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168 results on '"Josyf C. Mychaleckyj"'

1. A methylation risk score for chronic kidney disease: a HyperGEN study

Author

Alana C. Jones, Amit Patki, Vinodh Srinivasasainagendra, Bertha A. Hidalgo, Hemant K. Tiwari, Nita A. Limdi, Nicole D. Armstrong, Ninad S. Chaudhary, Bré Minniefield, Devin Absher, Donna K. Arnett, Leslie A. Lange, Ethan M. Lange, Bessie A. Young, Clarissa J. Diamantidis, Stephen S. Rich, Josyf C. Mychaleckyj, Jerome I. Rotter, Kent D. Taylor, Holly J. Kramer, Russell P. Tracy, Peter Durda, Silva Kasela, Tuuli Lappalinen, Yongmei Liu, W. Craig Johnson, David J. Van Den Berg, Nora Franceschini, Simin Liu, Charles P. Mouton, Parveen Bhatti, Steve Horvath, Eric A. Whitsel, and Marguerite R. Irvin

Subjects
Chronic kidney disease, eGFR, Methylation risk score, Epigenetics, Medicine, Science
Abstract

Abstract Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

Published
2024
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2. An Epigenome-Wide Association Study of DNA Methylation and Proliferative Retinopathy over 28 Years in Type 1 Diabetes

Author

Rachel G. Miller, PhD, Josyf C. Mychaleckyj, DPhil, Suna Onengut-Gumuscu, PhD, Trevor J. Orchard, MD, MMedSci, and Tina Costacou, PhD

Subjects
DNA methylation, Epigenetics, Proliferative diabetic retinopathy, Retina, Type 1 diabetes, Ophthalmology, RE1-994
Abstract

Purpose: To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D). Design: Prospective observational cohort study. Participants: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D. Methods: Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n = 265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed. Main Outcome Measures: Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up). Results: PDR incidence was 53% over 28-years’ follow-up. Greater DNAm of cg27512687 (KIF16B) was associated with reduced PDR incidence (P = 6.3 × 10−9; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs (P

Published
2024
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3. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Author

Markus Scholz, Katrin Horn, Janne Pott, Matthias Wuttke, Andreas Kühnapfel, M. Kamal Nasr, Holger Kirsten, Yong Li, Anselm Hoppmann, Mathias Gorski, Sahar Ghasemi, Man Li, Adrienne Tin, Jin-Fang Chai, Massimiliano Cocca, Judy Wang, Teresa Nutile, Masato Akiyama, Bjørn Olav Åsvold, Nisha Bansal, Mary L. Biggs, Thibaud Boutin, Hermann Brenner, Ben Brumpton, Ralph Burkhardt, Jianwen Cai, Archie Campbell, Harry Campbell, John Chalmers, Daniel I. Chasman, Miao Ling Chee, Miao Li Chee, Xu Chen, Ching-Yu Cheng, Renata Cifkova, Martha Daviglus, Graciela Delgado, Katalin Dittrich, Todd L. Edwards, Karlhans Endlich, J. Michael Gaziano, Ayush Giri, Franco Giulianini, Scott D. Gordon, Daniel F. Gudbjartsson, Stein Hallan, Pavel Hamet, Catharina A. Hartman, Caroline Hayward, Iris M. Heid, Jacklyn N. Hellwege, Bernd Holleczek, Hilma Holm, Nina Hutri-Kähönen, Kristian Hveem, Berend Isermann, Jost B. Jonas, Peter K. Joshi, Yoichiro Kamatani, Masahiro Kanai, Mika Kastarinen, Chiea Chuen Khor, Wieland Kiess, Marcus E. Kleber, Antje Körner, Peter Kovacs, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Mikko Kuokkanen, Mika Kähönen, Leslie A. Lange, James P. Lash, Terho Lehtimäki, Hengtong Li, Bridget M. Lin, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Patrik K. E. Magnusson, Nicholas G. Martin, Koichi Matsuda, Yuri Milaneschi, Pashupati P. Mishra, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Winfried März, Matthias Nauck, Kjell Nikus, Ilja M. Nolte, Raymond Noordam, Yukinori Okada, Isleifur Olafsson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Markus Perola, Nicola Pirastu, Ozren Polasek, David J. Porteous, Tanja Poulain, Bruce M. Psaty, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Humaira Rasheed, Dermot F. Reilly, Kenneth M. Rice, Anne Richmond, Paul M. Ridker, Jerome I. Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J. Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O. Svensson, E-Shyong Tai, Kent D. Taylor, Bamidele O. Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Laurent F. Thomas, Johanne Tremblay, Anke Tönjes, Peter J. van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B. Whitfield, Sarah H. Wild, James F. Wilson, Thomas W. Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y. Chu, Mary F. Feitosa, Unnur Thorsteinsdottir, Adriana M. Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, and Cristian Pattaro

Subjects
Science
Abstract

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Published
2024
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4. DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study

Author

Rachel G. Miller, Josyf C. Mychaleckyj, Suna Onengut-Gumuscu, Eleanor Feingold, Trevor J. Orchard, and Tina Costacou

Subjects
Type 1 diabetes, Epigenetics, DNA methylation, Cardiovascular disease, Coronary artery disease, Major adverse cardiovascular events, Medicine, Genetics, QH426-470
Abstract

Abstract Background The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (

Published
2023
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5. Genome-wide study investigating effector genes and polygenic prediction for kidney function in persons with ancestry from Africa and the Americas

Author

Odessica Hughes, Amy R. Bentley, Charles E. Breeze, Francois Aguet, Xiaoguang Xu, Girish Nadkarni, Quan Sun, Bridget M. Lin, Thomas Gilliland, Mariah C. Meyer, Jiawen Du, Laura M. Raffield, Holly Kramer, Robert W. Morton, Mateus H. Gouveia, Elizabeth G. Atkinson, Adan Valladares-Salgado, Niels Wacher-Rodarte, Nicole D. Dueker, Xiuqing Guo, Yang Hai, Adebowale Adeyemo, Lyle G. Best, Jianwen Cai, Guanjie Chen, Michael Chong, Ayo Doumatey, James Eales, Mark O. Goodarzi, Eli Ipp, Marguerite Ryan Irvin, Minzhi Jiang, Alana C. Jones, Charles Kooperberg, Jose E. Krieger, Ethan M. Lange, Matthew B. Lanktree, James P. Lash, Paulo A. Lotufo, Ruth J.F. Loos, Vy Thi Ha My, Jesús Peralta-Romero, Lihong Qi, Leslie J. Raffel, Stephen S. Rich, Erik J. Rodriquez, Eduardo Tarazona-Santos, Kent D. Taylor, Jason G. Umans, Jia Wen, Bessie A. Young, Zhi Yu, Ying Zhang, Yii-Der Ida Chen, Tanja Rundek, Jerome I. Rotter, Miguel Cruz, Myriam Fornage, Maria Fernanda Lima-Costa, Alexandre C. Pereira, Guillaume Paré, Pradeep Natarajan, Shelley A. Cole, April P. Carson, Leslie A. Lange, Yun Li, Eliseo J. Perez-Stable, Ron Do, Fadi J. Charchar, Maciej Tomaszewski, Josyf C. Mychaleckyj, Charles Rotimi, Andrew P. Morris, and Nora Franceschini

Subjects
kidney function, chronic kidney disease, genome-wide association study, multi-ancestry, admixed populations, eGFR, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p

Published
2024
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6. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

Author

Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner

Subjects
EWAS, DNA methylation, IgE, Asthma, RNA-Sequencing, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Published
2023
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7. 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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8. Oral rotavirus vaccine shedding as a marker of mucosal immunity

Author

Benjamin Lee, Md Abdul Kader, E. Ross Colgate, Marya Carmolli, Dorothy M. Dickson, Sean A. Diehl, Masud Alam, Sajia Afreen, Josyf C. Mychaleckyj, Uma Nayak, William A. Petri, Rashidul Haque, and Beth D. Kirkpatrick

Subjects
Medicine, Science
Abstract

Abstract Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries. Improved immune correlates of protection (CoP) for existing oral vaccines and novel strategies to evaluate the performance of next-generation vaccines are needed. Use of oral vaccines as challenge agents in controlled human infection models is a potential approach to CoP discovery that remains underexplored. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which RVA immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. Among 180 vaccinated infants who completed the parent study per protocol, the absence of fecal vaccine shedding following the second dose of Rotarix suggested intestinal mucosal immunity generated by the first dose and a decreased risk of RVA diarrhea through 2 years of life (RR 0.616, 95% CI 0.392–0.968). Further development of controlled human infection models for group A rotaviruses, especially in prospective studies with larger sample sizes, may be a promising tool to assess rotavirus vaccine efficacy and CoPs.

Published
2021
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9. Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study

Author

Peter Durda, Laura M. Raffield, Ethan M. Lange, Nels C. Olson, Nancy Swords Jenny, Mary Cushman, Pia Deichgraeber, Niels Grarup, Anna Jonsson, Torben Hansen, Josyf C. Mychaleckyj, Bruce M. Psaty, Alex P. Reiner, Russell P. Tracy, and Leslie A. Lange

Subjects
cardiovascular diseases, CD163 antigen, genome‐wide association study, humans, monocytes, risk factors, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome‐wide association study to identify sCD163‐associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow‐up was 26 years. Genome‐wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all‐cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04–1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09–1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04–1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12–1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome‐wide association studies identified 38 variants on chromosome 2 near MGAT5 (top result rs62165726, P=3.3×10−18),19 variants near chromosome 17 gene ASGR1 (rs55714927, P=1.5×10−14), and 18 variants near chromosome 11 gene ST3GAL4. These regions replicated in the European ancestry ADDITION‐PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo‐Danish‐Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 P=7.1×10−9) in the HLA region, and 3 variants (rs115391969 P=4.3×10−8) near the chromosome 16 gene MYLK3. Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular‐specific mortality and incident heart failure.

