCAD. Of 7568 individuals enrolled, 11 (0.15%) were found to have SCAD. Of the sequenced cases (9/11), pathogenic variants were identified (N = 9), including COL3A1 (N = 3), FBN1 (N = 2), TGFBR2 (N = 2), TGFBR1 (N = 1), and PRKG1 (N = 1). Individuals with SCAD had an increased frequency of iliac artery dissection (25.0% vs. 5.1%, p = 0.047). The prevalence of SCAD among individuals with TAD is low. The identification of pathogenic variants in genes previously described in individuals with SCAD, particularly those underlying vascular Ehlers–Danlos, Marfan syndrome, and Loeys–Dietz syndrome, is consistent with prior reports from clinical SCAD series. Further research is needed to identify specific genetic influences on SCAD risk.

Published
2022
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35. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Yingchang Lu, Felix R. Day, Stefan Gustafsson, Martin L. Buchkovich, Jianbo Na, Veronique Bataille, Diana L. Cousminer, Zari Dastani, Alexander W. Drong, Tõnu Esko, David M. Evans, Mario Falchi, Mary F. Feitosa, Teresa Ferreira, Åsa K. Hedman, Robin Haring, Pirro G. Hysi, Mark M. Iles, Anne E. Justice, Stavroula Kanoni, Vasiliki Lagou, Rui Li, Xin Li, Adam Locke, Chen Lu, Reedik Mägi, John R. B. Perry, Tune H. Pers, Qibin Qi, Marianna Sanna, Ellen M. Schmidt, William R. Scott, Dmitry Shungin, Alexander Teumer, Anna A. E. Vinkhuyzen, Ryan W. Walker, Harm-Jan Westra, Mingfeng Zhang, Weihua Zhang, Jing Hua Zhao, Zhihong Zhu, Uzma Afzal, Tarunveer Singh Ahluwalia, Stephan J. L. Bakker, Claire Bellis, Amélie Bonnefond, Katja Borodulin, Aron S. Buchman, Tommy Cederholm, Audrey C. Choh, Hyung Jin Choi, Joanne E. Curran, Lisette C. P. G. M. de Groot, Philip L. De Jager, Rosalie A. M. Dhonukshe-Rutten, Anke W. Enneman, Elodie Eury, Daniel S. Evans, Tom Forsen, Nele Friedrich, Frédéric Fumeron, Melissa E. Garcia, Simone Gärtner, Bok-Ghee Han, Aki S. Havulinna, Caroline Hayward, Dena Hernandez, Hans Hillege, Till Ittermann, Jack W. Kent, Ivana Kolcic, Tiina Laatikainen, Jari Lahti, Irene Mateo Leach, Christine G. Lee, Jong-Young Lee, Tian Liu, Youfang Liu, Stéphane Lobbens, Marie Loh, Leo-Pekka Lyytikäinen, Carolina Medina-Gomez, Karl Michaëlsson, Mike A. Nalls, Carrie M. Nielson, Laticia Oozageer, Laura Pascoe, Lavinia Paternoster, Ozren Polašek, Samuli Ripatti, Mark A. Sarzynski, Chan Soo Shin, Nina Smolej Narančić, Dominik Spira, Priya Srikanth, Elisabeth Steinhagen-Thiessen, Yun Ju Sung, Karin M. A. Swart, Leena Taittonen, Toshiko Tanaka, Emmi Tikkanen, Nathalie van der Velde, Natasja M. van Schoor, Niek Verweij, Alan F. Wright, Lei Yu, Joseph M. Zmuda, Niina Eklund, Terrence Forrester, Niels Grarup, Anne U. Jackson, Kati Kristiansson, Teemu Kuulasmaa, Johanna Kuusisto, Peter Lichtner, Jian'an Luan, Anubha Mahajan, Satu Männistö, Cameron D. Palmer, Janina S. Ried, Robert A. Scott, Alena Stancáková, Peter J. Wagner, Ayse Demirkan, Angela Döring, Vilmundur Gudnason, Douglas P. Kiel, Brigitte Kühnel, Massimo Mangino, Barbara Mcknight, Cristina Menni, Jeffrey R. O'Connell, Ben A. Oostra, Alan R. Shuldiner, Kijoung Song, Liesbeth Vandenput, Cornelia M. van Duijn, Peter Vollenweider, Charles C. White, Michael Boehnke, Yvonne Boettcher, Richard S. Cooper, Nita G. Forouhi, Christian Gieger, Harald Grallert, Aroon Hingorani, Torben Jørgensen, Pekka Jousilahti, Mika Kivimaki, Meena Kumari, Markku Laakso, Claudia Langenberg, Allan Linneberg, Amy Luke, Colin A. Mckenzie, Aarno Palotie, Oluf Pedersen, Annette Peters, Konstantin Strauch, Bamidele O. Tayo, Nicholas J. Wareham, David A. Bennett, Lars Bertram, John Blangero, Matthias Blüher, Claude Bouchard, Harry Campbell, Nam H. Cho, Steven R. Cummings, Stefan A. Czerwinski, Ilja Demuth, Rahel Eckardt, Johan G. Eriksson, Luigi Ferrucci, Oscar H. Franco, Philippe Froguel, Ron T. Gansevoort, Torben Hansen, Tamara B. Harris, Nicholas Hastie, Markku Heliövaara, Albert Hofman, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Paul B. Knekt, Seppo Koskinen, Peter Kovacs, Terho Lehtimäki, Lars Lind, Yongmei Liu, Eric S. Orwoll, Clive Osmond, Markus Perola, Louis Pérusse, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Treva K. Rice, Fernando Rivadeneira, Igor Rudan, Veikko Salomaa, Thorkild I. A. Sørensen, Michael Stumvoll, Anke Tönjes, Bradford Towne, Gregory J. Tranah, Angelo Tremblay, André G. Uitterlinden, Pim van der Harst, Erkki Vartiainen, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Henry Völzke, Mark Walker, Henri Wallaschofski, Sarah Wild, James F. Wilson, Loïc Yengo, D. Timothy Bishop, Ingrid B. Borecki, John C. Chambers, L. Adrienne Cupples, Abbas Dehghan, Panos Deloukas, Ghazaleh Fatemifar, Caroline Fox, Terrence S. Furey, Lude Franke, Jiali Han, David J. Hunter, Juha Karjalainen, Fredrik Karpe, Robert C. Kaplan, Jaspal S. Kooner, Mark I. McCarthy, Joanne M. Murabito, Andrew P. Morris, Julia A. N. Bishop, Kari E. North, Claes Ohlsson, Ken K. Ong, Inga Prokopenko, J. Brent Richards, Eric E. Schadt, Tim D. Spector, Elisabeth Widén, Cristen J. Willer, Jian Yang, Erik Ingelsson, Karen L. Mohlke, Joel N. Hirschhorn, John Andrew Pospisilik, M. Carola Zillikens, Cecilia Lindgren, Tuomas Oskari Kilpeläinen, and Ruth J. F. Loos

