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1. Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Author

Kavousi, Maryam, Bos, Maxime M, Barnes, Hanna J, Lino Cardenas, Christian L, Wong, Doris, Lu, Haojie, Hodonsky, Chani J, Landsmeer, Lennart PL, Turner, Adam W, Kho, Minjung, Hasbani, Natalie R, de Vries, Paul S, Bowden, Donald W, Chopade, Sandesh, Deelen, Joris, Benavente, Ernest Diez, Guo, Xiuqing, Hofer, Edith, Hwang, Shih-Jen, Lutz, Sharon M, Lyytikäinen, Leo-Pekka, Slenders, Lotte, Smith, Albert V, Stanislawski, Maggie A, van Setten, Jessica, Wong, Quenna, Yanek, Lisa R, Becker, Diane M, Beekman, Marian, Budoff, Matthew J, Feitosa, Mary F, Finan, Chris, Hilliard, Austin T, Kardia, Sharon LR, Kovacic, Jason C, Kral, Brian G, Langefeld, Carl D, Launer, Lenore J, Malik, Shaista, Hoesein, Firdaus AA Mohamed, Mokry, Michal, Schmidt, Reinhold, Smith, Jennifer A, Taylor, Kent D, Terry, James G, van der Grond, Jeroen, van Meurs, Joyce, Vliegenthart, Rozemarijn, Xu, Jianzhao, Young, Kendra A, Zilhão, Nuno R, Zweiker, Robert, Assimes, Themistocles L, Becker, Lewis C, Bos, Daniel, Carr, J Jeffrey, Cupples, L Adrienne, de Kleijn, Dominique PV, de Winther, Menno, den Ruijter, Hester M, Fornage, Myriam, Freedman, Barry I, Gudnason, Vilmundur, Hingorani, Aroon D, Hokanson, John E, Ikram, M Arfan, Išgum, Ivana, Jacobs, David R, Kähönen, Mika, Lange, Leslie A, Lehtimäki, Terho, Pasterkamp, Gerard, Raitakari, Olli T, Schmidt, Helena, Slagboom, P Eline, Uitterlinden, André G, Vernooij, Meike W, Bis, Joshua C, Franceschini, Nora, Psaty, Bruce M, Post, Wendy S, Rotter, Jerome I, Björkegren, Johan LM, O’Donnell, Christopher J, Bielak, Lawrence F, Peyser, Patricia A, Malhotra, Rajeev, van der Laan, Sander W, and Miller, Clint L

Subjects
Biological Sciences, Genetics, Heart Disease - Coronary Heart Disease, Human Genome, Cardiovascular, Prevention, Heart Disease, Atherosclerosis, 2.1 Biological and endogenous factors, Aetiology, Humans, Black People, Coronary Artery Disease, Genome-Wide Association Study, Risk Factors, European People, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Published
2023

5. Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Author

Adlam, David, Berrandou, Takiy-Eddine, Georges, Adrien, Nelson, Christopher, Giannoulatou, Eleni, Henry, Joséphine, Ma, Lijiang, Blencowe, Montgomery, Turley, Tamiel, Yang, Min-Lee, Chopade, Sandesh, Finan, Chris, Braund, Peter, Sadeg-Sayoud, Ines, Iismaa, Siiri, Kosel, Matthew, Zhou, Xiang, Hamby, Stephen, Cheng, Jenny, Liu, Lu, Tarr, Ingrid, Muller, David, dEscamard, Valentina, King, Annette, Brunham, Liam, Baranowska-Clarke, Ania, Debette, Stéphanie, Amouyel, Philippe, Olin, Jeffrey, Patil, Snehal, Hesselson, Stephanie, Junday, Keerat, Kanoni, Stavroula, Aragam, Krishna, Butterworth, Adam, Tweet, Marysia, Gulati, Rajiv, Combaret, Nicolas, Kadian-Dodov, Daniella, Kalman, Jonathan, Fatkin, Diane, Hingorani, Aroon, Saw, Jacqueline, Webb, Tom, Hayes, Sharonne, Yang, Xia, Ganesh, Santhi, Olson, Timothy, Kovacic, Jason, Graham, Robert, Samani, Nilesh, and Bouatia-Naji, Nabila

Subjects
Humans, Female, Genome-Wide Association Study, Vascular Diseases, Coronary Artery Disease, Myocardial Infarction
Abstract