Published
2022
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10. Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci

Author

Charles E. Breeze, Anna Batorsky, Mi Kyeong Lee, Mindy D. Szeto, Xiaoguang Xu, Daniel L. McCartney, Rong Jiang, Amit Patki, Holly J. Kramer, James M. Eales, Laura Raffield, Leslie Lange, Ethan Lange, Peter Durda, Yongmei Liu, Russ P. Tracy, David Van Den Berg, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group, Kathryn L. Evans, William E. Kraus, Svati Shah, Hermant K. Tiwari, Lifang Hou, Eric A. Whitsel, Xiao Jiang, Fadi J. Charchar, Andrea A. Baccarelli, Stephen S. Rich, Andrew P. Morris, Marguerite R. Irvin, Donna K. Arnett, Elizabeth R. Hauser, Jerome I. Rotter, Adolfo Correa, Caroline Hayward, Steve Horvath, Riccardo E. Marioni, Maciej Tomaszewski, Stephan Beck, Sonja I. Berndt, Stephanie J. London, Josyf C. Mychaleckyj, and Nora Franceschini

Subjects
Epigenetic, Kidney function, Gene regulation, Kidney development, DNA methylation, Medicine, Genetics, QH426-470
Abstract

Abstract Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

Published
2021
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11. The core clock gene, Bmal1, and its downstream target, the SNARE regulatory protein secretagogin, are necessary for circadian secretion of glucagon-like peptide-1

Author

Andrew D. Biancolin, Alexandre Martchenko, Emilia Mitova, Patrick Gurges, Everan Michalchyshyn, Jennifer A. Chalmers, Alessandro Doria, Josyf C. Mychaleckyj, Alice E. Adriaenssens, Frank Reimann, Fiona M. Gribble, Manuel Gil-Lozano, Brian J. Cox, and Patricia L. Brubaker

Subjects
Internal medicine, RC31-1245
Abstract

Objectives: The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian GLP-1 secretion parallels expression of the core clock gene Bmal1, the link between the two remains largely unknown. Secretagogin (Scgn) is an exocytotic SNARE regulatory protein that demonstrates circadian expression and is essential for insulin secretion from β-cells. The objective of the current study was to establish the necessity of the core clock gene Bmal1 and the SNARE protein SCGN as essential regulators of circadian GLP-1 secretion. Methods: Oral glucose tolerance tests were conducted at different times of the day on 4-hour fasted C57BL/6J, Bmal1 wild-type, and Bmal1 knockout mice. Mass spectrometry, RNA-seq, qRT-PCR and/or microarray analyses, and immunostaining were conducted on murine (m) and human (h) primary L-cells and mGLUTag and hNCI-H716 L-cell lines. At peak and trough GLP-1 secretory time points, the mGLUTag cells were co-stained for SCGN and a membrane-marker, ChIP was used to analyze BMAL1 binding sites in the Scgn promoter, protein interaction with SCGN was tested by co-immunoprecipitation, and siRNA was used to knockdown Scgn for GLP-1 secretion assay. Results: C57BL/6J mice displayed a circadian rhythm in GLP-1 secretion that peaked at the onset of their feeding period. Rhythmic GLP-1 release was impaired in Bmal1 knockout (KO) mice as compared to wild-type controls at the peak (p

Published
2020
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12. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

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

Subjects
Science
Abstract

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

Published
2019
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13. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans

Author

Meijian Guan, Jacob M. Keaton, Latchezar Dimitrov, Pamela J. Hicks, Jianzhao Xu, Nicholette D. Palmer, Lijun Ma, Swapan K. Das, Yii-Der I. Chen, Josef Coresh, Myriam Fornage, Nora Franceschini, Holly Kramer, Carl D. Langefeld, Josyf C. Mychaleckyj, Rulan S. Parekh, Wendy S. Post, Laura J. Rasmussen-Torvik, Stephen S. Rich, Jerome I. Rotter, John R. Sedor, Denyse Thornley-Brown, Adrienne Tin, James G. Wilson, Barry I. Freedman, Donald W. Bowden, Maggie C. Y. Ng, and FIND Consortium

Subjects
African Americans, Genome-wide association study, Type 2 diabetes, Diabetic kidney disease, End-stage kidney disease, Medicine, Genetics, QH426-470
Abstract

Abstract Background End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. Results Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P

Published
2019
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14. Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

Author

Andrew P. Morris, Thu H. Le, Haojia Wu, Artur Akbarov, Peter J. van der Most, Gibran Hemani, George Davey Smith, Anubha Mahajan, Kyle J. Gaulton, Girish N. Nadkarni, Adan Valladares-Salgado, Niels Wacher-Rodarte, Josyf C. Mychaleckyj, Nicole D. Dueker, Xiuqing Guo, Yang Hai, Jeffrey Haessler, Yoichiro Kamatani, Adrienne M. Stilp, Gu Zhu, James P. Cook, Johan Ärnlöv, Susan H. Blanton, Martin H. de Borst, Erwin P. Bottinger, Thomas A. Buchanan, Sylvia Cechova, Fadi J. Charchar, Pei-Lun Chu, Jeffrey Damman, James Eales, Ali G. Gharavi, Vilmantas Giedraitis, Andrew C. Heath, Eli Ipp, Krzysztof Kiryluk, Holly J. Kramer, Michiaki Kubo, Anders Larsson, Cecilia M. Lindgren, Yingchang Lu, Pamela A. F. Madden, Grant W. Montgomery, George J. Papanicolaou, Leslie J. Raffel, Ralph L. Sacco, Elena Sanchez, Holger Stark, Johan Sundstrom, Kent D. Taylor, Anny H. Xiang, Aleksandra Zivkovic, Lars Lind, Erik Ingelsson, Nicholas G. Martin, John B. Whitfield, Jianwen Cai, Cathy C. Laurie, Yukinori Okada, Koichi Matsuda, Charles Kooperberg, Yii-Der Ida Chen, Tatjana Rundek, Stephen S. Rich, Ruth J. F. Loos, Esteban J. Parra, Miguel Cruz, Jerome I. Rotter, Harold Snieder, Maciej Tomaszewski, Benjamin D. Humphreys, and Nora Franceschini

Subjects
Science
Abstract

Estimated glomerular filtration rate (eGFR) is a measure of kidney function used to define chronic kidney disease. Here, Morris et al. perform trans-ethnic genome-wide meta-analyses for eGFR in 312,468 individuals and identify novel loci and downstream putative causal genes.

Published
2019
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15. Association of APOL1 Genotypes With Measures of Microvascular and Endothelial Function, and Blood Pressure in MESA

Author

Teresa K. Chen, Ronit Katz, Michelle M. Estrella, Wendy S. Post, Holly Kramer, Jerome I. Rotter, Bamidele Tayo, Josyf C. Mychaleckyj, Christina L. Wassel, and Carmen A. Peralta

Subjects
APOL1, apolipoprotein L1, arterial stiffness, blood pressure, hypertension, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background APOL1 high‐risk genotypes are associated with increased risk for hypertension‐attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by APOL1 status; less is known about the variants' associations with systemic vascular and endothelial function. Whether APOL1 risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross‐sectional associations of APOL1 risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow‐mediated dilation, n=777). Using linear mixed‐effects models, we studied longitudinal associations of APOL1 risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% APOL1 high‐risk) Black participants in MESA (Multi‐Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000–2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow‐mediated dilation in participants with APOL1 high‐ versus low‐risk genotypes (P>0.05 for all). Over a mean follow‐up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by APOL1 risk status (between‐group differences of −0.20, −0.14, and −0.25, respectively; P>0.05 for all). Conclusions Among Black participants in MESA, APOL1 high‐risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of APOL1 with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.

Published
2020
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16. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 3; referees: 2 approved]

Author

Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London

Subjects
Genomics, Medicine, Science
Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018
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17. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 2; referees: 2 approved]

Author

Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London

Subjects
Genomics, Medicine, Science
Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018
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18. Environmental Enteropathy, Oral Vaccine Failure and Growth Faltering in Infants in Bangladesh

Author

Caitlin Naylor, Miao Lu, Rashidul Haque, Dinesh Mondal, Erica Buonomo, Uma Nayak, Josyf C. Mychaleckyj, Beth Kirkpatrick, Ross Colgate, Marya Carmolli, Dorothy Dickson, Fiona van der Klis, William Weldon, M. Steven Oberste, Jennie Z. Ma, and William A. Petri Jr

Subjects
Environmental enteropathy, Malnutrition, Oral vaccine failure***, Medicine, Medicine (General), R5-920
Abstract

Background: Environmental enteropathy (EE) is a subclinical enteric condition found in low-income countries that is characterized by intestinal inflammation, reduced intestinal absorption, and gut barrier dysfunction. We aimed to assess if EE impairs the success of oral polio and rotavirus vaccines in infants in Bangladesh. Methods: We conducted a prospective observational study of 700 infants from an urban slum of Dhaka, Bangladesh from May 2011 to November 2014. Infants were enrolled in the first week of life and followed to age one year through biweekly home visits with EPI vaccines administered and growth monitored. EE was operationally defied as enteric inflammation measured by any one of the fecal biomarkers reg1B, alpha-1-antitrypsin, MPO, calprotectin, or neopterin. Oral polio vaccine success was evaluated by immunogenicity, and rotavirus vaccine response was evaluated by immunogenicity and protection from disease. This study is registered with ClinicalTrials.gov, number NCT01375647. Findings: EE was present in greater than 80% of infants by 12 weeks of age. Oral poliovirus and rotavirus vaccines failed in 20.2% and 68.5% of the infants respectively, and 28.6% were malnourished (HAZ

Published
2015
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19. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author

Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Published
2022
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20. Leveraging type 1 diabetes human genetic and genomic data in the T1D Knowledge Portal

Author

Parul Kudtarkar, Maria C. Costanzo, Ying Sun, Dongkeun Jang, Ryan Koesterer, Josyf C Mychaleckyj, Uma Nayak, Suna Onengut-Gumuscu, Stephen S Rich, Jason A Flannick, Kyle J Gaulton, and Noël P Burtt

Subjects
Article
Abstract

Translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight can reveal novel biology and therapeutic targets but remains a major challenge. We developed the T1D Knowledge Portal (T1DKP), a disease-specific resource of genetic and functional annotation data that enables users to develop hypotheses for T1D-based research and target discovery. The T1DKP can be used to query genes and genomic regions for genetic associations, identify epigenomic features, access results of bioinformatic analyses, and obtain expert-curated resources. The T1DKP is available athttp://t1d.hugeamp.org.

