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1. Rare variant contribution to the heritability of coronary artery disease

Author

Ghislain Rocheleau, Shoa L. Clarke, Gaëlle Auguste, Natalie R. Hasbani, Alanna C. Morrison, Adam S. Heath, Lawrence F. Bielak, Kruthika R. Iyer, Erica P. Young, Nathan O. Stitziel, Goo Jun, Cecelia Laurie, Jai G. Broome, Alyna T. Khan, Donna K. Arnett, Lewis C. Becker, Joshua C. Bis, Eric Boerwinkle, Donald W. Bowden, April P. Carson, Patrick T. Ellinor, Myriam Fornage, Nora Franceschini, Barry I. Freedman, Nancy L. Heard-Costa, Lifang Hou, Yii-Der Ida Chen, Eimear E. Kenny, Charles Kooperberg, Brian G. Kral, Ruth J. F. Loos, Sharon M. Lutz, JoAnn E. Manson, Lisa W. Martin, Braxton D. Mitchell, Rami Nassir, Nicholette D. Palmer, Wendy S. Post, Michael H. Preuss, Bruce M. Psaty, Laura M. Raffield, Elizabeth A. Regan, Stephen S. Rich, Jennifer A. Smith, Kent D. Taylor, Lisa R. Yanek, Kendra A. Young, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Austin T. Hilliard, Catherine Tcheandjieu, Patricia A. Peyser, Ramachandran S. Vasan, Jerome I. Rotter, Clint L. Miller, Themistocles L. Assimes, Paul S. de Vries, and Ron Do

Subjects
Science
Abstract

Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Published
2024
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2. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Author

Lisa de las Fuentes, Karen L. Schwander, Michael R. Brown, Amy R. Bentley, Thomas W. Winkler, Yun Ju Sung, Patricia B. Munroe, Clint L. Miller, Hugo Aschard, Stella Aslibekyan, Traci M. Bartz, Lawrence F. Bielak, Jin Fang Chai, Ching-Yu Cheng, Rajkumar Dorajoo, Mary F. Feitosa, Xiuqing Guo, Fernando P. Hartwig, Andrea Horimoto, Ivana Kolčić, Elise Lim, Yongmei Liu, Alisa K. Manning, Jonathan Marten, Solomon K. Musani, Raymond Noordam, Sandosh Padmanabhan, Tuomo Rankinen, Melissa A. Richard, Paul M. Ridker, Albert V. Smith, Dina Vojinovic, Alan B. Zonderman, Maris Alver, Mathilde Boissel, Kaare Christensen, Barry I. Freedman, Chuan Gao, Franco Giulianini, Sarah E. Harris, Meian He, Fang-Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Tamar Sofer, Fumihiko Takeuchi, Bamidele O. Tayo, Peter J. van der Most, Niek Verweij, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Yiqiang Zhan, Najaf Amin, Dan E. Arking, Christie Ballantyne, Eric Boerwinkle, Jennifer A. Brody, Ulrich Broeckel, Archie Campbell, Mickaël Canouil, Xiaoran Chai, Yii-Der Ida Chen, Xu Chen, Kumaraswamy Naidu Chitrala, Maria Pina Concas, Ulf de Faire, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ahn Do, Jessica D. Faul, Virginia Fisher, James S. Floyd, Terrence Forrester, Yechiel Friedlander, Giorgia Girotto, C. Charles Gu, Göran Hallmans, Sami Heikkinen, Chew-Kiat Heng, Georg Homuth, Steven Hunt, M. Arfan Ikram, David R. Jacobs, Maryam Kavousi, Chiea Chuen Khor, Tuomas O. Kilpeläinen, Woon-Puay Koh, Pirjo Komulainen, Carl D. Langefeld, Jingjing Liang, Kiang Liu, Jianjun Liu, Kurt Lohman, Reedik Mägi, Ani W. Manichaikul, Colin A. McKenzie, Thomas Meitinger, Yuri Milaneschi, Matthias Nauck, Christopher P. Nelson, Jeffrey R. O’Connell, Nicholette D. Palmer, Alexandre C. Pereira, Thomas Perls, Annette Peters, Ozren Polašek, Olli T. Raitakari, Kenneth Rice, Treva K. Rice, Stephen S. Rich, Charumathi Sabanayagam, Pamela J. Schreiner, Xiao-Ou Shu, Stephen Sidney, Mario Sims, Jennifer A. Smith, John M. Starr, Konstantin Strauch, E. Shyong Tai, Kent D. Taylor, Michael Y. Tsai, André G. Uitterlinden, Diana van Heemst, Melanie Waldenberger, Ya-Xing Wang, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Diane M. Becker, Amélie Bonnefond, Donald W. Bowden, Richard S. Cooper, Ian J. Deary, Jasmin Divers, Tõnu Esko, Paul W. Franks, Philippe Froguel, Christian Gieger, Jost B. Jonas, Norihiro Kato, Timo A. Lakka, Karin Leander, Terho Lehtimäki, Patrik K. E. Magnusson, Kari E. North, Ioanna Ntalla, Brenda Penninx, Nilesh J. Samani, Harold Snieder, Beatrice Spedicati, Pim van der Harst, Henry Völzke, Lynne E. Wagenknecht, David R. Weir, Mary K. Wojczynski, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Daniel I. Chasman, Michele K. Evans, Ervin R. Fox, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Sharon L. R. Kardia, Jose Eduardo Krieger, Dennis O. Mook-Kanamori, Patricia A. Peyser, Michael M. Province, Bruce M. Psaty, Igor Rudan, Xueling Sim, Blair H. Smith, Rob M. van Dam, Cornelia M. van Duijn, Tien Yin Wong, Donna K. Arnett, Dabeeru C. Rao, James Gauderman, Ching-Ti Liu, Alanna C. Morrison, Jerome I. Rotter, and Myriam Fornage

Subjects
educational attainment, lipids, cholesterol, triglycerides, genome-wide association study, meta-analysis, Genetics, QH426-470
Abstract

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Published
2023
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3. 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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4. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author

Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Y. Zhang, Joseph Park, Stella Aslibekyan, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Lee-Ming Chuang, Ren-Hua Chung, Joanne E. Curran, Lisa de las Fuentes, Paul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy Heard-Costa, Bertha Hidalgo, Chii-Min Hwu, Marguerite R. Irvin, Tanika N. Kelly, Brian G. Kral, Leslie Lange, Xiaohui Li, Martin Lisa, Steven A. Lubitz, Ani W. Manichaikul, Preuss Michael, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Muagututia S. Reupena, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Russell P. Tracy, Michael Y. Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T. Wilkins, Lisa R. Yanek, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yii-Der Ida Chen, Adolfo Correa, L. Adrienne Cupples, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Jiang He, Robert C. Kaplan, Sharon L. R. Kardia, Ryan Kim, Charles Kooperberg, Ruth J. F. Loos, Karine A Viaud-Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Deborah Nickerson, Kari E. North, Bruce M. Psaty, Susan Redline, Alexander P. Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen Willer, Jerome I. Rotter, Daniel J. Rader, Xihong Lin, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Gina M. Peloso, and Pradeep Natarajan

Subjects
Science
Abstract

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Published
2022
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5. Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Author

Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, and John C. Chambers

Subjects
Biology (General), QH301-705.5
Abstract

Marie Loh, Weihua Zhang et al. use a genome-wide association study meta-analysis to examine variants associated with Type 2 diabetes (T2D) in South Asian and European ancestry cohorts. Their results provide further insights into the genetic mechanisms underlying T2D across ancestral populations.

Published
2022
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6. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Author

Julia K. Goodrich, Moriel Singer-Berk, Rachel Son, Abigail Sveden, Jordan Wood, Eleina England, Joanne B. Cole, Ben Weisburd, Nick Watts, Lizz Caulkins, Peter Dornbos, Ryan Koesterer, Zachary Zappala, Haichen Zhang, Kristin A. Maloney, Andy Dahl, Carlos A. Aguilar-Salinas, Gil Atzmon, Francisco Barajas-Olmos, Nir Barzilai, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Federico Centeno-Cruz, John C. Chambers, Nathalie Chami, Edmund Chan, Juliana Chan, Ching-Yu Cheng, Yoon Shin Cho, Cecilia Contreras-Cubas, Emilio Córdova, Adolfo Correa, Ralph A. DeFronzo, Ravindranath Duggirala, Josée Dupuis, Ma Eugenia Garay-Sevilla, Humberto García-Ortiz, Christian Gieger, Benjamin Glaser, Clicerio González-Villalpando, Ma Elena Gonzalez, Niels Grarup, Leif Groop, Myron Gross, Christopher Haiman, Sohee Han, Craig L. Hanis, Torben Hansen, Nancy L. Heard-Costa, Brian E. Henderson, Juan Manuel Malacara Hernandez, Mi Yeong Hwang, Sergio Islas-Andrade, Marit E. Jørgensen, Hyun Min Kang, Bong-Jo Kim, Young Jin Kim, Heikki A. Koistinen, Jaspal Singh Kooner, Johanna Kuusisto, Soo-Heon Kwak, Markku Laakso, Leslie Lange, Jong-Young Lee, Juyoung Lee, Donna M. Lehman, Allan Linneberg, Jianjun Liu, Ruth J. F. Loos, Valeriya Lyssenko, Ronald C. W. Ma, Angélica Martínez-Hernández, James B. Meigs, Thomas Meitinger, Elvia Mendoza-Caamal, Karen L. Mohlke, Andrew D. Morris, Alanna C. Morrison, Maggie C. Y. Ng, Peter M. Nilsson, Christopher J. O’Donnell, Lorena Orozco, Colin N. A. Palmer, Kyong Soo Park, Wendy S. Post, Oluf Pedersen, Michael Preuss, Bruce M. Psaty, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Jerome I. Rotter, Danish Saleheen, Claudia Schurmann, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Timothy D. Spector, Konstantin Strauch, Tim M. Strom, E. Shyong Tai, Claudia H. T. Tam, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Russell P. Tracy, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Rob M. van Dam, Ramachandran S. Vasan, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, AMP-T2D-GENES Consortia, Noël P. Burtt, Noah Zaitlen, Mark I. McCarthy, Michael Boehnke, Toni I. Pollin, Jason Flannick, Josep M. Mercader, Anne O’Donnell-Luria, Samantha Baxter, Jose C. Florez, Daniel G. MacArthur, and Miriam S. Udler