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Published
2023

7. Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins on cardiovascular and non-cardiovascular outcomes

Author

Schmidt, Amand F., Joshi, Roshni, Gordillo-Marañón, Maria, Drenos, Fotios, Charoen, Pimphen, Giambartolomei, Claudia, Bis, Joshua C., Gaunt, Tom R., Hughes, Alun D., Lawlor, Deborah A., Wong, Andrew, Price, Jackie F., Chaturvedi, Nishi, Wannamethee, Goya, Franceschini, Nora, Kivimaki, Mika, Hingorani, Aroon D., and Finan, Chris

Published
2023
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9. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Author

Storm, Catherine S, Kia, Demis A, Almramhi, Mona M, Bandres-Ciga, Sara, Finan, Chris, Hingorani, Aroon D, and Wood, Nicholas W

Subjects
Biotechnology, Genetics, Prevention, Aging, Neurosciences, Brain Disorders, Parkinson's Disease, Neurodegenerative, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Aetiology, 5.1 Pharmaceuticals, Neurological, Good Health and Well Being, Brain, Case-Control Studies, Cohort Studies, Disease Progression, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Mendelian Randomization Analysis, Parkinson Disease, Quantitative Trait Loci, Risk Factors, International Parkinson’s Disease Genomics Consortium
Abstract

Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson's disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson's disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson's disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson's disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson's disease drug development.

Published
2021

11. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

14. Identifying and visualising multimorbidity and comorbidity patterns in patients in the English National Health Service: a population-based study

Author

Alexander, Daniel C, Asiimwe, Innocent G, Ball, Simon, Bennett, Frances, Borges, Maria Carolina, Butterworth, Adam, Chaturvedi, Nishi, Chopade, Sandesh, Clarkson, Christopher, Cox, Martin, Dale, Caroline, Denaxas, Spiros, Dunca, Diana, Engmann, Jorgen E, Fernandez-Sanles, Alba, Finan, Chris, Fitzpatrick, Natalie, Gallagher, Jean, Gonzalez-Izquierdo, Arturo, Gratton, Jasmine, Gross, Christian, Hemingway, Harry, Henry, Albert, Hidajat, Mira, Hingorani, Aroon, Hukerikar, Nikita, Jorgensen, Andrea, Joshi, Roshni, Katsoulis, Michail, Kuan, Valerie, Kumar, Rashmi, Lai, Alvina G, Langenberg, Claudia, Lawlor, Deborah, Mancini, Mary, Miller, Diane, Ogden, Margaret, Ozyigit, Eda B, Patel, Shilpa, Pirmohamed, Munir, Roberts, Amanda, Ryan, David, Schmidt, Amand F, Shah, Anoop D, Shah, Tina, Sofat, Reecha, Takhar, Rohan, Torralbo, Ana, Ullah, Ayath, Walker, Lauren E, Warwick, Alasdair, Wheeler, Eleanor, Wright, Victoria L, Wu, Honghan, Zwierzyna, Magdalena, Patalay, Praveetha, Nitsch, Dorothea, Mathur, Rohini, Partridge, Linda, Wong, Ian C K, Hingorani, Melanie, and Hingorani, Aroon D

Published
2023
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15. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Author

