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3,148 results on '"Heckbert, Susan R."'

1. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate

Author

Mack, Taralynn M, Raddatz, Michael A, Pershad, Yash, Nachun, Daniel C, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O’Connell, Jeffrey R, Kenny, Eimear E, Loos, Ruth JF, Redline, Susan, Cade, Brian E, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Cho, Michael H, DeMeo, Dawn L, Levy, Daniel, Johnson, Andrew D, Mathias, Rasika A, Yanek, Lisa R, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Raffield, Laura M, Carson, April P, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Roden, Dan M, Kooperberg, Charles, Auer, Paul L, Desai, Pinkal, Blackwell, Thomas W, Smith, Albert V, Reiner, Alexander P, Jaiswal, Siddhartha, Weinstock, Joshua S, and Bick, Alexander G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Hematology, Genetics, Biotechnology, Aging, Human Genome, Stem Cell Research, Precision Medicine, Aetiology, 2.1 Biological and endogenous factors, Cancer, Good Health and Well Being, Clinical sciences
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Published
2024

2. Brain aging patterns in a large and diverse cohort of 49,482 individuals

Author

Yang, Zhijian, Wen, Junhao, Erus, Guray, Govindarajan, Sindhuja T., Melhem, Randa, Mamourian, Elizabeth, Cui, Yuhan, Srinivasan, Dhivya, Abdulkadir, Ahmed, Parmpi, Paraskevi, Wittfeld, Katharina, Grabe, Hans J., Bülow, Robin, Frenzel, Stefan, Tosun, Duygu, Bilgel, Murat, An, Yang, Yi, Dahyun, Marcus, Daniel S., LaMontagne, Pamela, Benzinger, Tammie L. S., Heckbert, Susan R., Austin, Thomas R., Waldstein, Shari R., Evans, Michele K., Zonderman, Alan B., Launer, Lenore J., Sotiras, Aristeidis, Espeland, Mark A., Masters, Colin L., Maruff, Paul, Fripp, Jurgen, Toga, Arthur W., O’Bryant, Sid, Chakravarty, Mallar M., Villeneuve, Sylvia, Johnson, Sterling C., Morris, John C., Albert, Marilyn S., Yaffe, Kristine, Völzke, Henry, Ferrucci, Luigi, Nick Bryan, R., Shinohara, Russell T., Fan, Yong, Habes, Mohamad, Lalousis, Paris Alexandros, Koutsouleris, Nikolaos, Wolk, David A., Resnick, Susan M., Shou, Haochang, Nasrallah, Ilya M., and Davatzikos, Christos

Published
2024
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3. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate

Author

Mack, Taralynn M., Raddatz, Michael A., Pershad, Yash, Nachun, Daniel C., Taylor, Kent D., Guo, Xiuqing, Shuldiner, Alan R., O’Connell, Jeffrey R., Kenny, Eimear E., Loos, Ruth J. F., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Cho, Michael H., DeMeo, Dawn L., Levy, Daniel, Johnson, Andrew D., Mathias, Rasika A., Yanek, Lisa R., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Raffield, Laura M., Carson, April P., Rotter, Jerome I., Rich, Stephen S., Manichaikul, Ani W., Gu, C. Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M. Benjamin, Roden, Dan M., Kooperberg, Charles, Auer, Paul L., Desai, Pinkal, Blackwell, Thomas W., Smith, Albert V., Reiner, Alexander P., Jaiswal, Siddhartha, Weinstock, Joshua S., and Bick, Alexander G.

Published
2024
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5. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Keener, Rebecca, Chhetri, Surya B, Connelly, Carla J, Taub, Margaret A, Conomos, Matthew P, Weinstock, Joshua, Ni, Bohan, Strober, Benjamin, Aslibekyan, Stella, Auer, Paul L, Barwick, Lucas, Becker, Lewis C, Blangero, John, Bleecker, Eugene R, Brody, Jennifer A, Cade, Brian E, Celedon, Juan C, Chang, Yi-Cheng, Cupples, L Adrienne, Custer, Brian, Freedman, Barry I, Gladwin, Mark T, Heckbert, Susan R, Hou, Lifang, Irvin, Marguerite R, Isasi, Carmen R, Johnsen, Jill M, Kenny, Eimear E, Kooperberg, Charles, Minster, Ryan L, Naseri, Take, Viali, Satupa’itea, Nekhai, Sergei, Pankratz, Nathan, Peyser, Patricia A, Taylor, Kent D, Telen, Marilyn J, Wu, Baojun, Yanek, Lisa R, Yang, Ivana V, Albert, Christine, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Bis, Joshua C, Blackwell, Thomas W, Boerwinkle, Eric, Burchard, Esteban G, Carson, April P, Chen, Zhanghua, Chen, Yii-Der Ida, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Gelb, Bruce D, Gilliland, Frank D, He, Jiang, Islam, Talat, Kaab, Stefan, Kardia, Sharon LR, Kelly, Shannon, Konkle, Barbara A, Kumar, Rajesh, Loos, Ruth JF, Martinez, Fernando D, McGarvey, Stephen T, Meyers, Deborah A, Mitchell, Braxton D, Montgomery, Courtney G, North, Kari E, Palmer, Nicholette D, Peralta, Juan M, Raby, Benjamin A, Redline, Susan, Rich, Stephen S, Roden, Dan, Rotter, Jerome I, Ruczinski, Ingo, Schwartz, David, Sciurba, Frank, Shoemaker, M Benjamin, Silverman, Edwin K, Sinner, Moritz F, Smith, Nicholas L, Smith, Albert V, Tiwari, Hemant K, Vasan, Ramachandran S, Weiss, Scott T, Williams, L Keoki, Zhang, Yingze, Ziv, Elad, Raffield, Laura M, Reiner, Alexander P, Arvanitis, Marios, Greider, Carol W, Mathias, Rasika A, and Battle, Alexis

Subjects
Biological Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Genome-Wide Association Study, Telomere, K562 Cells, Telomere Homeostasis, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024

6. Association Between Whole Blood–Derived Mitochondrial DNA Copy Number, Low‐Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk

Author

Liu, Xue, Sun, Xianbang, Zhang, Yuankai, Jiang, Wenqing, Lai, Meng, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Zhao, Wei, Pitsillides, Achilleas, Haessler, Jeffrey, Zheng, Yinan, Blackwell, Thomas W, Yao, Jie, Guo, Xiuqing, Qian, Yong, Thyagarajan, Bharat, Pankratz, Nathan, Rich, Stephen S, Taylor, Kent D, Peyser, Patricia A, Heckbert, Susan R, Seshadri, Sudha, Boerwinkle, Eric, Grove, Megan L, Larson, Nicholas B, Smith, Jennifer A, Vasan, Ramachandran S, Fitzpatrick, Annette L, Fornage, Myriam, Ding, Jun, Carson, April P, Abecasis, Goncalo, Dupuis, Josée, Reiner, Alexander, Kooperberg, Charles, Hou, Lifang, Psaty, Bruce M, Wilson, James G, Levy, Daniel, Rotter, Jerome I, Bis, Joshua C, Consortium, TOPMed mtDNA Working Group in NHLBI Trans‐Omics for Precision Medicine, Satizabal, Claudia L, Arking, Dan E, and Liu, Chunyu

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Obesity, Prevention, Heart Disease, Atherosclerosis, Heart Disease - Coronary Heart Disease, Aging, Cardiovascular, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Humans, DNA, Mitochondrial, Risk Factors, Cardiovascular Diseases, Cholesterol, LDL, DNA Copy Number Variations, Cross-Sectional Studies, Coronary Disease, Cholesterol, HDL, Diabetes Mellitus, Hypertension, cardiometabolic risk factors, cardiovascular disease, low-density lipoprotein cholesterol, Mendelian randomization, mitochondrial DNA copy number, vascular atherosclerosis, TOPMed mtDNA Working Group in NHLBI Trans‐Omics for Precision Medicine (TOPMed) Consortium, low‐density lipoprotein cholesterol, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P

Published
2023

7. Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum

Author

Wen, Junhao, Yang, Zhijian, Nasrallah, Ilya M., Cui, Yuhan, Erus, Guray, Srinivasan, Dhivya, Abdulkadir, Ahmed, Mamourian, Elizabeth, Hwang, Gyujoon, Singh, Ashish, Bergman, Mark, Bao, Jingxuan, Varol, Erdem, Zhou, Zhen, Boquet-Pujadas, Aleix, Chen, Jiong, Toga, Arthur W., Saykin, Andrew J., Hohman, Timothy J., Thompson, Paul M., Villeneuve, Sylvia, Gollub, Randy, Sotiras, Aristeidis, Wittfeld, Katharina, Grabe, Hans J., Tosun, Duygu, Bilgel, Murat, An, Yang, Marcus, Daniel S., LaMontagne, Pamela, Benzinger, Tammie L., Heckbert, Susan R., Austin, Thomas R., Launer, Lenore J., Espeland, Mark, Masters, Colin L., Maruff, Paul, Fripp, Jurgen, Johnson, Sterling C., Morris, John C., Albert, Marilyn S., Bryan, R. Nick, Resnick, Susan M., Ferrucci, Luigi, Fan, Yong, Habes, Mohamad, Wolk, David, Shen, Li, Shou, Haochang, and Davatzikos, Christos

Published
2024
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8. Plasma Interleukin-6 (IL-6), Angiopoietin-2, and C-Reactive Protein Levels Predict Subsequent Type 1 Myocardial Infarction in Persons With Treated HIV Infection

Author

Graham, Susan M, Nance, Robin M, Chen, Junmei, Wurfel, Mark M, Hunt, Peter W, Heckbert, Susan R, Budoff, Matthew J, Moore, Richard D, Jacobson, Jeffrey M, Martin, Jeffrey N, Crane, Heidi M, López, José A, and Liles, W Conrad

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Atherosclerosis, HIV/AIDS, Infectious Diseases, Cardiovascular, Sexually Transmitted Infections, Heart Disease - Coronary Heart Disease, Aging, Heart Disease, Humans, HIV Infections, Interleukin-6, C-Reactive Protein, Cohort Studies, Angiopoietin-2, Case-Control Studies, Myocardial Infarction, Biomarkers, HIV infection, angiopoietin-2, C-reactive protein, interleukin-6, myocardial infarction, Clinical Sciences, Public Health and Health Services, Virology, Clinical sciences, Epidemiology, Public health
Abstract

BackgroundHIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI).MethodsIn a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores.ResultsHigher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score.ConclusionsAmong PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression.