Subjects
Science
Abstract

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

Published
2021
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7. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author

Pradeep Natarajan, Akhil Pampana, Sarah E. Graham, Sanni E. Ruotsalainen, James A. Perry, Paul S. de Vries, Jai G. Broome, James P. Pirruccello, Michael C. Honigberg, Krishna Aragam, Brooke Wolford, Jennifer A. Brody, Lucinda Antonacci-Fulton, Moscati Arden, Stella Aslibekyan, Themistocles L. Assimes, Christie M. Ballantyne, Lawrence F. Bielak, Joshua C. Bis, Brian E. Cade, Ron Do, Harsha Doddapaneni, Leslie S. Emery, Yi-Jen Hung, Marguerite R. Irvin, Alyna T. Khan, Leslie Lange, Jiwon Lee, Rozenn N. Lemaitre, Lisa W. Martin, Ginger Metcalf, May E. Montasser, Jee-Young Moon, Donna Muzny, Jeffrey R. O’Connell, Nicholette D. Palmer, Juan M. Peralta, Patricia A. Peyser, Adrienne M. Stilp, Michael Tsai, Fei Fei Wang, Daniel E. Weeks, Lisa R. Yanek, James G. Wilson, Goncalo Abecasis, Donna K. Arnett, Lewis C. Becker, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yi-Cheng Chang, Yii-Der I. Chen, Won Jung Choi, Adolfo Correa, Joanne E. Curran, Mark J. Daly, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Barry I. Freedman, Stacey Gabriel, Soren Germer, Richard A. Gibbs, Jiang He, Kristian Hveem, Gail P. Jarvik, Robert C. Kaplan, Sharon L. R. Kardia, Eimear Kenny, Ryan W. Kim, Charles Kooperberg, Cathy C. Laurie, Seonwook Lee, Don M. Lloyd-Jones, Ruth J. F. Loos, Steven A. Lubitz, Rasika A. Mathias, Karine A. Viaud Martinez, Stephen T. McGarvey, Braxton D. Mitchell, Deborah A. Nickerson, Kari E. North, Aarno Palotie, Cheol Joo Park, Bruce M. Psaty, D. C. Rao, Susan Redline, Alexander P. Reiner, Daekwan Seo, Jeong-Sun Seo, Albert V. Smith, Russell P. Tracy, Ramachandran S. Vasan, Sekar Kathiresan, L. Adrienne Cupples, Jerome I. Rotter, Alanna C. Morrison, Stephen S. Rich, Samuli Ripatti, Cristen Willer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, FinnGen, and Gina M. Peloso

Subjects
Science
Abstract

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Published
2021
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8. APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale

Author

Barry I. Freedman, Marva M. Moxey-Mims, Amir A. Alexander, Brad C. Astor, Kelly A. Birdwell, Donald W. Bowden, Gordon Bowen, Jonathan Bromberg, Timothy E. Craven, Darshana M. Dadhania, Jasmin Divers, Mona D. Doshi, Elling Eidbo, Alessia Fornoni, Michael D. Gautreaux, Rasheed A. Gbadegesin, Patrick O. Gee, Giselle Guerra, Chi-yuan Hsu, Ana S. Iltis, Nichole Jefferson, Bruce A. Julian, David K. Klassen, Patrick P. Koty, Carl D. Langefeld, Krista L. Lentine, Lijun Ma, Roslyn B. Mannon, Madhav C. Menon, Sumit Mohan, J. Brian Moore, Barbara Murphy, Kenneth A. Newell, Jonah Odim, Mariella Ortigosa-Goggins, Nicholette D. Palmer, Meyeon Park, Afshin Parsa, Stephen O. Pastan, Emilio D. Poggio, Nishadi Rajapakse, Amber M. Reeves-Daniel, Sylvia E. Rosas, Laurie P. Russell, Deirdre Sawinski, S. Carrie Smith, Mitzie Spainhour, Robert J. Stratta, Matthew R. Weir, David M. Reboussin, Paul L. Kimmel, and Daniel C. Brennan

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation. Keywords: African Americans, APOL1, chronic kidney disease, graft failure, kidney transplantation, outcomes

Published
2020
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9. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Author

Margaret A. Taub, Matthew P. Conomos, Rebecca Keener, Kruthika R. Iyer, Joshua S. Weinstock, Lisa R. Yanek, John Lane, Tyne W. Miller-Fleming, Jennifer A. Brody, Laura M. Raffield, Caitlin P. McHugh, Deepti Jain, Stephanie M. Gogarten, Cecelia A. Laurie, Ali Keramati, Marios Arvanitis, Albert V. Smith, Benjamin Heavner, Lucas Barwick, Lewis C. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Esteban G. Burchard, Juan C. Celedón, Yen Pei C. Chang, Brian Custer, Dawood Darbar, Lisa de las Fuentes, Dawn L. DeMeo, Barry I. Freedman, Melanie E. Garrett, Mark T. Gladwin, Susan R. Heckbert, Bertha A. Hidalgo, Marguerite R. Irvin, Talat Islam, W. Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E. North, Patricia A. Peyser, Nicholas Rafaels, Christine Seidman, Daniel E. Weeks, Fayun Wen, Marsha M. Wheeler, L. Keoki Williams, Ivana V. Yang, Wei Zhao, Stella Aslibekyan, Paul L. Auer, Donald W. Bowden, Brian E. Cade, Zhanghua Chen, Michael H. Cho, L. Adrienne Cupples, Joanne E. Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E. Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M. Johnsen, Eimear E. Kenny, Albert M. Levin, Chunyu Liu, Ryan L. Minster, Take Naseri, Mehdi Nouraie, Muagututi‘a Sefuiva Reupena, Ester C. Sabino, Jennifer A. Smith, Nicholas L. Smith, Jessica Lasky-Su, James G. Taylor, VI, Marilyn J. Telen, Hemant K. Tiwari, Russell P. Tracy, Marquitta J. White, Yingze Zhang, Kerri L. Wiggins, Scott T. Weiss, Ramachandran S. Vasan, Kent D. Taylor, Moritz F. Sinner, Edwin K. Silverman, M. Benjamin Shoemaker, Wayne H.-H. Sheu, Frank Sciurba, David A. Schwartz, Jerome I. Rotter, Daniel Roden, Susan Redline, Benjamin A. Raby, Bruce M. Psaty, Juan M. Peralta, Nicholette D. Palmer, Sergei Nekhai, Courtney G. Montgomery, Braxton D. Mitchell, Deborah A. Meyers, Stephen T. McGarvey, Angel C.Y. Mak, Ruth J.F. Loos, Rajesh Kumar, Charles Kooperberg, Barbara A. Konkle, Shannon Kelly, Sharon L.R. Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D. Gilliland, Bruce D. Gelb, Myriam Fornage, Patrick T. Ellinor, Mariza de Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C. Barnes, Allison E. Ashley-Koch, Donna K. Arnett, Christine Albert, Cathy C. Laurie, Goncalo Abecasis, Deborah A. Nickerson, James G. Wilson, Stephen S. Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W. Blackwell, Timothy Thornton, Jeff O’Connell, Nancy J. Cox, James A. Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P. Reiner, and Rasika A. Mathias

Subjects
telomeres, telomere length genetics, trans-population genome-wide association study, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

Published
2022
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10. Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease

Author

Swapan K. Das, Hannah C. Ainsworth, Latchezar Dimitrov, Hayrettin Okut, Mary E. Comeau, Neeraj Sharma, Maggie C.Y. Ng, Jill M. Norris, Yii-der I. Chen, Lynne E. Wagenknecht, Donald W. Bowden, Fang-Chi Hsu, Kent D. Taylor, Carl D. Langefeld, and Nicholette D. Palmer

Subjects
Obesity, Metabolomics, Cardiometabolic disease, Minority populations, Internal medicine, RC31-1245
Abstract

Objective: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. Methods: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data. Results: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (PMA 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (PMA = 9.00 × 10−41, PAA = 2.31 × 10−10) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (PFDR = 6.64 × 10−07). Conclusions: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health.

Published
2021
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11. Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus

Author

Mingxia Liu, Cecilia Frej, Carl D. Langefeld, Jasmin Divers, Donald W. Bowden, J. Jeffrey Carr, Abraham K. Gebre, Jianzhao Xu, Benny Larsson, Björn Dahlbäck, Barry I. Freedman, and John S. Parks

Subjects
apolipoproteins, high density lipoprotein, atherosclerosis, clinical studies, ethnicity, apolipoprotein M, Biochemistry, QD415-436
Abstract

apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, P = 0.01] and plasma apoM (OR = 0.10, P = 0.02), but not HDL apoM (P = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.

Published
2019
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12. 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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13. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author

Tuomas O. Kilpeläinen, Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Lifelines Cohort Study, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao, and Ruth J. F. Loos

Subjects
Science
Abstract

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

Published
2019
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14. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan Sargurupremraj, Niina Pitkänen, Oscar Franzén, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih-Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, André G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Pasaniuc, Brenda W. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’Leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, Eric Boerwinkle, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline de Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. L. M. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimaki, Mike A. Nalls, Olle Melander, Olli Raitakari, Oscar H. Franco, Oscar L. Rueda-Ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, Reinhold Schmidt, Renée de Mutsert, Richard W. Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela McLachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf de Faire, Vincent Plagnol, Wayne D. Rosamond, Wendy Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, MEGASTROKE Consortium, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. van Duijn, Deborah A. Lawlor, Dennis O. Mook-Kanamori, Donald W. Bowden, Helena Schmidt, James F. Wilson, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo-Pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Gudnason, Aroon D. Hingorani, Johan L. M. Björkegren, Juan P. Casas, and Christopher J. O’Donnell

Subjects
Science
Abstract

Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.

