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Start Over Author "Eric A. Whitsel" Publisher cold spring harbor laboratory
8 results on '"Eric A. Whitsel"'

1. Epigenome-wide meta-analysis of BMI in nine cohorts: examining the utility of epigenetic BMI in predicting metabolic health

Author

Whitney L. Do, Dianjianyi Sun, Karlijn Meeks, Pierre-Antoine Dugue, Ellen Demerath, Weihua Guan, Shengxu Li, Wei Chen, Roger Milne, Abedowale Adeyemo, Charles Agyemang, Rami Nassir, JoAnn Manson, Aladdin H Shadyab, Lifang Hou, Steve Horvath, Themistocles L. Assimes, Parveen Bhatti, Kristina Jordahl, Andrea Baccarelli, Alicia Smith, Lisa R. Staimez, Aryeh Stein, Eric A. Whitsel, K.M. Venkat Narayan, and Karen Conneely

Abstract

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential utility of these cytosine-phosphate-guanine (CpG) sites in predicting metabolic health. We pooled summary statistics from six trans-ethnic EWAS of BMI representing nine cohorts (n=17058), replicated these findings in the Women’s Health Initiative (WHI, n=4822) and developed an epigenetic prediction score of BMI. In the pooled EWAS, 1265 CpG sites were associated with BMI (p

Published
2022

2. 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

3. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris

Subjects
0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Published
2020

4. Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

Author

Pinkal Desai, Ester Cerdeira Sabino, Dan M. Roden, Seyedeh M. Zekavat, Stephanie M. Gogarten, John Blangero, Hongsheng Gui, Jiang He, Patrick T. Ellinor, Benjamin L. Ebert, Mindy D. Szeto, Brian E. Cade, Sally E. Wenzel, Donald W. Bowden, Sharon L.R. Kardia, Arden Moscati, Cathy C. Laurie, Kathleen C. Barnes, Joanne E. Curran, Barbara A. Konkle, Cecelia A. Laurie, Jessica Lasky-Su, Sekar Kathiresan, Susan R. Heckbert, Jesse M. Engreitz, Laura M. Raffield, Barry I. Freedman, Braxton D. Mitchell, Lenore J. Launer, Quenna Wong, Rasika A. Mathias, Ramachandran S. Vasan, Adolfo Correa, Andrew D. Johnson, Donna K. Arnett, Esteban G. Burchard, Nicholette D. Palmer, Russell P. Tracy, Robert C. Kaplan, Susan Redline, Patricia A Peyser, JoAnn E. Manson, Lifang Hou, Erin J Buth, David A. Schwartz, Bruce D. Levy, Eric Boerwinkle, Jee-Young Moon, Stephen T. McGarvey, Kent D. Taylor, Hemant K. Tiwari, Eric A. Whitsel, Jiwon Lee, Jerome I. Rotter, Fei Fei Wang, Ida Yii-Der Chen, Sidd Jaiswal, Matthew Leventhal, Tanika N. Kelly, Marsha M. Wheeler, Priyadarshini Kachroo, Jill M. Johnsen, James E. Hixson, Scott T. Weiss, Albert V. Smith, L. Adrienne Cupples, Tasha E. Fingerlin, Margaret A. Taub, Wayne Huey-Herng Sheu, May E Montasser, Daniel Levy, Sebastian M. Armasu, Pradeep Natarajan, Joshua S. Weinstock, Lawrence F. Bielak, Dawood Darbar, Steven A. Lubitz, Stella Aslibekyan, Leslie A. Lange, Erik L. Bao, Hongyu Zhao, Alexander P. Reiner, Myriam Fornage, L. Keoki Williams, Marguerite R. Irvin, Alexander G. Bick, Charles P. Fulco, A.C.Y. Mak, Dabeeru C. Rao, Xiuqing Guo, Lewis C. Becker, Michelle Daya, Charles Kooperberg, Eric S. Lander, Ethan M. Lange, Juan M. Peralta, John A. Heit, M. Benjamin Shoemaker, Mariza de Andrade, Stephen S. Rich, Thomas W. Blackwell, Deborah A. Meyers, Bruce M. Psaty, Ruth J. F. Loos, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Vijay G. Sankaran, Edwin K. Silverman, Daniel E. Weeks, Jai G. Broome, Satish K. Nandakumar, Ivana V. Yang, James S. Floyd, Joseph Nasser, Eimear E. Kenny, Nicholas Rafaels, Joshua C. Bis, Kari E. North, James G. Wilson, Brian Custer, Michael H. Cho, and Paul L. Auer

Subjects
Genetics, 0303 health sciences, Somatic cell, Hematopoietic stem cell, Locus (genetics), Biology, Genome, Germline, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Genetic variation, medicine, CHEK2, Gene, 030304 developmental biology
Abstract