Published
2023

9. Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function

Author

Zhang, Yuankai, Liu, Xue, Wiggins, Kerri L, Kurniansyah, Nuzulul, Guo, Xiuqing, Rodrigue, Amanda L, Zhao, Wei, Yanek, Lisa R, Ratliff, Scott M, Pitsillides, Achilleas, Aguirre Patiño, Juan Sebastian, Sofer, Tamar, Arking, Dan E, Austin, Thomas R, Beiser, Alexa S, Blangero, John, Boerwinkle, Eric, Bressler, Jan, Curran, Joanne E, Hou, Lifang, Hughes, Timothy M, Kardia, Sharon LR, Launer, Lenore J, Levy, Daniel, Mosley, Thomas H, Nasrallah, Ilya M, Rich, Stephen S, Rotter, Jerome I, Seshadri, Sudha, Tarraf, Wassim, González, Kevin A, Ramachandran, Vasan, Yaffe, Kristine, Nyquist, Paul A, Psaty, Bruce M, DeCarli, Charles S, Smith, Jennifer A, Glahn, David C, González, Hector M, Bis, Joshua C, Fornage, Myriam, Heckbert, Susan R, Fitzpatrick, Annette L, Liu, Chunyu, Satizabal, Claudia L, Aguilera, Norma, Ament, Seth, Ammous, Farah, Arnett, Donna K, Becker, Diane, Bis, Joshua, Blue, Elizabeth, Breaux, Camille, Chaar, Dima, MHI, Clarkson-Townsend, Danielle, Cooper, Brigidann, Coresh, Josef, Correa, Adolfo, DeStefano, Anita, Ding, Jingzhong, Fardo, David, Fitzpatrick, Annette, French, Jennifer, Glahn, David, Gonzalez, Hector, Granot-Hershkovitz, Einat, Hanly, Patrick, Hayden, Kathleen, Heckbert, Susan, Heemann, Scott, Horvath, Steve, Hoth, Karin, Hughes, Timothy, Jaiswal, Sidd, Jian, Xueqiu, Katsumata, Yuriko, Kho, Minjung, Kooperberg, Charles, Launer, Lenore, Lin, Honghuang, Litkowski, Elizabeth, Longstreth, Will, Martin, Alexandra, Mayeux, Richard, Mikulla, Julie, Miller, Amy, Misra, Biswapriya, Mosley, Thomas, Nyquist, Paul, O'Connell, Jeff, Olivier, Michael, Peloso, Gina, Perry, James, Psaty, Bruce, Purcell, Shaun, and Raffield, Laura

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Behavioral and Social Science, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease, Dementia, Precision Medicine, Biomedical Imaging, Aging, Genetics, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Mental health, Neurological, Good Health and Well Being, Middle Aged, Humans, Female, Aged, Male, DNA, Mitochondrial, DNA Copy Number Variations, Prospective Studies, Cross-Sectional Studies, Alzheimer Disease, Magnetic Resonance Imaging, Cognition, Brain, NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (

Published
2023

10. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Author

Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O’Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, and Consortium, NHLBI Trans-Omics for Precision Medicine

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Lung, Genetic Testing, Clinical Research, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Humans, Middle Aged, Hematopoiesis, Mutation, Germ-Line Mutation, Mutation, Missense, Phenotype, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Published
2023

11. Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

Author

Young, William J, Haessler, Jeffrey, Benjamins, Jan-Walter, Repetto, Linda, Yao, Jie, Isaacs, Aaron, Harper, Andrew R, Ramirez, Julia, Garnier, Sophie, van Duijvenboden, Stefan, Baldassari, Antoine R, Concas, Maria Pina, Duong, ThuyVy, Foco, Luisa, Isaksen, Jonas L, Mei, Hao, Noordam, Raymond, Nursyifa, Casia, Richmond, Anne, Santolalla, Meddly L, Sitlani, Colleen M, Soroush, Negin, Thériault, Sébastien, Trompet, Stella, Aeschbacher, Stefanie, Ahmadizar, Fariba, Alonso, Alvaro, Brody, Jennifer A, Campbell, Archie, Correa, Adolfo, Darbar, Dawood, De Luca, Antonio, Deleuze, Jean-François, Ellervik, Christina, Fuchsberger, Christian, Goel, Anuj, Grace, Christopher, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Jackson, Rebecca D, Kors, Jan A, Lima-Costa, Maria Fernanda, Linneberg, Allan, Macfarlane, Peter W, Morrison, Alanna C, Navarro, Pau, Porteous, David J, Pramstaller, Peter P, Reiner, Alexander P, Risch, Lorenz, Schotten, Ulrich, Shen, Xia, Sinagra, Gianfranco, Soliman, Elsayed Z, Stoll, Monika, Tarazona-Santos, Eduardo, Tinker, Andrew, Trajanoska, Katerina, Villard, Eric, Warren, Helen R, Whitsel, Eric A, Wiggins, Kerri L, Arking, Dan E, Avery, Christy L, Conen, David, Girotto, Giorgia, Grarup, Niels, Hayward, Caroline, Jukema, J Wouter, Mook-Kanamori, Dennis O, Olesen, Morten Salling, Padmanabhan, Sandosh, Psaty, Bruce M, Pattaro, Cristian, Ribeiro, Antonio Luiz P, Rotter, Jerome I, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James G, Orini, Michele, Charron, Philippe, Watkins, Hugh, Kooperberg, Charles, Lin, Henry J, Wilson, James F, Kanters, Jørgen K, Sotoodehnia, Nona, Mifsud, Borbala, Lambiase, Pier D, Tereshchenko, Larisa G, and Munroe, Patricia B

Subjects
Humans, Cardiovascular Diseases, Electrocardiography, Risk Factors, Arrhythmias, Cardiac, Atrioventricular Block, Genome-Wide Association Study, Biomarkers, Human Genome, Cardiovascular, Genetics, Heart Disease
Abstract

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Published
2023

12. Deep Learning Based Detection of Enlarged Perivascular Spaces on Brain MRI

Author

Rashid, Tanweer, Liu, Hangfan, Ware, Jeffrey B., Li, Karl, Romero, Jose Rafael, Fadaee, Elyas, Nasrallah, Ilya M., Hilal, Saima, Bryan, R. Nick, Hughes, Timothy M., Davatzikos, Christos, Launer, Lenore, Seshadri, Sudha, Heckbert, Susan R., and Habes, Mohamad

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

BACKGROUND AND PURPOSE: Deep learning has been demonstrated effective in many neuroimaging applications. However, in many scenarios, the number of imaging sequences capturing information related to small vessel disease lesions is insufficient to support data-driven techniques. Additionally, cohort-based studies may not always have the optimal or essential imaging sequences for accurate lesion detection. Therefore, it is necessary to determine which imaging sequences are crucial for precise detection. This study introduces a novel deep learning framework to detect enlarged perivascular spaces (ePVS) and aims to find the optimal combination of MRI sequences for deep learning-based quantification. MATERIALS AND METHODS: We implemented an effective lightweight U-Net adapted for ePVS detection and comprehensively investigated different combinations of information from SWI, FLAIR, T1-weighted (T1w), and T2-weighted (T2w) MRI sequences. The training data included 21 participants, which were randomly selected from the MESA cohort. Participants had ePVS 683 lesions on average. For T1w, T2w, and FLAIR images, the MESA study collected 3D isotropic MRI scans at six different sites with Siemens scanners. Our training data included participants from all these sites and all the scanner models, and the proposed model was applied to the whole brain instead of selective regions. RESULTS: The experimental results showed that T2w MRI is the most important for accurate ePVS detection, and the incorporation of SWI, FLAIR and T1w MRI in the deep neural network had minor improvements in accuracy and resulted in the highest sensitivity and precision (sensitivity =0.82, precision =0.83). The proposed method achieved comparable accuracy at a minimal time cost compared to manual reading.