Franceschini, Nora, Giambartolomei, Claudia, de Vries, Paul S, Finan, Chris, Bis, Joshua C, Huntley, Rachael P, Lovering, Ruth C, Tajuddin, Salman M, Winkler, Thomas W, Graff, Misa, Kavousi, Maryam, Dale, Caroline, Smith, Albert V, Hofer, Edith, van Leeuwen, Elisabeth M, Nolte, Ilja M, Lu, Lingyi, Scholz, Markus, Sargurupremraj, Muralidharan, Pitkänen, Niina, Franzén, Oscar, Joshi, Peter K, Noordam, Raymond, Marioni, Riccardo E, Hwang, Shih-Jen, Musani, Solomon K, Schminke, Ulf, Palmas, Walter, Isaacs, Aaron, Correa, Adolfo, Zonderman, Alan B, Hofman, Albert, Teumer, Alexander, Cox, Amanda J, Uitterlinden, André G, Wong, Andrew, Smit, Andries J, Newman, Anne B, Britton, Annie, Ruusalepp, Arno, Sennblad, Bengt, Hedblad, Bo, Pasaniuc, Bogdan, Penninx, Brenda W, Langefeld, Carl D, Wassel, Christina L, Tzourio, Christophe, Fava, Cristiano, Baldassarre, Damiano, O'Leary, Daniel H, Teupser, Daniel, Kuh, Diana, Tremoli, Elena, Mannarino, Elmo, Grossi, Enzo, Boerwinkle, Eric, Schadt, Eric E, Ingelsson, Erik, Veglia, Fabrizio, Rivadeneira, Fernando, Beutner, Frank, Chauhan, Ganesh, Heiss, Gerardo, Snieder, Harold, Campbell, Harry, Völzke, Henry, Markus, Hugh S, Deary, Ian J, Jukema, J Wouter, de Graaf, Jacqueline, Price, Jacqueline, Pott, Janne, Hopewell, Jemma C, Liang, Jingjing, Thiery, Joachim, Engmann, Jorgen, Gertow, Karl, Rice, Kenneth, Taylor, Kent D, Dhana, Klodian, Kiemeney, Lambertus ALM, Lind, Lars, Raffield, Laura M, Launer, Lenore J, Holdt, Lesca M, Dörr, Marcus, Dichgans, Martin, Traylor, Matthew, Sitzer, Matthias, Kumari, Meena, Kivimaki, Mika, Nalls, Mike A, Melander, Olle, Raitakari, Olli, Franco, Oscar H, Rueda-Ochoa, Oscar L, Roussos, Panos, Whincup, Peter H, Amouyel, Philippe, and Giral, Philippe

Subjects
MEGASTROKE Consortium, Humans, Coronary Disease, Genetic Predisposition to Disease, Amino Acid Oxidoreductases, Protein-Lysine 6-Oxidase, Risk Factors, Lod Score, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Plaque, Atherosclerotic, Carotid Intima-Media Thickness, ADAMTS9 Protein, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018

17. Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation.

Author

van Vugt, Marion, Finan, Chris, Chopade, Sandesh, Providencia, Rui, Bezzina, Connie R., Asselbergs, Folkert W., van Setten, Jessica, and Schmidt, A. Floriaan

Subjects
*HEART diseases, *BLOOD proteins, *HEART failure, *DILATED cardiomyopathy, *DRUG target
Abstract

Background : Altered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease. Methods: Mendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy (NICM). Subsequently, we sourced data on 1567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways. Results: We identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines (p = 0.029) and DCM for acylcarnitines (p = 0.001). Metabolite involvement with AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF. RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis. Conclusions: This study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa

Author

Duncan, Laramie, Yilmaz, Zeynep, Gaspar, Helena, Walters, Raymond, Goldstein, Jackie, Anttila, Verneri, Bulik-Sullivan, Brendan, Ripke, Stephan, Thornton, Laura, Hinney, Anke, Daly, Mark, Sullivan, Patrick F, Zeggini, Eleftheria, Breen, Gerome, Bulik, Cynthia M, Gaspar, Héléna, Adan, Roger, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole, Aschauer, Harald, Baker, Jessica, Barrett, Jeffrey, Bencko, Vladimir, Bergen, Andrew, Berrettini, Wade, Birgegård, Andreas, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Cesta, Carolyn, Cichon, Sven, Clementi, Maurizio, Cohen-Woods, Sarah, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, Jim, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece, Dick, Danielle, Dikeos, Dimitris, Dina, Christian, Ding, Bo, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Espeseth, Thomas, Estivill, Xavier, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred, Finan, Chris, Fischer, Krista, Floyd, James, Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Fox, Caroline, Franklin, Christopher, Gaborieau, Valerie, Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Harrison, Rebecca, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske, Hendriks, Judith, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, and Hilliard, Christopher

Subjects
Serious Mental Illness, Mental Health, Anorexia, Eating Disorders, Brain Disorders, Nutrition, Human Genome, Genetics, Prevention, Pediatric, Mental health, Anorexia Nervosa, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Diabetes, GWAS, Metabolism, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveThe authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes.MethodFollowing uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes.ResultsResults were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes.ConclusionsAnorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Published
2017

20. Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Author

Schmidt, Amand F., Hunt, Nicholas B., Gordillo-Marañón, Maria, Charoen, Pimphen, Drenos, Fotios, Kivimaki, Mika, Lawlor, Deborah A., Giambartolomei, Claudia, Papacosta, Olia, Chaturvedi, Nishi, Bis, Joshua C., O’Donnell, Christopher J., Wannamethee, Goya, Wong, Andrew, Price, Jackie F., Hughes, Alun D., Gaunt, Tom R., Franceschini, Nora, Mook-Kanamori, Dennis O., Zwierzyna, Magdalena, Sofat, Reecha, Hingorani, Aroon D., and Finan, Chris

Published
2021
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22. Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

Author

Gordillo-Marañón, María, Zwierzyna, Magdalena, Charoen, Pimphen, Drenos, Fotios, Chopade, Sandesh, Shah, Tina, Engmann, Jorgen, Chaturvedi, Nishi, Papacosta, Olia, Wannamethee, Goya, Wong, Andrew, Sofat, Reecha, Kivimaki, Mika, Price, Jackie F., Hughes, Alun D., Gaunt, Tom R., Lawlor, Deborah A., Gaulton, Anna, Hingorani, Aroon D., Schmidt, Amand F., and Finan, Chris

Published
2021
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24. Associations Between Attention-Deficit/Hyperactivity Disorder and Various Eating Disorders: A Swedish Nationwide Population Study Using Multiple Genetically Informative Approaches

Author

Adan, Roger, Ando, Tetsuya, Baker, Jessica, Bergen, Andrew, Berrettini, Wade, Birgegård, Andreas, Boni, Claudette, Boraska Perica, Vesna, Brandt, Harry, Burghardt, Roland, Cassina, Matteo, Cesta, Carolyn, Clementi, Maurizio, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, James, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece, Dick, Danielle, Dikeos, Dimitris, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred, Finan, Chris, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Franklin, Christopher, Gaspar, Héléna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske, Hendriks, Judith, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hilliard, Christopher, Hinney, Anke, Huckins, Laura, Hudson, James, Huemer, Julia, Imgart, Hartmut, Inoko, Hidetoshi, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jenny, Juréus, Anders, Kalsi, Gursharan, Kaminska, Debora, Kaplan, Allan, Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien, Kaye, Walter, Kennedy, James, Kennedy, Martin, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly, Knudsen, Gun Peggy, Koeleman, Bobby, Koubek, Doris, La Via, Maria, Landén, Mikael, Levitan, Robert, Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lissowska, Jolanta, Magistretti, Pierre, Maj, Mario, Mannik, Katrin, Martin, Nicholas, McDevitt, Sara, McGuffin, Peter, Merl, Elisabeth, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Mortensen, Preben, Munn-Chernoff, Melissa, Nacmias, Benedetta, Nilsson, Ida, Norring, Claes, Ntalla, Ioanna, O’Toole, Julie, Pantel, Jacques, Papezova, Hana, Parker, Richard, Rabionet, Raquel, Raevuori, Anu, Rajewski, Andrzej, Ramoz, Nicolas, Rayner, N. William, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripke, Stephan, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Schmidt, Ulrike, Schork, Nicholas, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op’t Landt, Margarita, Slopien, Agnieszka, Smith, Tosha, Sorbi, Sandro, Strengman, Eric, Strober, Michael, Sullivan, Patrick, Szatkiewicz, Jin, Szeszenia-Dabrowska, Neonila, Tachmazidou, Ioanna, Tenconi, Elena, Thornton, Laura, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tziouvas, Konstantinos, van Elburg, Annemarie, van Furth, Eric, Wade, Tracey, Wagner, Gudrun, Walton, Esther, Watson, Hunna, Woodside, D. Blake, Yao, Shuyang, Yilmaz, Zeynep, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Alfredsson, Lars, Andreassen, Ole, Aschauer, Harald, Barrett, Jeffrey, Bencko, Vladimir, Carlberg, Laura, Cichon, Sven, Cohen-Woods, Sarah, Dina, Christian, Ding, Bo, Espeseth, Thomas, Floyd, James, Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Herms, Stefan, Janout, Vladimir, Julià, Antonio, Klareskog, Lars, Le Hellard, Stephanie, Leboyer, Marion, Lundervold, Astri, Marsal, Sara, Mattingsdal, Morten, Navratilova, Marie, Ophoff, Roel, Palotie, Aarno, Pinto, Dalila, Ripatti, Samuli, Rujescu, Dan, Scherer, Stephen, Scott, Laura, Sladek, Robert, Soranzo, Nicole, Southam, Lorraine, Steen, Vidar, Wichmann, H-Erich, Widen, Elisabeth, Breen, Gerome, Bulik, Cynthia, Kuja-Halkola, Ralf, Martin, Joanna, Lu, Yi, Hübel, Christopher, Almqvist, Catarina, Thornton, Laura M., Magnusson, Patrik K., Bulik, Cynthia M., and Larsson, Henrik

