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

Margaret A Taub¹, Matthew P Conomos², Rebecca Keener³, Kruthika R Iyer⁴, Joshua S Weinstock^{5

6}, Lisa R Yanek⁷, John Lane⁸, Tyne W Miller-Fleming⁹, Jennifer A Brody¹⁰, Laura M Raffield¹¹, Caitlin P McHugh², Deepti Jain², Stephanie M Gogarten², Cecelia A Laurie², Ali Keramati¹², Marios Arvanitis¹³, Albert V Smith^{5

6}, Benjamin Heavner², Lucas Barwick¹⁴, Lewis C Becker⁷, Joshua C Bis¹⁰, John Blangero¹⁵, Eugene R Bleecker^{16

17}, Esteban G Burchard^{18

19}, Juan C Celedón²⁰, Yen Pei C Chang²¹, Brian Custer^{22

23}, Dawood Darbar²⁴, Lisa de las Fuentes²⁵, Dawn L DeMeo^{26

27}, Barry I Freedman²⁸, Melanie E Garrett^{29

30}, Mark T Gladwin³¹, Susan R Heckbert^{32

33}, Bertha A Hidalgo³⁴, Marguerite R Irvin³⁴, Talat Islam³⁵, W Craig Johnson³⁶, Stefan Kaab^{37

38}, Lenore Launer³⁹, Jiwon Lee⁴⁰, Simin Liu⁴¹, Arden Moscati⁴², Kari E North⁴³, Patricia A Peyser⁴⁴, Nicholas Rafaels⁴⁵, Christine Seidman⁴⁶, Daniel E Weeks^{47

48}, Fayun Wen⁴⁹, Marsha M Wheeler⁵⁰, L Keoki Williams⁵¹, Ivana V Yang⁴⁵, Wei Zhao⁴⁴, Stella Aslibekyan³⁴, Paul L Auer⁵², Donald W Bowden⁵³, Brian E Cade^{54

27}, Zhanghua Chen³⁵, Michael H Cho²⁶, L Adrienne Cupples^{55

56}, Joanne E Curran¹⁵, Michelle Daya⁴⁵, Ranjan Deka⁵⁷, Celeste Eng¹⁸, Tasha E Fingerlin^{58

59}, Xiuqing Guo⁶⁰, Lifang Hou⁶¹, Shih-Jen Hwang⁶², Jill M Johnsen^{63

64}, Eimear E Kenny^{65

42}, Albert M Levin⁶⁶, Chunyu Liu^{56

67}, Ryan L Minster⁴⁷, Take Naseri^{68

69}, Mehdi Nouraie³¹, Muagututi'a Sefuiva Reupena⁷⁰, Ester C Sabino⁷¹, Jennifer A Smith⁴⁴, Nicholas L Smith^{32

33}, Jessica Lasky Su^{26

27}, James G Taylor⁴⁹, Marilyn J Telen^{29

72}, Hemant K Tiwari⁷³, Russell P Tracy⁷⁴, Marquitta J White¹⁸, Yingze Zhang³¹, Kerri L Wiggins¹⁰, Scott T Weiss^{26

27}, Ramachandran S Vasan^{75

56}, Kent D Taylor⁶⁰, Moritz F Sinner^{37

38}, Edwin K Silverman^{26

27}, M Benjamin Shoemaker⁷⁶, Wayne H-H Sheu⁷⁷, Frank Sciurba⁷⁸, David A Schwartz⁴⁵, Jerome I Rotter⁷⁹, Daniel Roden⁸⁰, Susan Redline^{54

81}, Benjamin A Raby^{82

83}, Bruce M Psaty⁸⁴, Juan M Peralta¹⁵, Nicholette D Palmer⁵³, Sergei Nekhai⁴⁹, Courtney G Montgomery⁸⁵, Braxton D Mitchell^{21

86}, Deborah A Meyers^{16

17}, Stephen T McGarvey⁶⁹; NHLBI CARE Network; Angel Cy Mak¹⁸, Ruth Jf Loos^{42

87}, Rajesh Kumar⁸⁸, Charles Kooperberg⁸⁹, Barbara A Konkle^{63

64}, Shannon Kelly^{22

90}, Sharon Lr Kardia⁴⁴, Robert Kaplan⁹¹, Jiang He⁹², Hongsheng Gui⁵¹, Frank D Gilliland³⁵, Bruce D Gelb⁹³, Myriam Fornage^{94

95}, Patrick T Ellinor⁹⁶, Mariza de Andrade⁹⁷, Adolfo Correa⁹⁸, Yii-Der Ida Chen⁶⁰, Eric Boerwinkle⁹⁹, Kathleen C Barnes⁴⁵, Allison E Ashley-Koch^{29