Published
2022

13. Association of Obesity With Cognitive Decline in Black and White Americans

Author

Quaye, Emmanuel, Galecki, Andrzej T, Tilton, Nicholas, Whitney, Rachael, Briceño, Emily M, Elkind, Mitchell SV, Fitzpatrick, Annette L, Gottesman, Rebecca F, Griswold, Michael, Gross, Alden L, Heckbert, Susan R, Hughes, Timothy M, Longstreth, WT, Sacco, Ralph L, Sidney, Stephen, Windham, B Gwen, Yaffe, Kristine, and Levine, Deborah A

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Neurosciences, Obesity, Brain Disorders, Neurodegenerative, Acquired Cognitive Impairment, Clinical Research, Nutrition, Aging, Dementia, Stroke, Female, Humans, Male, Middle Aged, Cognition, Cognitive Dysfunction, Risk Factors, White, Black or African American, Aged, United States, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesThere are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.MethodsWe pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).ResultsObese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; p < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; p = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; p = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; p < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline (p = 0.34).DiscussionThese results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

Published
2023

14. Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Author

Tin, Adrienne, Fohner, Alison E, Yang, Qiong, Brody, Jennifer A, Davies, Gail, Yao, Jie, Liu, Dan, Caro, Ilana, Lindbohm, Joni V, Duggan, Michael R, Meirelles, Osorio, Harris, Sarah E, Gudmundsdottir, Valborg, Taylor, Adele M, Henry, Albert, Beiser, Alexa S, Shojaie, Ali, Coors, Annabell, Fitzpatrick, Annette L, Langenberg, Claudia, Satizabal, Claudia L, Sitlani, Colleen M, Wheeler, Eleanor, Tucker-Drob, Elliot M, Bressler, Jan, Coresh, Josef, Bis, Joshua C, Candia, Julián, Jennings, Lori L, Pietzner, Maik, Lathrop, Mark, Lopez, Oscar L, Redmond, Paul, Gerszten, Robert E, Rich, Stephen S, Heckbert, Susan R, Austin, Thomas R, Hughes, Timothy M, Tanaka, Toshiko, Emilsson, Valur, Vasan, Ramachandran S, Guo, Xiuqing, Zhu, Yineng, Tzourio, Christophe, Rotter, Jerome I, Walker, Keenan A, Ferrucci, Luigi, Kivimäki, Mika, Breteler, Monique MB, Cox, Simon R, Debette, Stephanie, Mosley, Thomas H, Gudnason, Vilmundur G, Launer, Lenore J, Psaty, Bruce M, Seshadri, Sudha, and Fornage, Myriam

Subjects
Biochemistry and Cell Biology, Biological Sciences, Brain Disorders, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Clinical Research, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Middle Aged, Humans, Aged, Alzheimer Disease, Cognition, Cognitive Dysfunction, Neurons, Biomarkers, Biological sciences, Biomedical and clinical sciences
Abstract

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Published
2023

15. Rare genetic variants explain missing heritability in smoking.

Author

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

Subjects
Smoking, Gene Frequency, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Tobacco, Genetics, Tobacco Smoke and Health, Human Genome, 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

16. Tobacco smoking and binge alcohol use are associated with incident venous thromboembolism in an HIV cohort.

Author

Luu, Brandon, Ruderman, Stephanie, Nance, Robin, Delaney, Joseph AC, Ma, Jimmy, Hahn, Andrew, Heckbert, Susan R, Budoff, Matthew J, Crothers, Kristina, Mathews, William C, Christopolous, Katerina, Hunt, Peter W, Eron, Joseph, Moore, Richard, Keruly, Jeanne, Lober, William B, Burkholder, Greer A, Willig, Amanda, Chander, Geetanjali, McCaul, Mary E, Cropsey, Karen, O'Cleirigh, Conall, Peter, Inga, Feinstein, Matthew, Tsui, Judith I, Lindstroem, Sara, Saag, Michael, Kitahata, Mari M, Crane, Heidi M, Drumright, Lydia N, and Whitney, Bridget M

Subjects
Humans, HIV Infections, Ethanol, Proportional Hazards Models, Risk Factors, Prospective Studies, Venous Thromboembolism, Binge Drinking, Tobacco Smoking, HIV, binge drinking, smoking, substance use, venous thromboembolism, Substance Misuse, Alcoholism, Alcohol Use and Health, Tobacco Smoke and Health, Prevention, Clinical Research, HIV/AIDS, Tobacco, Prevention of disease and conditions, and promotion of well-being, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Cancer, Stroke, Cardiovascular, Respiratory, Good Health and Well Being, Clinical Sciences, Virology
Abstract

BackgroundPeople with HIV (PWH) are at increased risk of cardiovascular comorbidities and substance use is a potential predisposing factor. We evaluated associations of tobacco smoking and alcohol use with venous thromboembolism (VTE) in PWH.MethodsWe assessed incident, centrally adjudicated VTE among 12 957 PWH within the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort between January 2009 and December 2018. Using separate Cox proportional hazards models, we evaluated associations of time-updated alcohol and cigarette use with VTE, adjusting for demographic and clinical characteristics. Smoking was evaluated as pack-years and never, former, or current use with current cigarettes per day. Alcohol use was parameterized using categorical and continuous alcohol use score, frequency of use, and binge frequency.ResultsDuring a median of 3.6 years of follow-up, 213 PWH developed a VTE. One-third of PWH reported binge drinking and 40% reported currently smoking. In adjusted analyses, risk of VTE was increased among both current (HR: 1.44, 95% CI: 1.02-2.03) and former (HR: 1.44, 95% CI: 0.99-2.07) smokers compared to PWH who never smoked. Additionally, total pack-years among ever-smokers (HR: 1.10 per 5 pack-years; 95% CI: 1.03-1.18) was associated with incident VTE in a dose-dependent manner. Frequency of binge drinking was associated with incident VTE (HR: 1.30 per 7 days/month, 95% CI: 1.11-1.52); however, alcohol use frequency was not. Severity of alcohol use was not significantly associated with VTE.ConclusionsCurrent smoking and pack-year smoking history were dose-dependently associated with incident VTE among PWH in CNICS. Binge drinking was also associated with VTE. Interventions for smoking and binge drinking may decrease VTE risk among PWH.

Published
2022

18. AI-enabled left atrial volumetry in coronary artery calcium scans (AI-CACTM) predicts atrial fibrillation as early as one year, improves CHARGE-AF, and outperforms NT-proBNP: The multi-ethnic study of atherosclerosis

Author

Naghavi, Morteza, Yankelevitz, David, Reeves, Anthony P., Budoff, Matthew J., Li, Dong, Atlas, Kyle, Zhang, Chenyu, Atlas, Thomas L., Lirette, Seth, Wasserthal, Jakob, Roy, Sion K., Henschke, Claudia, Wong, Nathan D., Defilippi, Christopher, Heckbert, Susan R., and Greenland, Philip

Published
2024
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20. Genetic insights into resting heart rate and its role in cardiovascular disease

Author

van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian’an, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne U., Bielak, Lawrence F., Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus E., Guo, Xiuqing, Lin, Henry J., Pavani, Francesca, Galesloot, Tessel E., Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina E., den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten E., Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling S., Li, Hengtong L., van der Most, Peter J., Nolte, Ilja M., Lyytikäinen, Leo-Pekka, Said, M. Abdullah, Witte, Daniel R., Iribarren, Carlos, Launer, Lenore, Ring, Susan M., de Vries, Paul S., Sever, Peter, Linneberg, Allan, Bottinger, Erwin P., Padmanabhan, Sandosh, Psaty, Bruce M., Sotoodehnia, Nona, Kolcic, Ivana, Arnar, David O., Gudbjartsson, Daniel F., Holm, Hilma, Balkau, Beverley, Silva, Claudia T., Newton-Cheh, Christopher H., Nikus, Kjell, Salo, Perttu, Mohlke, Karen L., Peyser, Patricia A., Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru C., Cornelis, Marilyn C., Faul, Jessica D., Smith, Jennifer A., Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, Sinner, Moritz F., Strauch, Konstantin, Delgado, Graciela E., Taylor, Kent D., Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renée, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre, Macfarlane, Peter W., Tarasov, Kirill V., Tan, Nicholas, Felix, Stephan B., Tai, E-Shyong, Quek, Debra Q., Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia, Morris, Andrew P., Raitakari, Olli T., Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur, Timpson, Nicholas J., Morrison, Alanna C., Munroe, Patricia B., Strachan, David P., Grarup, Niels, Loos, Ruth J. F., Heckbert, Susan R., Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif, Wareham, Nicholas J., van Duijn, Cornelia M., Feitosa, Mary F., O’Donnell, Christopher J., Kähönen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes, Porteous, David J., Eriksson, Johan G., Bouchard, Claude, Moebus, Susanne, Kraft, Peter, Weir, David R., Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kääb, Stefan, Peters, Annette, Chambers, John C., Kooner, Jaspal S., März, Winfried, Rotter, Jerome I., Hicks, Andrew A., Smith, J. Gustav, Kiemeney, Lambertus A. L. M., Mook-Kanamori, Dennis O., Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James F., Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Dörr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi, Oldehinkel, Albertine J., Riese, Harriette, Lehtimäki, Terho, Verweij, Niek, and van der Harst, Pim

Published
2023
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21. Life's Simple 7 Cardiovascular Health Score in Relation to Arrhythmias on Extended Ambulatory Electrocardiographic Monitoring (from the Multi-Ethnic Study of Atherosclerosis)

Author

Ma, Yuyang, Floyd, James S, Austin, Thomas R, Chen, Lin Yee, Horwich, Tamara, Post, Wendy S, Michos, Erin D, and Heckbert, Susan R