Published
2019
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25. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

Author

Holmes, Michael V, Dale, Caroline E, Zuccolo, Luisa, Silverwood, Richard J, Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A, Pikhart, Hynek, Swerdlow, Daniel I, Panayiotou, Andrie G, Borinskaya, Svetlana A, Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B, Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M, Rayaprolu, Sruti, Ross, Owen A, McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A, Adamkova, Vera, Flicker, Leon, Bockxmeer, Frank M van, Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G, Ferro, Jose M, Paulos-Pinheiro, Sofia, Humphries, Steve E, Talmud, Philippa J, Mateo Leach, Irene, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A, Cramer, Maarten J, van der Harst, Pim, Klungel, Olaf H, Dowling, Nicole F, Dominiczak, Anna F, Kumari, Meena, Nicolaides, Andrew N, Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R, Price, Jackie F, Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I, Tamosiunas, Abdonas, Maitland-van der Zee, Anke H, Norman, Paul E, Hankey, Graeme J, Bergmann, Manuela M, Hofman, Albert, Franco, Oscar H, Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, de Jong, Pim A, Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G, Ikram, M Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P, Wareham, Nicholas J, Khaw, Kay-Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S, Rimm, Eric, Beulens, Joline WJ, and Verschuren, WM Monique

Subjects
InterAct Consortium, Humans, Coronary Disease, Alcohol Dehydrogenase, Genetic Markers, Models, Statistical, Alcohol Drinking, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Stroke, Mendelian Randomization Analysis, Biomarkers, General & Internal Medicine, Clinical Sciences, Public Health and Health Services
Abstract

ObjectiveTo use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.DesignMendelian randomisation meta-analysis of 56 epidemiological studies.Participants261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.Main outcome measuresOdds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.ResultsCarriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).ConclusionsIndividuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Published
2014

29. Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog

Author

Hingorani, Aroon D, primary, Gratton, Jasmine, additional, Finan, Chris, additional, Schmidt, A Floriaan, additional, Patel, Riyaz, additional, Sofat, Reecha, additional, Kuan, Valerie, additional, Langenberg, Claudia, additional, Hemingway, Harry, additional, Morris, Joan K, additional, and Wald, Nicholas J, additional

Published
2023
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31. Genetic architecture of host proteins involved in SARS-CoV-2 infection

Author

Pietzner, Maik, Wheeler, Eleanor, Carrasco-Zanini, Julia, Raffler, Johannes, Kerrison, Nicola D., Oerton, Erin, Auyeung, Victoria P. W., Luan, Jian’an, Finan, Chris, Casas, Juan P., Ostroff, Rachel, Williams, Steve A., Kastenmüller, Gabi, Ralser, Markus, Gamazon, Eric R., Wareham, Nicholas J., Hingorani, Aroon D., and Langenberg, Claudia

Published
2020
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35. Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer cardiotoxicity

Author

Schmidt, Amand F., primary, Bourfiss, Mimount, additional, Alasiri, Abdulrahman, additional, Puyol-Anton, Esther, additional, Chopade, Sandesh, additional, van Vugt, Marion, additional, van der Laan, Sander W., additional, Gross, Christian, additional, Clarkson, Chris, additional, Henry, Albert, additional, Lumbers, Tom R., additional, van der Harst, Pim, additional, Franceschini, Nora, additional, Bis, Joshua C., additional, Velthuis, Birgitta K., additional, te Riele, Anneline S. J. M., additional, Hingorani, Aroon D., additional, Ruijsink, Bram, additional, Asselbergs, Folkert W., additional, van Setten, Jessica, additional, and Finan, Chris, additional

Published
2023
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36. Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer cardiotoxicity