Subjects
Science
Abstract

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2016
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36. Cardiorespiratory Fitness After Open Repair for Acute Type A Aortic Dissection – A Prospective Study

Author

Reilly D. Hobbs, Kuan-Han H. Wu, Bo Yang, Sara Saberi, Jacob Sitzmann, Whitney E. Hornsby, Cristen J. Willer, Elizabeth L. Norton, Melvyn Rubenfire, and Samantha Fink

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, 030204 cardiovascular system & hematology, Thoracic aortic aneurysm, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Heart rate, medicine, Humans, Aerobic exercise, Obesity, Prospective Studies, Prospective cohort study, Aortic dissection, Aortic Aneurysm, Thoracic, business.industry, Cardiorespiratory fitness, General Medicine, Middle Aged, medicine.disease, Aortic Dissection, Treatment Outcome, Blood pressure, Cardiorespiratory Fitness, 030228 respiratory system, Quality of Life, Cardiology, Surgery, Cardiology and Cardiovascular Medicine, business, Body mass index
Abstract

Cardiorespiratory fitness (as measured by peak oxygen consumption [VO2peak]) is an independent predictor of cardiovascular disease and all-cause mortality. Limited data exist on VO2peak following repair for an acute type A aortic dissection (ATAAD) or proximal thoracic aortic aneurysm (pTAA). This study prospectively evaluated VO2peak, functional capacity, and health-related quality of life (HR-QOL) following open repair. Participants with a history of an ATAAD (n = 21) or pTAA (n = 43) performed cardiopulmonary exercise testing (CPX), 6-minute walk testing, and HR-QOL at 3 (early) and 15 (late) months following open repair. The median age at time of surgery was 55-years-old and 60-years-old in the ATAAD and pTAA groups, respectively. Body mass index significantly increased between early and late timepoints for both ATAAD (p = 0.0245, 56% obese) and pTAA groups (p = 0.0045, 54% obese). VO2peak modestly increased by 0.8 mLO2·kg−1·min−1 within the ATAAD group (p = 0.2312) while VO2peak significantly increased by 2.2 mLO2·kg−1·min−1 within the pTAA group (p = 0.0003). Anxiety significantly decreased in the ATAAD group whereas functional capacity and HR-QOL metrics (social roles and activities, physical function) significantly improved in the pTAA group (p values 1 year after repair. CPX should be considered post-operatively to evaluate exercise tolerance and blood pressure response to determine whether mild-to-moderate aerobic exercise should be recommended to reduce future risk of morbidity and mortality.