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cardiovascular, Clinical Research, Heart Disease, Aging, Good Health and Well Being, Aged, Atherosclerosis, Atrial Fibrillation, Cardiovascular Diseases, Electrocardiography, Ambulatory, Exercise, Humans, Longitudinal Studies, Male, Risk Factors, United States, Ventricular Premature Complexes, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

The Life's Simple 7 (LS7) metric consists of 7 modifiable health behaviors and measures that are known health factors for cardiovascular wellness. Relatively little is known about the association of LS7 score with cardiac arrhythmias. In the setting of the Multi-Ethnic Study of Atherosclerosis, we studied the LS7 score (range 0 to 14), assessed at the 2010 to 2102 study visit, in relation to cardiac arrhythmias assessed by Zio Patch ambulatory electrocardiographic monitoring in 2016 to 2018. In participants free of clinically recognized cardiovascular disease and atrial fibrillation, we used logistic and linear regression to examine the association of total LS7 score with atrial fibrillation, supraventricular ectopy, and ventricular ectopy. In 1,329 participants in the analysis, the mean (SD) age was 67 (8) years and 48% were men. A more favorable total LS7 score was associated with fewer premature ventricular contractions (PVCs) per hour (ratio of geometric means for optimal [11 to 14] versus inadequate [0 to 7] score 0.52 [95% confidence interval 0.34 to 0.81]). After adjustment for sociodemographic characteristics, the association was attenuated (0.66 [0.43 to 1.01]). =Among the LS7 components, a more favorable body mass index was associated with less ventricular ectopy. We did not detect associations of total LS7 score with atrial arrhythmias. In conclusion, in this longitudinal study of older participants free of clinically recognized cardiovascular disease, there was little evidence of association of the LS7 cardiovascular health score with subclinical cardiac arrhythmias. However, there was a suggestion that a more favorable LS7 score was associated with fewer PVCs and specifically, that a more favorable body mass index was associated with fewer PVCs.

Published
2022

22. Risk factors for atrial fibrillation in a multicenter United States clinical cohort of people with HIV infection

Author

Nance, Robin M, Delaney, Joseph AC, Floyd, James S, Saag, Michael S, Moore, Richard D, Keruly, Jeanne C, Kitahata, Mari M, Whitney, Bridget M, Mathews, W Chris, Cachay, Edward R, Burkholder, Greer, Willig, Amanda L, Eron, Joseph J, Napravnik, Sonia, Crane, Heidi M, and Heckbert, Susan R

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Cardiovascular, Clinical Research, Prevention, Heart Disease, Clinical Trials and Supportive Activities, Infectious Diseases, Patient Safety, HIV/AIDS, Aetiology, 2.1 Biological and endogenous factors, Infection, Anti-Retroviral Agents, Atrial Fibrillation, Cohort Studies, HIV Infections, Humans, Risk Factors, United States, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Virology, Biomedical and clinical sciences, Health sciences
Abstract

To assess atrial fibrillation risk factors in people with HIV, we identified incident atrial fibrillation in a large clinical cohort of people receiving care. Compared with 970 controls without atrial fibrillation, the 97 with adjudicated incident atrial fibrillation were older, less likely Hispanic, and had more coronary disease, heart failure, and chronic obstructive pulmonary disease. In multivariable analysis, nonuse of antiretroviral therapy and prescription of antiretroviral regimens with multiple core agents were associated with increased atrial fibrillation risk.

Published
2022

23. Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

Author

Nauffal, Victor, Morrill, Valerie N, Jurgens, Sean J, Choi, Seung Hoan, Hall, Amelia W, Weng, Lu-Chen, Halford, Jennifer L, Austin-Tse, Christina, Haggerty, Christopher M, Harris, Stephanie L, Wong, Eugene K, Alonso, Alvaro, Arking, Dan E, Benjamin, Emelia J, Boerwinkle, Eric, Min, Yuan-I, Correa, Adolfo, Fornwalt, Brandon K, Heckbert, Susan R, National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium, Kooperberg, Charles, Lin, Henry J, J F Loos, Ruth, Rice, Kenneth M, Gupta, Namrata, Blackwell, Thomas W, Mitchell, Braxton D, Morrison, Alanna C, Psaty, Bruce M, Post, Wendy S, Redline, Susan, Rehm, Heidi L, Rich, Stephen S, Rotter, Jerome I, Soliman, Elsayed Z, Sotoodehnia, Nona, Lunetta, Kathryn L, Ellinor, Patrick T, Lubitz, Steven A, and TOPMed Investigators

Subjects
National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Investigators, Humans, Long QT Syndrome, Electrocardiography, Heterozygote, Multifactorial Inheritance, Genome-Wide Association Study, Whole Genome Sequencing, QT interval, long QT syndrome, monogenic, polygenic, sudden cardiac death, Human Genome, Heart Disease, Prevention, Cardiovascular, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

BackgroundRare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population.MethodsWe performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed.ResultsFifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS).ConclusionsQTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

Published
2022

24. Brief Report: Insomnia and Risk of Myocardial Infarction Among People With HIV

Author

Luu, Brandon R, Nance, Robin M, Delaney, Joseph AC, Ruderman, Stephanie A, Heckbert, Susan R, Budoff, Matthew J, Mathews, William C, Moore, Richard D, Feinstein, Matthew J, Burkholder, Greer A, Mugavero, Michael J, Eron, Joseph J, Saag, Michael S, Kitahata, Mari M, Crane, Heidi M, and Whitney, Bridget M

Subjects
Clinical Research, Heart Disease, Prevention, HIV/AIDS, Heart Disease - Coronary Heart Disease, Infectious Diseases, Cardiovascular, Good Health and Well Being, Acquired Immunodeficiency Syndrome, HIV Infections, Humans, Longitudinal Studies, Myocardial Infarction, Sleep Initiation and Maintenance Disorders, HIV, insomnia, myocardial infarction, type 1 myocardial infarction, type 2 myocardial infarction, Clinical Sciences, Public Health and Health Services, Virology
Abstract

BackgroundInsomnia is common among people with HIV (PWH) and may be associated with increased risk of myocardial infarction (MI). This study examines the association between insomnia and MI by MI type among PWH.SettingLongitudinal cohort study of PWH at 5 Centers for AIDS Research Network of Integrated Clinical Systems sites.MethodsClinical data and patient-reported measures and outcomes from PWH in care between 2005 and 2018 were used in this study. Insomnia, measured at baseline, was defined as having difficulty falling or staying asleep with bothersome symptoms. The Centers for AIDS Research Network of Integrated Clinical Systems centrally adjudicates MIs using expert reviewers, with distinction between type 1 MI (T1MI) and type 2 MI (T2MI). Associations between insomnia and first incident MI by MI type were measured using separate Cox proportional hazard models adjusted for age, sex, race/ethnicity, traditional cardiovascular disease risk factors (hypertension, dyslipidemia, poor kidney function, diabetes, and smoking), HIV markers (antiretroviral therapy, viral suppression, and CD4 cell count), and stimulant use (cocaine/crack and methamphetamine).ResultsAmong 12,448 PWH, 48% reported insomnia. Over a median of 4.4 years of follow-up, 158 T1MIs and 109 T2MIs were identified; approximately half of T2MIs were attributed to sepsis or stimulant use. After adjustment for potential confounders, we found no association between insomnia and T1MI (hazard ratio = 1.05, 95% confidence interval: 0.76 to 1.45) and a 65% increased risk of T2MI among PWH reporting insomnia compared with PWH without insomnia (hazard ratio = 1.65, 95% confidence interval: 1.11 to 2.45).ConclusionsPWH reporting insomnia are at an increased risk of T2MI, but not T1MI, compared with PWH without insomnia, highlighting the importance of distinguishing MI types among PWH.

Published
2022

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

Author

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

Subjects
Cardiovascular, Genetics, Aging, Heart Disease, Heart Disease - Coronary Heart Disease, Human Genome, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
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

26. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data

Author

Wainschtein, Pierrick, Jain, Deepti, Zheng, Zhili, Cupples, L Adrienne, Shadyab, Aladdin H, McKnight, Barbara, Shoemaker, Benjamin M, Mitchell, Braxton D, Psaty, Bruce M, Kooperberg, Charles, Liu, Ching-Ti, Albert, Christine M, Roden, Dan, Chasman, Daniel I, Darbar, Dawood, Lloyd-Jones, Donald M, Arnett, Donna K, Regan, Elizabeth A, Boerwinkle, Eric, Rotter, Jerome I, O’Connell, Jeffrey R, Yanek, Lisa R, de Andrade, Mariza, Allison, Matthew A, McDonald, Merry-Lynn N, Chung, Mina K, Fornage, Myriam, Chami, Nathalie, Smith, Nicholas L, Ellinor, Patrick T, Vasan, Ramachandran S, Mathias, Rasika A, Loos, Ruth JF, Rich, Stephen S, Lubitz, Steven A, Heckbert, Susan R, Redline, Susan, Guo, Xiuqing, Chen, Y-D Ida, Laurie, Cecelia A, Hernandez, Ryan D, McGarvey, Stephen T, Goddard, Michael E, Laurie, Cathy C, North, Kari E, Lange, Leslie A, Weir, Bruce S, Yengo, Loic, Yang, Jian, and Visscher, Peter M

Subjects
Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Alleles, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide, TOPMed Anthropometry Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

Published
2022

27. A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C.

Published
2024
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28. Subclinical vascular composites predict clinical cardiovascular disease, stroke, and dementia: The Multi-Ethnic Study of Atherosclerosis (MESA)

Author

Hughes, Timothy M., Tanley, Jordan, Chen, Haiying, Schaich, Christopher L., Yeboah, Joseph, Espeland, Mark A., Lima, Joao A.C., Ambale-Venkatesh, Bharath, Michos, Erin D., Ding, Jingzhong, Hayden, Kathleen, Casanova, Ramon, Craft, Suzanne, Rapp, Stephen R., Luchsinger, José A., Fitzpatrick, Annette L., Heckbert, Susan R., Post, Wendy S., and Burke, Gregory L.