Published
2023

21. Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease

Author

Yang, Pan, Xiao, Sun, Xuenan, Mi, Zhijie, Huang, Yenchih, Hsu, James E, Hixson, Donna, Munzy, Ginger, Metcalf, Nora, Franceschini, Adrienne, Tin, Anna, Köttgen, Michael, Francis, Jennifer A, Brody, Bryan, Kestenbaum, Colleen M, Sitlani, Josyf C, Mychaleckyj, Holly, Kramer, Leslie A, Lange, Xiuqing, Guo, Shih-Jen, Hwang, Marguerite R, Irvin, Jennifer A, Smith, Lisa R, Yanek, Dhananjay, Vaidya, Yii-Der Ida, Chen, Myriam, Fornage, Donald M, Lloyd-Jones, Lifang, Hou, Rasika A, Mathias, Braxton D, Mitchell, Patricia A, Peyser, Sharon L R, Kardia, Donna K, Arnett, Adolfo, Correa, Laura M, Raffield, Ramachandran S, Vasan, L Adrienne, Cupple, Daniel, Levy, Robert C, Kaplan, Kari E, North, Jerome I, Rotter, Charles, Kooperberg, Alexander P, Reiner, Bruce M, Psaty, Russell P, Tracy, Richard A, Gibbs, Alanna C, Morrison, Harold, Feldman, Eric, Boerwinkle, Jiang, He, and Tanika N, Kelly

Subjects
Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

Published
2022

22. Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci

Author

Adolfo Correa, David Van Den Berg, Sonja I. Berndt, Elizabeth R. Hauser, Anna Batorsky, Ethan M. Lange, Andrea A. Baccarelli, Leslie A. Lange, Fadi J. Charchar, Nora Franceschini, Steve Horvath, Mindy D. Szeto, James Eales, Stephan Beck, Xiao Jiang, Laura M. Raffield, Kathryn L. Evans, Russell P. Tracy, Andrew P. Morris, William E. Kraus, Xiaoguang Xu, Maciej Tomaszewski, Stephanie J. London, Daniel L. McCartney, Caroline Hayward, Hermant K Tiwari, Jerome I. Rotter, Josyf C. Mychaleckyj, Eric A. Whitsel, Mi Kyeong Lee, Peter Durda, Lifang Hou, Donna K. Arnett, Holly Kramer, Amit Patki, Marguerite R. Irvin, Riccardo E. Marioni, Rong Jiang, Yongmei Liu, Charles E Breeze, Svati H. Shah, and Stephen S. Rich

Subjects
Epigenomics, Kidney Disease, Kidney development, QH426-470, Kidney, Kidney Function Tests, Epigenesis, Genetic, 0302 clinical medicine, Genetics (clinical), Regulation of gene expression, Genetics, 0303 health sciences, DNA methylation, Epigenetic, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, Medicine, Molecular Medicine, Glomerular Filtration Rate, Population, Quantitative Trait Loci, Clinical Sciences, Renal and urogenital, Context (language use), Biology, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Kidney function, Genetic, Humans, Epigenetics, Heritable, Molecular Biology, 030304 developmental biology, Research, Human Genome, Racial Groups, Genetic Variation, dNaM, Epigenome, Gene regulation, Genetics, Population, Gene Expression Regulation, TOPMed MESA Multi-Omics Working Group, CpG Islands, Epigenesis, Genome-Wide Association Study
Abstract

Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

Published
2021
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23. Oral rotavirus vaccine shedding as a marker of mucosal immunity

Author

Abdul Kader, Sean A. Diehl, Dorothy M. Dickson, Uma Nayak, Beth D. Kirkpatrick, Benjamin Lee, E. Ross Colgate, Marya P. Carmolli, Masud Alam, Josyf C. Mychaleckyj, Sajia Afreen, Rashidul Haque, and William A. Petri

Subjects
Rotavirus, Science, Administration, Oral, Paediatric research, Vaccines, Attenuated, medicine.disease_cause, Article, Rotavirus Infections, Cohort Studies, Feces, Immunity, medicine, Humans, Viral shedding, Prospective cohort study, Immunity, Mucosal, Mucosal immunity, Vaccines, Multidisciplinary, business.industry, Rotavirus Vaccines, Infant, Rotavirus vaccine, Gastroenteritis, Diarrhea, Immunology, Medicine, medicine.symptom, business
Abstract

Rotavirus remains a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries (LMIC). Improved immune correlates of protection (CoP) for existing oral vaccines and novel strategies to evaluate the performance of next-generation vaccines are needed. Use of oral vaccines as challenge agents in controlled human infection models is a potential approach to CoP discovery that remains underexplored. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which rotavirus immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. Among 180 vaccinated infants who completed the parent study per protocol, the absence of fecal vaccine shedding following the second dose of Rotarix suggested intestinal mucosal immunity generated by the first dose and a decreased risk of rotavirus diarrhea through 2 years of life (RR 0.616, 95% CI 0.392-0.968). Further development of controlled human infection models for rotavirus, especially in prospective studies with larger sample sizes, may be a promising tool to assess rotavirus vaccine efficacy and CoPs.

Published
2021
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24. Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

Author

Rachel G. Miller, Erkka Valo, Jani K. Haukka, Tina Costacou, Barbara E.K. Klein, Beata Gyorgy, Joseph V. Bonventre, Katalin Susztak, Hillary A. Keenan, James H. Warram, Marlon Pragnell, Ivan G. Shabalin, Andrew D. Paterson, Stephen S. Rich, Takaharu Ichimura, Jingjing Cao, Suna Onengut-Gumuscu, Ronald Klein, Kristina O’Neil, Eiichiro Satake, Marcus G. Pezzolesi, Josyf C. Mychaleckyj, Niina Sandholm, Christian Dina, Andrzej T. Galecki, George L. King, Trevor J. Orchard, Samy Hadjadj, Per-Henrik Groop, Adam M. Smiles, Carol Forsblom, Andrzej S. Krolewski, David-Alexandre Trégouët, Tarunveer S. Ahluwalia, Peter Rossing, Ron Korstanje, 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), CAMM - Research Program for Clinical and Molecular Metabolism, HUS Abdominal Center, Nefrologian yksikkö, Research Programs Unit, Clinicum, Medicum, Department of Medicine, and Per Henrik Groop / Principal Investigator

Subjects
Gene-based tests, GENES, GENETICS, NEPHROPATHY, DURATION, 030209 endocrinology & metabolism, Hydroxysteroid 17-beta dehydrogenase 14, Diabetic nephropathy, Biology, 03 medical and health sciences, 0302 clinical medicine, Gene expression, medicine, Coding region, GENOME-WIDE ASSOCIATION, Diabetic kidney disease, PREDICTORS, Gene, Exome, 030304 developmental biology, RISK, 0303 health sciences, Type 1 diabetes, Kidney, COMPLICATIONS, End stage kidney disease, MICROALBUMINURIA, Rare variants, General Medicine, medicine.disease, RENAL DECLINE, medicine.anatomical_structure, Nephrology, 3121 General medicine, internal medicine and other clinical medicine, Cancer research, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Kidney disease
Abstract

Background Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other chronic kidney disease-associated renal pathologies. Conclusions HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Published
2021
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25. Associations between ambient air pollutants and clonal hematopoiesis of indeterminate potential (CHIP)

Author

Claire L. Leiser, Josyf C. Mychaleckyj, Sabah M. Quraishi, Russell P. Tracy, Stephen S. Rich, Kent D. Taylor, Adam A. Szpiro, Alex Bick, Albert V. Smith, Jerome I. Rotter, Eric A. Whitsel, Joel D. Kaufman, Charles Kooperberg, and Alexander P. Reiner

Subjects
Pollutant, Environmental chemistry, Clonal hematopoiesis, General Earth and Planetary Sciences, Biology, Indeterminate, General Environmental Science, Ambient air
Published
2021
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26. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author

Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Costa Rica, Male, Pulmonary and Respiratory Medicine, Adolescent, Vital Capacity, Single-nucleotide polymorphism, Pedigree chart, Critical Care and Intensive Care Medicine, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Polymorphism (computer science), Forced Expiratory Volume, Humans, Medicine, SNP, 030212 general & internal medicine, Child, Asthma, Whole Genome Sequencing, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Minor allele frequency, 030228 respiratory system, Genetic epidemiology, Child, Preschool, Interferon Regulatory Factors, Immunology, Respiratory Physiological Phenomena, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules
Abstract