Published
2022
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37. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Author

Masahiro Kanai, Roy Elzur, Wei Zhou, Mark J. Daly, Hilary K. Finucane, Kuan-Han H. Wu, Humaira Rasheed, Kristin Tsuo, Jibril B. Hirbo, Ying Wang, Arjun Bhattacharya, Huiling Zhao, Shinichi Namba, Ida Surakka, Brooke N. Wolford, Valeria Lo Faro, Esteban A. Lopera-Maya, Kristi Läll, Marie-Julie Favé, Juulia J. Partanen, Sinéad B. Chapman, Juha Karjalainen, Mitja Kurki, Mutaamba Maasha, Ben M. Brumpton, Sameer Chavan, Tzu-Ting Chen, Michelle Daya, Yi Ding, Yen-Chen A. Feng, Lindsay A. Guare, Christopher R. Gignoux, Sarah E. Graham, Whitney E. Hornsby, Nathan Ingold, Said I. Ismail, Ruth Johnson, Triin Laisk, Kuang Lin, Jun Lv, Iona Y. Millwood, Sonia Moreno-Grau, Kisung Nam, Priit Palta, Anita Pandit, Michael H. Preuss, Chadi Saad, Shefali Setia-Verma, Unnur Thorsteinsdottir, Jasmina Uzunovic, Anurag Verma, Matthew Zawistowski, Xue Zhong, Nahla Afifi, Kawthar M. Al-Dabhani, Asma Al Thani, Yuki Bradford, Archie Campbell, Kristy Crooks, Geertruida H. de Bock, Scott M. Damrauer, Nicholas J. Douville, Sarah Finer, Lars G. Fritsche, Eleni Fthenou, Gilberto Gonzalez-Arroyo, Christopher J. Griffiths, Yu Guo, Karen A. Hunt, Alexander Ioannidis, Nomdo M. Jansonius, Takahiro Konuma, Ming Ta Michael Lee, Arturo Lopez-Pineda, Yuta Matsuda, Riccardo E. Marioni, Babak Moatamed, Marco A. Nava-Aguilar, Kensuke Numakura, Snehal Patil, Nicholas Rafaels, Anne Richmond, Agustin Rojas-Muñoz, Jonathan A. Shortt, Peter Straub, Ran Tao, Brett Vanderwerff, Manvi Vernekar, Yogasudha Veturi, Kathleen C. Barnes, Marike Boezen, Zhengming Chen, Chia-Yen Chen, Judy Cho, George Davey Smith, Lude Franke, Eric R. Gamazon, Andrea Ganna, Tom R. Gaunt, Tian Ge, Hailiang Huang, Jennifer Huffman, Nicholas Katsanis, Jukka T. Koskela, Clara Lajonchere, Matthew H. Law, Liming Li, Cecilia M. Lindgren, Ruth J.F. Loos, Stuart MacGregor, Koichi Matsuda, Catherine M. Olsen, David J. Porteous, Jordan A. Shavit, Harold Snieder, Tomohiro Takano, Richard C. Trembath, Judith M. Vonk, David C. Whiteman, Stephen J. Wicks, Cisca Wijmenga, John Wright, Jie Zheng, Xiang Zhou, Philip Awadalla, Michael Boehnke, Carlos D. Bustamante, Nancy J. Cox, Segun Fatumo, Daniel H. Geschwind, Caroline Hayward, Kristian Hveem, Eimear E. Kenny, Seunggeun Lee, Yen-Feng Lin, Hamdi Mbarek, Reedik Mägi, Hilary C. Martin, Sarah E. Medland, Yukinori Okada, Aarno V. Palotie, Bogdan Pasaniuc, Daniel J. Rader, Marylyn D. Ritchie, Serena Sanna, Jordan W. Smoller, Kari Stefansson, David A. van Heel, Robin G. Walters, Sebastian Zöllner, null Biobank of the Americas, null Biobank Japan Project, null BioMe, null BioVU, null CanPath - Ontario Health Study, null China Kadoorie Biobank Collaborative Group, null Colorado Center for Personalized Medicine, null deCODE Genetics, null Estonian Biobank, FinnGen, null Generation Scotland, null Genes & Health Research Team, null LifeLines, null Mass General Brigham Biobank, null Michigan Genomics Initiative, null National Biobank of Korea, null Penn Medicine BioBank, null Qatar Biobank, null The Qskin Sun and Health Study, null Taiwan Biobank, null The Hunt Study, null Ucla Atlas Community Health Initiative, null Uganda Genome Resource, null Uk Biobank, Alicia R. Martin, Cristen J. Willer, Benjamin M. Neale, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Data Science Genetic Epidemiology Lab, Research Programs Unit, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and University of Helsinki

Subjects
biobank, meta-analysis, genome-wide association study, fine-mapping, Genetics, 1184 Genetics, developmental biology, physiology, GWAS, 3111 Biomedicine, heterogeneity, summary statistics, Biochemistry, Genetics and Molecular Biology (miscellaneous), linkage disequilibrium, miscalibration
Abstract

Funding Information: We acknowledge all the participants and researchers of the 23 biobanks that have contributed to the GBMI. Biobank-specific acknowledgments are included in the Data S3 . We thank H. Huang, A.R. Martin, B.M. Neale, Y. Okada, K. Tsuo, J.C. Ulirsch, Y. Wang, and all the members of Finucane and Daly labs for their helpful feedback. M.K. was supported by a Nakajima Foundation Fellowship and the Masason Foundation . H.K.F. was funded by NIH grant DP5 OD024582 . Publisher Copyright: © 2022 The Author(s) Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10−4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.