Published
2024
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31. Blood Pressure and Later-Life Cognition in Hispanic and White Adults (BP-COG): A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, MESA, and NOMAS.

Author

Levine, Deborah A, Gross, Alden L, Briceño, Emily M, Tilton, Nicholas, Whitney, Rachael, Han, Dehua, Giordani, Bruno J, Sussman, Jeremy B, Hayward, Rodney A, Burke, James F, Elkind, Mitchell SV, Moran, Andrew E, Tom, Sarah, Gottesman, Rebecca F, Gaskin, Darrell J, Sidney, Stephen, Yaffe, Kristine, Sacco, Ralph L, Heckbert, Susan R, Hughes, Timothy M, Lopez, Oscar L, Allen, Norrina Bai, and Galecki, Andrzej T

Subjects
Biological Psychology, Psychology, Aging, Brain Disorders, Acquired Cognitive Impairment, Dementia, Behavioral and Social Science, Neurosciences, Clinical Research, Cardiovascular, Aged, Blood Pressure, Cognition, Cohort Studies, Female, Hispanic or Latino, Humans, Male, Risk Factors, White People, Blood pressure, cognition, dementia, ethnic groups, Hispanic Americans, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundEthnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain.ObjectiveDetermine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals.MethodsPooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years.ResultsWe included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change.ConclusionWe found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

Published
2022

32. Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes

Author

Halford, Jennifer L, Morrill, Valerie N, Choi, Seung Hoan, Jurgens, Sean J, Melloni, Giorgio, Marston, Nicholas A, Weng, Lu-Chen, Nauffal, Victor, Hall, Amelia W, Gunn, Sophia, Austin-Tse, Christina A, Pirruccello, James P, Khurshid, Shaan, Rehm, Heidi L, Benjamin, Emelia J, Boerwinkle, Eric, Brody, Jennifer A, Correa, Adolfo, Fornwalt, Brandon K, Gupta, Namrata, Haggerty, Christopher M, Harris, Stephanie, Heckbert, Susan R, Hong, Charles C, Kooperberg, Charles, Lin, Henry J, Loos, Ruth JF, Mitchell, Braxton D, Morrison, Alanna C, Post, Wendy, Psaty, Bruce M, Redline, Susan, Rice, Kenneth M, Rich, Stephen S, Rotter, Jerome I, Schnatz, Peter F, Soliman, Elsayed Z, Sotoodehnia, Nona, Wong, Eugene K, Sabatine, Marc S, Ruff, Christian T, Lunetta, Kathryn L, Ellinor, Patrick T, and Lubitz, Steven A

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P

Published
2022

33. Prognostic value of a left atrioventricular coupling index in pre- and post-menopausal women from the Multi-Ethnic Study of Atherosclerosis

Author

Pezel, Théo, Michos, Erin D, Varadarajan, Vinithra, Shabani, Mahsima, Venkatesh, Bharath Ambale, Vaidya, Dhananjay, Kato, Yoko, De Vasconcellos, Henrique Doria, Heckbert, Susan R, Wu, Colin O, Post, Wendy S, Bluemke, David A, Allison, Matthew A, Henry, Patrick, and Lima, Joao AC

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Aging, Prevention, Clinical Research, Estrogen, Heart Disease, Cardiovascular, Multi-Ethnic Study of Atherosclerosis, menopause, left atrioventricular coupling, cardiovascular magnetic resonanace, prognosis, sex hormones, cardiovascular events, Cardiovascular medicine and haematology
Abstract

BackgroundSex hormones associated with both the left atrial (LA) and left ventricular (LV) structures in women, but the association of menopause status with left atrioventricular coupling is not established.AimTo assess the prognostic value of a left atrioventricular coupling index (LACI) in peri-menopausal women without a history of cardiovascular disease (CVD).Materials and methodsIn all women participating in MESA study with baseline cardiovascular MRI, the LACI was measured as the ratio of the LA end-diastolic volume to the LV end-diastolic volume. Cox models were used to assess the association between the LACI and the outcomes of atrial fibrillation (AF), heart failure (HF), coronary heart disease (CHD) death, and hard CVD.ResultsAmong the 2,087 women participants (61 ± 10 years), 485 cardiovascular events occurred (mean follow-up: 13.2 ± 3.3 years). A higher LACI was independently associated with AF (HR 1.70; 95%CI [1.51-1.90]), HF (HR 1.62; [1.33-1.97]), CHD death (HR 1.36; [1.10-1.68]), and hard CVD (HR 1.30; [1.13-1.51], all p < 0.001). Adjusted models with the LACI showed significant improvement in model discrimination and reclassification when compared to traditional models to predict: incident AF (C-statistic: 0.82 vs. 0.79; NRI = 0.325; IDI = 0.036), HF (C-statistic: 0.84 vs. 0.81; NRI = 0.571; IDI = 0.023), CHD death (C-statistic: 0.87 vs. 0.85; NRI = 0.506; IDI = 0.012), hard CVD (C-statistic: 0.78 vs. 0.76; NRI = 0.229; IDI = 0.012). The prognostic value of the LACI had a better discrimination and reclassification than individual LA or LV parameters.ConclusionIn a multi-ethnic population of pre- and post-menopausal women, the LACI is an independent predictor of HF, AF, CHD death, and hard CVD.Clinical trial registration[https://clinicaltrials.gov/], identifier [NCT00005487].

Published
2022

34. SPARE-Tau: A flortaucipir machine-learning derived early predictor of cognitive decline

Author

Toledo, Jon B, Rashid, Tanweer, Liu, Hangfan, Launer, Lenore, Shaw, Leslie M, Heckbert, Susan R, Weiner, Michael, Seshadri, Sudha, Habes, Mohamad, and Initiative, for the Alzheimer’s Disease Neuroimaging

Subjects
Epidemiology, Health Sciences, Aging, Brain Disorders, Neurodegenerative, Bioengineering, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Acquired Cognitive Impairment, Biomedical Imaging, Neurosciences, Clinical Research, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Humans, Aged, tau Proteins, Cross-Sectional Studies, Cognitive Dysfunction, Alzheimer Disease, Positron-Emission Tomography, Biomarkers, Machine Learning, Amyloid beta-Peptides, Alzheimer’s Disease Neuroimaging Initiative, General Science & Technology
Abstract

BackgroundRecently, tau PET tracers have shown strong associations with clinical outcomes in individuals with cognitive impairment and cognitively unremarkable elderly individuals. flortaucipir PET scans to measure tau deposition in multiple brain areas as the disease progresses. This information needs to be summarized to evaluate disease severity and predict disease progression. We, therefore, sought to develop a machine learning-derived index, SPARE-Tau, which successfully detects pathology in the earliest disease stages and accurately predicts progression compared to a priori-based region of interest approaches (ROI).Methods587 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort had flortaucipir scans, structural MRI scans, and an Aβ biomarker test (CSF or florbetapir PET) performed on the same visit. We derived the SPARE-Tau index in a subset of 367 participants. We evaluated associations with clinical measures for CSF p-tau, SPARE-MRI, and flortaucipir PET indices (SPARE-Tau, meta-temporal, and average Braak ROIs). Bootstrapped multivariate adaptive regression splines linear regression analyzed the association between the biomarkers and baseline ADAS-Cog13 scores. Bootstrapped multivariate linear regression models evaluated associations with clinical diagnosis. Cox-hazards and mixed-effects models investigated clinical progression and longitudinal ADAS-Cog13 changes. The Aβ positive cognitively unremarkable participants, not included in the SPARE-Tau training, served as an independent validation group.ResultsCompared to CSF p-tau, meta-temporal, and averaged Braak tau PET ROIs, SPARE-Tau showed the strongest association with baseline ADAS-cog13 scores and diagnosis. SPARE-Tau also presented the strongest association with clinical progression in cognitively unremarkable participants and longitudinal ADAS-Cog13 changes. Results were confirmed in the Aβ+ cognitively unremarkable hold-out sample participants. CSF p-tau showed the weakest cross-sectional associations and longitudinal prediction.DiscussionFlortaucipir indices showed the strongest clinical association among the studied biomarkers (flortaucipir, florbetapir, structural MRI, and CSF p-tau) and were predictive in the preclinical disease stages. Among the flortaucipir indices, the machine-learning derived SPARE-Tau index was the most sensitive clinical progression biomarker. The combination of different biomarker modalities better predicted cognitive performance.