30}, Donna K Arnett¹⁰⁰; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Hematology and Hemostasis Working Group; TOPMed Structural Variation Working Group; Cathy C Laurie², Goncalo Abecasis^{5

101}, Deborah A Nickerson⁵⁰, James G Wilson¹⁰², Stephen S Rich¹⁰³, Daniel Levy^{56

67}, Ingo Ruczinski¹, Abraham Aviv¹⁰⁴, Thomas W Blackwell^{5

6}, Timothy Thornton¹⁰⁵, Jeff O'Connell^{106

107}, Nancy J Cox¹⁰⁸, James A Perry²¹, Mary Armanios¹⁰⁹, Alexis Battle^{3

110}, Nathan Pankratz⁸, Alexander P Reiner^{111

89}, Rasika A Mathias⁷

Affiliations

¹ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
² Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
³ Department of Biomedical Engineering, Johns Hopkins Whiting School of Engineering, Baltimore, MD, USA.
⁴ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
⁵ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁷ GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore MD USA.
⁸ Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA.
⁹ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹² Department of Cardiology, Johns Hopkins School of Medicine, Baltimore MD USA.
¹³ Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore MD USA.
¹⁴ LTRC Data Coordinating Center, The Emmes Company, LLC, Rockville, MD, USA.
¹⁵ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁶ Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
¹⁷ Division of Pharmacogenomics, University of Arizona, Tucson, AZ, USA.
¹⁸ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁹ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
²⁰ Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
²¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
²² Vitalant Research Institute, San Francisco, CA, USA.
²³ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
²⁴ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
²⁵ Cardiovascular Division, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
²⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁷ Harvard Medical School, Boston, MA, USA.
²⁸ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁹ Department of Medicine and Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC, USA.
³⁰ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
³¹ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³² Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
³³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁴ Department of Epidemiology, University of Alabama Birmingham, Birmingham, AL, USA.
³⁵ Division of Environmental Health, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Biostatistics, Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA.
³⁷ Department of Medicine I, University Hospital Munich, Ludwig-Maximilian's University, Munich, Germany.
³⁸ German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany.
³⁹ Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴⁰ Department of Medicine, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴¹ Department of Epidemiology and Brown Center for Global Cardiometabolic Health, Brown University, Providence, RI, USA.
⁴² The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴³ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁴⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁵ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
⁴⁶ Genetics, Harvard Medical School, Boston, MA, USA.
⁴⁷ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁸ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁹ Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University, Washington, DC 20059 USA.
⁵⁰ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁵¹ Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁵² Zilber School of Public Health, University of Wisconsin Milwaukee, Milwaukee WI, USA.
⁵³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵⁴ Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵⁶ The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.
⁵⁷ Department of Environmental and Public Health Sciences, University of Cincinnati, Cincinnati, OH, USA.
⁵⁸ Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
⁵⁹ Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, Colorado, USA.
⁶⁰ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶¹ Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
⁶² Population Sciences Branch, Division of Intramural Research, National Heart Lung and Blood Institute, National Institute of Health, Bethesda, MD, USA.
⁶³ Bloodworks Northwest, Research Institute, Seattle, WA, USA.
⁶⁴ University of Washington, Department of Medicine, Seattle, WA, USA.
⁶⁵ Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁶ Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
⁶⁷ The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
⁶⁸ Ministry of Health, Government of Samoa, Apia, Samoa.
⁶⁹ Department of Epidemiology & International Health Institute, School of Public Health, Brown University, Providence, USA.
⁷⁰ Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.
⁷¹ Instituto de Medicina Tropical da Faculdade de Medicina da Uiversidade de Sao Paulo, Sao Paulo, Brazil.
⁷² Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC, USA.
⁷³ Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA.
⁷⁴ Departments of Pathology & Laboratory Medicine and Biochemistry, Larrner College of Medicine, University of Vermont, Colchester, VT, USA.
⁷⁵ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁷⁶ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷⁷ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁷⁸ Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁷⁹ The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁸⁰ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁸¹ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁸² Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸³ Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.
⁸⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
⁸⁵ Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
⁸⁶ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁸⁷ The Mindich Child Health and Development Institute, Icahn Schoold of Medicine at Mount Sinai, New York, NY, USA.
⁸⁸ Division of Allergy and Clinical Immunology, The Ann and Robert H. Lurie Children's Hospital of Chicago, and Department of Pediatrics Northwestern University, Chicago, IL, USA.
⁸⁹ Division of Public Health Sciences, Fred Htutchinson Cancer Research Center, Seattle WA, USA.
⁹⁰ UCSF Benioff Children's Hospital, Oakland, CA, USA.
⁹¹ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁹² Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
⁹³ Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹⁴ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹⁵ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹⁶ Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA.
⁹⁷ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN,USA.
⁹⁸ Jackson Heart Study and Departments of Medicine and Population Health Science, Jackson, MS, USA.
⁹⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁰⁰ College of Public Health, University of Kentucky, Lexington, KY, USA.
¹⁰¹ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
¹⁰² Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MI, USA.
¹⁰³ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁰⁴ Center of Human Development and Aging, Rutgers, New Jersey Medical School, Newark, NJ, USA.
¹⁰⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁰⁶ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰⁷ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰⁸ Vanderbilt Genetics Institute and Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰⁹ Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹⁰ Departments of Computer Science and Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.