Published
2022

38. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps

Author

Ricardo A. Verdugo, Palmira Granados Moreno, Amy C. Sturm, Alicia Zhou, Masahiro Kanai, Mary K. Balaconis, Charles N. Rotimi, J. Brent Richards, Elisabeth Widen, Saskia C. Sanderson, Anna C. F. Lewis, Genevieve L. Wojcik, Cristen J. Willer, Bartha Maria Knoppers, Samuli Ripatti, Kazuto Kato, Chani J. Hodonsky, Adebowale Adeyemo, Deanna R. Darnes, Alicia R. Martin, Segun Fatumo, Yukinori Okada, Michael Inouye, Michelle N. Meyer, Lucas Richter, and Mark I. McCarthy

Subjects
business.industry, Environmental health, Medicine, Polygenic risk score, General Medicine, business, General Biochemistry, Genetics and Molecular Biology
Published
2021
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39. Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Author

John Michael Gaziano, Snehal Patil, Cassiane Robinson-Cohen, Thomas W. Winkler, Humaira Rasheed, Anna Köttgen, Christopher J. O'Donnell, Sarah E. Graham, Stein Hallan, Brett R Vanderweff, Kira J Stanzick, Cristian Pattaro, Matthias Wuttke, Bjørn Olav Åsvold, Iris M. Heid, Adriana M. Hung, Bryce X Rowan, Pascal Schlosser, Klaus Stark, VA Million Veteran Program, Cristen J. Willer, André Gessner, Yong Li, Mathias Gorski, and Laurent F. Thomas

Subjects
0301 basic medicine, Science, Quantitative Trait Loci, 610 Medizin, General Physics and Astronomy, Renal function, Genome-wide association study, RNA-Seq, Computational biology, Biology, Quantitative trait locus, Kidney, Genome-wide association studies, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Chronic kidney disease, Genetics research, Databases, Genetic, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Gene, Genetic association, ddc:610, Multidisciplinary, Kidney metabolism, General Chemistry, medicine.disease, Cystatins, Europe, 030104 developmental biology, Gene Expression Regulation, Organ Specificity, Creatinine, Single-Cell Analysis, Biomarkers, 030217 neurology & neurosurgery, Genome-Wide Association Study, Glomerular Filtration Rate, Kidney disease
Abstract

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up., Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

Published
2021

40. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk.

Author

Ingrid Brænne, Lingyao Zeng, Christina Willenborg, Vinicius Tragante, Thorsten Kessler, CARDIoGRAM Consortium, CARDIoGRAMplusC4D Consortium, Cristen J Willer, Markku Laakso, Lars Wallentin, Paul W Franks, Veikko Salomaa, Abbas Dehghan, Thomas Meitinger, Nilesh J Samani, Folkert W Asselbergs, Jeanette Erdmann, and Heribert Schunkert

Subjects
Medicine, Science
Abstract

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

Published
2017
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41. Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association

Author

Jack W, O'Sullivan, Sridharan, Raghavan, Carla, Marquez-Luna, Jasmine A, Luzum, Scott M, Damrauer, Euan A, Ashley, Christopher J, O'Donnell, Cristen J, Willer, and Pradeep, Natarajan

Subjects
Adult, Multifactorial Inheritance, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Physiology (medical), Humans, Genetic Predisposition to Disease, American Heart Association, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation‚ which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care–associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.

Published
2022

42. Development and Validation of a Polygenic Risk Score for Stroke in the Chinese Population

Author

Zhanyun Ren, Jianfeng Huang, Wuzhuang Tang, Xian-Ping Wu, Hongbing Shen, Zhongying Liu, Keyong Huang, Xigui Wu, Cristen J. Willer, Huan Zhang, Jianxin Li, Fanghong Lu, Xueli Yang, Ying Li, Chong Shen, Yingxin Zhao, Hongfan Li, Laiyuan Wang, Ling Yu, Zhibin Hu, Xiaoqing Liu, Shufeng Chen, Dongfeng Gu, Jie Cao, Xiangfeng Lu, Dongsheng Hu, Fangchao Liu, and Xiao-Ge Niu

Subjects
Adult, Male, China, Multifactorial Inheritance, medicine.medical_specialty, Risk Assessment, Cohort Studies, Asian People, Meta-Analysis as Topic, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Family history, Stroke, Aged, Models, Statistical, Framingham Risk Score, Proportional hazards model, business.industry, Incidence, Incidence (epidemiology), Absolute risk reduction, Case-control study, Reproducibility of Results, Middle Aged, medicine.disease, Heart Disease Risk Factors, Case-Control Studies, Female, Neurology (clinical), business, Research Article, Genome-Wide Association Study, Cohort study
Abstract

ObjectiveTo construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.MethodsUsing a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.ResultsDuring a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66–2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%–27.7%) and 13.6% (95% CI 11.6%–15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%–49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%).ConclusionsOur metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.Classification of EvidenceThis study provides Class I evidence that metaPRS is predictive of stroke risk.