Published
2018
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15. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Author

Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, and John C. Chambers

Subjects
Biology (General), QH301-705.5
Published
2022
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16. An Exome-wide Association Study 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, James G. Wilson, Barry I. Freedman, Donald W. Bowden, and Maggie C.Y. Ng

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs. Methods: Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations (P < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals. Results: A total of 11 suggestive T2D-ESKD associations (P < 1 x 10−4) from 8 loci (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) were apparent in the meta-analysis. Exclusion of APOL1 renal-risk genotype carriers identified 3 additional suggestive loci (OTUD7B, IFITM3, DLGAP5). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P = 1.2 x 10−6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals). Conclusion: Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs. Keywords: African Americans, chronic kidney disease, end-stage kidney disease, exome sequencing, genetics, type 2 diabetes

Published
2018
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17. Associations of coronary artery calcified plaque density with mortality in type 2 diabetes: the Diabetes Heart Study

Author

Laura M. Raffield, Amanda J. Cox, Michael H. Criqui, Fang-Chi Hsu, James G. Terry, Jianzhao Xu, Barry I. Freedman, J. Jeffrey Carr, and Donald W. Bowden

Subjects
Coronary artery calcification, Plaque density, Type 2 diabetes, Mortality, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Coronary artery calcified plaque (CAC) is strongly predictive of cardiovascular disease (CVD) events and mortality, both in general populations and individuals with type 2 diabetes at high risk for CVD. CAC is typically reported as an Agatston score, which is weighted for increased plaque density. However, the role of CAC density in CVD risk prediction, independently and with CAC volume, remains unclear. Methods We examined the role of CAC density in individuals with type 2 diabetes from the family-based Diabetes Heart Study and the African American-Diabetes Heart Study. CAC density was calculated as mass divided by volume, and associations with incident all-cause and CVD mortality [median follow-up 10.2 years European Americans (n = 902, n = 286 deceased), 5.2 years African Americans (n = 552, n = 93 deceased)] were examined using Cox proportional hazards models, independently and in models adjusted for CAC volume. Results In European Americans, CAC density, like Agatston score and volume, was consistently associated with increased risk of all-cause and CVD mortality (p ≤ 0.002) in models adjusted for age, sex, statin use, total cholesterol, HDL, systolic blood pressure, high blood pressure medication use, and current smoking. However, these associations were no longer significant when models were additionally adjusted for CAC volume. CAC density was not significantly associated with mortality, either alone or adjusted for CAC volume, in African Americans. Conclusions CAC density is not associated with mortality independent from CAC volume in European Americans and African Americans with type 2 diabetes.

Published
2018
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18. Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes

Author

Jasmin Divers, Nicholette D. Palmer, Carl D. Langefeld, W. Mark Brown, Lingyi Lu, Pamela J. Hicks, S. Carrie Smith, Jianzhao Xu, James G. Terry, Thomas C. Register, Lynne E. Wagenknecht, John S. Parks, Lijun Ma, Gary C. Chan, Sarah G. Buxbaum, Adolfo Correa, Solomon Musani, James G. Wilson, Herman A. Taylor, Donald W. Bowden, John Jeffrey Carr, and Barry I. Freedman

Subjects
African Americans, Coronary artery calcified atherosclerotic plaque, Genome-wide association study, Cardiovascular disease, Type 2 diabetes, Genetics, QH426-470
Abstract

Abstract Background Coronary artery calcified atherosclerotic plaque (CAC) predicts cardiovascular disease (CVD). Despite exposure to more severe conventional CVD risk factors, African Americans (AAs) are less likely to develop CAC, and when they do, have markedly lower levels than European Americans. Genetic factors likely contribute to the observed ethnic differences. To identify genes associated with CAC in AAs with type 2 diabetes (T2D), a genome-wide association study (GWAS) was performed using the Illumina 5 M chip in 691 African American-Diabetes Heart Study participants (AA-DHS), with replication in 205 Jackson Heart Study (JHS) participants with T2D. Genetic association tests were performed on the genotyped and 1000 Genomes-imputed markers separately for each study, and combined in a meta-analysis. Results Single nucleotide polymorphisms (SNPs), rs11353135 (2q22.1), rs16879003 (6p22.3), rs5014012, rs58071836 and rs10244825 (all on chromosome 7), rs10918777 (9q31.2), rs13331874 (16p13.3) and rs4459623 (18q12.1) were associated with presence and/or quantity of CAC in the AA-DHS and JHS, with meta-analysis p-values ≤8.0 × 10−7. The strongest result in AA-DHS alone was rs6491315 in the 13q32.1 region (parameter estimate (SE) = −1.14 (0.20); p-value = 9.1 × 10−9). This GWAS peak replicated a previously reported AA-DHS CAC admixture signal (rs7492028, LOD score 2.8). Conclusions Genetic association between SNPs on chromosomes 2, 6, 7, 9, 16 and 18 and CAC were detected in AAs with T2D from AA-DHS and replicated in the JHS. These data support a role for genetic variation on these chromosomes as contributors to CAC in AAs with T2D, as well as to variation in CAC between populations of African and European ancestry.

Published
2017
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19. Prevalence and determinants of electrocardiographic abnormalities in African Americans with type 2 diabetes

Author

Matthew B. Sellers, Jasmin Divers, Lingyi Lu, Jianzhao Xu, S. Carrie Smith, Donald W. Bowden, David Herrington, Barry I. Freedman, and Elsayed Z. Soliman

Subjects
Electrocardiogram, Diabetes, African Americans, Heart, Hypertension, Cardiovascular disease, Public aspects of medicine, RA1-1270
Abstract

Background: Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes. Methods: Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities. Results: Participants were 56% women with a mean age of 56 years; 60% had at least one minor or major ECG abnormality [23% ⩾1 major (or major plus minor), and 37% ⩾1 minor (with no major)]. Men had a higher prevalence of ⩾1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p = 0.0089). In univariate analysis, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67, 0.93]), statin use (0.79 [0.67, 0.93]) and diabetes duration (1.03 [1.0, 1.05]) remained statistically significant. Conclusions: Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model.

Published
2019
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20. Predicting Mortality in African Americans With Type 2 Diabetes Mellitus: Soluble Urokinase Plasminogen Activator Receptor, Coronary Artery Calcium, and High‐Sensitivity C‐Reactive Protein

Author

Salim S. Hayek, Jasmin Divers, Mohamad Raad, Jianzhao Xu, Donald W. Bowden, Melissa Tracy, Jochen Reiser, and Barry I. Freedman

Subjects
biomarker, calcium score, soluble urokinase plasminogen activator receptor, urokinase, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundType 2 diabetes mellitus is a major risk factor for cardiovascular disease; however, outcomes in individual patients vary. Soluble urokinase plasminogen activator receptor (suPAR) is a bone marrow–derived signaling molecule associated with adverse cardiovascular and renal outcomes in many populations. We characterized the determinants of suPAR in African Americans with type 2 diabetes mellitus and assessed whether levels were useful for predicting mortality beyond clinical characteristics, coronary artery calcium (CAC), and high‐sensitivity C‐reactive protein (hs‐CRP). Methods and ResultsWe measured plasma suPAR levels in 500 African Americans with type 2 diabetes mellitus enrolled in the African American‐Diabetes Heart Study. We used Kaplan‐Meier curves and Cox proportional hazards models adjusting for clinical characteristics, CAC, and hs‐CRP to examine the association between suPAR and all‐cause mortality. Last, we report the change in C‐statistics comparing the additive values of suPAR, hs‐CRP, and CAC to clinical models for prediction of mortality. The suPAR levels were independently associated with female sex, smoking, insulin use, decreased kidney function, albuminuria, and CAC. After a median 6.8‐year follow‐up, a total of 68 deaths (13.6%) were recorded. In a model incorporating suPAR, CAC, and hs‐CRP, only suPAR was significantly associated with mortality (hazard ratio 2.66, 95% confidence interval 1.63‐4.34). Addition of suPAR to a baseline clinical model significantly improved the C‐statistic for all‐cause death (Δ0.05, 95% confidence interval 0.01‐0.10), whereas addition of CAC or hs‐CRP did not. ConclusionsIn African Americans with type 2 diabetes mellitus, suPAR was strongly associated with mortality and improved risk discrimination metrics beyond traditional risk factors, CAC and hs‐CRP. Studies addressing the clinical usefulness of measuring suPAR concentrations are warranted.

Published
2018
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21. Montreal Cognitive Assessment and Modified Mini Mental State Examination in African Americans

Author

Kaycee M. Sink, Suzanne Craft, S. Carrie Smith, Joseph A. Maldjian, Donald W. Bowden, Jianzhao Xu, Barry I. Freedman, and Jasmin Divers

Subjects
Geriatrics, RC952-954.6
Abstract

Background. Sparse data limit the interpretation of Montreal Cognitive Assessment (MoCA) scores, particularly in minority populations. Additionally, there are no published data on how MoCA scores compare to the widely used Modified Mini Mental State Examination (3MSE). We provide performance data on the MoCA in a large cohort of African Americans and compare 3MSE and MoCA scores, providing a “crosswalk” for interpreting scores. Methods. Five hundred and thirty African Americans with type 2 diabetes were enrolled in African American-Diabetes Heart Study-MIND, a cross-sectional study of cognition and structural and functional brain imaging. After excluding participants with possible cognitive impairment (n=115), mean (SD) MoCA and 3MSE scores are presented stratified by age and education. Results. Participant mean age was 58.2 years (range: 35-83); 61% were female; and 64.9% had >12 years of education. Mean (SD) 3MSE and MoCA scores were 86.9 (8.2) and 19.8 (3.8), respectively. 93.5% of the cohort had a “positive” screen on the MoCA, scoring

Published
2015
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22. Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study

Author

Kathryn P. Burdon, Megan E. Rudock, Allison B. Lehtinen, Carl D. Langefeld, Donald W. Bowden, Thomas C. Register, Yongmei Liu, Barry I. Freedman, J. Jeffrey Carr, Catherine C. Hedrick, and Stephen S. Rich

Subjects
Pathology, RB1-214
Abstract

Aims. Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms in ALOX12, ALOX15, ALOX5, and ALOX5AP genes are associated with subclinical atherosclerosis in multiple vascular beds. Methods. Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic (n=828) and nondiabetic (n=170) siblings were genotyped for SNPs in the ALOX12, ALOX15, ALOX5, and ALOX5AP genes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained. Results. Associations were observed between ALOX12 with CorCP, ALOX5 with CorCP, AorCP, and IMT, and ALOX5AP with CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP). Conclusions. Polymorphisms within ALOX12, ALOX5, and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease.