Author

Onderzoek Precision medicine, CDL Onderzoek Pasterkamp, Circulatory Health, Gezonde Vaten, Researchgr. Hart-brein as., Brain, Arts Assistenten Cardiologie, Team Medisch, Schmidt, Amand F, Bourfiss, Mimount, Alasiri, Abdulrahman, Puyol-Anton, Esther, Chopade, Sandesh, van Vugt, Marion, van der Laan, Sander W, Gross, Christian, Clarkson, Chris, Henry, Albert, Lumbers, Tom R, van der Harst, Pim, Franceschini, Nora, Bis, Joshua C, Velthuis, Birgitta K, Te Riele, Anneline S J M, Hingorani, Aroon D, Ruijsink, Bram, Asselbergs, Folkert W, van Setten, Jessica, Finan, Chris, Onderzoek Precision medicine, CDL Onderzoek Pasterkamp, Circulatory Health, Gezonde Vaten, Researchgr. Hart-brein as., Brain, Arts Assistenten Cardiologie, Team Medisch, Schmidt, Amand F, Bourfiss, Mimount, Alasiri, Abdulrahman, Puyol-Anton, Esther, Chopade, Sandesh, van Vugt, Marion, van der Laan, Sander W, Gross, Christian, Clarkson, Chris, Henry, Albert, Lumbers, Tom R, van der Harst, Pim, Franceschini, Nora, Bis, Joshua C, Velthuis, Birgitta K, Te Riele, Anneline S J M, Hingorani, Aroon D, Ruijsink, Bram, Asselbergs, Folkert W, van Setten, Jessica, and Finan, Chris

Published
2023

37. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

Author

White, Jon, Sofat, Reecha, Hemani, Gibran, Shah, Tina, Engmann, Jorgen, Dale, Caroline, Shah, Sonia, Kruger, Felix A, Giambartolomei, Claudia, Swerdlow, Daniel I, Palmer, Tom, McLachlan, Stela, Langenberg, Claudia, Zabaneh, Delilah, Lovering, Ruth, Cavadino, Alana, Jefferis, Barbara, Finan, Chris, Wong, Andrew, Amuzu, Antoinette, Ong, Ken, Gaunt, Tom R, Warren, Helen, Davies, Teri-Louise, Drenos, Fotios, Cooper, Jackie, Ebrahim, Shah, Lawlor, Debbie A, Talmud, Philippa J, Humphries, Steve E, Power, Christine, Hypponen, Elina, Richards, Marcus, Hardy, Rebecca, Kuh, Diana, Wareham, Nicholas, Ben-Shlomo, Yoav, Day, Ian N, Whincup, Peter, Morris, Richard, Strachan, Mark W J, Price, Jacqueline, Kumari, Meena, Kivimaki, Mika, Plagnol, Vincent, Whittaker, John C, Smith, George Davey, Dudbridge, Frank, Casas, Juan P, Holmes, Michael V, and Hingorani, Aroon D

Published
2016
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38. Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

Author

Henry, Albert, Gordillo-Maranon, Maria, Finan, Chris, Schmidt, Amand F., Ferreira, Joao Pedro, Karra, Ravi, Sundström, Johan, Lind, Lars, Ärnlöv, Johan, Zannad, Faiez, Mälarstig, Anders, Hingorani, Aroon D., Lumbers, R. Thomas, University College of London [London] (UCL), University Medical Center [Utrecht], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Duke University Medical Center, Uppsala Universitet [Uppsala], University of New South Wales [Sydney] (UNSW), Karolinska Institutet [Stockholm], Dalarna University, Pfizer, This work is supported by the University College London (UCL) Hospitals National Institute for Health Research (NIHR) Biomedical Research Centre, the British Heart Foundation (BHF) Research Accelerator Award (AA/18/6/34223), and UK Research and Innovation / NIHR funded Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1). A. H. (FS/18/65/34186) and M.G. (FS/17/70/33482) acknowledge support by the BHF Cardiovascular Biomedicine PhD studentship. A.D.H. is an NIHR Senior Investigator. A.F.S is supported by BHF grant PG/18/503383, and acknowledges support by grant R01 LM010098 from the National Institutes of Health (USA). R.K. acknowledges support by the Walker-Inman Endowment, the Mandel Foundation, and by grant R03 HL144812-01. L.L. is supported by a grant from the Swedish Heart-Lung Foundation. J.Ä. is supported by grants from Swedish Research Council (2019-01015 and 2020-00243), the Swedish Heart-Lung Foundation (20180343 and 20210357). R.T.L. is supported by a UK Research and Innovation Rutherford Fellowship hosted by Health Data Research UK (MR/S003754/1) and BigData@Heart Consortium funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No. 116074. C.F., A.F.S., and R.T.L. acknowledge additional support from UCL Hospitals NIHR Biomedical Research Centre., and BOZEC, Erwan