Published
2021
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43. An Asian-specific MPL genetic variant alters JAK–STAT signaling and influences platelet count in the population

Author

Santhi K. Ganesh, Yan Zhang, Karen Sl Lam, Haiyi Yu, Yujun Dong, Yong Huo, Min-Lee Yang, Wei Zhou, He Zhang, Cristen J. Willer, Hung Fat Tse, Y. Eugene Chen, Chloe Y Y Cheung, Wei Gao, Pak C. Sham, Clara S. Tang, Jia Jia, Ming Xu, Yi Fu, and Pengfei Sun

Subjects
Population, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genetics, medicine, Humans, SNP, Allele, Association Studies Article, education, Molecular Biology, Gene, Allele frequency, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Platelet Count, General Medicine, medicine.disease, Leukemia, Receptors, Thrombopoietin, Genome-Wide Association Study, Signal Transduction
Abstract

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)–trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10−13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK–STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

Published
2021
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44. Complex and Potentially Harmful Medication Patterns in Heart Failure with Preserved Ejection Fraction

Author

Mary E. Tinetti, Michael P. Dorsch, Jennifer McNamara, Parag Goyal, Cristen J. Willer, Matthew C. Konerman, Scott L. Hummel, Lina M. Brinker, and Pedram Navid

Subjects
Male, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Adverse drug effects, Beers Criteria, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, Chart review, medicine, Humans, 030212 general & internal medicine, Intensive care medicine, Potentially Inappropriate Medication List, Aged, Heart Failure, Geriatrics, Polypharmacy, business.industry, Potentially Inappropriate Medications, Stroke Volume, General Medicine, Middle Aged, medicine.disease, United States, Heart failure, Female, Heart failure with preserved ejection fraction, business
Abstract

Background Complex medication regimens, often present in heart failure with preserved ejection fraction, may increase the risk of adverse drug effects and harm. We sought to characterize this complexity by determining the prevalence of polypharmacy, potentially inappropriate medications, and therapeutic competition (where a medication for 1 condition may worsen another condition) in 1 of the few dedicated heart failure with preserved ejection fraction programs in the United States. Methods We conducted chart review on 231 patients with heart failure with preserved ejection fraction seen in the University of Michigan's Heart Failure with Preserved Ejection Fraction Clinic between July 2016 and September 2019. We recorded: 1) standing medications to determine the presence of polypharmacy, defined as ≥10 medications; 2) potentially inappropriate medications based on the 2016 American Heart Association Scientific Statement on drugs that pose a major risk of causing or exacerbating heart failure, the 2019 Beers Criteria update, or a previously described list of medications associated with geriatric syndromes; and 3) competing conditions and subsequent medications that could create therapeutic competition. Results The prevalence of polypharmacy was 74%, and the prevalence of potentially inappropriate medications was 100%. Competing conditions were present in 81% of patients, of whom 49% took a medication that created therapeutic competition. Conclusion In addition to confirming that polypharmacy was highly prevalent, we found that potentially inappropriate medications and therapeutic competition were also frequently present. This supports the urgent need to develop patient-centered approaches to mitigate the negative effects of complex medication regimens endemic to adults with heart failure with preserved ejection fraction.

Published
2021
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45. Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease

Author

Jacqueline S. Dron, Aniruddh P. Patel, Yiyi Zhang, Sean J. Jurgens, Dimitri J. Maamari, Minxian Wang, Eric Boerwinkle, Alanna C. Morrison, Paul S. de Vries, Myriam Fornage, Lifang Hou, Donald M. Lloyd-Jones, Bruce M. Psaty, Russell P. Tracy, Joshua C. Bis, Ramachandran S. Vasan, Daniel Levy, Nancy Heard-Costa, Stephen S. Rich, Xiuqing Guo, Kent D. Taylor, Richard A. Gibbs, Jerome I. Rotter, Cristen J. Willer, Elizabeth C. Oelsner, Andrew E. Moran, Gina M. Peloso, Pradeep Natarajan, and Amit V. Khera

Subjects
Cardiology and Cardiovascular Medicine
Abstract

ImportanceProtein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.ObjectiveTo evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.Design, Setting, and ParticipantsThis studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.ExposuresPTVs in APOB and PCSK9.Main Outcomes and MeasuresEstimated untreated LDL cholesterol levels and CHD.ResultsAmong 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).Conclusions and RelevanceAmong 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

Published
2023
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46. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author