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2–4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

Published
2019
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5. Methylome-Wide Association Study of Central Adiposity Implicate Genes Involved in Immune and Endocrine Systems

Author

Penny Gordon-Larsen, Phillip E. Melton, Yun Li, Ching-Ti Liu, Rae-Chi Huang, Rahul Gondalia, Eric Boerwinkle, Anne E. Justice, Karen N. Conneely, Lifang Hou, Ellen W. Demerath, Myriam Fornage, Daniel Levy, Annie Green Howard, Megan L. Grove, Geetha Chittoor, Kari E. North, James D. Stewart, L. Adrienne Cupples, Eric A. Whitsel, Andrea A. Baccarelli, Trevor A. Mori, Lawrence J. Beilin, Elise Lim, Lindsay Fernández-Rhodes, Weihua Guan, Nancy L. Heard-Costa, and Jan Bressler

Subjects
2. Zero hunger, 0303 health sciences, Waist, business.industry, Physiology, Methylation, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, CpG site, DNA methylation, Endocrine system, Medicine, business, Body mass index, 030217 neurology & neurosurgery, TXNIP, 030304 developmental biology
Abstract

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist- to-hip ratio, and waist-to-height ratio adjusted for body mass index, in 2684 African American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated Cytosine-phosphate-Guanine methylation sites (CpGs) among adults using the Women’s Health Initiative and Framingham Heart Study participants (combined N=5743) and generalized associations in adolescents from The Raine Study (N=820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and 2 in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1, and RAP1GAP2 that had not previously been associated with obesity-related traits.

Published
2019
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6. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author

Lorenz Risch, Igor Rudan, Hilma Holm, Christopher P. Nelson, Jan A. Kors, Stefanie Aeschbacher, Stefan Kääb, Peter W. Macfarlane, Lars Lind, Amanda A. Seyerle, Ozren Polasek, Daniel F. Gudbjartsson, Xiuqing Guo, Nilesh J. Samani, Bruce M. Psaty, Rosa B. Thorolfsdottir, Elsayed Z. Soliman, Yong Qian, Mary L. Biggs, Antti Jula, Vilmundur Gudnason, Paul L. Huang, Tamara B. Harris, Gianfranco Sinagra, Luisa Foco, Anubha Mahajan, Mika Kähönen, Lu-Chen Weng, Borbala Mifsud, Stefan van Duijvenboden, Terho Lehtimäki, Jennifer A. Brody, Paolo Gasparini, Kathleen A. Ryan, Marten E. van den Berg, James J. Cranley, Eric Boerwinkle, Cathy C. Laurie, Annette Peters, Joshua C. Bis, Raymond Noordam, Andrew P. Morris, Johan Sundström, Lenore J. Launer, Stefan Weiss, Rebecca D. Jackson, Alison D. Murray, Jeffrey R. O'Connell, Aki S. Havulinna, Dennis O. Mook-Kanamori, Sheila Ulivi, Renée de Mutsert, Eric A. Whitsel, Adrienne M. Stilp, James P. Cook, Nona Sotoodehnia, Antonio Luiz Pinho Ribeiro, Seung Hoan Choi, Mark J. Caulfield, Sébastien Thériault, Henry J. Lin, Dan M. Roden, J. Wouter Jukema, James F. Wilson, Veikko Salomaa, Honghuang Lin, Andrew A. Hicks, Christy L. Avery, Nina Mononen, Dan E. Arking, Ruth J. F. Loos, Yalda Jamshidi, André G. Uitterlinden, Nina Hutri-Kähönen, Andrew Tinker, Gudmar Thorleifsson, Daniel Levy, Martina Müller-Nurasyid, Alexander P. Reiner, Bruno H. Stricker, Caroline Hayward, Yordi J. van de Vegte, Ioanna Ntalla, Tim D. Spector, Niek Verweij, Michael R. Barnes, Martin Gögele, Nathan R. Tucker, Arie C. Maan, Eduardo Tarazona-Santos, Katri Sääksjärvi, Maria Pina Concas, Pim van der Harst, Georg Ehret, Cecilia M. Lindgren, David Conen, Cornelia M. van Duijn, Muhammad B. Riaz, Leo-Pekka Lyytikäinen, Amelia W. Hall, Peter P. Pramstaller, Maria Fernanda Lima-Costa, Vilmantas Giedraitis, Emelia J. Benjamin, M. Fabiola Del Greco, Thomas Meitinger, Erwin P. Bottinger, Francesco Cucca, Aaron Isaacs, Carolina Roselli, James H. Cartwright, Massimo Mangino, Adolfo Correa, Patrick Sulem, Thibaud Boutin, Michiel Rienstra, Stephan B. Felix, Julia Ramirez, Kathleen F. Kerr, Jonathan Marten, David J. Porteous, Kent D. Taylor, Patrick T. Ellinor, Michele Orini, Susan R. Heckbert, Olli T. Raitakari, Girish N. Nadkarni, Edward G. Lakatta, Anna F. Dominiczak, Jie Yao, Erik Ingelsson, Christopher Newton-Cheh, Katharina Schramm, Jerome I. Rotter, Michael J. Cutler, Pashupati P. Mishra, Diane Fatkin, Marcus Dörr, Ulrike Peters, Solmaz Assa, Christian Fuchsberger, M. Abdullah Said, Catriona L. K. Barnes, Peter K. Joshi, M. Yldau van der Ende, Alvaro Alonso, James G. Wilson, Jun Ding, Kathryn L. Lunetta, Kjell Nikus, Helen R. Warren, Charles Kooperberg, Moritz F. Sinner, Sandosh Padmanabhan, Patricia B. Munroe, Jeffrey Haessler, Albert V. Smith, Alan R. Shuldiner, Morten S. Olesen, Konstantin Strauch, Steven A. Lubitz, J. Gustav Smith, Renan P. Souza, Michael Preuss, Kirill V. Tarasov, M. Benjamin Shoemaker, Barry London, Melanie Waldenberger, Cristian Pattaro, David O. Arnar, Gardar Sveinbjornsson, Alessandro De Grandi, Ian Ford, Kenneth Rice, Mark Chaffin, Kari Stefansson, Hao Mei, Uwe Völker, Blair H. Smith, Nathalia M. Araujo, Harry Campbell, Pier D. Lambiase, Stephanie M. Gogarten, May E. Montasser, Unnur Thorsteinsdottir, Ivana Kolcic, and Stella Trompet

