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1. Polygenic basis and biomedical consequences of telomere length variation

Author

Christopher P. Nelson, Veryan Codd, John R Thompson, Crispin Musicha, Tao Jiang, Angela M. Wood, Shilpi Sheth, Charley A. Budgeon, Willem H. Ouwehand, Emanuele Di Angelantonio, Svetlana Stoma, Vasiliki Bountziouka, Matthew Denniff, Peter S. Braund, James Eales, Stephen E. Hamby, Sophie C Warner, Dominika E Nanus, Qingning Wang, Stephen Kaptoge, Chloe Swinfield, Amit Khera, Manolo Papakonstantinou, Nilesh J. Samani, Adam S. Butterworth, John Danesh, Minxian Wang, Elias Allara, Codd, Veryan [0000-0002-9430-8254], Allara, Elias [0000-0002-1634-8330], Braund, Peter S. [0000-0001-8540-5709], Papakonstantinou, Manolo [0000-0003-2664-9046], Wang, Minxian [0000-0002-3753-508X], Khera, Amit V. [0000-0001-6535-5839], Eales, James [0000-0001-6238-5952], Ouwehand, Willem H. [0000-0002-7744-1790], Thompson, John R. [0000-0003-4819-1611], Butterworth, Adam S. [0000-0002-6915-9015], Samani, Nilesh J. [0000-0002-3286-8133], Apollo - University of Cambridge Repository, Braund, Peter S [0000-0001-8540-5709], Khera, Amit V [0000-0001-6535-5839], Ouwehand, Willem H [0000-0002-7744-1790], Thompson, John R [0000-0003-4819-1611], Butterworth, Adam S [0000-0002-6915-9015], Samani, Nilesh J [0000-0002-3286-8133], Kaptoge, Stephen [0000-0002-1155-4872], Ouwehand, Willem [0000-0002-7744-1790], Di Angelantonio, Emanuele [0000-0001-8776-6719], Wood, Angela [0000-0002-7937-304X], Butterworth, Adam [0000-0002-6915-9015], and Danesh, John [0000-0003-1158-6791]

Subjects
Senescence, Multifactorial Inheritance, media_common.quotation_subject, Quantitative Trait Loci, 631/208/205/2138, 45/43, Computational biology, Biology, Genome-wide association studies, Health data, Length variation, Genetics research, Genetics, Humans, media_common, Basis (linear algebra), Genome, Human, Longevity, 692/308/2056, article, Telomere Homeostasis, Mendelian Randomization Analysis, Biobank, Phenotype, Genetic architecture, Telomere, Evolutionary biology, Function (biology), Genome-Wide Association Study
Abstract

Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607)., Funder: Health Data Research UK, Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Published
2021

2. Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses

Author

Adam S. Butterworth, Scott C. Ritchie, Nilesh J. Samani, Steven Bell, Stephen Kaptoge, Matthew Arnold, Michael Inouye, Qi Guo, Frank Dudbridge, Christopher P. Nelson, Lisa Pennells, Emanuele Di Angelantonio, John R. Thompson, Angela M. Wood, Eleni Sofianopoulou, John Danesh, David Stevens, Stephen Burgess, Gad Abraham, Luanluan Sun, Thomas A. W. Bolton, Pennells, Lisa [0000-0002-8594-3061], Nelson, Christopher P. [0000-0001-8025-2897], Ritchie, Scott C. [0000-0002-8454-9548], Arnold, Matthew [0000-0001-6339-1115], Bell, Steven [0000-0001-6774-3149], Burgess, Stephen [0000-0001-5365-8760], Dudbridge, Frank [0000-0002-8817-8908], Stevens, David [0000-0001-8874-7122], Thompson, John R. [0000-0003-4819-1611], Wood, Angela [0000-0002-7937-304X], Samani, Nilesh J. [0000-0002-3286-8133], Inouye, Michael [0000-0001-9413-6520], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Nelson, Christopher P [0000-0001-8025-2897], Ritchie, Scott C [0000-0002-8454-9548], Thompson, John R [0000-0003-4819-1611], and Samani, Nilesh J [0000-0002-3286-8133]