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Published
2019
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27. The core clock gene, Bmal1, and its downstream target, the SNARE regulatory protein secretagogin, are necessary for circadian secretion of glucagon-like peptide-1

Author

Andrew D. Biancolin, Patrick Gurges, Manuel Gil-Lozano, Brian J. Cox, Frank Reimann, Patricia L. Brubaker, Alice E. Adriaenssens, Alexandre Martchenko, Everan Michalchyshyn, Jennifer A. Chalmers, Alessandro Doria, Emilia Mitova, Josyf C. Mychaleckyj, Fiona M. Gribble, Reimann, Frank [0000-0001-9399-6377], Gribble, Fiona [0000-0002-4232-2898], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, lcsh:Internal medicine, endocrine system, Circadian clock, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Glucagon-Like Peptide 1, Circadian Clocks, Animals, Secretion, Circadian rhythm, education, lcsh:RC31-1245, Molecular Biology, Regulation of gene expression, Mice, Knockout, Gene knockdown, education.field_of_study, digestive, oral, and skin physiology, Circadian, ARNTL Transcription Factors, Secretagogin, Cell Biology, Glucose Tolerance Test, 3. Good health, Cell biology, CLOCK, Mice, Inbred C57BL, Bmal1, 030104 developmental biology, Knockout mouse, Female, Original Article, GLP-1, L-cell, SECRETAGOGIN, Secretagogins
Abstract

Objectives The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian GLP-1 secretion parallels expression of the core clock gene Bmal1, the link between the two remains largely unknown. Secretagogin (Scgn) is an exocytotic SNARE regulatory protein that demonstrates circadian expression and is essential for insulin secretion from β-cells. The objective of the current study was to establish the necessity of the core clock gene Bmal1 and the SNARE protein SCGN as essential regulators of circadian GLP-1 secretion. Methods Oral glucose tolerance tests were conducted at different times of the day on 4-hour fasted C57BL/6J, Bmal1 wild-type, and Bmal1 knockout mice. Mass spectrometry, RNA-seq, qRT-PCR and/or microarray analyses, and immunostaining were conducted on murine (m) and human (h) primary L-cells and mGLUTag and hNCI-H716 L-cell lines. At peak and trough GLP-1 secretory time points, the mGLUTag cells were co-stained for SCGN and a membrane-marker, ChIP was used to analyze BMAL1 binding sites in the Scgn promoter, protein interaction with SCGN was tested by co-immunoprecipitation, and siRNA was used to knockdown Scgn for GLP-1 secretion assay. Results C57BL/6J mice displayed a circadian rhythm in GLP-1 secretion that peaked at the onset of their feeding period. Rhythmic GLP-1 release was impaired in Bmal1 knockout (KO) mice as compared to wild-type controls at the peak (p, Highlights • Murine GLP-1 secretion is circadian and is regulated by the clock gene Bmal1. • The regulatory SNARE protein, secretagogin, is expressed in all intestinal L-cells. • Secretagogin expression is circadian and regulated by BMAL1 in intestinal L-cells. • Secretagogin translocates to the cell membrane upon L-cell stimulation. • Secretagogin knockdown impairs rhythmic secretion of glucagon-like peptide-1.

Published
2019

28. A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies

Author

Pradipta R. Ray, Alessandro Doria, Petra A. Lenzini, Bruce A. Perkins, Alison A. Motsinger-Reif, Brian C. Callaghan, Michael J. Wagner, Rodica Pop-Busui, Yaling Tang, Hetal Shah, Sharon Cresci, John B. Buse, Hannah Campbell, Theodore J. Price, and Josyf C. Mychaleckyj

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Complications, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Diabetic Neuropathies, Gene Frequency, Internal medicine, Databases, Genetic, Prevalence, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, Allele frequency, Alleles, Aged, business.industry, Incidence, Odds ratio, Middle Aged, medicine.disease, Minor allele frequency, 030104 developmental biology, Peripheral neuropathy, Diabetes Mellitus, Type 2, Genetic Loci, Chromosomes, Human, Pair 2, Female, business, Genome-Wide Association Study
Abstract

Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two well-characterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPN-negative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P < 5 × 10−8) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency = 0.14) decreased DPN odds by 36% (odds ratio [OR] 0.64, 95% CI 0.55–0.74, P = 1.9 × 10−9). This effect was not influenced by ACCORD treatment assignments (P for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95% CI 0.42–0.80, P = 9 × 10−4; summary P = 7.9 × 10−12). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene (SCN2A) coding for human voltage-gated sodium channel NaV1.2 (P = 9 × 10−4). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions.

Published
2019
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29. Population sequencing data reveal a compendium of mutational processes in the human germ line

Author

Scott T. Weiss, Ryan D. Hernandez, Evan M. Koch, Eric Boerwinkle, Kathleen C. Barnes, Josyf C. Mychaleckyj, Lisa de las Fuentes, Stephen S. Rich, Adolfo Correa, Ani Manichaikul, Christian Gilissen, Leslie S. Emery, Vladimir B. Seplyarskiy, Shamil R. Sunyaev, Lawrence F. Bielak, Edwin K. Silverman, Braxton D. Mitchell, Esteban G. Burchard, D. C. Rao, John Blangero, Courtney G. Montgomery, Peter V. Kharchenko, Timothy D. O’Connor, Jennifer A. Smith, Jerome I. Rotter, Jakob M. Goldmann, Sharon L.R. Kardia, Ryan J. McGinty, Patricia A. Peyser, Ramachandran S. Vasan, Susan Redline, Stephen T. McGarvey, Patrick T. Ellinor, Jennifer A. Brody, Wendy S.W. Wong, Yii-Der Ida Chen, Chii-Min Hwu, Donna K. Arnett, Ruslan A. Soldatov, Nicholette D. Palmer, Jiang He, and Kent D. Taylor

Subjects
DNA Replication, Transcription, Genetic, DNA Mutational Analysis, Population, Computational biology, Biology, medicine.disease_cause, Genome, Germline mutation, All institutes and research themes of the Radboud University Medical Center, medicine, Humans, education, Germ-Line Mutation, Replication timing, Mutation, education.field_of_study, Multidisciplinary, Genome, Human, DNA replication, Genetic Variation, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], DNA Demethylation, Germ Cells, Long Interspersed Nucleotide Elements, DNA demethylation, Mutagenesis, Oocytes, CpG Islands, Algorithms, DNA Damage
Abstract

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

Published
2021

30. Additional file 1 of Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci

Author

Breeze, Charles E., Batorsky, Anna, Lee, Mi Kyeong, Szeto, Mindy D., Xiaoguang Xu, McCartney, Daniel L., Jiang, Rong, Patki, Amit, Kramer, Holly J., Eales, James M., Raffield, Laura, Lange, Leslie, Lange, Ethan, Durda, Peter, Yongmei Liu, Tracy, Russ P., Van Den Berg, David, Evans, Kathryn L., Kraus, William E., Svati Shah, Hermant K. Tiwari, Lifang Hou, Whitsel, Eric A., Jiang, Xiao, Charchar, Fadi J., Baccarelli, Andrea A., Rich, Stephen S., Morris, Andrew P., Irvin, Marguerite R., Arnett, Donna K., Hauser, Elizabeth R., Rotter, Jerome I., Correa, Adolfo, Hayward, Caroline, Horvath, Steve, Marioni, Riccardo E., Tomaszewski, Maciej, Beck, Stephan, Berndt, Sonja I., London, Stephanie J., Josyf C. Mychaleckyj, and Franceschini, Nora

Abstract

Additional file 1: Supplementary Figures. Figure S1 to S7. Study design, QQ plots, Manhattan plots, forest plots and eFORGE/FORGE2 analyses.

Published
2021
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31. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

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

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

Published
2021
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32. Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (

Author

Josyf C, Mychaleckyj, Erkka, Valo, Takaharu, Ichimura, Tarunveer S, Ahluwalia, Christian, Dina, Rachel G, Miller, Ivan G, Shabalin, Beata, Gyorgy, JingJing, Cao, Suna, Onengut-Gumuscu, Eiichiro, Satake, Adam M, Smiles, Jani K, Haukka, David-Alexandre, Tregouet, Tina, Costacou, Kristina, O'Neil, Andrew D, Paterson, Carol, Forsblom, Hillary A, Keenan, Marcus G, Pezzolesi, Marlon, Pragnell, Andrzej, Galecki, Stephen S, Rich, Niina, Sandholm, Ronald, Klein, Barbara E, Klein, Katalin, Susztak, Trevor J, Orchard, Ron, Korstanje, George L, King, Samy, Hadjadj, Peter, Rossing, Joseph V, Bonventre, Per-Henrik, Groop, James H, Warram, and Andrzej S, Krolewski

Subjects
Adult, Male, 17-Hydroxysteroid Dehydrogenases, Gene Expression, Genetic Variation, Middle Aged, Kidney Tubules, Proximal, Survival Rate, Mice, Diabetes Mellitus, Type 1, Case-Control Studies, Reperfusion Injury, Up Front Matters, Disease Progression, Animals, Humans, Kidney Failure, Chronic, Diabetic Nephropathies, Exome, Female, Protein Structural Elements, Retrospective Studies
Abstract

Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (Protein coding variants in the hydroxysteroid 17

Published
2020

33. Genetic Landscape of Gullah African Americans

Author

Uma Nayak, Lee H Moultrie, Carl D. Langefeld, Gary S. Gilkeson, Melinda C. Aldrich, Keith L. Keene, Kip D. Zimmerman, Michèle M. Sale, Ida J. Spruill, Paula S. Ramos, Queen Quet, Theodore G. Schurr, Jasmin Divers, Josyf C. Mychaleckyj, W. Timothy Garvey, Wei-Min Chen, Jyotika K. Fernandes, Diane L. Kamen, Kelly J. Hunt, and David Reich