Published
2010
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24. Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS)

Author

Hayrettin Okut, Yingchang Lu, Nicholette D. Palmer, Yii-Der Ida Chen, Kent D. Taylor, Jill M. Norris, Carlos Lorenzo, Jerome I. Rotter, Carl D. Langefeld, Lynne E. Wagenknecht, Donald W. Bowden, and Maggie C. Y. Ng

Subjects
African Americans, Endocrinology, Diabetes and Metabolism, Prevention, Clinical Biochemistry, Diabetes, Clinical Sciences, Atherosclerosis, Glucose homeostasis, Biochemistry, Analytical Chemistry, Black or African American, Glucose, Glutamates, Clinical Research, Diabetes Mellitus, Humans, Homeostasis, Metabolomics, Obesity, Biochemistry and Cell Biology, Insulin Resistance, Type 2, Metabolic and endocrine, Nutrition
Abstract

Introduction African Americans are at increased risk for type 2 diabetes. Objectives This work aimed to examine metabolomic signature of glucose homeostasis in African Americans. Methods We used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (SI, insulin sensitivity; AIR, acute insulin response; DI, disposition index; and SG, glucose effectiveness) and basal (HOMA-IR and HOMA-B) measures of glucose homeostasis using univariate and regularized regression models. We also compared the results with our previous findings in the IRAS-FS Mexican Americans. Results We confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans. Conclusion We extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.

Published
2023

26. 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

27. Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy

Author

Jie Jin Wang, Robert P. Igo, Barry I. Freedman, Jerome I. Rotter, Kathyrn P. Burdon, Alan D. Penman, Albert V. Smith, Xiaohui Li, Jamie E. Craig, Paul Mitchell, Brian L. Yaspan, Mary Frances Cotch, John M. Rouhana, Ayellet V. Segrè, Barbara E.K. Klein, Ashley Li, Richard A. Jensen, Gayatri Susarla, Lynn K. Stanwyck, Sudha K. Iyengar, Maggie C.Y. Ng, Ching J. Chen, Kent D. Taylor, Donald W. Bowden, Lucia Sobrin, Tien Yin Wong, Emily Y. Chew, Sharon G. Adler, Samuela Pollack, and Jane Z. Kuo

Subjects
Lipid catabolic process, Clinical Sciences, Genome-wide association study, Type 2 diabetes, Biology, Ophthalmology & Optometry, Polymorphism, Single Nucleotide, Article, Opthalmology and Optometry, Risk Factors, Diabetes Mellitus, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Interferon gamma, Polymorphism, Aetiology, Eye Disease and Disorders of Vision, Gene, Metabolic and endocrine, Lipid Transport, Diabetic Retinopathy, Catabolism, Diabetes, Human Genome, Single Nucleotide, medicine.disease, Ophthalmology, Diabetes Mellitus, Type 2, Public Health and Health Services, Lipid digestion, Type 2, Biotechnology, Genome-Wide Association Study, medicine.drug
Abstract

To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.MethodsWe analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was

Published
2022

29. Rare genetic variants explain missing heritability in smoking

Author

Seon-Kyeong Jang, Luke Evans, Allison Fialkowski, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, Diane M. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Meher Preethi Boorgula, Donald W. Bowden, Jennifer A. Brody, Brian E. Cade, Brenda W. Campbell Jenkins, April P. Carson, Sameer Chavan, L. Adrienne Cupples, Brian Custer, Scott M. Damrauer, Sean P. David, Mariza de Andrade, Carla L. Dinardo, Tasha E. Fingerlin, Myriam Fornage, Barry I. Freedman, Melanie E. Garrett, Sina A. Gharib, David C. Glahn, Jeffrey Haessler, Susan R. Heckbert, John E. Hokanson, Lifang Hou, Shih-Jen Hwang, Matthew C. Hyman, Renae Judy, Anne E. Justice, Robert C. Kaplan, Sharon L. R. Kardia, Shannon Kelly, Wonji Kim, Charles Kooperberg, Daniel Levy, Donald M. Lloyd-Jones, Ruth J. F. Loos, Ani W. Manichaikul, Mark T. Gladwin, Lisa Warsinger Martin, Mehdi Nouraie, Olle Melander, Deborah A. Meyers, Courtney G. Montgomery, Kari E. North, Elizabeth C. Oelsner, Nicholette D. Palmer, Marinelle Payton, Anna L. Peljto, Patricia A. Peyser, Michael Preuss, Bruce M. Psaty, Dandi Qiao, Daniel J. Rader, Nicholas Rafaels, Susan Redline, Robert M. Reed, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, David A. Schwartz, Aladdin H. Shadyab, Edwin K. Silverman, Nicholas L. Smith, J. Gustav Smith, Albert V. Smith, Jennifer A. Smith, Weihong Tang, Kent D. Taylor, Marilyn J. Telen, Ramachandran S. Vasan, Victor R. Gordeuk, Zhe Wang, Kerri L. Wiggins, Lisa R. Yanek, Ivana V. Yang, Kendra A. Young, Kristin L. Young, Yingze Zhang, Dajiang J. Liu, Matthew C. Keller, and Scott Vrieze

Subjects
Social Psychology, Tobacco Smoke and Health, Smoking, Human Genome, Experimental and Cognitive Psychology, Single Nucleotide, Polymorphism, Single Nucleotide, Article, Behavioral Neuroscience, Phenotype, Gene Frequency, Tobacco, Genetics, Polymorphism, Genome-Wide Association Study, Cancer
Abstract

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Published
2022

30. 140-OR: Machine Learning for Metabolite Estimation to Examine Contributors to Glucose Homeostasis and Adiposity: The GUARDIAN Consortium

Author

NICHOLETTE ALLRED, HANNAH C. AINSWORTH, XIUQING GUO, ADRIENNE W. MACKAY, FESTUS NYASIMI, OWEN MELIA, YANYU LIANG, DONALD W. BOWDEN, KENT TAYLOR, LESLIE J. RAFFEL, THOMAS A. BUCHANAN, RICHARD M. WATANABE, JEROME I. ROTTER, LYNNE E. WAGENKNECHT, CARL D. LANGEFELD, and HAE K. IM

Subjects
Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract

Diabetes is characterized by metabolic dysregulation. Metabolomics captures interactions of cellular processes and environmental exposures to promote disease and can improve mechanistic understanding to identify clinically relevant targets. However, use is limited by cost and sample availability. To facilitate investigation, machine learning approaches were used in the Insulin Resistance Atherosclerosis Family Study (n=943 Mexican Americans) with empiric metabolites (Metabolon HD4) and GWAS data to generate genetically regulated metabolite estimation models for broad application. 950 metabolites were heritable. Ridge and LASSO regression had cross validated correlation >0.1 for 448 metabolites. In an independent set, LASSO (enforcing sparsity) outperformed Ridge (full polygenic architecture) regression. Estimation was extended to the GUARDIAN Consortium (n∼4377) to assess the association of genetically predicted metabolites with glucose homeostasis and adiposity. Multiple associations (FDR P In conclusion, we have developed algorithms for estimating 448 metabolites using genetic data that had good performance in an independent dataset. Estimation models were used to assess association with glucose homeostasis and adiposity highlighting known and novel associations and demonstrating utility. Future work will expand genetic coverage to include rare variants and phenotypic associations to further characterize metabolic dysregulation. Disclosure N.Allred: None. L.J.Raffel: None. T.A.Buchanan: None. R.M.Watanabe: None. J.I.Rotter: None. L.E.Wagenknecht: None. C.D.Langefeld: None. H.K.Im: None. H.C.Ainsworth: None. X.Guo: None. A.W.Mackay: None. F.Nyasimi: None. O.Melia: None. Y.Liang: None. D.W.Bowden: None. K.Taylor: None. Funding R01DK118062

Published
2022

31. Association of Visceral Adipose Tissue and Insulin Resistance with Incident Metabolic Syndrome Independent of Obesity Status: The IRAS Family Study

Author

Lynne E. Wagenknecht, Carlos Lorenzo, Nicolette D Palmer, Janet A. Tooze, Kristen G. Hairston, Jill M. Norris, Morgana Mongraw-Chaffin, Donald W. Bowden, Yii-Der Ida Chen, and Anthony J. Hanley

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, 030209 endocrinology & metabolism, Intra-Abdominal Fat, Logistic regression, Article, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, parasitic diseases, medicine, Humans, Obesity, 030212 general & internal medicine, Abdominal obesity, Metabolic Syndrome, Nutrition and Dietetics, business.industry, nutritional and metabolic diseases, Odds ratio, Atherosclerosis, medicine.disease, Homeostatic model assessment, Insulin Resistance, medicine.symptom, Metabolic syndrome, business, tissues, human activities
Abstract

Objective Although increasing evidence suggests that visceral adipose tissue (VAT) is a major underlying cause of metabolic syndrome (MetS), few studies have measured VAT at multiple time points in diverse populations. VAT and insulin resistance were hypothesized to differ by MetS status within BMI category in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study and, further, that baseline VAT and insulin resistance and increases over time are associated with incident MetS. Methods Generalized estimating equations were used for differences in body fat distribution and insulin resistance by MetS status. Mixed effects logistic regression was used for the association of baseline and change in adiposity and insulin resistance with incident MetS across 5 years, adjusted for age, sex, race/ethnicity, and family correlation. Results VAT and insulin sensitivity differed significantly by MetS status and BMI category at baseline. VAT and homeostatic model assessment of insulin resistance (HOMA-IR) at baseline (VAT odds ratio [OR] = 1.16 [95% CI: 1.12-2.31]; HOMA-IR OR = 1.85 [95% CI: 1.32-2.58]) and increases over time (VAT OR = 1.55 [95% CI: 1.22-1.98]; HOMA-IR OR = 3.23 [95% CI: 2.20-4.73]) were associated with incident MetS independent of BMI category. Conclusions Differing levels of VAT may be driving metabolic heterogeneity within BMI categories. Both overall and abdominal obesity (VAT) may play a role in the development of MetS. Increased VAT over time contributed additional risk.