Subjects
Male, Epidemiology, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Biochemistry, Vascular Medicine, Cohort Studies, Welsh, 0302 clinical medicine, Medical Conditions, Endocrinology, Agency (sociology), Coronary Heart Disease, 030212 general & internal medicine, Incidence, General Medicine, Middle Aged, Medical research, C-Reactive Proteins, Lipids, Social research, Stroke, Cholesterol, Neurology, Cardiovascular Diseases, language, Medicine, Female, Cohort study, Research Article, Adult, medicine.medical_specialty, Endocrine Disorders, Cerebrovascular Diseases, Cardiology, Library science, Risk Assessment, 03 medical and health sciences, Political science, medicine, Diabetes Mellitus, Humans, Ischemic Stroke, Aged, Medicine and health sciences, Government, Biology and life sciences, Public health, Proteins, Cardiovascular Disease Risk, language.human_language, United Kingdom, Heart Disease Risk Factors, Medical Risk Factors, Metabolic Disorders, Polygenic risk score, Biomarkers
Abstract

Background Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD. Methods and findings Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to, Luanluan Sun and colleagues investigate whether adding polygenic risk scores to conventional risk factors of cardiovascular disease helps predict disease risk., Author summary Why was this study done? Application of polygenic risk scores (PRSs) has opened opportunities to enhance risk stratification and prevention for common diseases. The clinical utility of PRSs in cardiovascular disease (CVD) risk prediction is, however, uncertain. Previous analyses have generally focused only on coronary heart disease (CHD) rather than the composite outcome of CHD and stroke, and have often lacked modelling of clinical implications of initiating guideline-recommended interventions (e.g., statin therapy). What did the researchers do and find? We quantified the incremental predictive gain with PRSs on top of conventional risk factors using data on 306,654 individuals from UK Biobank. We modelled the population health implications of initiating statin therapy as recommended by current guidelines using data from 2.1 million individuals from the Clinical Practice Research Datalink. Addition of information on PRSs to a conventional risk prediction model increased the C-index (a measure of risk discrimination) and improved risk classification of cases and non-cases. We estimated that targeted assessment of PRSs among people at intermediate (i.e., 5% to