Subjects
0106 biological sciences, Male, African american population, demography, Genotype, Geographic isolation, Demographic history, Genetic genealogy, Population structure, Population, Black People, 010603 evolutionary biology, 01 natural sciences, Sierra leone, West Africa, Humans, 0601 history and archaeology, education, Research Articles, education.field_of_study, 060101 anthropology, Native american, ancestry, 06 humanities and the arts, slavery, Black or African American, Europe, Geography, Anthropology, Africa, Genetic structure, admixture, Ethnology, Anatomy, Research Article
Abstract

ObjectivesGullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West and Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah.Materials and MethodsWe leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, Sierra Leone Africans, and population reference panels from Africa and Europe, to infer population structure, ancestry proportions, and global estimates of admixture.ResultsRelative to southeastern non-Gullah African Americans, the Gullah exhibit higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and stronger male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations.DiscussionThis study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.Research HighlightsUsing genomic data, we show that the Gullah have lower European and higher West African genomic background compared to non-Gullah African Americans, confirming their diverse African ancestry and rejecting a model that asserts a predominant Sierra Leone origin.Our data reveal a largely shared demographic history with southeastern non-Gullah African Americans, but also subtle differences related to high African genetic ancestry due to isolation in the Sea Islands.

Published
2020
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34. Association of APOL1 Genotypes With Measures of Microvascular and Endothelial Function, and Blood Pressure in MESA

Author

Michelle M. Estrella, Bamidele O. Tayo, Christina L. Wassel, Carmen A. Peralta, Jerome I. Rotter, Teresa K. Chen, Ronit Katz, Josyf C. Mychaleckyj, Holly Kramer, and Wendy S. Post

Subjects
Male, Aging, Kidney Disease, Outcome Assessment, Apolipoprotein L1, Epidemiology, 030232 urology & nephrology, Blood Pressure, 030204 cardiovascular system & hematology, Cardiorespiratory Medicine and Haematology, Cardiovascular, Gastroenterology, 0302 clinical medicine, Risk Factors, Genotype, Outcome Assessment, Health Care, Ethnicity, 2.1 Biological and endogenous factors, Aetiology, APOL1, Original Research, Kidney, biology, medicine.diagnostic_test, Arteries, Middle Aged, medicine.anatomical_structure, arterial stiffness, Female, Kidney Diseases, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, apolipoprotein L1, Race and Ethnicity, hypertension, 03 medical and health sciences, Clinical Research, Internal medicine, Vascular, Biopsy, medicine, Genetics, Humans, Endothelium, Aged, business.industry, Prevention, medicine.disease, Atherosclerosis, United States, Health Care, Increased risk, Blood pressure, Cross-Sectional Studies, Case-Control Studies, biology.protein, Arterial stiffness, Endothelium, Vascular, business, Kidney disease
Abstract

Background APOL1 high‐risk genotypes are associated with increased risk for hypertension‐attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by APOL1 status; less is known about the variants' associations with systemic vascular and endothelial function. Whether APOL1 risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross‐sectional associations of APOL1 risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow‐mediated dilation, n=777). Using linear mixed‐effects models, we studied longitudinal associations of APOL1 risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% APOL1 high‐risk) Black participants in MESA (Multi‐Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000–2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow‐mediated dilation in participants with APOL1 high‐ versus low‐risk genotypes ( P >0.05 for all). Over a mean follow‐up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by APOL1 risk status (between‐group differences of −0.20, −0.14, and −0.25, respectively; P >0.05 for all). Conclusions Among Black participants in MESA, APOL1 high‐risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of APOL1 with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.

Published
2020

35. Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates

Author

Patrick Concannon, A. S. G. Faruque, Priya Duggal, Beth D. Kirkpatrick, Poonum S. Korpe, Rashidul Haque, Chelsea Marie, Alexander J. Mentzer, Stephen S. Rich, Genevieve L. Wojcik, William A. Petri, Tommy Carstensen, Josyf C. Mychaleckyj, Mentzer, Alexander J [0000-0002-4502-2209], and Apollo - University of Cambridge Repository

Subjects
Male, Pediatrics, Cryptosporidiosis, Genome-wide association study, Disease, Feces, Risk Factors, genetics, Prospective Studies, genome analysis, 2. Zero hunger, 0303 health sciences, education.field_of_study, Bangladesh, biology, 1. No poverty, Cryptosporidium, QR1-502, 3. Good health, Diarrhea, Cohort, Female, Disease Susceptibility, medicine.symptom, Research Article, medicine.medical_specialty, Protein Kinase C-alpha, Population, Single-nucleotide polymorphism, Microbiology, Polymorphism, Single Nucleotide, Host-Microbe Biology, 03 medical and health sciences, Meta-Analysis as Topic, Virology, medicine, Humans, education, 030304 developmental biology, 030306 microbiology, business.industry, Genome, Human, Infant, Newborn, Infant, medicine.disease, biology.organism_classification, Malnutrition, business, Genome-Wide Association Study
Abstract

Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism., Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P = 3.73 × 10−8), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha (PRKCA). Each additional risk allele conferred 2.4 times the odds of Cryptosporidium-associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation.

Published
2020

36. Population sequencing data reveal a compendium of mutational processes in human germline

Author

Josyf C. Mychaleckyj, Timothy D. O’Connor, Eric Boerwinkle, Yii-Der Ida Chen, Chii-Min Hwu, John Blangero, D. C. Rao, Patricia A. Peyser, Susan Redline, Shamil R. Sunyaev, Christian Gilissen, Esteban G. Burchard, Jerome I. Rotter, Ryan D. Hernandez, Braxton D. Mitchell, Courtney G. Montgomery, Stephen T. McGarvey, Sharon L.R. Kardia, Jakob M. Goldmann, Kathleen C. Barnes, Lisa de las Fuentes, Lawrence F. Bielak, Jiang He, Patrick T. Ellinor, Jennifer A. Smith, Peter V. Kharchenko, Ani Manichaikul, Wendy S.W. Wong, Adolfo Correa, Vladimir B. Seplyarskiy, Donna K. Arnett, Scott T. Weiss, Ruslan A. Soldatov, Edwin K. Silverman, Nicholette D. Palmer, Ryan J. McGinty, Stephen S. Rich, Leslie S. Emery, Vasan S. Ramachandran, and Jennifer A. Brody

Subjects
Whole genome sequencing, 0303 health sciences, Replication timing, Mutation rate, education.field_of_study, DNA damage, Population, Computational biology, Biology, Genome, Germline, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, education, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

Published
2020
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37. PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes: findings from accord-lipid

Author

Ronald J. Sigal, Hannah Campbell, Guillaume Paré, Peter Kraft, Hetal Shah, Luana Mercuri, Elisabetta Patorno, Emily Y. Chew, Vincenzo Trischitta, Petra A. Lenzini, Marcus G. Pezzolesi, Alessandro Doria, Daniel M. Rotroff, Alison A. Motsinger-Reif, Santica M. Marcovina, He Gao, Josyf C. Mychaleckyj, Henry N. Ginsberg, Mario Luca Morieri, Laura C. Lovato, Sharon Cresci, Assunta Pandolfi, Sabrina Prudente, John B. Buse, Hertzel C. Gerstein, Michael J. Wagner, and Jennifer Sjaarda

Subjects
0301 basic medicine, medicine.medical_specialty, cardiovascular disease, fenofibrate, diabetes, medicine.drug_class, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Fibrate, Type 2 diabetes, Placebo, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, PPARA Gene, CCL11, Fenofibrate, business.industry, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, 030104 developmental biology, Endocrinology, Simvastatin, business, Mace, medicine.drug
Abstract

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide-significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported White subjects treated with simvastatin and randomized to fenofibrate or placebo in the Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD) Lipid Trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (HR=0.49; 95%C.I. 0.34-0.72) whereas no benefit was observed for other genotypes (p for interaction=3.7x10-4). The “rs6008845-by-fenofibrate” interaction on MACE was replicated in African-Americans from ACCORD (N=585, p=0.02) and in external cohorts (ACCORD-Blood-Pressure, ORIGIN, and TRIUMPH, total N=3059, p=0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11 - a pro-inflammatory and atherogenic chemokine also known as eotaxin (p for rs6008845-by-fenofibrate interaction=0.003). The Genotype-Tissue Expression (GTEx) dataset revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify T2D patients who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