Published
2022

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

Author

Taub, Margaret A, Conomos, Matthew P, Keener, Rebecca, Iyer, Kruthika R, Weinstock, Joshua S, Yanek, Lisa R, Lane, John, Miller-Fleming, Tyne W, Brody, Jennifer A, Raffield, Laura M, McHugh, Caitlin P, Jain, Deepti, Gogarten, Stephanie M, Laurie, Cecelia A, Keramati, Ali, Arvanitis, Marios, Smith, Albert V, Heavner, Benjamin, Barwick, Lucas, Becker, Lewis C, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Burchard, Esteban G, Celedón, Juan C, Chang, Yen Pei C, Custer, Brian, Darbar, Dawood, de las Fuentes, Lisa, DeMeo, Dawn L, Freedman, Barry I, Garrett, Melanie E, Gladwin, Mark T, Heckbert, Susan R, Hidalgo, Bertha A, Irvin, Marguerite R, Islam, Talat, Johnson, W Craig, Kaab, Stefan, Launer, Lenore, Lee, Jiwon, Liu, Simin, Moscati, Arden, North, Kari E, Peyser, Patricia A, Rafaels, Nicholas, Seidman, Christine, Weeks, Daniel E, Wen, Fayun, Wheeler, Marsha M, Williams, L Keoki, Yang, Ivana V, Zhao, Wei, Aslibekyan, Stella, Auer, Paul L, Bowden, Donald W, Cade, Brian E, Chen, Zhanghua, Cho, Michael H, Cupples, L Adrienne, Curran, Joanne E, Daya, Michelle, Deka, Ranjan, Eng, Celeste, Fingerlin, Tasha E, Guo, Xiuqing, Hou, Lifang, Hwang, Shih-Jen, Johnsen, Jill M, Kenny, Eimear E, Levin, Albert M, Liu, Chunyu, Minster, Ryan L, Naseri, Take, Nouraie, Mehdi, Reupena, Muagututi A Sefuiva, Sabino, Ester C, Smith, Jennifer A, Smith, Nicholas L, Lasky-Su, Jessica, Taylor, James G, Telen, Marilyn J, Tiwari, Hemant K, Tracy, Russell P, White, Marquitta J, Zhang, Yingze, Wiggins, Kerri L, Weiss, Scott T, Vasan, Ramachandran S, Taylor, Kent D, Sinner, Moritz F, Silverman, Edwin K, Shoemaker, M Benjamin, Sheu, Wayne H-H, Sciurba, Frank, Schwartz, David A, Rotter, Jerome I, Roden, Daniel, Redline, Susan, and Raby, Benjamin A

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, NHLBI CARE Network, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
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

Published
2022

36. Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

Author

DiCorpo, Daniel, Gaynor, Sheila M, Russell, Emily M, Westerman, Kenneth E, Raffield, Laura M, Majarian, Timothy D, Wu, Peitao, Sarnowski, Chloé, Highland, Heather M, Jackson, Anne, Hasbani, Natalie R, de Vries, Paul S, Brody, Jennifer A, Hidalgo, Bertha, Guo, Xiuqing, Perry, James A, O’Connell, Jeffrey R, Lent, Samantha, Montasser, May E, Cade, Brian E, Jain, Deepti, Wang, Heming, D’Oliveira Albanus, Ricardo, Varshney, Arushi, Yanek, Lisa R, Lange, Leslie, Palmer, Nicholette D, Almeida, Marcio, Peralta, Juan M, Aslibekyan, Stella, Baldridge, Abigail S, Bertoni, Alain G, Bielak, Lawrence F, Chen, Chung-Shiuan, Chen, Yii-Der Ida, Choi, Won Jung, Goodarzi, Mark O, Floyd, James S, Irvin, Marguerite R, Kalyani, Rita R, Kelly, Tanika N, Lee, Seonwook, Liu, Ching-Ti, Loesch, Douglas, Manson, JoAnn E, Minster, Ryan L, Naseri, Take, Pankow, James S, Rasmussen-Torvik, Laura J, Reiner, Alexander P, Reupena, Muagututi’a Sefuiva, Selvin, Elizabeth, Smith, Jennifer A, Weeks, Daniel E, Xu, Huichun, Yao, Jie, Zhao, Wei, Parker, Stephen, Alonso, Alvaro, Arnett, Donna K, Blangero, John, Boerwinkle, Eric, Correa, Adolfo, Cupples, L Adrienne, Curran, Joanne E, Duggirala, Ravindranath, He, Jiang, Heckbert, Susan R, Kardia, Sharon LR, Kim, Ryan W, Kooperberg, Charles, Liu, Simin, Mathias, Rasika A, McGarvey, Stephen T, Mitchell, Braxton D, Morrison, Alanna C, Peyser, Patricia A, Psaty, Bruce M, Redline, Susan, Shuldiner, Alan R, Taylor, Kent D, Vasan, Ramachandran S, Viaud-Martinez, Karine A, Florez, Jose C, Wilson, James G, Sladek, Robert, Rich, Stephen S, Rotter, Jerome I, Lin, Xihong, Dupuis, Josée, Meigs, James B, Wessel, Jennifer, and Manning, Alisa K

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Good Health and Well Being, Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States, Biological sciences, Biomedical and clinical sciences
Abstract

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

Published
2022

37. Epigenetic Age and the Risk of Incident Atrial Fibrillation

Author

Roberts, Jason D, Vittinghoff, Eric, Lu, Ake T, Alonso, Alvaro, Wang, Biqi, Sitlani, Colleen M, Mohammadi-Shemirani, Pedrum, Fornage, Myriam, Kornej, Jelena, Brody, Jennifer A, Arking, Dan E, Lin, Honghuang, Heckbert, Susan R, Prokic, Ivana, Ghanbari, Mohsen, Skanes, Allan C, Bartz, Traci M, Perez, Marco V, Taylor, Kent D, Lubitz, Steven A, Ellinor, Patrick T, Lunetta, Kathryn L, Pankow, James S, Paré, Guillaume, Sotoodehnia, Nona, Benjamin, Emelia J, Horvath, Steve, and Marcus, Gregory M

Subjects
Epidemiology, Health Sciences, Genetics, Aging, Heart Disease, Clinical Research, Cardiovascular, Good Health and Well Being, Aged, Atrial Fibrillation, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Follow-Up Studies, Humans, Incidence, Male, Mendelian Randomization Analysis, Middle Aged, Models, Cardiovascular, Models, Genetic, atrial fibrillation, aging, genetics, epigenomics, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Sports science and exercise
Abstract

BackgroundThe most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.MethodsMeasures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.ResultsAmong 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P

Published
2021

38. Individual non-esterified fatty acids and incident atrial fibrillation late in life

Author

Pellegrini, Cara N, Buzkova, Petra, Lichtenstein, Alice H, Matthan, Nirupa R, Ix, Joachim H, Siscovick, David S, Heckbert, Susan R, Tracy, Russell P, Mukamal, Kenneth J, Djoussé, Luc, and Kizer, Jorge R

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Prevention, Clinical Research, Cardiovascular, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Atrial Fibrillation, Biomarkers, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Prospective Studies, Risk Assessment, Risk Factors, United States, atrial fibrillation, epidemiology, metabolic syndrome, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

ObjectiveObesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.MethodsThe present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.ResultsThe study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p

Published
2021

39. Association of mitochondrial DNA copy number with cardiometabolic diseases

Author

Liu, Xue, Longchamps, Ryan J, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Zhao, Wei, Pitsillides, Achilleas, Blackwell, Thomas W, Yao, Jie, Guo, Xiuqing, Kurniansyah, Nuzulul, Thyagarajan, Bharat, Pankratz, Nathan, Rich, Stephen S, Taylor, Kent D, Peyser, Patricia A, Heckbert, Susan R, Seshadri, Sudha, Cupples, L Adrienne, Boerwinkle, Eric, Grove, Megan L, Larson, Nicholas B, Smith, Jennifer A, Vasan, Ramachandran S, Sofer, Tamar, Fitzpatrick, Annette L, Fornage, Myriam, Ding, Jun, Correa, Adolfo, Abecasis, Goncalo, Psaty, Bruce M, Wilson, James G, Levy, Daniel, Rotter, Jerome I, Bis, Joshua C, Consortium, TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine, Satizabal, Claudia L, Arking, Dan E, and Liu, Chunyu

Subjects
Biological Sciences, Genetics, Aging, Metabolic and endocrine, Generic health relevance, Good Health and Well Being, TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (

Published
2021

40. A System for Phenotype Harmonization in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Program

Author

Stilp, Adrienne M, Emery, Leslie S, Broome, Jai G, Buth, Erin J, Khan, Alyna T, Laurie, Cecelia A, Wang, Fei Fei, Wong, Quenna, Chen, Dongquan, D'Augustine, Catherine M, Heard-Costa, Nancy L, Hohensee, Chancellor R, Johnson, William Craig, Juarez, Lucia D, Liu, Jingmin, Mutalik, Karen M, Raffield, Laura M, Wiggins, Kerri L, de Vries, Paul S, Kelly, Tanika N, Kooperberg, Charles, Natarajan, Pradeep, Peloso, Gina M, Peyser, Patricia A, Reiner, Alex P, Arnett, Donna K, Aslibekyan, Stella, Barnes, Kathleen C, Bielak, Lawrence F, Bis, Joshua C, Cade, Brian E, Chen, Ming-Huei, Correa, Adolfo, Cupples, L Adrienne, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Franceschini, Nora, Gan, Weiniu, Ganesh, Santhi K, Graffelman, Jan, Grove, Megan L, Guo, Xiuqing, Hawley, Nicola L, Hsu, Wan-Ling, Jackson, Rebecca D, Jaquish, Cashell E, Johnson, Andrew D, Kardia, Sharon LR, Kelly, Shannon, Lee, Jiwon, Mathias, Rasika A, McGarvey, Stephen T, Mitchell, Braxton D, Montasser, May E, Morrison, Alanna C, North, Kari E, Nouraie, Seyed Mehdi, Oelsner, Elizabeth C, Pankratz, Nathan, Rich, Stephen S, Rotter, Jerome I, Smith, Jennifer A, Taylor, Kent D, Vasan, Ramachandran S, Weeks, Daniel E, Weiss, Scott T, Wilson, Carla G, Yanek, Lisa R, Psaty, Bruce M, Heckbert, Susan R, and Laurie, Cathy C

Subjects
Epidemiology, Health Sciences, Human Genome, Lung, Genetics, Clinical Research, Cardiovascular, Good Health and Well Being, Data Aggregation, Genetic Association Studies, Humans, Information Dissemination, National Heart, Lung, and Blood Institute (U.S.), Phenomics, Phenotype, Precision Medicine, Program Evaluation, United States, cardiovascular disease, common data elements, hematologic disease, information dissemination, lung diseases, phenotypes, sleep-wake disorders, Mathematical Sciences, Medical and Health Sciences
Abstract

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.