Published
2021

32. Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer’s disease and myocardial infarction

Author

Vilmundur Gudnason, Solomon K. Musani, Yi-Ping Fu, Albert V. Smith, Yii-Der Ida Chen, Annapurna Kuppa, Xiuqing Guo, Matthew A. Allison, Sharon L.R. Kardia, Donald W. Bowden, Gudny Eirksdottir, Jill M. Norris, Jian Yang, Bratati Kahali, Yanhua Chen, Thomas H. Mosley, Elizabeth K. Speliotes, Lenore J. Launer, James G. Terry, Brian D. Halligan, Jerome I. Rotter, Matthew J. Budoff, Kent D. Taylor, Kathleen A. Ryan, Breland F. Crudup, Adolfo Correa, Lawrence F. Bielak, Jeffrey R. O'Connell, Michael A. Province, Patricia A. Peyser, Nicholette D. Palmer, Christopher J. O'Donnell, Mary F. Feitosa, Lynne E. Wagenknecht, J. Jeffrey Carr, and Xiaomeng Du

Subjects
Liver Cirrhosis, 0301 basic medicine, Apolipoprotein E, Aging, Cirrhosis, Myocardial Infarction, Disease, Neurodegenerative, Alzheimer's Disease, Chronic liver disease, Medical and Health Sciences, Gastroenterology, Oral and gastrointestinal, Hepatitis, Liver disease, 0302 clinical medicine, Gene Frequency, Risk Factors, Non-alcoholic Fatty Liver Disease, Databases, Genetic, Nonalcoholic fatty liver disease, 2.1 Biological and endogenous factors, Exome, Aetiology, Association Studies Article, Genetics (clinical), Genetics & Heredity, Liver Disease, Fatty liver, Alanine Transaminase, Single Nucleotide, General Medicine, Biological Sciences, Prognosis, Phenotype, Liver, Biotechnology, medicine.medical_specialty, Chronic Liver Disease and Cirrhosis, Biology, Polymorphism, Single Nucleotide, Databases, 03 medical and health sciences, Apolipoproteins E, Genetic, Alzheimer Disease, Internal medicine, Acquired Cognitive Impairment, Genetics, medicine, Humans, Obesity, Polymorphism, Molecular Biology, Triglycerides, Alleles, Prevention, Human Genome, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, Brain Disorders, 030104 developmental biology, Dementia, Steatosis, Digestive Diseases, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P

Published
2021

33. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author

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

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

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

Published
2021

34. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author

Tetsushi, Nakao, Alexander G, Bick, Margaret A, Taub, Seyedeh M, Zekavat, Md M, Uddin, Abhishek, Niroula, Cara L, Carty, John, Lane, Michael C, Honigberg, Joshua S, Weinstock, Akhil, Pampana, Christopher J, Gibson, Gabriel K, Griffin, Shoa L, Clarke, Romit, Bhattacharya, Themistocles L, Assimes, Leslie S, Emery, Adrienne M, Stilp, Quenna, Wong, Jai, Broome, Cecelia A, Laurie, Alyna T, Khan, Albert V, Smith, Thomas W, Blackwell, Veryan, Codd, Christopher P, Nelson, Zachary T, Yoneda, Juan M, Peralta, Donald W, Bowden, Marguerite R, Irvin, Meher, Boorgula, Wei, Zhao, Lisa R, Yanek, Kerri L, Wiggins, James E, Hixson, C Charles, Gu, Gina M, Peloso, Dan M, Roden, Muagututi'a S, Reupena, Chii-Min, Hwu, Dawn L, DeMeo, Kari E, North, Shannon, Kelly, Solomon K, Musani, Joshua C, Bis, Donald M, Lloyd-Jones, Jill M, Johnsen, Michael, Preuss, Russell P, Tracy, Patricia A, Peyser, Dandi, Qiao, Pinkal, Desai, Joanne E, Curran, Barry I, Freedman, Hemant K, Tiwari, Sameer, Chavan, Jennifer A, Smith, Nicholas L, Smith, Tanika N, Kelly, Bertha, Hidalgo, L Adrienne, Cupples, Daniel E, Weeks, Nicola L, Hawley, Ryan L, Minster, Ranjan, Deka, Take T, Naseri, Lisa, de Las Fuentes, Laura M, Raffield, Alanna C, Morrison, Paul S, Vries, Christie M, Ballantyne, Eimear E, Kenny, Stephen S, Rich, Eric A, Whitsel, Michael H, Cho, M Benjamin, Shoemaker, Betty S, Pace, John, Blangero, Nicholette D, Palmer, Braxton D, Mitchell, Alan R, Shuldiner, Kathleen C, Barnes, Susan, Redline, Sharon L R, Kardia, Gonçalo R, Abecasis, Lewis C, Becker, Susan R, Heckbert, Jiang, He, Wendy, Post, Donna K, Arnett, Ramachandran S, Vasan, Dawood, Darbar, Scott T, Weiss, Stephen T, McGarvey, Mariza, de Andrade, Yii-Der Ida, Chen, Robert C, Kaplan, Deborah A, Meyers, Brian S, Custer, Adolfo, Correa, Bruce M, Psaty, Myriam, Fornage, JoAnn E, Manson, Eric, Boerwinkle, Barbara A, Konkle, Ruth J F, Loos, Jerome I, Rotter, Edwin K, Silverman, Charles, Kooperberg, John, Danesh, Nilesh J, Samani, Siddhartha, Jaiswal, Peter, Libby, Patrick T, Ellinor, Nathan, Pankratz, Benjamin L, Ebert, Alexander P, Reiner, Rasika A, Mathias, Ron, Do, and Pradeep, Natarajan

Subjects
Multidisciplinary
Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Published
2022

35. Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

Author

George Hindy, Peter Dornbos, Mark D. Chaffin, Dajiang J. Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A. Aguilar-Salinas, Lucinda Antonacci-Fulton, Diego Ardissino, Donna K. Arnett, Stella Aslibekyan, Gil Atzmon, Christie M. Ballantyne, Francisco Barajas-Olmos, Nir Barzilai, Lewis C. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Matthew J. Bown, Jennifer A. Brody, Jai G. Broome, Noël P. Burtt, Brian E. Cade, Federico Centeno-Cruz, Edmund Chan, Yi-Cheng Chang, Yii-Der I. Chen, Ching-Yu Cheng, Won Jung Choi, Rajiv Chowdhury, Cecilia Contreras-Cubas, Emilio J. Córdova, Adolfo Correa, L. Adrienne Cupples, Joanne E. Curran, John Danesh, Paul S. de Vries, Ralph A. DeFronzo, Harsha Doddapaneni, Ravindranath Duggirala, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Jose C. Florez, Myriam Fornage, Barry I. Freedman, Valentin Fuster, Ma. Eugenia Garay-Sevilla, Humberto García-Ortiz, Soren Germer, Richard A. Gibbs, Christian Gieger, Benjamin Glaser, Clicerio Gonzalez, Maria Elena Gonzalez-Villalpando, Mariaelisa Graff, Sarah E. Graham, Niels Grarup, Leif C. Groop, Xiuqing Guo, Namrata Gupta, Sohee Han, Craig L. Hanis, Torben Hansen, Jiang He, Nancy L. Heard-Costa, Yi-Jen Hung, Mi Yeong Hwang, Marguerite R. Irvin, Sergio Islas-Andrade, Gail P. Jarvik, Hyun Min Kang, Sharon L.R. Kardia, Tanika Kelly, Eimear E. Kenny, Alyna T. Khan, Bong-Jo Kim, Ryan W. Kim, Young Jin Kim, Heikki A. Koistinen, Charles Kooperberg, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Leslie A. Lange, Jiwon Lee, Juyoung Lee, Seonwook Lee, Donna M. Lehman, Rozenn N. Lemaitre, Allan Linneberg, Jianjun Liu, Ruth J.F. Loos, Steven A. Lubitz, Valeriya Lyssenko, Ronald C.W. Ma, Lisa Warsinger Martin, Angélica Martínez-Hernández, Rasika A. Mathias, Stephen T. McGarvey, Ruth McPherson, James B. Meigs, Thomas Meitinger, Olle Melander, Elvia Mendoza-Caamal, Ginger A. Metcalf, Xuenan Mi, Karen L. Mohlke, May E. Montasser, Jee-Young Moon, Hortensia Moreno-Macías, Alanna C. Morrison, Donna M. Muzny, Sarah C. Nelson, Peter M. Nilsson, Jeffrey R. O’Connell, Marju Orho-Melander, Lorena Orozco, Colin N.A. Palmer, Nicholette D. Palmer, Cheol Joo Park, Kyong Soo Park, Oluf Pedersen, Juan M. Peralta, Patricia A. Peyser, Wendy S. Post, Michael Preuss, Bruce M. Psaty, Qibin Qi, D.C. Rao, Susan Redline, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Nilesh Samani, Heribert Schunkert, Claudia Schurmann, Daekwan Seo, Jeong-Sun Seo, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Adrienne M. Stilp, E. Shyong Tai, Claudia H.T. Tam, Kent D. Taylor, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Michael Y. Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Miriam S. Udler, Rob M. van Dam, Ramachandran S. Vasan, Karine A. Viaud Martinez, Fei Fei Wang, Xuzhi Wang, Hugh Watkins, Daniel E. Weeks, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, Lisa R. Yanek, Sekar Kathiresan, Daniel J. Rader, Jerome I. Rotter, Michael Boehnke, Mark I. McCarthy, Cristen J. Willer, Pradeep Natarajan, Jason A. Flannick, Amit V. Khera, Gina M. Peloso, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Clinicum, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, and Department of Public Health

Subjects
APOC3, Blood Glucose, Multifactorial Inheritance, gene-based association, Polymorphism, Single Nucleotide, Article, Open Reading Frames, ANGPTL3, lipid, OF-FUNCTION MUTATIONS, BINDING, Databases, Genetic, SEQUENCE VARIANTS, Genetics, Humans, Exome, Genetic Predisposition to Disease, SINUSOIDAL ENDOTHELIAL-CELLS, Genetics (clinical), Alleles, RISK, IDENTIFICATION, 1184 Genetics, developmental biology, physiology, association, cholesterol, Genetic Variation, Computational Biology, Molecular Sequence Annotation, PERILIPIN, Lipid Metabolism, Lipids, Genetics, Population, Phenotype, Diabetes Mellitus, Type 2, Liver, Case-Control Studies, exome sequencing, TRIGLYCERIDES, Genome-Wide Association Study
Abstract