Subjects
0303 health sciences, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cardiomyopathy, Atrial fibrillation, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Endophenotype, Cardiac conduction, medicine, Cardiology, PR interval, business, education, 030304 developmental biology
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Published
2019

7. GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations Swenson Hispanic/Latino QRS GWAS

Author

Susan Cheng, Natalie A. Bello, Amanda A. Seyerle, Tamar Sofer, Brenton R. Swenson, Heather M. Highland, Cathy C. Laurie, Raul Mendez-Giraldez, Jennifer E. Below, Timothy A. Thornton, Tin Louie, Nona Sotoodehnia, Charles Kooperberg, Christy L. Avery, Elsayed Z. Soliman, Lauren E. Petty, Kent D. Taylor, Daniel S. Evans, Henry J. Lin, Kathleen F. Kerr, Kelli K. Ryckman, Barbara McKnight, Xuejiang Guo, Jerome I. Rotter, Dawood Darbar, Eric A. Whitsel, Craig L. Hanis, Mike A. Nalls, Susan R. Heckbert, and Jie Yao

Subjects
0303 health sciences, business.industry, Hispanic latino, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Sudden death, 03 medical and health sciences, QRS complex, 0302 clinical medicine, Genotype, Medicine, cardiovascular diseases, 1000 Genomes Project, business, 030304 developmental biology, Demography, Genetic association
Abstract

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n=15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (P−8), including two novel loci:MYOCD, a nuclear protein expressed in the heart, andSYT1, an integral membrane protein. The top association in theMYOCDlocus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was for intronic SNP rs3922344 (P= 8.56×10−26) inSCN5A/SCN10A. Three additional previously identified loci,CDKN1A,VTI1A, andHAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.ConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

Published
2018
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8. GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

Author

John R. B. Perry, Steve Horvath, Andrea A. Baccarelli, Devin Absher, Allan F. McRae, Felix R. Day, Pei-Chien Tsai, James D. Stewart, Abraham Aviv, Jordana T. Bell, Lifang Hou, Morgan E. Levine, Roby Joehanes, Riccardo E. Marioni, Philip S. Tsao, Ken K. Ong, Massimo Mangino, Daniel Levy, Eric A. Whitsel, Brian H. Chen, Luting Xue, Naomi R. Wray, Toshiko Tanaka, Elias Salfati, Alexander P. Reiner, Kathryn L. Lunetta, Joanne M. Murabito, Austin Quach, Douglas P. Kiel, Alexia Cardona, Peter M. Visscher, Themistocles L. Assimes, Ian J. Deary, Ken Raj, Ake T. Lu, Idil Yet, Luigi Ferrucci, and Yun Li

Subjects
Genetics, 0303 health sciences, Mendelian Randomization Analysis, Genome-wide association study, Locus (genetics), Biology, Telomere, 03 medical and health sciences, 0302 clinical medicine, Ageing, 030220 oncology & carcinogenesis, DNA methylation, Epigenetics, Gene, 030304 developmental biology
Abstract

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P-11). Causal modelling indicatesTERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

Published
2017
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