Published
2020

38. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author

Cashell E. Jaquish, Craig P. Hersh, Emily Barron-Casella, Larry Phillips, James S. Pankow, JoAnn E. Manson, Mariza de Andrade, Vivien A. Sheehan, Norann A. Zaghloul, Yongmei Liu, Sergei Nekhai, Russell P. Tracy, Bruce S. Weir, Pankaj Qasba, Adrienne M. Stilp, Tasha E. Fingerlin, Heather M. Ochs-Balcom, L. Adrienne Cupples, Rongze Yang, David A. Schwartz, Shannon Kelly, Scott E. Devine, Tanja Smith, G.L. Kinney, Beverly Snively, Kent D. Taylor, Manolis Kellis, Ruth J. F. Loos, Seth A. Ament, Kathleen C. Barnes, Robert C. Kaplan, Ulrich Broeckel, Hemant K. Tiwari, Karin F. Hoth, Peter Durda, Julie L. Mikulla, Charles B. Eaton, Cotton Seed, Merry Lynn McDonald, Eric Boerwinkle, Josh Smith, Honghuang Lin, Ingrid B. Borecki, Jeffrey L. Curtis, Emelia J. Benjamin, Kenneth Rice, Sharon L.R. Kardia, Nicholas L. Smith, Coleen M. Damcott, Jeffrey Haessler, Kimberly L. Jones, Elaine Cornell, Nona Sotoodehnia, Adolfo Correa, Rich Johnston, C. Charles Gu, Chii Min Hwu, Peter C. Anderson, Lesley F. Tinker, Colleen Davis, R. Graham Barr, Scott T. Weiss, Leanna Farnam, Chao Hsiung, Brian Silver, Patrick F. McArdle, Lisa W. Martin, Yii-Der Ida Chen, John Barnard, Holly Kramer, Sekar Kathiresan, Gonçalo R. Abecasis, Barry Make, Michael C. Mahaney, Marco V Perez, Donna K. Arnett, Mark Chaffin, Xiuqing Guo, Joshua C. Bis, Pamela Russell, Paul L. Auer, James G. Wilson, Marilyn J. Telen, David K. Levine, Jennifer A. Smith, Christopher Scheller, Meher Preethi Boorgula, Aakrosh Ratan, Kari E. North, Dan E. Arking, Elizabeth A. Regan, Margaret G. Parker, Andres Metspalu, Jai G. Broome, Daniel Taliun, Lynette Ekunwe, Alyna T. Khan, Hao Mei, Dhananjay Vaidya, Ellen M. Schmidt, Stanford Mwasongwe, Joshua P. Lewis, Stacey Gabriel, Christine E. Seidman, Margery Gass, Deborah A. Nickerson, Nicola L. Hawley, Rebecca L. Beer, Afshin Parsa, Steven L. Salzberg, Terri H. Beaty, Stella Aslibekyan, Girish N. Nadkarni, Wei Zhao, David L. Tirschwell, Karen Bunting, Dawn L. DeMeo, Laura J. Rasmussen-Torvik, Julia Powers Becker, Dmitry Prokopenko, Karen Schwander, Bruce D. Gelb, Stephanie Krauter, Laura M. Raffield, Michael E. Hall, Frank C. Sciurba, Lauren Margolin, Nora Franceschini, Daniel N. Harris, Seyedeh M. Zekavat, Dawood Darbar, Keng-Han Lin, Haley Huston, Steven A. Lubitz, Andrea Ganna, Carole Sztalryd, Cathy C. Laurie, Christy Chang, James E. Hixson, Steven A. McCarroll, Barbara A. Konkle, Michael D. Kessler, Scott I. Vrieze, Yingze Zhang, Sarah Ruuska, George J. Papanicolaou, Weiniu Gan, Maris Alver, Elizabeth A. Streeten, Fei Fei Wang, Lu-Chen Weng, Braxton D. Mitchell, Lee-Ming Chuang, Sean P. David, Wei-Min Chen, Susan R. Heckbert, Ryan D. Hernandez, Andrew D. Johnson, Cristen J. Willer, Ani Manichaikul, Jonathan M. Bloom, Timothy D. O’Connor, Sylvia Smoller, Marguerite R. Irvin, Seung Hoan Choi, Ida Surakka, Veikko Salomaa, Diane M. Becker, Ron Do, W. Craig Johnson, Cecelia A. Laurie, Meryl S. LeBoff, Aniket Shetty, Tõnu Esko, Michael C. Zody, Xiaoqi Geng, Da Wei Gong, Snow Xueyan Zhao, Esteban G. Burchard, Xiuwen Zheng, Cara L. Carty, Alexander P. Reiner, Tim Assimes, Deborah A. Meyers, Mina K. Chung, Harald H H Göring, Benjamin M. Neale, Pradeep Natarajan, Yan Gao, Stephen S. Rich, Yun Ju Sung, Susan K. Dutcher, Ferdouse Begum, Stephanie M. Gogarten, John Blangero, Jonathan Cardwell, Kayleen Williams, Rakhi P. Naik, Amol C. Shetty, Sayantan Das, Myriam Fornage, May E. Montasser, Michelle Daya, Edwin K. Silverman, Daniel E. Weeks, Laura J. Kaufman, Dimitrios Avramopoulos, Michael Y. Tsai, Christine M. Albert, Vijay G. Sankaran, Jeffrey R. O'Connell, Thomas W. Blackwell, Stephen T. McGarvey, Robert M. Reed, Leslie A. Lange, Qing Duan, Bruce M. Psaty, Leslie S. Emery, Bertha Hidalgo, Jennifer A. Brody, L. Keoki Williams, Soren Germer, Zhaohui S. Qin, Deepti Jain, Deborah Applebaum-Bowden, Carla Wilson, Degui Zhi, Christoph Lange, Elliott Hong, L.F. Bielak, Wen Jane Lee, Yue Guan, Tarik Walker, Rebecca D. Jackson, Charles R. Farber, Mark J. Daly, Stephanie M. Fullerton, John E. Hokanson, Karol E. Watson, James Luo, Richard Casaburi, Seunggeun Lee, Jill M. Johnsen, Margaret A. Taub, Ryan L. Minster, Ravi Duggirala, Susan K. Mathai, Yun Li, Quenna Wong, Matthew Flickinger, Huichun Xu, Susan Redline, Ulrike Peters, Ivana V. Yang, Jesse M. Engreitz, Sanni Ruotsalainen, Sean K. McFarland, Avram D Walts, Patricia A. Peyser, Allison E. Ashley-Koch, Lewis C. Becker, Nicholette Palmer Allred, James A. Perry, Jody S. Sylvia, Tamar Sofer, Vasan S. Ramachandran, Laura Almasy, Matthew J. Budoff, Ranjan Deka, David M. Herrington, Simeon I. Taylor, Daniel Levy, Chaojie Yang, Sameer Chavan, Kathleen A. Ryan, Josyf C. Mychaleckyj, Ingo Ruczinski, Sebastian Zoellner, Michael Preuss, Tim Poterba, Wendy S. Post, Amber L. Beitelshees, Ben Heavner, Carolina Roselli, Namiko Abe, Jonathon LeFaive, Mark T. Gladwin, Brian Custer, Robert B. Wallace, Simin Liu, Michael H. Cho, Robert E. Handsaker, Dabeeru C. Rao, Bo Juen Chen, Wayne Hui Heng Sheu, Xiang Zhou, Marcos Bezerra, Solomon K. Musani, Eimear E. Kenny, James F. Casella, Kathryn L. Lunetta, Nancy Min, Nicholas Rafaels, Lisa R. Yanek, Min A. Jhun, David C. Glahn, Rasika A. Mathias, Mollie A. Minear, Russell P. Bowler, Jason Ernst, Carolyn J. Crandall, Sara Penchev, Alvaro Alonso, Timothy A. Thornton, Toni I. Pollin, Charles Kooperberg, Ethan M. Lange, Juan M. Peralta, Pramod Anugu, Lucinda Fulton, Adam A. Szpiro, Michael R. DeBaun, M. Benjamin Shoemaker, Sam Phillips, Dan M. Roden, Mao Fu, Daniel I. Chasman, James D. Crapo, Hua Tang, Gina M. Peloso, Hyun Min Kang, Samuli Ripatti, Phuwanat Sakornsakolpat, Christopher R. Gignoux, Peter VandeHaar, Jerome I. Rotter, Dandi Qiao, Emily S. Wan, Shabnam Salimi, Kevin Sandow, Jiang He, Patrick T. Ellinor, Joanne E. Curran, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Clinicum, Doctoral Programme in Population Health, Department of Public Health, and Complex Disease Genetics

Subjects
0301 basic medicine, Apolipoprotein B, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Lipoprotein particle, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, Aetiology, lcsh:Science, African Continental Ancestry Group, Genetics, Multidisciplinary, Genome, biology, CHOLESTEROL, Adaptor Proteins, Lipoprotein(a), Single Nucleotide, NHLBI TOPMed Lipids Working Group, 3142 Public health care science, environmental and occupational health, 3. Good health, Cholesterol, Heart Disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, RARE VARIANTS, lipids (amino acids, peptides, and proteins), LOW-FREQUENCY, Human, DNA Copy Number Variations, Science, Quantitative Trait Loci, European Continental Ancestry Group, Black People, POPULATION-SCALE, Quantitative trait locus, Article, White People, General Biochemistry, Genetics and Molecular Biology, LDL, Structural variation, 03 medical and health sciences, COMPONENTS-ANALYSIS, RISK-FACTOR, Humans, CORONARY-HEART-DISEASE, Polymorphism, Whole Genome Sequencing, Prevention, Human Genome, General Chemistry, Atherosclerosis, Vesicular Transport, Good Health and Well Being, 030104 developmental biology, chemistry, biology.protein, lcsh:Q, 3111 Biomedicine, Lipoprotein, Genome-Wide Association Study
Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Published
2018
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39. Histo–Blood Group Antigen Phenotype Determines Susceptibility to Genotype-Specific Rotavirus Infections and Impacts Measures of Rotavirus Vaccine Efficacy

Author

Benjamin, Lee, Dorothy M, Dickson, Allan C, deCamp, E, Ross Colgate, Sean A, Diehl, Muhammad Ikhtear, Uddin, Salma, Sharmin, Shahidul, Islam, Taufiqur Rahman, Bhuiyan, Masud, Alam, Uma, Nayak, Josyf C, Mychaleckyj, Mami, Taniuchi, William A, Petri, Rashidul, Haque, Firdausi, Qadri, and Beth D, Kirkpatrick

Subjects
Diarrhea, Bangladesh, Genotype, Errata, Rotavirus Vaccines, Infant, vaccine efficacy, Vaccines, Attenuated, vaccination, Rotavirus Infections, secretor, Major Articles and Brief Reports, fluids and secretions, rotavirus, Lewis, Viruses, Blood Group Antigens, Humans
Abstract

Background Lewis and secretor histo–blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE. Methods In infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD. Results A vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36–.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort. Conclusions Host HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status. Clinical Trials Registration NCT01375647., Histo–blood group antigens were associated with genotype-specific susceptibility to rotavirus infections. Nonsecretors were at decreased risk of P[4] infections, while Lewis-negative children were at increased risk of P[6] infections. These effects may impact oral rotavirus vaccine efficacy estimates.