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels. This work was supported by a grant from the Swedish Research Council (2016-06830) and grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL142711 and R01HL127564. Please refer to the supplemental information for the full acknowledgements. Sí

Published
2022

36. Symptoms Suggestive of Gastroparesis in a Community-Based Cohort of European Americans and African Americans with Type 2 Diabetes Mellitus

Author

Kenneth L. Koch, Donald W. Bowden, Landon K. Brown, Jianzhao Xu, Fang-Chi Hsu, and Barry I. Freedman

Subjects
Male, medicine.medical_specialty, Gastroparesis, Physiology, Population, Severity of Illness Index, White People, Article, Cohort Studies, Quality of life, Internal medicine, Diabetes mellitus, North Carolina, Prevalence, medicine, Humans, education, Depression (differential diagnoses), Aged, education.field_of_study, business.industry, Gastroenterology, Type 2 Diabetes Mellitus, Middle Aged, medicine.disease, Black or African American, Diabetes Mellitus, Type 2, Cohort, Anxiety, Female, medicine.symptom, business
Abstract

BACKGROUND: Although gastroparesis is seen in patients with type 2 diabetes mellitus (T2DM), the prevalence of symptoms suggestive of gastroparesis in patients with T2DM is unknown, particularly among African Americans. AIMS: To determine the prevalence of symptoms associated with gastroparesis in a large community-based population of European Americans and African Americans with T2DM. METHODS: Individuals with T2DM in the Diabetes Heart Study were asked to complete the gastroparesis cardinal symptom index (GCSI) and other GI-related questionnaires. GCSI total score ≥ 18 represented moderate or worse symptoms suggestive of gastroparesis. RESULTS: A total of 1253 participants (700 female, 553 male) completed the GCSI: 750 were European American and 503 African American. GCSI scores ≥ 18 were recorded in 72 participants: 38 (5%) of European Americans and 34 (7%) of African Americans. The average GCSI was 24.1 in European Americans and 24.6 in African Americans, indicating moderate to severe symptoms. Compared to European Americans with GCSI scores ≥ 18, African Americans were younger (59.4 vs. 53.3 years, p = 0.004), had earlier onset of T2DM (46.3 vs. 40.1 years, p = 0.01), higher HbA1c (7.6 vs. 9.1, p = 0.0009), underwent fewer upper endoscopies (55.3% vs. 26.5%, p = 0.02), and had more anxiety and depression (p < 0.001). CONCLUSIONS: Moderate or greater symptoms suggestive of gastroparesis are present in 5–7% of European and African American patients with T2DM in community-based populations. Symptoms suggestive of gastroparesis may be underappreciated in patients with T2DM and account for upper gastrointestinal symptoms, unexplained glycemic control issues, and decreased quality of life.

Published
2019

37. APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale

Author

Jonathan S. Bromberg, Darshana Dadhania, Donald W. Bowden, Laurie P Russell, Emilio D. Poggio, Barry I. Freedman, Timothy E. Craven, Madhav C. Menon, Krista L. Lentine, Bruce A. Julian, Jasmin Divers, Roslyn B. Mannon, Sylvia E. Rosas, Afshin Parsa, Nishadi Rajapakse, Nichole Jefferson, Amber Reeves-Daniel, Alessia Fornoni, Ana S. Iltis, Giselle Guerra, Elling Eidbo, Robert J. Stratta, Chi-yuan Hsu, Lijun Ma, Mitzie Spainhour, Michael D. Gautreaux, Daniel C. Brennan, Paul L. Kimmel, Nicholette D. Palmer, Mariella Ortigosa-Goggins, Matthew R. Weir, J. Brian Moore, Sumit Mohan, Carl D. Langefeld, Meyeon Park, Stephen O. Pastan, Patrick O. Gee, Amir A. Alexander, Mona D. Doshi, David K. Klassen, S. Carrie Smith, Deirdre Sawinski, Marva Moxey-Mims, David M. Reboussin, Kelly A. Birdwell, Rasheed Gbadegesin, Brad C. Astor, Kenneth A. Newell, Patrick P. Koty, Gordon Bowen, Jonah Odim, and Barbara Murphy

Subjects
United Network for Organ Sharing, medicine.medical_specialty, graft failure, 030232 urology & nephrology, kidney transplantation, 030204 cardiovascular system & hematology, lcsh:RC870-923, outcomes, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, medicine, Family history, APOL1, Kidney transplantation, African Americans, urogenital system, business.industry, lcsh:Diseases of the genitourinary system. Urology, medicine.disease, Institutional review board, 3. Good health, Histocompatibility, Transplantation, Nephrology, Family medicine, Donation, business, chronic kidney disease, Kidney disease
Abstract

Introduction Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation., Graphical abstract

Published
2019

38. Clonal hematopoiesis is driven by aberrant activation of TCL1A

Author

Joshua S. Weinstock, Jayakrishnan Gopakumar, Bala Bharathi Burugula, Md Mesbah Uddin, Nikolaus Jahn, Julia A. Belk, Bence Daniel, Nghi Ly, Taralyn M. Mack, Cecelia A. Laurie, Jai G. Broome, Kent D. Taylor, Xiuqing Guo, Moritz F. Sinner, Aenne S. von Falkenhausen, Stefan Kääb, Alan R. Shuldiner, Jeffrey R. O’Connell, Joshua P. Lewis, Eric Boerwinkle, Kathleen C. Barnes, Nathalie Chami, Eimear E. Kenny, Ruth J. Loos, Myriam Fornage, Lifang Hou, Donald M. Lloyd-Jones, Susan Redline, Brian E. Cade, Bruce M. Psaty, Joshua C. Bis, Jennifer A. Brody, Edwin K. Silverman, Jeong H. Yun, Dandi Qiao, Nicholette D. Palmer, Barry I. Freedman, Donald W. Bowden, Michael H. Cho, Dawn L. DeMeo, Ramachandran S. Vasan, Lisa R. Yanek, Lewis C. Becker, Sharon Kardia, Patricia A. Peyser, Jiang He, Michiel Rienstra, Pim Van der Harst, Robert Kaplan, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Donna K. Arnett, Marguerite R. Irvin, Hemant Tiwari, Michael J. Cutler, Stacey Knight, J Brent. Muhlestein, Adolfo Correa, Laura M. Raffield, Yan Gao, Mariza de Andrade, Jerome I. Rotter, Stephen S. Rich, Russell P. Tracy, Barbara A. Konkle, Jill M. Johnsen, Marsha M. Wheeler, J. Gustav Smith, Olle Melander, Peter M. Nilsson, Brian S. Custer, Ravindranath Duggirala, Joanne E. Curran, John Blangero, Stephen McGarvey, L. Keoki Williams, Shujie Xiao, Mao Yang, C. Charles. Gu, Yii-Der Ida. Chen, Wen-Jane Lee, Gregory M. Marcus, John P. Kane, Clive R. Pullinger, M. Benjamin Shoemaker, Dawood Darbar, Dan Roden, Christine Albert, Charles Kooperberg, Ying Zhou, JoAnn E. Manson, Pinkal Desai, Andrew Johnson, Rasika Mathias, Thomas W. Blackwell, Goncalo R. Abecasis, Albert V. Smith, Hyun M. Kang, Ansuman T. Satpathy, Pradeep Natarajan, Jacob Kitzman, Eric Whitsel, Alexander P. Reiner, Alexander G. Bick, and Sidd Jaiswal

Abstract

A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.

Published
2021

39. A framework for detecting noncoding rare variant associations of large-scale whole-genome sequencing studies

Author

Adolfo Correa, Corbin Quick, Jennifer A. Brody, Daniel E. Weeks, Rounak Dey, Joanne E. Curran, Charles Kooperberg, Wei Zhao, Brian G. Kral, Lisa W. Martin, Christen J. Willer, Donald W. Bowden, Eric Boerwinkle, Theodore Arapoglou, Joshua C. Bis, Barry I. Freedman, Leslie A. Lange, Ryan Sun, James G. Wilson, Lawrence F. Bielak, May E. Montasser, Kent D. Taylor, Jerome I. Rotter, Ramachandran S. Vasan, L. Adrienne Cupples, Rita R. Kalyani, Hufeng Zhou, Ani Manichaikul, John Blangero, Han Chen, Patricia A. Peyser, Stephen S. Rich, Brian E. Cade, Sheila M. Gaynor, Paul S. de Vries, Xihong Lin, Susan Redline, Thomas W. Blackwell, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, Xihao Li, Bruce M. Psaty, Ravindranath Duggirala, Matthew P. Conomos, Kenneth Rice, Donna K. Arnett, Muagututi‘a Sefuiva Reupena, Alanna C. Morrison, Nicholette D. Palmer, Jennifer A. Smith, Harald H H Göring, Alexander P. Reiner, Lisa R. Yanek, Braxton D. Mitchell, Laura M. Raffield, Yaowu Liu, Xiuqing Guo, Gina M. Peloso, Zilin Li, Pradeep Natarajan, and Take Naseri

Subjects
Whole genome sequencing, Technology, Genome, Whole Genome Sequencing, Human Genome, Genetic Variation, Scale (descriptive set theory), Computational biology, Replicate, TOPMed Lipids Working Group, Biological Sciences, Biology, Medical and Health Sciences, Annotation, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Phenotype, Good Health and Well Being, Genetics, Humans, Generic health relevance, Genome-Wide Association Study, Biotechnology, Developmental Biology, Genetic association
Abstract

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare variants’ (RVs) associations with complex human traits. Variant set analysis is a powerful approach to study RV association, and a key component of it is constructing RV sets for analysis. However, existing methods have limited ability to define analysis units in the noncoding genome. Furthermore, there is a lack of robust pipelines for comprehensive and scalable noncoding RV association analysis. Here we propose a computationally-efficient noncoding RV association-detection framework that uses STAAR (variant-set test for association using annotation information) to group noncoding variants in gene-centric analysis based on functional categories. We also propose SCANG (scan the genome)-STAAR, which uses dynamic window sizes and incorporates multiple functional annotations, in a non-gene-centric analysis. We furthermore develop STAARpipeline to perform flexible noncoding RV association analysis, including gene-centric analysis as well as fixed-window-based and dynamic-window-based non-gene-centric analysis. We apply STAARpipeline to identify noncoding RV sets associated with four quantitative lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several noncoding RV associations in an additional 9,123 TOPMed samples.