Published
2021

3. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Author

Aragam, Krishna G, Jiang, Tao, Goel, Anuj, Kanoni, Stavroula, Wolford, Brooke N, Atri, Deepak S, Weeks, Elle M, Wang, Minxian, Hindy, George, Zhou, Wei, Grace, Christopher, Roselli, Carolina, Marston, Nicholas A, Kamanu, Frederick K, Surakka, Ida, Venegas, Loreto Muñoz, Sherliker, Paul, Koyama, Satoshi, Ishigaki, Kazuyoshi, Åsvold, Bjørn O, Brown, Michael R, Brumpton, Ben, De Vries, Paul S, Giannakopoulou, Olga, Giardoglou, Panagiota, Gudbjartsson, Daniel F, Güldener, Ulrich, Haider, Syed M Ijlal, Helgadottir, Anna, Ibrahim, Maysson, Kastrati, Adnan, Kessler, Thorsten, Kyriakou, Theodosios, Konopka, Tomasz, Li, Ling, Ma, Lijiang, Meitinger, Thomas, Mucha, Sören, Munz, Matthias, Murgia, Federico, Nielsen, Jonas B, Nöthen, Markus M, Pang, Shichao, Reinberger, Tobias, Schnitzler, Gavin, Smedley, Damian, Thorleifsson, Gudmar, Von Scheidt, Moritz, Ulirsch, Jacob C, Danesh, John, Arnar, David O, Burtt, Noël P, Costanzo, Maria C, Flannick, Jason, Ito, Kaoru, Jang, Dong-Keun, Kamatani, Yoichiro, Khera, Amit V, Komuro, Issei, Kullo, Iftikhar J, Lotta, Luca A, Nelson, Christopher P, Roberts, Robert, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Webb, Thomas R, Baras, Aris, Björkegren, Johan LM, Boerwinkle, Eric, Dedoussis, George, Holm, Hilma, Hveem, Kristian, Melander, Olle, Morrison, Alanna C, Orho-Melander, Marju, Rallidis, Loukianos S, Ruusalepp, Arno, Sabatine, Marc S, Stefansson, Kari, Zalloua, Pierre, Ellinor, Patrick T, Farrall, Martin, Ruff, Christian T, Finucane, Hilary K, Hopewell, Jemma C, Clarke, Robert, Gupta, Rajat M, Erdmann, Jeanette, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, Willer, Cristen J, Deloukas, Panos, Kathiresan, Sekar, Butterworth, Adam S, Aragam, Krishna G [0000-0003-3223-9131], Goel, Anuj [0000-0003-2307-4021], Kanoni, Stavroula [0000-0002-1691-9615], Wolford, Brooke N [0000-0003-3153-1552], Atri, Deepak S [0000-0001-8139-5419], Weeks, Elle M [0000-0002-4317-4444], Wang, Minxian [0000-0002-3753-508X], Zhou, Wei [0000-0001-7719-0859], Roselli, Carolina [0000-0001-5267-6756], Kamanu, Frederick K [0000-0001-7208-1047], Koyama, Satoshi [0000-0002-9286-0360], Ishigaki, Kazuyoshi [0000-0003-2881-0657], Åsvold, Bjørn O [0000-0003-3837-2101], Brumpton, Ben [0000-0002-3058-1059], Gudbjartsson, Daniel F [0000-0002-5222-9857], Güldener, Ulrich [0000-0001-5052-8610], Helgadottir, Anna [0000-0002-1806-2467], Kessler, Thorsten [0000-0003-3326-1621], Li, Ling [0000-0002-3280-9475], Mucha, Sören [0000-0002-1647-2526], Munz, Matthias [0000-0002-4728-3357], Murgia, Federico [0000-0002-3608-845X], Pang, Shichao [0000-0002-4111-2864], Smedley, Damian [0000-0002-5836-9850], Thorleifsson, Gudmar [0000-0003-4623-9087], von Scheidt, Moritz [0000-0001-7159-8271], Ulirsch, Jacob C [0000-0002-7947-0827], Costanzo, Maria C [0000-0001-9043-693X], Flannick, Jason [0000-0002-3618-795X], Ito, Kaoru [0000-0003-1843-773X], Khera, Amit V [0000-0001-6535-5839], Komuro, Issei [0000-0002-0714-7182], Kullo, Iftikhar J [0000-0002-6524-3471], Roberts, Robert [0000-0002-6792-4633], Webb, Thomas R [0000-0001-5998-8226], Baras, Aris [0000-0002-6830-3396], Björkegren, Johan LM [0000-0003-1945-7425], Holm, Hilma [0000-0002-9517-6636], Morrison, Alanna C [0000-0001-6381-4296], Orho-Melander, Marju [0000-0002-3578-2503], Stefansson, Kari [0000-0003-1676-864X], Farrall, Martin [0000-0003-4564-2165], Finucane, Hilary K [0000-0003-3864-9828], Clarke, Robert [0000-0002-9802-8241], Erdmann, Jeanette [0000-0002-4486-6231], Samani, Nilesh J [0000-0002-3286-8133], Schunkert, Heribert [0000-0001-6428-3001], Watkins, Hugh [0000-0002-5287-9016], Willer, Cristen J [0000-0001-5645-4966], Kathiresan, Sekar [0000-0002-3711-7101], Butterworth, Adam S [0000-0002-6915-9015], and Apollo - University of Cambridge Repository

Subjects
692/699/75/2, 631/208/205/2138, article, Humans, Coronary Artery Disease, Genome-Wide Association Study
Abstract