Subjects
Heart Failure, Proteomics, Kardiologi, Mendelian randomization analysis, heart failure, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Adrenomedullin, proteomics, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Humans, Cardiac and Cardiovascular Systems, drug target prediction, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. Methods: We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis -protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis. Results: Forty-four of ninety proteins were positively associated with risk of incident HF ( P –4 ). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. Conclusions: We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

Published
2022

40. Identifying and visualising multimorbidity and comorbidity patterns in patients in the English National Health Service: a population-based study

Author

Kuan, Valerie, primary, Denaxas, Spiros, additional, Patalay, Praveetha, additional, Nitsch, Dorothea, additional, Mathur, Rohini, additional, Gonzalez-Izquierdo, Arturo, additional, Sofat, Reecha, additional, Partridge, Linda, additional, Roberts, Amanda, additional, Wong, Ian C K, additional, Hingorani, Melanie, additional, Chaturvedi, Nishi, additional, Hemingway, Harry, additional, Hingorani, Aroon D, additional, Alexander, Daniel C, additional, Asiimwe, Innocent G, additional, Ball, Simon, additional, Bennett, Frances, additional, Borges, Maria Carolina, additional, Butterworth, Adam, additional, Chopade, Sandesh, additional, Clarkson, Christopher, additional, Cox, Martin, additional, Dale, Caroline, additional, Dunca, Diana, additional, Engmann, Jorgen E, additional, Fernandez-Sanles, Alba, additional, Finan, Chris, additional, Fitzpatrick, Natalie, additional, Gallagher, Jean, additional, Gratton, Jasmine, additional, Gross, Christian, additional, Henry, Albert, additional, Hidajat, Mira, additional, Hingorani, Aroon, additional, Hukerikar, Nikita, additional, Jorgensen, Andrea, additional, Joshi, Roshni, additional, Katsoulis, Michail, additional, Kuan, Valerie, additional, Kumar, Rashmi, additional, Lai, Alvina G, additional, Langenberg, Claudia, additional, Lawlor, Deborah, additional, Mancini, Mary, additional, Miller, Diane, additional, Ogden, Margaret, additional, Ozyigit, Eda B, additional, Patel, Shilpa, additional, Pirmohamed, Munir, additional, Ryan, David, additional, Schmidt, Amand F, additional, Shah, Anoop D, additional, Shah, Tina, additional, Takhar, Rohan, additional, Torralbo, Ana, additional, Ullah, Ayath, additional, Walker, Lauren E, additional, Warwick, Alasdair, additional, Wheeler, Eleanor, additional, Wright, Victoria L, additional, Wu, Honghan, additional, and Zwierzyna, Magdalena, additional

Published
2023
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45. Association between alcohol and cardiovascular disease : Mendelian randomisation analysis based on individual participant data

Author

IMPROVE study group, The InterAct Consortium, Holmes, Michael V, Dale, Caroline E, Zuccolo, Luisa, Silverwood, Richard J, Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A, Pikhart, Hynek, Swerdlow, Daniel I, Panayiotou, Andrie G, Borinskaya, Svetlana A, Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B, Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M, Rayaprolu, Sruti, Ross, Owen A, McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A, Adamkova, Vera, Flicker, Leon, van Bockxmeer, Frank M, Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G, Ferro, Jose M, Paulos-Pinheiro, Sofia, Humphries, Steve E, Talmud, Philippa J, Leach, Irene Mateo, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A, Cramer, Maarten J, van der Harst, Pim, Klungel, Olaf H, Dowling, Nicole F, Dominiczak, Anna F, Kumari, Meena, Nicolaides, Andrew N, Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R, Price, Jackie F, Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I, Tamosiunas, Abdonas, Maitland-vanderZee, Anke H, Norman, Paul E, Hankey, Graeme J, Bergmann, Manuela M, Hofman, Albert, Franco, Oscar H, Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, de Jong, Pim A, Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G, Ikram, M Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P, Wareham, Nicholas J, Khaw, Kay-Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S, Rimm, Eric, Beulens, Joline W J, Verschuren, W M Monique, Onland-Moret, N Charlotte, Hofker, Marten H, Wannamethee, S Goya, Whincup, Peter H, Morris, Richard, Vicente, Astrid M, Watkins, Hugh, Farrall, Martin, Jukema, J Wouter, Meschia, James, Cupples, L Adrienne, Sharp, Stephen J, Fornage, Myriam, Kooperberg, Charles, LaCroix, Andrea Z, Dai, James Y, Lanktree, Matthew B, Siscovick, David S, Jorgenson, Eric, Spring, Bonnie, Coresh, Josef, Li, Yun R, Buxbaum, Sarah G, Schreiner, Pamela J, Curtis, R, Y Tsai, Michael, Patel, Sanjay R, Redline, Susan, Johnson, Andrew D, Hoogeveen, Ron C, Hakonarson, Hakon, Rotter, Jerome I, Boerwinkle, Eric, de Bakker, Paul I W, Kivimaki, Mika, Asselbergs, Folkert W, Sattar, Naveed, Lawlor, Debbie A, Whittaker, John, Smith, George Davey, Mukamal, Kenneth, Psaty, Bruce M, Wilson, James G, Lange, Leslie A, Hamidovic, Ajna, Hingorani, Aroon D, Nordestgaard, Børge G, Bobak, Martin, Leon, David A, Langenberg, Claudia, Palmer, Tom M, Reiner, Alex P, Keating, Brendan J, Dudbridge, Frank, and Casas, Juan P