Nancy L. Heard-Costa, Lucas Barwick, Clary B. Clish, Celeste Eng, Joanne M. Murabito, Esteban G. Burchard, Yii-Der Ida Chen, Daniel I. Chasman, Robert C. Kaplan, James B. Meigs, Deborah A. Nickerson, Cashell E. Jaquish, Eric Boerwinkle, Jennifer A. Brody, Charles Kooperberg, Mark T. Gladwin, Sebastian Schoenherr, Keng-Han Lin, John Barnard, Ryan D. Hernandez, Andrew D. Johnson, Edwin K. Silverman, Mollie A. Minear, Michelle Daya, Barbara A. Konkle, Sharon R. Browning, Daniel E. Weeks, Wendy S. Post, Alexander P. Reiner, Kathryn L. Lunetta, Gina M. Peloso, David Van Den Berg, Dan E. Arking, Seung-been Lee, Leslie A. Lange, Cristen J. Willer, Zachary A. Szpiech, Tasha E. Fingerlin, Wayne E. Clarke, Xutong Zhao, Stephen S. Rich, Nora Franceschini, Sudha Seshadri, Chloé Sarnowski, Hyun Min Kang, Sayantan Das, Michael C. Zody, Stephanie M. Fullerton, Dean Bobo, Alanna C. Morrison, Brian Custer, Nona Sotoodehnia, Shannon Kelly, Thomas W. Blackwell, Bruce M. Psaty, Yingze Zhang, Susan R. Heckbert, Robert E. Gerszten, M. Benjamin Shoemaker, Daniel Taliun, Leslie S. Emery, André Corvelo, Michael H. Cho, Braxton D. Mitchell, Xiaoming Liu, Stella Aslibekyan, Paul L. Auer, Brandon Chalazan, Sarah C. Nelson, Seung Hoan Choi, Jeong-Sun Seo, Matthew P. Conomos, Anne-Katrin Emde, Lawrence F. Bielak, Alisa K. Manning, Allison E. Ashley-Koch, Diane Fatkin, Xiaowen Tian, Emelia J. Benjamin, D. C. Rao, Mina K. Chung, Myriam Fornage, Daniel Levy, Michael D. Kessler, Weihong Tang, Daniel J. Gottlieb, Pradeep Natarajan, Jessica Lasky-Su, Amol C. Shetty, Cathy C. Laurie, Dan M. Roden, Timothy D. O’Connor, Jedidiah Carlson, Lewis C. Becker, Achilleas N. Pitsillides, Karine A. Viaud-Martinez, Raul Torres, Adolfo Correa, Christian Fuchsberger, Deborah A. Meyers, Alvaro Alonso, Sanghamitra Mohanty, Jonathon LeFaive, Soren Germer, Julie L. Mikulla, François Aguet, Susan K. Dutcher, Sarah A Gagliano Taliun, Ani Manichaikul, Lori Garman, Xiuqing Guo, Timothy A. Thornton, David D. McManus, Albert V. Smith, Kristin G. Ardlie, Anna Köttgen, Sharon L.R. Kardia, Quenna Wong, Jill M. Johnsen, Andrea Natale, Richard A. Gibbs, Douglas P. Kiel, Ingo Ruczinski, Susan Redline, Lukas Forer, Scott I. Vrieze, May E. Montasser, Rasika A. Mathias, Jerome I. Rotter, Jacob Pleiness, Chunyu Liu, Brian L. Browning, James G. Wilson, Weiniu Gan, Christine M. Albert, Marilyn J. Telen, Courtney G. Montgomery, Steven A. Lubitz, Robert Klemmer, Ramachandran S. Vasan, Nathan Pankratz, Mariza de Andrade, Vivien A. Sheehan, Kenneth Rice, Xihong Lin, Eimear E. Kenny, Stephanie M. Gogarten, John Blangero, Donna K. Arnett, Jiang He, Pankaj Qasba, James F. Casella, Patrick T. Ellinor, Nicholette D. Palmer, R. Graham Barr, Scott T. Weiss, Joanne E. Curran, Bruce S. Weir, Kari E. North, L. Adrienne Cupples, Dawn L. DeMeo, Tanika N. Kelly, Angel C.Y. Mak, Russell P. Tracy, David A. Schwartz, Kent D. Taylor, Rebecca L. Beer, Daniel N. Harris, George J. Papanicolaou, Marguerite R. Irvin, Stephen T. McGarvey, Sebastian Zöllner, Patricia A. Peyser, Brian E. Cade, Ruth J. F. Loos, Douglas Loesch, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Michael E. Hall, Lu-Chen Weng, Jeffrey R. O'Connell, Adrienne M. Stilp, Donald W. Bowden, Kathleen C. Barnes, Stacey Gabriel, Michael Boehnke, Wayne Huey-Herng Sheu, and Dawood Darbar