Published
2018

40. Associations of autozygosity with a broad range of human phenotypes

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), 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), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - 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M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019
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41. Genome-wide association study of cryptosporidiosis in infants implicatesPRKCA

Author

Genevieve L. Wojcik, Chelsea Marie, Priya Duggal, Stephen S. Rich, William A. Petri, Rashidul Haque, Beth D. Kirkpatrick, Poonum S. Korpe, Patrick Concannon, A. S. G. Faruque, and Josyf C. Mychaleckyj

Subjects
2. Zero hunger, 0303 health sciences, education.field_of_study, Pediatrics, medicine.medical_specialty, business.industry, 030231 tropical medicine, Population, 1. No poverty, Single-nucleotide polymorphism, Genome-wide association study, Disease, medicine.disease, 3. Good health, 03 medical and health sciences, Diarrhea, Malnutrition, 0302 clinical medicine, Cohort, Medicine, medicine.symptom, business, education, 030304 developmental biology, Genetic association
Abstract

Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and Sub-Saharan Africa where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh: the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for height-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P=3.73×10−8), an intronic SNP and eQTL ofPRKCA. Each additional risk allele conferred 2.4 times the odds of cryptosporidiosis in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation. This article was submitted to an online preprint archive.(1)ImportanceGlobally, one of the major causes of pediatric morbidity and mortality remains diarrhea. The initial symptoms of diarrhea can often lead to long term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase c alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

Published
2019
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42. 321-OR: A Genetic Locus on Chromosome 1p36 Associated with Cardiovascular Autonomic Neuropathy in Type 2 Diabetes

Author

Yaling Tang, Michael J. Wagner, Alison A. Motsinger-Reif, Xiuqin Sun, Josyf C. Mychaleckyj, Rodica Pop-Busui, Alessandro Doria, John B. Buse, Hetal Shah, and Bruce A. Perkins

Subjects
medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Disease, medicine.disease, Logistic regression, Diabetes mellitus, Internal medicine, Cohort, Internal Medicine, medicine, business, Glycemic
Abstract

Cardiovascular autonomic neuropathy (CAN) is an independent predictor of cardiovascular disease (CVD) morbidity and all-cause and CVD mortality in diabetes. In light of its significant heritability, we aimed to identify genetic predictors of CAN through an unbiased genome-wide association study (GWAS) among whites in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohort, comprising individuals with type 2 diabetes (T2D) and high CVD risk. CAN was defined based on indices of heart rate variability derived from 10-s resting electrocardiograms, namely, as the lowest quartile of standard deviation of normally conducted R-R intervals (SDNN 104.32%). Applying logistic regression models, we conducted a GWAS testing 6.8 million common single nucleotide polymorphisms (SNPs), with cases (N=807) having CAN at baseline and/or during follow-up and controls (N=3,144) being without CAN at end of follow-up. The top signal, rs779142, on chromosome 1p36, was associated with 35% increased odds of CAN (OR=1.35 [1.20-1.51], P=1.9 ×10-7). Among incident cases (N=499), this SNP reached GWAS significance (OR=1.48 [1.29-1.69], P=1.7 ×10-8). In a time-to-event analysis, rs779142 was associated with increased risk of progression to CAN (HR=1.45 [1.28-1.64], P=6.9 ×10-9) - an effect that was independent of the glycemic control arm assignments within the trial (P for interaction = 0.40). Genes lying within 1Mb of the lead SNP included KCNAB2 - a potassium voltage-gated channel associated with fatal cardiac arrhythmia, and PER3 - period circadian clock 3, which is involved in the regulation of the cardiac sympathovagal balance. To conclude, we have identified a locus on 1p36 having a genome-wide significant effect on the development of incident CAN in T2D. Pending further studies, these findings may provide better mechanistic insights into CAN pathophysiology as well as potential new therapeutic targets against this complication. Disclosure Y. Tang: None. H. Shah: None. X. Sun: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. M.J. Wagner: None. A. Motsinger-Reif: None. J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc. J. Mychaleckyj: None. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. A. Doria: Research Support; Self; Sanofi-Aventis. Funding National Institutes of Health

Published
2019
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43. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans

Author

Jianzhao Xu, Nora Franceschini, Pamela J. Hicks, Meijian Guan, Wendy S. Post, Swapan K Das, Lijun Ma, Barry I. Freedman, John R. Sedor, Yii-Der Ida Chen, Denyse Thornley-Brown, Laura J. Rasmussen-Torvik, Donald W. Bowden, Josef Coresh, Jacob M. Keaton, Carl D. Langefeld, Maggie C.Y. Ng, Adrienne Tin, Holly Kramer, Josyf C. Mychaleckyj, Jerome I. Rotter, Stephen S. Rich, Nicholette D. Palmer, Myriam Fornage, Latchezar Dimitrov, Rulan S. Parekh, and James G. Wilson

Subjects
Genome-wide association study, medicine.medical_specialty, lcsh:QH426-470, lcsh:Medicine, Locus (genetics), Type 2 diabetes, Disease, 03 medical and health sciences, Internal medicine, Drug Discovery, Genotype, Genetics, Genetic predisposition, Medicine, Diabetic kidney disease, 1000 Genomes Project, Molecular Biology, African Americans, 0303 health sciences, business.industry, lcsh:R, 030305 genetics & heredity, End-stage kidney disease, medicine.disease, 3. Good health, lcsh:Genetics, Molecular Medicine, Primary Research, business, Kidney disease
Abstract

Background End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. Results Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P

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

Author

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

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

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

Published
2019
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45. Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy

Author

Andrzej T. Galecki, Stephanie Croall, Valma Harjutsalo, Stephen S. Rich, Josyf C. Mychaleckyj, Helen Nickerson, Chun Yi Wu, David-Alexandre Trégouët, Kevin P. McDonnell, Maria Lajer, Samy Hadjadj, Beata Gyorgy, Andrzej S. Krolewski, Peter Rossing, Michel Marre, Erkka Valo, Per-Henrik Groop, Jan Skupien, Adam M. Smiles, Niina Sandholm, Marlon Pragnell, Marcus G. Pezzolesi, Carol Forsblom, Tarunveer S. Ahluwalia, Clinicum, Research Programs Unit, Nefrologian yksikkö, Department of Medicine, University of Helsinki, Diabetes and Obesity Research Program, Per Henrik Groop / Principal Investigator, HUS Abdominal Center, and HUS Internal Medicine and Rehabilitation

Subjects
Male, CARDIOVASCULAR MORTALITY, Endocrinology, Diabetes and Metabolism, Denmark, Blood Pressure, urologic and male genital diseases, KIDNEY-FUNCTION, Diabetic nephropathy, 0302 clinical medicine, Risk Factors, Diabetic Nephropathies, 030212 general & internal medicine, Prospective Studies, Finland, ALL-CAUSE MORTALITY, Hazard ratio, PROTEINURIA, Middle Aged, 3. Good health, PREDICTS, Cholesterol, Creatinine, Disease Progression, Female, France, DETERIORATION, Glomerular Filtration Rate, Adult, medicine.medical_specialty, Renal function, 030209 endocrinology & metabolism, Nephropathy, End stage renal disease, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Albuminuria, Humans, Pathophysiology/Complications, Proportional Hazards Models, Advanced and Specialized Nursing, Glycated Hemoglobin, Type 1 diabetes, DECLINE, business.industry, medicine.disease, Diabetes Mellitus, Type 1, 3121 General medicine, internal medicine and other clinical medicine, ONSET, PATTERNS, Kidney Failure, Chronic, business, FOLLOW-UP, Kidney disease, Follow-Up Studies
Abstract

OBJECTIVE Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1–3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3–18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.