PMID: 35530816
PMCID: PMC9075703
DOI: 10.1016/j.xgen.2021.100084

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

Margaret A Taub et al. Cell Genom. 2022.

. 2022 Jan 12;2(1):100084.

doi: 10.1016/j.xgen.2021.100084. Epub 2022 Jan 13.

Authors

Affiliations

¹ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
² Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
³ Department of Biomedical Engineering, Johns Hopkins Whiting School of Engineering, Baltimore, MD, USA.
⁴ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
⁵ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁷ GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore MD USA.
⁸ Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA.
⁹ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹² Department of Cardiology, Johns Hopkins School of Medicine, Baltimore MD USA.
¹³ Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore MD USA.
¹⁴ LTRC Data Coordinating Center, The Emmes Company, LLC, Rockville, MD, USA.
¹⁵ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁶ Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
¹⁷ Division of Pharmacogenomics, University of Arizona, Tucson, AZ, USA.
¹⁸ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁹ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
²⁰ Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
²¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
²² Vitalant Research Institute, San Francisco, CA, USA.
²³ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
²⁴ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
²⁵ Cardiovascular Division, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
²⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁷ Harvard Medical School, Boston, MA, USA.
²⁸ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁹ Department of Medicine and Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC, USA.
³⁰ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
³¹ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³² Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
³³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁴ Department of Epidemiology, University of Alabama Birmingham, Birmingham, AL, USA.
³⁵ Division of Environmental Health, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Biostatistics, Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA.
³⁷ Department of Medicine I, University Hospital Munich, Ludwig-Maximilian's University, Munich, Germany.
³⁸ German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany.
³⁹ Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴⁰ Department of Medicine, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴¹ Department of Epidemiology and Brown Center for Global Cardiometabolic Health, Brown University, Providence, RI, USA.
⁴² The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴³ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁴⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁵ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
⁴⁶ Genetics, Harvard Medical School, Boston, MA, USA.
⁴⁷ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁸ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁹ Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University, Washington, DC 20059 USA.
⁵⁰ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁵¹ Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁵² Zilber School of Public Health, University of Wisconsin Milwaukee, Milwaukee WI, USA.
⁵³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵⁴ Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵⁶ The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.
⁵⁷ Department of Environmental and Public Health Sciences, University of Cincinnati, Cincinnati, OH, USA.
⁵⁸ Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
⁵⁹ Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, Colorado, USA.
⁶⁰ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶¹ Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
⁶² Population Sciences Branch, Division of Intramural Research, National Heart Lung and Blood Institute, National Institute of Health, Bethesda, MD, USA.
⁶³ Bloodworks Northwest, Research Institute, Seattle, WA, USA.
⁶⁴ University of Washington, Department of Medicine, Seattle, WA, USA.
⁶⁵ Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁶ Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
⁶⁷ The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
⁶⁸ Ministry of Health, Government of Samoa, Apia, Samoa.
⁶⁹ Department of Epidemiology & International Health Institute, School of Public Health, Brown University, Providence, USA.
⁷⁰ Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.
⁷¹ Instituto de Medicina Tropical da Faculdade de Medicina da Uiversidade de Sao Paulo, Sao Paulo, Brazil.
⁷² Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC, USA.
⁷³ Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA.
⁷⁴ Departments of Pathology & Laboratory Medicine and Biochemistry, Larrner College of Medicine, University of Vermont, Colchester, VT, USA.
⁷⁵ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁷⁶ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷⁷ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁷⁸ Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁷⁹ The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁸⁰ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁸¹ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁸² Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸³ Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.
⁸⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
⁸⁵ Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
⁸⁶ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁸⁷ The Mindich Child Health and Development Institute, Icahn Schoold of Medicine at Mount Sinai, New York, NY, USA.
⁸⁸ Division of Allergy and Clinical Immunology, The Ann and Robert H. Lurie Children's Hospital of Chicago, and Department of Pediatrics Northwestern University, Chicago, IL, USA.
⁸⁹ Division of Public Health Sciences, Fred Htutchinson Cancer Research Center, Seattle WA, USA.
⁹⁰ UCSF Benioff Children's Hospital, Oakland, CA, USA.
⁹¹ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁹² Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
⁹³ Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹⁴ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹⁵ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹⁶ Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA.
⁹⁷ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN,USA.
⁹⁸ Jackson Heart Study and Departments of Medicine and Population Health Science, Jackson, MS, USA.
⁹⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁰⁰ College of Public Health, University of Kentucky, Lexington, KY, USA.
¹⁰¹ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
¹⁰² Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MI, USA.
¹⁰³ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁰⁴ Center of Human Development and Aging, Rutgers, New Jersey Medical School, Newark, NJ, USA.
¹⁰⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁰⁶ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰⁷ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰⁸ Vanderbilt Genetics Institute and Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰⁹ Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹⁰ Departments of Computer Science and Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.