Published
2021

41. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Author

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

Published
2023
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43. DEEPMIR: A DEEP neural network for differential detection of cerebral Microbleeds and IRon deposits in MRI

Author

Rashid, Tanweer, Abdulkadir, Ahmed, Nasrallah, Ilya M., Ware, Jeffrey B., Liu, Hangfan, Spincemaille, Pascal, Romero, J. Rafael, Bryan, R. Nick, Heckbert, Susan R., and Habes, Mohamad

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Lobar cerebral microbleeds (CMBs) and localized non-hemorrhage iron deposits in the basal ganglia have been associated with brain aging, vascular disease and neurodegenerative disorders. Particularly, CMBs are small lesions and require multiple neuroimaging modalities for accurate detection. Quantitative susceptibility mapping (QSM) derived from in vivo magnetic resonance imaging (MRI) is necessary to differentiate between iron content and mineralization. We set out to develop a deep learning-based segmentation method suitable for segmenting both CMBs and iron deposits. We included a convenience sample of 24 participants from the MESA cohort and used T2-weighted images, susceptibility weighted imaging (SWI), and QSM to segment the two types of lesions. We developed a protocol for simultaneous manual annotation of CMBs and non-hemorrhage iron deposits in the basal ganglia. This manual annotation was then used to train a deep convolution neural network (CNN). Specifically, we adapted the U-Net model with a higher number of resolution layers to be able to detect small lesions such as CMBs from standard resolution MRI. We tested different combinations of the three modalities to determine the most informative data sources for the detection tasks. In the detection of CMBs using single class and multiclass models, we achieved an average sensitivity and precision of between 0.84-0.88 and 0.40-0.59, respectively. The same framework detected non-hemorrhage iron deposits with an average sensitivity and precision of about 0.75-0.81 and 0.62-0.75, respectively. Our results showed that deep learning could automate the detection of small vessel disease lesions and including multimodal MR data (particularly QSM) can improve the detection of CMB and non-hemorrhage iron deposits with sensitivity and precision that is compatible with use in large-scale research studies.

Published
2020

44. Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

Author

Choi, Seung Hoan, Jurgens, Sean J, Haggerty, Christopher M, Hall, Amelia W, Halford, Jennifer L, Morrill, Valerie N, Weng, Lu-Chen, Lagerman, Braxton, Mirshahi, Tooraj, Pettinger, Mary, Guo, Xiuqing, Lin, Henry J, Alonso, Alvaro, Soliman, Elsayed Z, Kornej, Jelena, Lin, Honghuang, Moscati, Arden, Nadkarni, Girish N, Brody, Jennifer A, Wiggins, Kerri L, Cade, Brian E, Lee, Jiwon, Austin-Tse, Christina, Blackwell, Tom, Chaffin, Mark D, Lee, Christina J-Y, Rehm, Heidi L, Roselli, Carolina, Regeneron Genetics Center, Redline, Susan, Mitchell, Braxton D, Sotoodehnia, Nona, Psaty, Bruce M, Heckbert, Susan R, Loos, Ruth JF, Vasan, Ramachandran S, Benjamin, Emelia J, Correa, Adolfo, Boerwinkle, Eric, Arking, Dan E, Rotter, Jerome I, Rich, Stephen S, Whitsel, Eric A, Perez, Marco, Kooperberg, Charles, Fornwalt, Brandon K, Lunetta, Kathryn L, Ellinor, Patrick T, Lubitz, Steven A, and NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Subjects
Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Humans, Long QT Syndrome, Death, Sudden, Cardiac, Genetic Predisposition to Disease, Electrocardiography, Heterozygote, Female, Male, Genetic Variation, Exome Sequencing, death, sudden, cardiac, epidemiology, genetics, genome, population, Clinical Research, Cardiovascular, Genetics, Heart Disease, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, death, sudden, cardiac
Abstract

BackgroundAlterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.MethodsUsing a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).ResultsWe found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.ConclusionsOur findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Published
2021

45. Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study

Author

Chen, Yan, Zelnick, Leila R, Huber, Matthew P, Wang, Ke, Bansal, Nisha, Hoofnagle, Andrew N, Paranji, Rajan K, Heckbert, Susan R, Weiss, Noel S, Go, Alan S, Hsu, Chi-yuan, Feldman, Harold I, Waikar, Sushrut S, Mehta, Rupal C, Srivastava, Anand, Seliger, Stephen L, Lash, James P, Porter, Anna C, Raj, Dominic S, Kestenbaum, Bryan R, Investigators, CRIC Study, Appel, Lawrence J, He, Jiang, Rao, Panduranga S, Rahman, Mahboob, and Townsend, Raymond R

Subjects
Kidney Disease, Clinical Research, Cardiovascular, Prevention, Heart Disease, Renal and urogenital, Aged, Albuminuria, Chromatography, Liquid, Cohort Studies, Cresols, Female, Glomerular Filtration Rate, Glycine, Heart Failure, Humans, Incidence, Indican, Kidney Tubules, Kynurenic Acid, Male, Middle Aged, Myocardial Infarction, Organic Anion Transporters, Proportional Hazards Models, Prospective Studies, Pyridoxic Acid, Renal Insufficiency, Chronic, Ribonucleosides, Stroke, Sulfuric Acid Esters, Tandem Mass Spectrometry, Xanthines, CRIC Study Investigators, cardiovascular disease, chronic kidney disease, cinnamoylglycine, glomerular filtration rate, heart failure, indoxyl sulfate, isovalerylglycine, kynurenic acid, myocardial infarction, p-cresol sulfate, protein-bound, proximal tubule, pyridoxic acid, renal function, secretory solute clearance, stroke, tiglylglycine, tubular secretion, tubular secretory clearance, uremic toxins, xanthosine, Clinical Sciences, Public Health and Health Services, Urology & Nephrology
Abstract

Rationale & objectiveThe clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain.Study designA multicenter, prospective, cohort study.Setting & participantsWe evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study.ExposuresBaseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS).OutcomesIncident heart failure, myocardial infarction, and stroke events.Analytical approachWe used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders.ResultsParticipants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR.LimitationsExclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.ConclusionsIn a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

Published
2021

46. HIV Viremia and Risk of Stroke Among People Living with HIV Who Are Using Antiretroviral Therapy.

Author

Harding, Barbara N, Avoundjian, Tigran, Heckbert, Susan R, Whitney, Bridget M, Nance, Robin M, Ruderman, Stephanie A, Kalani, Rizwan, Tirschwell, David L, Ho, Emily L, Becker, Kyra J, Zunt, Joseph, Chow, Felicia, Huffer, Andrew, Mathews, W Christopher, Eron, Joseph, Moore, Richard D, Marra, Christina M, Burkholder, Greer, Saag, Michael S, Kitahata, Mari M, Crane, Heidi M, and Delaney, Joseph C

Subjects
Humans, Viremia, HIV Infections, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Viral Load, United States, Stroke, HIV/AIDS, Clinical Research, Brain Disorders, Rehabilitation, Infectious Diseases, Infection, HIV, viremia, viral load, stroke, ischemic stroke, hemorrhagic stroke, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundRates of stroke are higher in people living with HIV compared with age-matched uninfected individuals. Causes of elevated stroke risk, including the role of viremia, are poorly defined.MethodsBetween 1 January 2006 and 31 December 2014, we identified incident strokes among people living with HIV on antiretroviral therapy at five sites across the United States. We considered three parameterizations of viral load (VL) including (1) baseline (most recent VL before study entry), (2) time-updated, and (3) cumulative VL (copy-days/mL of virus). We used Cox proportional hazards models to estimate hazard ratios (HRs) for stroke risk comparing the 75th percentile ("high VL") to the 25th percentile ("low VL") of baseline and time-updated VL. We used marginal structural Cox models, with most models adjusted for traditional stroke risk factors, to estimate HRs for stroke associated with cumulative VL.ResultsAmong 15,974 people living with HIV, 139 experienced a stroke (113 ischemic; 18 hemorrhagic; eight were unknown type) over a median follow-up of 4.2 years. Median baseline VL was 38 copies/mL (interquartile interval: 24, 3,420). High baseline VL was associated with increased risk of both ischemic (HR: 1.3; 95% CI = 0.96-1.7) and hemorrhagic stroke (HR: 3.1; 95% CI = 1.6-5.9). In time-updated models, high VL was also associated with an increased risk of any stroke (HR: 1.8; 95% CI = 1.4-2.3). We observed no association between cumulative VL and stroke risk.ConclusionsOur findings are consistent with the hypothesis that elevated HIV VL may increase stroke risk, regardless of previous VL levels.