Funder: K.G.A. has received support from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP3384001), a KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from the Harvard Catalyst (KL2 TR002542), and the NIH (1K08HL153937)., Funder: B.N.W is supported by the National Science Foundation Graduate Research Program (DGE 1256260)., Funder: I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School., Funder: I.K., S.Ko., and K.It. are funded by the Japan Agency for Medical Research and Development, AMED, under Grant Numbers JP16ek0109070h0003, JP18kk0205008h0003, JP18kk0205001s0703, JP20km0405209, and JP20ek0109487. The BioBank Japan is supported by AMED under Grant Number JP20km0605001., Funder: J.L.M.B. acknowledges research support from NIH R01HL125863, American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265) and the Foundation Leducq (PlaqueOmics: Novel Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture, 18CVD02., Funder: P.S.dV was supported by American Heart Association grant number 18CDA34110116 and National Heart, Lung, and Blood Institute grant R01HL146860. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research., Funder: O.G. has received funding from the British Heart Foundation (BHF) (FS/14/66/3129)., Funder: T.K. is supported by the Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02)., Funder: D.S.A. has received support from a training grant from the NIH (T32HL007604)., Funder: N.P.B., M.C.C., J.F., and D.-K.J. have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (2UM1DK105554)., Funder: A.V.K. has been funded by 1K08HG010155 from the National Human Genome Research Institute., Funder: C.P.N. and T.R.W received funding from the British Heart Foundation (SP/16/4/32697)., Funder: The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology; and Central Norway Regional Health Authority. Whole genome sequencing for the HUNT study was funded by HL109946., Funder: O.M. was funded by the Swedish Heart- and Lung Foundation, the Swedish Research Council, the European Research Council ERC-AdG-2019-885003 and Lund University Infrastructure grant ”Malmö population-based cohorts” (STYR 2019/2046)., Funder: This work was supported by the European Commission (HEALTH-F2–2013-601456) and the TriPartite Immunometabolism Consortium [TrIC]- NovoNordisk Foundation (NNF15CC0018486), VIAgenomics (SP/19/2/344612), the British Heart Foundation, a Wellcome Trust core award (M.F., H.W., 203141/Z/16/Z) and support from the NIHR Oxford Biomedical Research Centre. M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health., Funder: J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator., Funder: J.C.H. acknowledges personal funding from the British Heart Foundation (FS/14/55/30806) and is a member of the Oxford BHF Centre of Research Excellence (RE/13/1/30181)., Funder: R.C. has received funding from the British Heart Foundation and British Heart Foundation Centre of Research Excellence., Funder: This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application number 9922)., Funder: The GerMIFs gratefully acknowledge the support of the Bavarian State Ministry of Health and Care, furthermore founded this work within its framework of DigiMed Bayern (grant No: DMB-1805-0001), the German Federal Ministry of Education and Research (BMBF) within the framework of ERA-NET on Cardiovascular Disease (Druggable-MI-genes: 01KL1802), within the scheme of target validation (BlockCAD: 16GW0198K), within the framework of the e:Med research and funding concept (AbCD-Net: 01ZX1706C), the British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)-collaboration (VIAgenomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02) and the Sonderforschungsbereich SFB TRR 267 (B05)., Funder: C.J.W. is funded by NIH grant R35-HL135824., Funder: This work was supported by the British Heart Foundation (BHF) grant RG/14/5/30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR)., The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Published
2022
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4. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

Stacey, David, Chen, Lingyan, Stanczyk, Paulina J, Howson, Joanna MM, Mason, Amy M, Burgess, Stephen, MacDonald, Stephen, Langdown, Jonathan, McKinney, Harriett, Downes, Kate, Farahi, Neda, Peters, James E, Basu, Saonli, Pankow, James S, Tang, Weihong, Pankratz, Nathan, Sabater-Lleal, Maria, De Vries, Paul S, Smith, Nicholas L, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, Van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward-Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook-Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank WG, Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Conomos, Matthew P, Liu, Melissa, Brown, Michael R, Jhun, Min-A, Chen, Ming-Huei, De Maat, Moniek PM, Peyser, Patricia A, Elliot, Paul, Wei, Peng, Wild, Philipp S, Morange, Pierre E, Van Der Harst, Pim, Yang, Qiong, Le, Ngoc-Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Koenig, Wolfgang, Jukema, J Wouter, Guo, Xiuqing, Gelinas, Amy D, Schneider, Daniel J, Janjic, Nebojsa, Samani, Nilesh J, Ye, Shu, Summers, Charlotte, Chilvers, Edwin R, Danesh, John, Paul, Dirk S, Chen, Lingyan [0000-0003-3750-6761], Howson, Joanna MM [0000-0001-7618-0050], Mason, Amy M [0000-0002-8019-0777], Burgess, Stephen [0000-0001-5365-8760], Peters, James E [0000-0002-9415-3440], Pankow, James S [0000-0001-7076-483X], Pankratz, Nathan [0000-0001-5958-693X], Sabater-Lleal, Maria [0000-0002-0128-379X], Schneider, Daniel J [0000-0001-6830-0905], Samani, Nilesh J [0000-0002-3286-8133], Ye, Shu [0000-0002-4126-4278], Summers, Charlotte [0000-0002-7269-2873], Chilvers, Edwin R [0000-0002-4230-9677], Paul, Dirk S [0000-0002-8230-0116], and Apollo - University of Cambridge Repository