Published
2019

46. Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium

Author

Shabnam Salimi, Laura M. Raffield, Steve T. Turner, Margaret R Irvin, Tanika N. Kelly, Xiaoming Liu, Chao A Hsiung, Yoichiro Kamatani, L. Adrienne Cupples, James P. Lash, Leslie J. Baier, James A. Perry, Wei Zhao, Sharon R. Browning, Robert L. Hanson, Betsi A Young, Daniel Levy, Sharon L.R. Kardia, Donna K. Arnett, Jiang He, Timothy A. Thornton, Josyf C. Mychaleckyj, Leslie A. Lange, Dhananjay Vaidya, Charles Kooperberg, Shih-Jen Hwang, Danyu Lin, Eric Boerwinkle, Lisa R. Yanek, Yukihide Momozawa, Koichi Matsuda, Ramachandran S. Vasan, Yun Li, Jerome I. Rotter, George J. Papanicolaou, Solomon K. Musani, Braxton D. Mitchell, Saori Sakaue, Lisa de las Fuentes, Bridget M Lin, Charles E Breeze, Stephen S. Rich, Jennifer A. Smith, Yukinori Okada, Rasika A. Mathias, Bruce M. Psaty, Afshin Parsa, Benjamin D. Heavner, Sayuko Kobes, Jennifer A. Brody, Adrienne Tin, Kelsey Grinde, Huijun Qian, Wayne H-H Sheu, Yi-Jen Hung, Adolfo Correa, Deepti Jain, Anna Köttgen, Deborah A. Nickerson, Gonzalo Abecasis, Xuenan Mi, Xiuqing Guo, Alexander P. Reiner, Kent D. Taylor, Robert B. Wallace, Kenichi Yamamoto, Holly Kramer, Jianwen Cai, Albert V. Smith, Alan R. Shuldiner, Ida Yii-Der Chen, and Nora Franceschini

Subjects
Male, 0301 basic medicine, lcsh:Medicine, Ancestry-specific variants, 0302 clinical medicine, Gene Frequency, and Blood Institute (U.S.), 2.1 Biological and endogenous factors, Public Health Surveillance, Aetiology, Precision Medicine, Lung, Genetics, lcsh:R5-920, Single Nucleotide, Genomics, General Medicine, 030220 oncology & carcinogenesis, Public Health and Health Services, lcsh:Medicine (General), Biotechnology, Glomerular Filtration Rate, Research Paper, Clinical Sciences, Genetic relationship, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, Humans, Genetic Predisposition to Disease, Polymorphism, Heritable, Gene, Alleles, Kidney traits, Whole genome sequencing, Whole Genome Sequencing, Human Genome, lcsh:R, Rare variants, National Heart, Omics, Precision medicine, United States, Minor allele frequency, Good Health and Well Being, 030104 developmental biology, National Heart, Lung, and Blood Institute (U.S.), Genome-Wide Association Study
Abstract

BackgroundGenetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.MethodsWe combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.FindingsWhen testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P=6.1×10-11; METTL8, rs116951054, MAF 0.09%, P=4.5×10-9; and MATK, rs539182790, MAF 0.05%, P=3.4×10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P=1.2×10-9, nearest gene GATM, and rs71147340, MAF=0.34, P=3.3×10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.InterpretationThis study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Published
2021
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47. Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial

Author

Gaia Chiara Mannino, Hertzel C. Gerstein, Guillaume Paré, He Gao, Alison A. Motsinger-Reif, Jan Skupien, John B. Buse, Santica M. Marcovina, Timothy Hastings, Michael J. Wagner, Christine Mendonca, Peter Kraft, Hetal Shah, Patinut Buranasupkajorn, Alessandro Doria, Skylar W. Marvel, Josyf C. Mychaleckyj, Ronald J. Sigal, and Mario Luca Morieri

Subjects
0301 basic medicine, Blood Glucose, Male, medicine.medical_specialty, Glycated Hemoglobin A, Genotype, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Type 2 diabetes, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypoglycemic Agents, Middle Aged, Proportional Hazards Models, Randomized Controlled Trials as Topic, Risk Factors, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Diabetes Mellitus, Polymorphism, Intensive care medicine, Glycemic, Advanced and Specialized Nursing, Glycated Hemoglobin, Proportional hazards model, business.industry, Hazard ratio, Single Nucleotide, medicine.disease, 3. Good health, 030104 developmental biology, Cohort, business, Type 2, Emerging Science, Concepts, and Approach to Precision Medicine, Cohort study
Abstract

OBJECTIVE To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality. RESULTS Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10−9 and P = 2 × 10−8, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07–0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54–1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82–5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029). CONCLUSIONS Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.

Published
2016

48. Delayed Dosing of Oral Rotavirus Vaccine Demonstrates Decreased Risk of Rotavirus Gastroenteritis Associated With Serum Zinc: A Randomized Controlled Trial

Author

Dorothy M. Dickson, Marya P. Carmolli, Uma Nayak, Beth D. Kirkpatrick, E. Ross Colgate, Firdausi Qadri, Josyf C. Mychaleckyj, K. Zaman, Sean A. Diehl, Masud Alam, William A. Petri, Mary Claire Walsh, and Rashidul Haque

Subjects
Male, Rotavirus, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Administration, Oral, medicine.disease_cause, Rotavirus Infections, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Seroconversion, Bangladesh, business.industry, Incidence, Incidence (epidemiology), Infant, Newborn, Rotavirus Vaccines, Odds ratio, Rotavirus vaccine, Gastroenteritis, Vaccination, Zinc, Diarrhea, 030104 developmental biology, Infectious Diseases, Immunology, Female, medicine.symptom, business, Breast feeding
Abstract

Background Rotavirus is the world's leading cause of childhood diarrheal death. Despite successes, oral rotavirus vaccines are less effective in developing countries. In an urban slum of Dhaka, we performed active diarrhea surveillance to evaluate monovalent G1P[8] rotavirus vaccine (RV1) efficacy and understand variables contributing to risk of rotavirus diarrhea (RVD). Methods We performed a randomized controlled trial of monovalent oral rotavirus vaccine (RV1). Seven hundred healthy infants received RV1 or no RV1 (1:1) using delayed dosing (10 and 17 weeks) and were followed for 1 year. Intensive diarrhea surveillance was performed. The primary outcome was ≥1 episode of RVD. Nutritional, socioeconomic, and immunologic factors were assessed by logistic regression best-subsets analysis for association with risk of RVD and interactions with vaccine arm. Results Incidence of all RVD was 38.3 cases per 100 person-years. Per-protocol RV1 efficacy was 73.5% (95% confidence interval [CI], 45.8%-87.0%) against severe RVD and 51% (95% CI, 33.8%-63.7%) against all RVD. Serum zinc level (odds ratio [OR], 0.77; P = .002) and lack of rotavirus immunoglobulin A (IgA) seroconversion (OR, 1.95; P = .018) were associated with risk of RVD, independent of vaccination status. Water treatment and exclusive breastfeeding were of borderline significance. Factors not associated with RVD included height for age at 10 weeks, vitamin D, retinol binding protein, maternal education, household income, and sex. Conclusions In an urban slum with high incidence of RVD, the efficacy of RV1 against severe RVD was higher than anticipated in the setting of delayed dosing. Lower serum zinc level and lack of IgA seroconversion were associated with increased risk of RVD independent of vaccination. Clinical trials registration NCT01375647.

Published
2016
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49. Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes

Author

Carolyn F. Pedley, Lois A. Katz, Debra L. Simmons, John B. Buse, Faramarz Ismail-Beigi, Josyf C. Mychaleckyj, Ronald J. Sigal, Vasilios Papademetriou, Amy K. Mottl, and Timothy E. Craven

Subjects
Adult, Male, Blood Glucose, medicine.medical_specialty, Simvastatin, Time Factors, Epidemiology, medicine.medical_treatment, Renal function, Blood Pressure, Type 2 diabetes, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Kidney, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Fenofibrate, Renal Dialysis, Diabetes mellitus, Internal medicine, medicine, Albuminuria, Hypoglycemic Agents, Humans, Diabetic Nephropathies, 030212 general & internal medicine, Dialysis, Antihypertensive Agents, Glycemic, Aged, Hypolipidemic Agents, Glycated Hemoglobin, Transplantation, business.industry, Hazard ratio, Editorials, Original Articles, Middle Aged, medicine.disease, Confidence interval, Diabetes Mellitus, Type 2, Nephrology, Creatinine, Kidney Failure, Chronic, Female, business, Music, Glomerular Filtration Rate
Abstract

BACKGROUND AND OBJECTIVES: In people with type 2 diabetes, aggressive control of glycemia, BP, and lipids have resulted in conflicting short-term (

Published
2018

50. Trans-ethnic genome-wide association study of kidney function provides novel insight into effector genes and causal effects on kidney-specific disease aetiologies

Author

Nicole Dueker, Leslie J. Raffel, Andrew P. Morris, Nicholas G. Martin, Fadi J. Charchar, Gu Zhu, George Davey Smith, Eli Ipp, Nora Franceschini, Charles Kooperberg, Benjamin D. Humphreys, James P. Cook, Xiuqing Guo, Ali G. Gharavi, Anubha Mahajan, Miguel Cruz, Pamela A. F. Madden, Cathy C. Laurie, Johan Ärnlöv, Stephen S. Rich, Thu H. Le, Esteban J. Parra, Niels Wacher-Rodarte, Maciej Tomaszewski, John Whitfield, Susan H. Blanton, Harold Snieder, Erik Ingelsson, Ralph L. Sacco, Vilmantas Giedraitis, Adrienne M. Stilp, Johan Sundstrom, Koichi Matsuda, Peter J. van der Most, Yingchang Lu, Yii-Der Ida Chen, Erwin P. Bottinger, Krzysztof Kiryluk, Yoichiro Kamatani, Martin H. de Borst, Andrew C. Heath, Elena Sanchez, Girish N. Nadkarni, Yang Hai, Thomas A. Buchanan, Artur Akbarov, James Eales, Haojia Wu, Yukinori Okada, Jerome I. Rotter, Cecilia M. Lindgren, Tanja Rundek, Anders Larsson, Michiaki Kubo, Grant W. Montgomery, Adan Valladares-Salgado, Kyle J Gaulton, Gibran Hemani, Ruth J. F. Loos, Jeffrey Haessler, Jeffrey Damman, Holly J Mattix-Kramer, Anny H. Xiang, Josyf C. Mychaleckyj, Jianwen Cai, Lars Lind, George J. Papanicolaou, and Kent D. Taylor

Subjects
0303 health sciences, Kidney, EZH2, Renal function, Genome-wide association study, Disease, Biology, medicine.disease, Bioinformatics, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Kidney disease, Genetic association
Abstract

Chronic kidney disease (CKD) affects ∼10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Published
2018
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