Published
2021

47. Types of Stroke Among People Living With HIV in the United States.

Author

Crane, Heidi M, Nance, Robin M, Avoundjian, Tigran, Harding, Barbara N, Whitney, Bridget M, Chow, Felicia C, Becker, Kyra J, Marra, Christina M, Zunt, Joseph R, Ho, Emily L, Kalani, Rizwan, Huffer, Andrew, Burkholder, Greer A, Willig, Amanda L, Moore, Richard D, Mathews, William C, Eron, Joseph J, Napravnik, Sonia, Lober, William B, Barnes, Greg S, McReynolds, Justin, Feinstein, Matthew J, Heckbert, Susan R, Saag, Michael S, Kitahata, Mari M, Delaney, Joseph AC, and Tirschwell, David L

Subjects
Brain Disorders, Clinical Research, Neurosciences, HIV/AIDS, Infectious Diseases, Stroke, Prevention, Good Health and Well Being, Adult, Atherosclerosis, CD4 Lymphocyte Count, Cohort Studies, Female, HIV Infections, Humans, Hypertension, Male, Middle Aged, Risk Factors, United States, HIV, stroke, ischemic stroke, hemorrhagic stroke, stroke subtypes, Clinical Sciences, Public Health and Health Services, Virology
Abstract

BackgroundMost studies of stroke in people living with HIV (PLWH) do not use verified stroke diagnoses, are small, and/or do not differentiate stroke types and subtypes.SettingCNICS, a U.S. multisite clinical cohort of PLWH in care.MethodsWe implemented a centralized adjudication stroke protocol to identify stroke type, subtype, and precipitating conditions identified as direct causes including infection and illicit drug use in a large diverse HIV cohort.ResultsAmong 26,514 PLWH, there were 401 strokes, 75% of which were ischemic. Precipitating factors such as sepsis or same-day cocaine use were identified in 40% of ischemic strokes. Those with precipitating factors were younger, had more severe HIV disease, and fewer traditional stroke risk factors such as diabetes and hypertension. Ischemic stroke subtypes included cardioembolic (20%), large vessel atherosclerosis (13%), and small vessel (24%) ischemic strokes. Individuals with small vessel strokes were older, were more likely to have a higher current CD4 cell count than those with cardioembolic strokes and had the highest mean blood pressure of the ischemic stroke subtypes.ConclusionIschemic stroke, particularly small vessel and cardioembolic subtypes, were the most common strokes among PLWH. Traditional and HIV-related risk factors differed by stroke type/subtype. Precipitating factors including infections and drug use were common. These results suggest that there may be different biological phenomena occurring among PLWH and that understanding HIV-related and traditional risk factors and in particular precipitating factors for each type/subtype may be key to understanding, and therefore preventing, strokes among PLWH.

Published
2021

48. n–6 fatty acid biomarkers and incident atrial fibrillation: an individual participant-level pooled analysis of 11 international prospective studies

Author

Garg, Parveen K., Guan, Weihua, Nomura, Sarah, Weir, Natalie L., Tintle, Nathan, Virtanen, Jyrki K., Hirakawa, Yoichiro, Qian, Frank, Sun, Qi, Rimm, Eric, Lemaitre, Rozenn N., Jensen, Paul N., Heckbert, Susan R., Imamura, Fumiaki, Steur, Marinka, Leander, Karin, Laguzzi, Federica, Voortman, Trudy, Ninomiya, Toshiharu, Mozaffarian, Dariush, Harris, William S., Siscovick, David S., and Tsai, Michael Y.

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

Author

Taliun, Daniel, Harris, Daniel N, Kessler, Michael D, Carlson, Jedidiah, Szpiech, Zachary A, Torres, Raul, Taliun, Sarah A Gagliano, Corvelo, André, Gogarten, Stephanie M, Kang, Hyun Min, Pitsillides, Achilleas N, LeFaive, Jonathon, Lee, Seung-been, Tian, Xiaowen, Browning, Brian L, Das, Sayantan, Emde, Anne-Katrin, Clarke, Wayne E, Loesch, Douglas P, Shetty, Amol C, Blackwell, Thomas W, Smith, Albert V, Wong, Quenna, Liu, Xiaoming, Conomos, Matthew P, Bobo, Dean M, Aguet, François, Albert, Christine, Alonso, Alvaro, Ardlie, Kristin G, Arking, Dan E, Aslibekyan, Stella, Auer, Paul L, Barnard, John, Barr, R Graham, Barwick, Lucas, Becker, Lewis C, Beer, Rebecca L, Benjamin, Emelia J, Bielak, Lawrence F, Blangero, John, Boehnke, Michael, Bowden, Donald W, Brody, Jennifer A, Burchard, Esteban G, Cade, Brian E, Casella, James F, Chalazan, Brandon, Chasman, Daniel I, Chen, Yii-Der Ida, Cho, Michael H, Choi, Seung Hoan, Chung, Mina K, Clish, Clary B, Correa, Adolfo, Curran, Joanne E, Custer, Brian, Darbar, Dawood, Daya, Michelle, de Andrade, Mariza, DeMeo, Dawn L, Dutcher, Susan K, Ellinor, Patrick T, Emery, Leslie S, Eng, Celeste, Fatkin, Diane, Fingerlin, Tasha, Forer, Lukas, Fornage, Myriam, Franceschini, Nora, Fuchsberger, Christian, Fullerton, Stephanie M, Germer, Soren, Gladwin, Mark T, Gottlieb, Daniel J, Guo, Xiuqing, Hall, Michael E, He, Jiang, Heard-Costa, Nancy L, Heckbert, Susan R, Irvin, Marguerite R, Johnsen, Jill M, Johnson, Andrew D, Kaplan, Robert, Kardia, Sharon LR, Kelly, Tanika, Kelly, Shannon, Kenny, Eimear E, Kiel, Douglas P, Klemmer, Robert, Konkle, Barbara A, Kooperberg, Charles, Köttgen, Anna, Lange, Leslie A, Lasky-Su, Jessica, Levy, Daniel, Lin, Xihong, Lin, Keng-Han, Liu, Chunyu, and Loos, Ruth JF

Subjects
Genetics, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Cytochrome P-450 CYP2D6, Genetic Variation, Genome, Human, Genomics, Haplotypes, Heterozygote, Humans, INDEL Mutation, Loss of Function Mutation, Mutagenesis, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Population Density, Precision Medicine, Quality Control, Sample Size, United States, Whole Genome Sequencing, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, General Science & Technology
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%.

Published
2021

50. Brief Report: Differences in Types of Myocardial Infarctions Among People Aging With HIV.

Author

Crane, Heidi M, Nance, Robin M, Whitney, Bridget M, Heckbert, Susan R, Budoff, Matthew, High, Kevin, Landay, Alan, Feinstein, Matthew, Moore, Richard D, Mathews, William Christopher, Christopoulos, Katerina, Saag, Michael S, Willig, Amanda, Eron, Joseph J, Kitahata, Mari M, and Delaney, Joseph AC

Subjects
Aging, HIV/AIDS, Cardiovascular, Infectious Diseases, Good Health and Well Being, Adult, Aged, Cohort Studies, Female, HIV Infections, Humans, Incidence, Longitudinal Studies, Male, Middle Aged, Myocardial Infarction, Plaque, Atherosclerotic, myocardial infarction, type 1 MI, type 2 MI, aging, HIV, Centers for AIDS Research Network of Clinical Information Systems, Clinical Sciences, Public Health and Health Services, Virology
Abstract

BackgroundType 1 myocardial infarctions (T1MIs) result from atherosclerotic plaque instability, rupture, and/or erosion. Type 2 MIs (T2MIs) are secondary to causes such as sepsis and cocaine-induced vasospasm resulting in an oxygen demand-supply mismatch and are associated with higher mortality than T1MIs. T2MIs account for a higher proportion of MIs among people living with HIV (PLWH) compared with the general population. We compared MI rates by type among aging PLWH. We hypothesized that increases in MI rates with older age would differ by MI types, and T2MIs would be more common than T1MIs in younger individuals.MethodsPotential MIs from 6 sites were centrally adjudicated using physician notes, electrocardiograms, procedure results, and laboratory results. Reviewers categorized MIs by type and identified causes of T2MIs. We calculated T1MI and T2MI incidence rates. Incidence rate ratios were calculated for T2MI vs. T1MI rates per decade of age.ResultsWe included 462 T1MIs (52%) and 413 T2MIs (48%). T1MI rates increased with older age, although T1MIs occurred in all age decades including young adults. T2MI rates were significantly higher than T1MI rates for PLWH younger than 40 years. T1MI rates were similar or higher than T2MI rates among those older than 40 years (significantly higher for those aged 50-59 and 60-69 years).ConclusionsRates of T2MIs were higher than T1MIs until age 40 years among PLWH, differing from the general population, but rates of both were high among older PLWH. Given prognostic differences between MI types, these results highlight the importance of differentiating MI types among PLWH.

Published
2021

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