PMID: 35530816
PMCID: PMC9075703
DOI: 10.1016/j.xgen.2021.100084

Abstract

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS 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-value <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 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 our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.

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Conflict of interest statement

Declaration of Interests: The authors declare the following competing interests: J.C.C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. B.I.F. is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI L.W. is on the advisory board for GlaxoSmithKline and receives grant funding from NIAID, NHLBI, and NIDDK, NIH I.V.Y. is a consultant for ElevenP15 S.A. receives equity and salary from 23andMe, Inc. M.H.C. receives grant support from GlaxoSmithKline S.T.W. receives royalties from UpToDate E.K.S. received grant support from GlaxoSmithKline and Bayer in the past three years. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. F.D.M. is supported by grants from NIH/NHLBI (HL139054,HL091889,HL132523,HL130045,HL098112,HL056177), the NIH/NIEHS (ES006614), the NIH/NIAID (AI126614), and the NIH/ Office of Director (OD023282). Vifor Pharmaceuticals provided medicine and additional funding to support recruitment for HL130045. Dr. Martinez is a council member for the Council for the Developing Child. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Dr. Ellinor has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. K.C.B. receives royalties from UpToDate G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.M. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.B. is a consultant for Third Rock Ventures, LLC and holds stock in Google, Inc. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis

Figures

**Figure 1**
Genome-wide Manhattan plot (A) Pie chart showing population groups based on HARE for samples included in analysis: European (green, n = 51,654), African (orange, n = 29,260), Hispanic/Latino (purple, n = 18,019), Asian (red, n = 5,683), and Other/Mixed/Unknown (gray, n = 4,506). (B) Trans-population genome-wide tests for association using 163 million sequence-identified variants on n = 109,122 samples with sequence-generated telomere length from TOPMed. All loci had a peak p < 5 × 10⁻⁹ in the pooled trans-population analysis. Previously reported loci for TL are indicated in red, and loci newly associated in the present study are indicated in blue. Note the shift in scale above the y axis break; no peak variants had a p value within the y axis break.

**Figure 2**
LocusZoom plots for multi-hit loci and *TINF2* (A) LocusZoom plots for all loci with >1 sentinel variant. Linkage disequilibrium (LD) was calculated from the set of samples used in the analysis with respect to the peak variant in the pooled trans-population primary analysis, thereby reflecting LD patterns specific to the TOPMed samples. For each figure, the peak sentinel variant from the pooled trans-population analysis is indexed and labeled in purple, and all of the independent variants identified through the iterative conditional approach are labeled in green and highlighted with green dotted lines. (B) LocusZoom plots for 4 population groups for the *TINF2* locus. (C) Forest plots displaying effect sizes and standard errors, as well as minor allele frequencies, by population group for the 3 sentinel variants in *TINF2*. See also Table S2.

**Figure 3**
Fine-mapping of multiple *OBFC1* signals (A) LocusZoom plot of the *OBFC1* locus, where green dotted lines indicate each independent signal, as in Figure 2. (B) Roadmap Epigenomics Consortium data in hg19 coordinates for skeletal muscle tissue, Primary T CD4⁺ memory cells from peripheral blood, and primary T CD8⁺ naive cells from peripheral blood (Roadmap samples E108, E037, and E047, respectively; data were not available for sun-exposed skin). The ChromHMM state model is shown for the 18-state auxiliary model. The state model suggests the primary (rs9420907), secondary (rs111447985), and tertiary (rs112163720) signals are in the promoter region, while the quaternary signal (rs10883948) is in an enhancer region in all Roadmap blood cell types but is transcriptional for peripheral blood monocytes and CD19⁺ B cells. (C–E) GWAS and eQTL results for the primary (C), tertiary (D), and quaternary (E) signals. The top panels are the GWAS summary statistics from the primary, and iterative conditional analyses that were used to perform colocalization analysis (secondary signal was rare and not available for colocalization). Bottom panels are eQTLs for *OBFC1* in the indicated tissue from GTEx. The GTEx eQTLs for these tissues do not colocalize with one another (PPH4 < 4.4 × 10⁻⁷), and each signal did not significantly colocalize in the other tissues. LD was calculated from the pooled trans-population samples with respect to the sentinel (black diamond). See also Figures S4 and S5 and Table S5.

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References

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

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

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Conflict of interest statement

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