Published
2021

40. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author

Akhil Pampana, Xiuqing Guo, Tanika N. Kelly, Yii-Der Ida Chen, Charles Kooperberg, Chii-Min Hwu, Mariaelisa Graff, Jiang He, Xihao Li, Patrick T. Ellinor, Joshua C. Bis, Kari E. North, Nancy L. Heard-Costa, Joseph Park, Stacey Gabriel, Joanne E. Curran, Braxton D. Mitchell, Lee-Ming Chuang, Ravindranath Duggirala, Jerome I. Rotter, Robert C. Kaplan, Soren Germer, Pradeep Natarajan, Take Naseri, Xihong Lin, Susan K. Dutcher, Stella Aslibekyan, Ryan W. Kim, Daniel J. Rader, Richard A. Gibbs, Myriam Fornage, Eric Boerwinkle, Bertha Hidalgo, Muagututi’a S. Reupena, Deborah A. Nickerson, Zhe Wang, Donald W. Bowden, Yuxuan Wang, Alanna C. Morrison, Stephen S. Rich, David Zhang, Gina M. Peloso, Xiaohui Li, Martin Lisa, Lisa de las Fuentes, Zilin Li, Alexander P. Reiner, Jennifer A. Brody, Lisa R. Yanek, Marguerite R. Irvin, Bruce M. Psaty, Bao Wei, Preuss Michael, Leslie A. Lange, John T. Wilkins, Russell P. Tracy, Paul S. de Vries, Wei Zhao, Rasika A. Mathias, Susan Redline, Xiao Sun, Kent D. Taylor, Barry I. Freedman, Ani Manichaikul, Donna K. Arnett, Nicholette D. Palmer, Cristen J. Willer, Steven A. Lubitz, Sharon L.R. Kardia, L. Adrienne Cupples, Ramachandran S. Vasan, May E. Montasser, Ren-Hua Chung, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, Ruth J. F. Loos, Jennifer A. Smith, John Blangero, Brian G. Kral, Karine A. Viaud Martinez, Stephen T. McGarvey, Adolfo Correa, Michael Y. Tsai, Patricia A. Peyser, and Brian E. Cade

Subjects
Genetics, Whole genome sequencing, Genome Scan, Blood lipids, Biology, medicine.disease, Genome, symbols.namesake, Mendelian inheritance, symbols, medicine, lipids (amino acids, peptides, and proteins), Allele, Gene, Dyslipidemia
Abstract

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rareLDLRintronic variants associated with markedly increased LDL-C, similar to rareLDLRexonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Published
2021

41. Whole genome sequence analysis of blood lipid levels in66,000 individuals

Author

Margaret Sunitha, Selvaraj, Xihao, Li, Zilin, Li, Akhil, Pampana, David Y, Zhang, Joseph, Park, Stella, Aslibekyan, Joshua C, Bis, Jennifer A, Brody, Brian E, Cade, Lee-Ming, Chuang, Ren-Hua, Chung, Joanne E, Curran, Lisa, de Las Fuentes, Paul S, de Vries, Ravindranath, Duggirala, Barry I, Freedman, Mariaelisa, Graff, Xiuqing, Guo, Nancy, Heard-Costa, Bertha, Hidalgo, Chii-Min, Hwu, Marguerite R, Irvin, Tanika N, Kelly, Brian G, Kral, Leslie, Lange, Xiaohui, Li, Martin, Lisa, Steven A, Lubitz, Ani W, Manichaikul, Preuss, Michael, May E, Montasser, Alanna C, Morrison, Take, Naseri, Jeffrey R, O'Connell, Nicholette D, Palmer, Patricia A, Peyser, Muagututia S, Reupena, Jennifer A, Smith, Xiao, Sun, Kent D, Taylor, Russell P, Tracy, Michael Y, Tsai, Zhe, Wang, Yuxuan, Wang, Wei, Bao, John T, Wilkins, Lisa R, Yanek, Wei, Zhao, Donna K, Arnett, John, Blangero, Eric, Boerwinkle, Donald W, Bowden, Yii-Der Ida, Chen, Adolfo, Correa, L Adrienne, Cupples, Susan K, Dutcher, Patrick T, Ellinor, Myriam, Fornage, Stacey, Gabriel, Soren, Germer, Richard, Gibbs, Jiang, He, Robert C, Kaplan, Sharon L R, Kardia, Ryan, Kim, Charles, Kooperberg, Ruth J F, Loos, Karine A, Viaud-Martinez, Rasika A, Mathias, Stephen T, McGarvey, Braxton D, Mitchell, Deborah, Nickerson, Kari E, North, Bruce M, Psaty, Susan, Redline, Alexander P, Reiner, Ramachandran S, Vasan, Stephen S, Rich, Cristen, Willer, Jerome I, Rotter, Daniel J, Rader, Xihong, Lin, Gina M, Peloso, and Sebastian, Zoellner

Subjects
Multidisciplinary, Whole Genome Sequencing, General Physics and Astronomy, Humans, General Chemistry, Cholesterol, LDL, Lipids, General Biochemistry, Genetics and Molecular Biology, Alleles, Genome-Wide Association Study
Abstract

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Published
2021

42. Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes

Author

Stefan Weiss, Gauti Kjartan Gislason, Matthew J. Budoff, Valborg Gudmundsdottir, Xiuqing Guo, Lawrence F. Bielak, Joshua C. Bis, Jie Yao, Latchezar Dimitrov, Leslie A. Lange, Patricia A. Peyser, Lingyi Lu, Vilmundur Gudnason, Jerome I. Rotter, Barry I. Freedman, Lihua Wang, M. Arfan Ikram, Mohsen Ghanbari, Yingchang Lu, Jiaxi Zhu, Elias F Gudmundsson, Gerardo Heiss, Yi-Ping Fu, Maryam Kavousi, Shih-Jen Hwang, Sharon L.R. Kardia, Laura M. Raffield, André G. Uitterlinden, Carl D. Langefeld, Donald W. Bowden, Ping An, Daniel Bos, Kent D. Taylor, Ulf Schminke, Albert V. Smith, Bruce M. Psaty, James G. Wilson, Shyh-Huei Chen, Maggie C.Y. Ng, Christopher J. O'Donnell, Mary F. Feitosa, Nora Franceschini, Epidemiology, Radiology & Nuclear Medicine, and Internal Medicine

Subjects
0301 basic medicine, Aging, Carotid arteries, Genome-wide association study, Type 2 diabetes, 030204 cardiovascular system & hematology, Cardiovascular, Coronary artery disease, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Diabetes, General Medicine, Heart Disease, cardiovascular system, Cardiology, medicine.symptom, Type 2, coronary artery disease, medicine.medical_specialty, carotid intima-media thickness, Black People, Asymptomatic, White People, Article, Diabetes Complications, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes Mellitus, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Heart Disease - Coronary Heart Disease, genome-wide association study, business.industry, Prevention, Human Genome, nutritional and metabolic diseases, Atherosclerosis, medicine.disease, Good Health and Well Being, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Subclinical atherosclerosis, Coronary artery calcification, business, Genome-Wide Association Study
Abstract

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. Results: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B ) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1 ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P =2.0×10 -8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations ( P -4 ) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

Published
2021

43. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center

Subjects
Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Published
2019

44. Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent

Author

Rajendra Bansal, Swapan K Das, Christopher A. Girkin, Lama A. Al-Aswad, Radha Ayyagari, Felipe A. Medeiros, Xiuqing Guo, Joseph F. Panarelli, Jeffrey M. Liebmann, Harvey Dubiner, Yii-Der Ida Chen, Yang Hai, Jasmin Divers, Kent D. Taylor, Garvin H. Davis, Donald W. Bowden, Barry I. Freedman, Robert N. Weinreb, Celso Tello, Nicholas P. Bell, Jeremy Cotliar, Robert Ritch, Paul A Sidoti, John P Mitchell, Nicholette D. Palmer, George A. Cioffi, Lauren S. Blieden, Sung Chul Park, Maggie C.Y. Ng, Brian C Samuels, Jerome I. Rotter, Linda M. Zangwill, Dana M. Blumberg, Carl D. Langefeld, African Descent, and Robert M. Feldman

Subjects
medicine.medical_specialty, genetic structures, Open angle glaucoma, business.industry, Glaucoma, Single-nucleotide polymorphism, Genome-wide association study, medicine.disease, Population stratification, eye diseases, Minor allele frequency, Ophthalmology, Internal medicine, Medicine, business, Allele frequency, Imputation (genetics)
Abstract

Purpose To find genetic contributions to glaucoma in African Americans. Design Cross-sectional, case-control study. Participants One thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine. Methods MegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs). Main Outcome Measures Primary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946). Results Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 β, 0.36; standard error, 0.065; P Conclusions A novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

Published
2019

45. PSOAS AND PARASPINOUS MUSCLE MEASUREMENTS ON COMPUTED TOMOGRAPHY PREDICT MORTALITY IN EUROPEAN AMERICANS WITH TYPE 2 DIABETES MELLITUS

Author

Leon Lenchik, Susan Carrie Smith, F. C. Hsu, Barry I. Freedman, Bryan M. Tucker, Thomas C. Register, J. Xu, Donald W. Bowden, and Mariana Murea

Subjects
Male, medicine.medical_specialty, Paraspinal Muscles, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, National Death Index, White People, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, Humans, Medicine, Aged, Psoas Muscles, business.industry, Proportional hazards model, Hazard ratio, Type 2 Diabetes Mellitus, Skeletal muscle, General Medicine, Middle Aged, medicine.disease, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Cardiology, Female, Tomography, X-Ray Computed, business, Body mass index
Abstract