Subjects
Quality Control, Heterozygote, Genomics, Computational biology, Biology, Polymorphism, Single Nucleotide, Genome, Article, DNA sequencing, INDEL Mutation, Loss of Function Mutation, Genetics research, Genetic variation, Humans, Precision Medicine, Genetic association, Population Density, Multidisciplinary, Whole Genome Sequencing, Genome, Human, Genetic Variation, Rare variants, United States, Genetic architecture, Phenotype, Cytochrome P-450 CYP2D6, Haplotypes, Mutagenesis, Sample Size, Next-generation sequencing, National Heart, Lung, and Blood Institute (U.S.), Imputation (genetics), Reference genome
Abstract

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Published
2021
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47. A survey of aortic disease biorepository participants’ preferences for return of research genetic results

Author

J. Scott Roberts, Wendy R. Uhlmann, Whitney E. Hornsby, Jamie Love-Nichols, Patricia Arscott, and Cristen J. Willer

Subjects
Male, medicine.medical_specialty, business.industry, Genetic counseling, Aortic Diseases, Infant, Newborn, Patient portal, Genetic Counseling, Genomics, Primary care, Aortic disease, Biobank, Article, Biorepository, Informed consent, Neoplasms, Surveys and Questionnaires, Family medicine, Humans, Medicine, Female, business, Uncertain significance, Genetics (clinical)
Abstract

There is ongoing debate on whether and what research genetic results to return to study participants. To date, no study in this area has focused on aortopathy populations despite known genes that are clinically actionable. Participants (n = 225, 79% male, mean age = 61 years) with an aortopathy were surveyed to assess preferences for receiving research genetic results. Participants were 'very' or 'extremely likely' to want results for pathogenic variants in aortopathy genes with implications for family members (81%) or that would change medical management (76%). Similarly, participants were 'very' or 'extremely likely' to want actionable secondary findings related to cancer (75%) or other cardiac diseases (70%). Significantly lower interest was observed for non-actionable findings-pathogenic variants in aortopathy genes that would not change medical management (51%) and variants of uncertain significance (38%) (p .0001). Higher health and genomic literacy were positively associated with interest in actionable findings. Most participants (63%) were accepting of any means of return; however, a substantial minority (18%-38%) deemed certain technological means unacceptable (e.g., patient portal). Over 90% of participants reported that a range of health professionals, including cardiovascular specialists, genetics specialists, and primary care providers, were acceptable to return results. Participants with aortopathies are highly interested in research genetic results perceived to be medically actionable for themselves or family members. Participants are accepting of a variety of means for returning results. Findings suggest that research participants should be asked what results are preferred at time of informed consent and that genetic counseling may clarify implications of results that are not personally medically actionable.

Published
2020
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48. Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Author

David J. Carey, Cristen J. Willer, Anthony Marcketta, Claudia Schurmann, Leland Barnard, John Penn, Suganthi Balasubramanian, Daren Liu, Joseph B. Leader, Gonçalo R. Abecasis, Marcus B. Jones, John C. Whittaker, Ashutosh K. Pandey, Ida Surakka, David H. Ledbetter, Evan Maxwell, John D. Overton, Andrew Blumenfeld, Michael N. Cantor, Robert A. Scott, Wendy K. Chung, Alexander H. Li, Alexander Lopez, Joshua D. Backman, Matthew R. Nelson, Jeffrey Staples, Giovanni Coppola, Jonathan Marchini, Xiaodong Bai, Kavita Praveen, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Aris N. Economides, Shareef Khalid, William J Salerno, Bin Ye, Cristopher V. Van Hout, Kristian Hveem, Jeffrey G. Reid, Colm O'Dushlaine, Joshua D. Hoffman, Laura M. Yerges-Armstrong, Nilanjana Banerjee, Sean O'Keeffe, Ioanna Tachmazidou, Lon R. Cardon, Alicia Hawes, Aris Baras, Ashish Yadav, George D. Yancopoulos, and Lukas Habegger

Subjects
Male, 0301 basic medicine, Genes, BRCA2, Genes, BRCA1, Hasso-Plattner-Institut für Digital Engineering GmbH, Penetrance, 030204 cardiovascular system & hematology, Ion Channels, 0302 clinical medicine, Bone Density, Loss of Function Mutation, Neoplasms, Databases, Genetic, Genetics research, Genotype, Exome, Exome sequencing, Biological Specimen Banks, education.field_of_study, Multidisciplinary, Genomics, Middle Aged, Biobank, Pedigree, Phenotype, ras GTPase-Activating Proteins, Female, Kidney Diseases, Population, Collagen Type VI, Computational biology, Biology, Article, DNA sequencing, Varicose Veins, 03 medical and health sciences, Exome Sequencing, Humans, education, Alleles, Aged, Demography, Rare variants, Peptide Fragments, United Kingdom, 030104 developmental biology, ddc:000, Next-generation sequencing
Abstract

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community., Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Published
2020
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49. Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses

Author

Yoonsu Cho, Ben Michael Brumpton, Jaakko Kaprio, Johan Håkon Bjørngaard, Elliot M. Tucker-Drob, Tim T Morris, Neil M Davies, Sean Harrison, Laurence J. Howe, Wei-Min Chen, Nancy L. Pedersen, Gunnhild Åberge Vie, Kristian Hveem, Karl Heilbron, Fernando Pires Hartwig, Michel G. Nivard, Gibran Hemani, Laura D Howe, George Davey Smith, David M. Evans, Michael C. Neale, Bjørn Olav Åsvold, Eleanor Sanderson, Adam Auton, Andrew D. Grotzinger, Shuai Li, Amanda Hughes, Cristen J. Willer, Chandra A. Reynolds, Frank Windmeijer, Dorret I. Boomsma, John L. Hopper, Alexandra Havdahl, Institute for Molecular Medicine Finland, Department of Public Health, University of Helsinki, HUS Helsinki and Uusimaa Hospital District, APH - Methodology, APH - Mental Health, Biological Psychology, Brumpton, Ben [0000-0002-3058-1059], Sanderson, Eleanor [0000-0001-5188-5775], Hartwig, Fernando Pires [0000-0003-3729-0710], Harrison, Sean [0000-0002-7966-0700], Vie, Gunnhild Åberge [0000-0003-1552-5291], Cho, Yoonsu [0000-0001-6118-6652], Havdahl, Alexandra [0000-0002-9268-0423], Neale, Michael [0000-0003-4887-659X], Nivard, Michel G [0000-0003-2015-1888], Grotzinger, Andrew [0000-0001-7852-9244], Morris, Tim [0000-0001-8178-6815], Willer, Cristen [0000-0001-5645-4966], Evans, David M [0000-0003-0663-4621], Kaprio, Jaakko [0000-0002-3716-2455], Davey Smith, George [0000-0002-1407-8314], Hemani, Gibran [0000-0003-0920-1055], Davies, Neil M [0000-0002-2460-0508], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), gene-environment correlation, Epidemiology, General Physics and Astronomy, Matematikk og Naturvitenskap: 400::Basale biofag: 470 [VDP], Body Mass Index, 0302 clinical medicine, HEIGHT, Risk Factors, Genetics research, genetics, 030212 general & internal medicine, lcsh:Science, Multidisciplinary, Confounding, Mendelian Randomization Analysis, ASSOCIATION, 3142 Public health care science, environmental and occupational health, educational attainment, Female, TRAITS, TRANSMISSION, Science, Biology, Population stratification, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, BMI, 03 medical and health sciences, Medical research, SDG 3 - Good Health and Well-being, Mendelian randomization, Genetics, LINKAGE, Humans, Matematikk og Naturvitenskap: 400 [VDP], COMMON, Linkage (software), EDUCATIONAL-ATTAINMENT, Assortative mating, Gene-environment correlation, General Chemistry, confounding, BODY-MASS INDEX, 3141 Health care science, 030104 developmental biology, Matematikk og Naturvitenskap: 400::Basale biofag: 470::Genetikk og genomikk: 474 [VDP], INFERENCE, lcsh:Q, DISEQUILIBRIUM, Body mass index, height, Demography
Abstract

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies., Family-based study designs have been applied to resolve confounding by population stratification, dynastic effects and assortative mating in genetic association analyses. Here, Brumpton et al. describe theory and simulations for overcoming such biases in Mendelian randomization through within-family studies.

Published
2020
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50. A Novel Variant in APOB Gene Causes Extremely Low LDL-C Without Known Adverse Effects

Author

Robert D. Brook, Whitney E. Hornsby, Melvyn Rubenfire, Richard L. Weinberg, Cristen J. Willer, Kristian Hveem, Lars G. Fritsche, Y. Eugene Chen, Linda Farhat, and Ida Surakka

Subjects
0301 basic medicine, medicine.medical_specialty, Apolipoprotein B, Apob gene, Low density lipoprotein cholesterol, Case Report, 030105 genetics & heredity, apolipoprotein B loss-of-function, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Clinical Case, Internal medicine, medicine, Diseases of the circulatory (Cardiovascular) system, FHBL, familial hypobetalipoproteinemia, Adverse effect, Lipoprotein cholesterol, low-density lipoprotein cholesterol, apoB, apolipoprotein B, biology, business.industry, hypobetalipoproteinemia, medicine.disease, Endocrinology, RC666-701, LoF, loss-of-function, biology.protein, lipids (amino acids, peptides, and proteins), LDL-C, low-density lipoprotein cholesterol, Hypobetalipoproteinemia, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract

A novel frameshift variant was identified in APOB that segregates in a dominant manner with low levels of low-density lipoprotein cholesterol. Affected family members show no apparent clinical complications. There is no consensus regarding clinical management, and the long-term consequences of low levels of low-density lipoprotein cholesterol remain unknown. (Level of Difficulty: Advanced.), Graphical abstract, A novel frameshift variant was identified in APOB that segregates in a dominant manner with low levels of low-density lipoprotein cholesterol…

Published
2020

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