Subjects
13/31, 13/1, 692/4019/592/2727, 45/43, article, 631/208/212/2301, 45/88, 13/106
Abstract

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Published
2022

5. 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, Samoan Obesity, Lifestyle And Genetic Adaptations Study (OLaGA) Group, 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, Correa, Adolfo, Psaty, Bruce M, Fornage, Myriam, Manson, JoAnn E, Boerwinkle, Eric, Konkle, Barbara A, Loos, Ruth JF, Rotter, Jerome I, Silverman, Edwin K, Kooperberg, Charles, Danesh, John, Samani, Nilesh J, Jaiswal, Siddhartha, Libby, Peter, Ellinor, Patrick T, Pankratz, Nathan, Ebert, Benjamin L, Reiner, Alexander P, Mathias, Rasika A, Do, Ron, NHLBI Trans-Omics For Precision Medicine (TOPMed) Consortium, Natarajan, Pradeep, Nakao, Tetsushi [0000-0001-9979-2682], Bick, Alexander G [0000-0001-5824-9595], Zekavat, Seyedeh M [0000-0003-4026-8944], Uddin, Md M [0000-0003-1846-0411], Niroula, Abhishek [0000-0002-5904-0635], Carty, Cara L [0000-0002-6378-8195], Lane, John [0000-0002-3582-5825], Honigberg, Michael C [0000-0001-8630-5021], Weinstock, Joshua S [0000-0001-7013-1899], Pampana, Akhil [0000-0002-4167-0540], Griffin, Gabriel K [0000-0002-4042-6757], Clarke, Shoa L [0000-0002-6592-1172], Bhattacharya, Romit [0000-0002-0782-4753], Assimes, Themistocles L [0000-0003-2349-0009], Emery, Leslie S [0000-0002-9070-9886], Stilp, Adrienne M [0000-0002-3910-0776], Wong, Quenna [0000-0002-9027-2100], Broome, Jai [0000-0001-7638-0749], Khan, Alyna T [0000-0002-2240-7931], Smith, Albert V [0000-0003-1942-5845], Codd, Veryan [0000-0002-9430-8254], Nelson, Christopher P [0000-0001-8025-2897], Yoneda, Zachary T [0000-0002-2055-732X], Peralta, Juan M [0000-0002-8811-5579], Yanek, Lisa R [0000-0001-7117-1075], Wiggins, Kerri L [0000-0003-2749-1279], Gu, C Charles [0000-0002-8527-8145], Peloso, Gina M [0000-0002-5355-8636], Roden, Dan M [0000-0002-6302-0389], Hwu, Chii-Min [0000-0002-8209-9627], North, Kari E [0000-0002-8903-0366], Bis, Joshua C [0000-0002-3409-1110], Lloyd-Jones, Donald M [0000-0003-0847-6110], Johnsen, Jill M [0000-0002-2279-2550], Preuss, Michael [0000-0001-5266-8465], Tracy, Russell P [0000-0002-0080-2420], Peyser, Patricia A [0000-0002-9717-8459], Qiao, Dandi [0000-0001-9450-205X], Curran, Joanne E [0000-0002-6898-155X], Freedman, Barry I [0000-0003-0275-5530], Chavan, Sameer [0000-0002-0220-0845], Smith, Jennifer A [0000-0002-3575-5468], Kelly, Tanika N [0000-0002-7348-4451], Hidalgo, Bertha [0000-0002-2556-1969], Weeks, Daniel E [0000-0001-9410-7228], Hawley, Nicola L [0000-0002-2601-3454], Minster, Ryan L [0000-0001-7382-6717], de Las Fuentes, Lisa [0000-0002-4689-325X], Raffield, Laura M [0000-0002-7892-193X], Ballantyne, Christie M [0000-0002-6432-1730], Kenny, Eimear E [0000-0001-9198-759X], Rich, Stephen S [0000-0003-3872-7793], Whitsel, Eric A [0000-0003-4843-3641], Cho, Michael H [0000-0002-4907-1657], Palmer, Nicholette D [0000-0001-8883-2511], Mitchell, Braxton D [0000-0003-4920-4744], Shuldiner, Alan R [0000-0001-9921-4305], Redline, Susan [0000-0002-6585-1610], Heckbert, Susan R [0000-0002-7100-512X], He, Jiang [0000-0002-8286-9652], Post, Wendy [0000-0002-8655-5204], Arnett, Donna K [0000-0003-2219-657X], Vasan, Ramachandran S [0000-0001-7357-5970], Weiss, Scott T [0000-0001-7196-303X], McGarvey, Stephen T [0000-0003-1233-6970], Custer, Brian S [0000-0001-6251-366X], Correa, Adolfo [0000-0002-9501-600X], Manson, JoAnn E [0000-0002-9426-7595], Konkle, Barbara A [0000-0002-3959-8797], Loos, Ruth JF [0000-0002-8532-5087], Rotter, Jerome I [0000-0001-7191-1723], Silverman, Edwin K [0000-0002-3641-3822], Kooperberg, Charles [0000-0002-7986-8560], Samani, Nilesh J [0000-0002-3286-8133], Jaiswal, Siddhartha [0000-0002-9597-0477], Libby, Peter [0000-0002-1502-502X], Ellinor, Patrick T [0000-0002-2067-0533], Pankratz, Nathan [0000-0001-5958-693X], Ebert, Benjamin L [0000-0003-0197-5451], Mathias, Rasika A [0000-0002-2282-9042], Do, Ron [0000-0002-3144-3627], Natarajan, Pradeep [0000-0001-8402-7435], Apollo - University of Cambridge Repository, and Danesh, John [0000-0003-1158-6791]