Published
2014

47. Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins

Author

Schmidt, Amand, primary, Joshi, Roshni, additional, Kivimaki, Mika, additional, Hughes, Alun, additional, Lawlor, Deborah, additional, Price, Jackie, additional, Maranon, Maria, additional, Gaunt, Tom, additional, Charoen, Pimphen, additional, Wong, Andrew, additional, Chaturvedi, Nish, additional, Wannamethee, Goya, additional, Bis, Joshua, additional, Franceschini, Nora, additional, Giambartolomei, Claudia, additional, Hingorani, Aroon, additional, Finan, Chris, additional, and Drenos, Fotios, additional

Published
2022
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49. Adiposity and grip strength: a Mendelian randomisation study in UK Biobank

Author

Pinto Pereira, Snehal, Garfield, Victoria, Farmaki, Aliki-Eleni, Tomlinson, David, Fatemifar, Ghazaleh, Denaxas, Spiros, Finan, Chris, Cooper, Rachel, Pinto Pereira, Snehal, Garfield, Victoria, Farmaki, Aliki-Eleni, Tomlinson, David, Fatemifar, Ghazaleh, Denaxas, Spiros, Finan, Chris, and Cooper, Rachel

Abstract

Background: Muscle weakness, which increases in prevalence with age, is a major public health concern. Grip strength is commonly used to identify weakness and an improved understanding of its determinants is required. We aimed to investigate if total and central adiposity are causally associated with grip strength. Methods: Up to 470,786 UK Biobank participants, aged 38-73 years, with baseline data on four adiposity indicators (body mass index (BMI), body fat percentage (BF%), waist circumference (WC) and waist-hip-ratio (WHR)) and maximum grip strength were included. We examined sex-specific associations between each adiposity indicator and grip strength. We explored whether associations varied by age, by examining age-stratified associations (<50y,50-59y,60-64y,65y+). Using Mendelian randomisation (MR), we estimated the strength of the adiposity―grip strength associations using genetic instruments for each adiposity trait as our exposure. Results: In males, observed and MR associations were generally consistent: higher BMI and WC were associated with stronger grip; higher BF% and WHR were associated with weaker grip: 1-SD higher BMI was associated with 0.49kg(95%CI:0.45kg,0.53kg) stronger grip; 1-SD higher WHR was associated with 0.45kg(95%CI:0.41kg,0.48kg) weaker grip (covariate adjusted observational analyses). Associations of BMI and WC with grip strength were weaker at older ages: in males aged <50y and 65y+, 1-SD higher BMI was associated with 0.93kg(95%CI:0.84kg,1.01kg) and 0.13kg(95%CI:0.05kg,0.21kg) stronger grip, respectively. In females, higher BF% was associated with weaker grip and higher WC was associated with stronger grip; other associations were inconsistent. Conclusions: Using different methods to triangulate evidence, our findings suggest causal links between adiposity and grip strength. Specifically, higher BF% (in both sexes) and WHR (males only) were associated with weaker grip strength.

Published
2022

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