Background: Appendicular skeletal muscle mass index and muscle attenuation (density) are negatively associated with mortality in European-derived populations. Objectives: The present analyses assessed association between axial skeletal muscle density and muscle index with mortality in European Americans with type 2 diabetes mellitus (T2D). Design: Single-center observational study. Setting: Diabetes Heart Study. Participants: 839 European Americans with T2D. Methods: Computed tomography-measured psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (Hounsfield Units) were assessed in all participants. A Cox proportional hazards model was computed. The fully-adjusted model included covariates age, sex, body mass index, smoking, alcohol use, diabetes duration, insulin use, hormone replacement therapy (women), prevalent cardiovascular disease (CVD), hypertension, and coronary artery calcified atherosclerotic plaque mass score. Deaths were recorded in the National Death Index data through December 31, 2015. Results: Participants included 428 women and 411 men with median (25th, 75th quartile) age 62.8 (56.1, 69.1) years and diabetes duration 8.0 (5.0, 14.0) years. After 11.9 (9.4, 13.3) years of follow-up, 314 (37.4%) of participants were deceased. In the fully-adjusted model, psoas muscle density (hazard ratio [HR] 0.81, p

Published
2019

46. The African Descent and Glaucoma Evaluation Study (ADAGES) III

Author

Lama A. Al-Aswad, Xiuqing Guo, Yii-Der Ida Chen, Linda M. Zangwill, Swapan K Das, Paul A Sidoti, Sung Chul Park, Mark Christopher, Garvin H. Davis, Barry I. Freedman, Maggie C.Y. Ng, Robert N. Weinreb, Luke J. Saunders, Eunice Williams-Steppe, Nicholas P. Bell, Jeffrey M. Liebmann, Harvey Dubiner, Keri Dirkes, Nicholette D. Palmer, Rigby Slight, Daniel A. Auerbach, Kevin Sandow, Robert Ritch, Jasmin Divers, Lauren S. Blieden, Suzanne Vega, Brian C Samuels, Donald W. Bowden, Jeremy Cotliar, Matthew Holmann, Joseph F. Panarelli, Jerome I. Rotter, Kathryn Roll, Radha Ayyagari, African Descent, Robert M. Feldman, John P Mitchell, George A. Cioffi, Christopher A. Girkin, Dana M. Blumberg, Carl D. Langefeld, Naama Hammel, Celso Tello, Felipe A. Medeiros, Kent D. Taylor, and Rajendra Bansal

Subjects
0301 basic medicine, medicine.medical_specialty, Intraocular pressure, genetic structures, Cross-sectional study, medicine.medical_treatment, Population, Glaucoma, 03 medical and health sciences, 0302 clinical medicine, Ophthalmology, medicine, Glaucoma surgery, education, education.field_of_study, Glaucoma medication, business.industry, Diabetic retinopathy, medicine.disease, eye diseases, 030104 developmental biology, Specimen collection, 030221 ophthalmology & optometry, sense organs, business
Abstract

PURPOSE:To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN:Cross-sectional, case-control study. PARTICIPANTS:Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS:Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES:Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS:The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS:With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.

Published
2019

47. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author

Carly J. van der Heide, Jessica N. Cooke Bailey, Susan Williams, Dan Milea, José Paulo Cabral de Vasconcellos, Sadiq M. Abdullahi, Douglas E. Gaasterland, Ifeoma N. Asimadu, Sayoko E. Moroi, Hasnaa Lamari, Sarah J. Garnai, Janey L. Wiggs, Donald L. Budenz, R. Rand Allingham, Julia E. Richards, Jonathan L. Haines, Jerome I. Rotter, Michael G. Anderson, Xiuqing Guo, Robert M. Feldman, Michael A. Hauser, Yii-Der Ida Chen, Hugo Freire Nunes, Leon W. Herndon, John F. Ervin, Stephen Akafo, Radha Ayyagari, Thomas J. Hoffmann, Rachel W. Kuchtey, Michèle Ramsay, Prisca Biangoup Nyamsi, Zheng Li, Eric Jorgenson, Kar Seng Sim, Ebenezer Obeng-Nyarkoh, William C. Bromley, Christopher A. Girkin, Robert N. Weinreb, Alberta A H J Thiadens, Serge Resnikoff, William E. Sponsel, Maggie C.Y. Ng, Christine M. Hulette, Donald W. Bowden, Saydou Bakayoko, Jeffrey M. Liebmann, Harvey Dubiner, Suhanya Okeke, Abba Hydara, Ruth J. F. Loos, Adeyinka O. Ashaye, Olusegun Olaniyi, Mahmoud B. Alhassan, Khaled K. Abu-Amero, Christopher J Hammond, Tin Aung, John H. Fingert, Robert P. Igo, Shih-Hsiu Wang, Rui Barroso Schimiti, Pratap Challa, Robert F. Mullins, Rodolfo A. Perez-Grossmann, Nouhoum Guirou, Margaret A. Pericak-Vance, Anthony Okeke, Pieter W.M. Bonnemaijer, Paulo Vinicius Svidnicki, Abdoulaye Napo, Louise R. Pasquale, Joyce Kabwe, Chiea Chuen Khor, Mônica Barbosa de Melo, Girish N. Nadkarni, CM Chuka-Okosa, Neil Risch, Nkiru Kizor-Akaraiwe, Miles J. Flamme-Wiese, Cornelia M. van Duijn, N J Uche, Joseph Msosa, Olusola Olawoye, Linda M. Zangwill, Mariana B. Oliveira, Caroline C W Klaver, Allison E. Ashley Koch, Vital Paulino Costa, Ngoy Janvier Kilangalanga, Trevor R. Carmichael, Xue Qin, Kent D. Taylor, Yutao Liu, Dianne A. Cruz, Epidemiology, and Ophthalmology

Subjects
Male, medicine.medical_specialty, Genotype, genetic structures, Open angle glaucoma, Population, Black People, Glaucoma, Genome-wide association study, Polymorphism, Single Nucleotide, 01 natural sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Interquartile range, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, 0101 mathematics, education, Adaptor Proteins, Signal Transducing, Aged, Original Investigation, education.field_of_study, Amyloid beta-Peptides, business.industry, 010102 general mathematics, Case-control study, General Medicine, Odds ratio, Middle Aged, medicine.disease, Immunohistochemistry, eye diseases, Case-Control Studies, Female, Risk assessment, business, Glaucoma, Open-Angle, Genome-Wide Association Study
Abstract

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Published
2019

48. Erratum to Gene Set Enrichment Analyses Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy. Am J Ophthalmol 2022;233:111-123

Author

Lucia Sobrin, Gayatri Susarla, Lynn Stanwyck, John M. Rouhana, Ashley Li, Samuela Pollack, Robert P. Igo, Richard A. Jensen, Xiaohui Li, Maggie C.Y. Ng, Albert V. Smith, Jane Z. Kuo, Kent D. Taylor, Barry I. Freedman, Donald W. Bowden, Alan Penman, Ching J. Chen, Jamie E. Craig, Sharon G. Adler, Emily Y. Chew, Mary Frances Cotch, Brian Yaspan, Paul Mitchell, Jie Jin Wang, Barbara E.K. Klein, Tien Y. Wong, Jerome I. Rotter, Kathyrn P. Burdon, Sudha K. Iyengar, and Ayellet V. Segrè

Subjects
Ophthalmology
Published
2022

49. The trans-ancestral genomic architecture of glycemic traits

Author

Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)

Subjects
Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Published
2021

50. Bidirectional Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of intermediate potential

Author

Dan M. Roden, John Blangero, Myriam Fornage, Kerri L. Wiggins, Benjamin L. Ebert, Gina M. Peloso, Tetsushi Nakao, John Lane, Russell P. Tracy, Lisa de las Fuentes, Ryan L. Minster, Donna K. Arnett, Seyedeh M. Zekavat, Laura M. Raffield, Akhil Pampana, Stephen S. Rich, Kathleen C. Barnes, R. Mathias, Alyna T. Khan, Lewis C. Becker, James E. Hixson, Gabriel K. Griffin, Nicholas L. Smith, JoAnn E. Manson, Robert C. Kaplan, Gonçalo R. Abecasis, Nathan Pankratz, Alexander P. Reiner, Donald M. Lloyd-Jones, Sharon L.R. Kardia, C. Charles Gu, Wendy Post, Lisa R. Yanek, Tanika N. Kelly, Hemant K. Tiwari, Jennifer A. Smith, Shoa L. Clarke, Ramachandran S. Vasan, Themistocles L. Assimes, Betty S. Pace, Jill M. Johnsen, Cara L. Carty, Pinkal Desai, Barry I. Freedman, Pradeep Natarajan, Margaret A. Taub, S Redline, Adrienne M. Stilp, Ranjan Deka, Alexander G. Bick, Donald W. Bowden, Mariza de Andrade, Abhishek Niroula, Joanne E. Curran, Quenna Wong, Siddhartha Jaiswal, Chii-Min Hwu, Michael Preuss, Christie M. Ballantyne, Shannon Kelly, Patrick T. Ellinor, Sameer Chavan, Dandi Qiao, Nicola L. Hawley, Charles Kooperberg, Juan M. Peralta, Braxton D. Mitchell, Solomon K. Musani, Jerome I. Rotter, Ruth J.F. Loos, Zachary T. Yoneda, Bruce M. Psaty, Christopher J. Gibson, Ron Do, Barbara A. Konkle, Marguerite R. Irvin, Jai G. Broome, Take Naseri, Alanna C. Morrison, L. Adrienne Cupples, Bertha A. Hildalgo, Jiang He, Mesbah Uddin, Dawood Darbar, Cecelia A. Laurie, Eric A. Whitsel, Patricia A. Peyser, Brian Custer, Michael H. Cho, Scott T. Weiss, Peter Libby, Susan R. Heckbert, Albert V. Smith, Joshua S. Weinstock, Meher Preethi Boorgula, M. Benjamin Shoemaker, Muagututi’a S. Reupena, Michael C. Honigberg, Nicholette D. Palmer, Wei Zhao, Paul S. Vries, Edwin K. Silverman, Daniel E. Weeks, Romit Bhattacharya, Joshua C. Bis, Kari E. North, Thomas W. Blackwell, Dawn L. DeMeo, Stephen T. McGarvey, Leslie S. Emery, A. R. Shuldiner, Yii-Der Ida Chen, Eric Boerwinkle, Adolfo Correa, Deborah A. Meyers, and Eimear E. Kenny

Subjects
Mendelian randomization, Locus (genetics), Telomerase reverse transcriptase, CAD, Computational biology, Biology, Causality, Germline, Telomere, Genetic association
Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Published
2021

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