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group
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
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6. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

Stacey, David, Chen, Lingyan, Stanczyk, Paulina J., Howson, Joanna M.M., Mason, Amy M., Burgess, Stephen, MacDonald, Stephen, Langdown, Jonathan, McKinney, Harriett, Downes, Kate, Farahi, Neda, Peters, James E., Basu, Saonli, Pankow, James S., Tang, Weihong, Pankratz, Nathan, Sabater-Lleal, Maria, de Vries, Paul S., Smith, Nicholas L., Dehghan, Abbas, Heath, Adam S., Morrison, Alanna C., Reiner, Alex P., Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M., Hayward, Caroline, Ward-Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P., Tregouet, David A., Mook-Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W., Leebeek, Frank W.G., Rosendaal, Frits R., Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A., Bressler, Jan, Kavousi, Maryam, Brown, Michael R., de Maat, Moniek P.M., Chen, Lingyan [0000-0003-3750-6761], Howson, Joanna MM [0000-0001-7618-0050], Mason, Amy [0000-0002-8019-0777], Burgess, Stephen [0000-0001-5365-8760], Peters, James E [0000-0002-9415-3440], Pankow, James S [0000-0001-7076-483X], Pankratz, Nathan [0000-0001-5958-693X], Sabater-Lleal, Maria [0000-0002-0128-379X], Schneider, Daniel J [0000-0001-6830-0905], Samani, Nilesh J [0000-0002-3286-8133], Ye, Shu [0000-0002-4126-4278], Summers, Charlotte [0000-0002-7269-2873], Chilvers, Edwin R [0000-0002-4230-9677], Danesh, John [0000-0003-1158-6791], Paul, Dirk [0000-0002-8230-0116], Apollo - University of Cambridge Repository, Adult Psychiatry, Infectious diseases, Mason, Amy M [0000-0002-8019-0777], Paul, Dirk S [0000-0002-8230-0116], Hematology, and Epidemiology

Subjects
CHARGE Hemostasis Working Group, 45/43, General Physics and Astronomy, cell surface receptor, 631/208/212/2301, 45/88, Receptors, Cell Surface, 13/106, Crosses, Cardiovascular, General Biochemistry, Genetics and Molecular Biology, 13/1, SDG 3 - Good Health and Well-being, Genetic, Antigens, CD, 692/4019/592/2727, PROCR protein, human, Receptors, Genetics, 2.1 Biological and endogenous factors, Humans, endothelium cell, human, Antigens, Aetiology, Heart Disease - Coronary Heart Disease, Crosses, Genetic, leukocyte antigen, Multidisciplinary, genetic cross, Prevention, Inflammatory and immune system, article, Endothelial Cells, Endothelial Protein C Receptor, Thrombosis, General Chemistry, Hematology, Venous Thromboembolism, Atherosclerosis, CD, 13/31, Heart Disease, Cell Surface, metabolism, Protein C
Abstract

Funder: Wellcome Trust, Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Published
2022

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