Author: "Claudia Langenberg" / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

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202 results on '"Claudia Langenberg"'

1. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author: Richard A. Jensen, Denis Rybin, Jaakko Tuomilehto, Reedik Mägi, Inga Prokopenko, Jeffrey R. O'Connell, Marcus E. Kleber, Han Chen, Geoffrey A. Walford, Allan Linnenberg, Anke Tönjes, Francis S. Collins, Sonsoles Morcillo, Gemma Rojo-Martínez, Kenneth Rice, Jose C. Florez, Leif Groop, Manuel Serrano-Ríos, Josée Dupuis, Alisa K. Manning, Peter Kovacs, Torben Jørgensen, Graciela E. Delgado, Alena Stančáková, Hans-Ulrich Häring, Claudia Langenberg, Joshua P. Lewis, Norbert Stefan, Markku Laakso, Torben Hansen, Bruce M. Psaty, Jian'an Luan, Michael Stumvoll, Mark O. Goodarzi, Robert A. Scott, Oluf Pedersen, Ching-Ti Liu, Michael N. Weedon, Michael Boehnke, Ulf Smith, David S. Siscovick, Aaron Leong, Weijia Xie, James B. Meigs, Claes Landenvall, Anne U. Jackson, Joseph M. Zmuda, Mary L. Biggs, Jerome I. Rotter, Federico Soriguer, Winfried März, Zhongyang Zhang, May E. Montasser, Arturo Corbatón-Anchuelo, J M Gómez-Zumaquero, Günther Silbernagel, Kristine Færch, Karen L. Mohlke, Heikki A. Koistinen, Yii-Der Ida Chen, Jaeyoung Hong, Gracia María Martín-Núñez, María Teresa Martínez-Larrad, Emil V. R. Appel, Niels Grarup, Harald Staiger, Johanna Kuusisto, Lars Lind, Nicholas J. Wareham, Andreas Fritsche, Stefan Gustafsson, Andrew P. Morris, Richard N. Bergman, Mark Walker, Cecilia M. Lindgren, Erik Ingelsson, Jorge R. Kizer, Timothy M. Frayling, and Fausto Machicao
Subjects: 0301 basic medicine, Male, Insulin Receptor Substrate Proteins, Endocrinology, Diabetes and Metabolism, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Insulin resistance, Genotype, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic association, Genetics, business.industry, Insulin sensitivity, Genetics/Genomes/Proteomics/Metabolomics, 11 Medical And Health Sciences, medicine.disease, IRS1, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Chemokines, CC, Female, Insulin Resistance, business, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
Published: 2023
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2. Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region

Author: Fiona M. Gribble, Robert Hansford, Maik Pietzner, Nicholas Bowker, A. Mesut Erzurumluoglu, Christopher N. Foley, Nicholas J. Wareham, Pallav Bhatnagar, Frank Reimann, Isobel D. Stewart, Eleanor Wheeler, Victoria P W Auyeung, Claudia Langenberg, Stephen Burgess, and Matthew P. Coghlan
Subjects: Adult, Male, Apolipoprotein E, medicine.medical_specialty, Linkage disequilibrium, Genotype, Endocrinology, Diabetes and Metabolism, Gastric Inhibitory Polypeptide, Type 2 diabetes, Receptors, Gastrointestinal Hormone, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, Humans, Medicine, Genetic Predisposition to Disease, Allele, Finland, Aged, Glycemic, business.industry, Confounding, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, Odds ratio, Middle Aged, medicine.disease, United Kingdom, Endocrinology, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Female, business, Genome-Wide Association Study
Abstract: There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials.
Published: 2021

3. Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Author: Yvonne T. van der Schouw, Eva Ardanaz, Ju-Sheng Zheng, Adam S. Butterworth, Maik Pietzner, Guy Fagherazzi, María José Sánchez, Rudolf Kaaks, Anne Tjønneland, Anja Olsen, Elio Riboli, Elisabete Weiderpass, Peter M. Nilsson, Luca A. Lotta, Thomas E. Gundersen, Olov Rolandsson, Claudia Langenberg, Nasser Laouali, Nita G. Forouhi, Pilar Amiano, Núria Sala, Kim Overvad, Sabina Sieri, Fulvio Ricceri, John Danesh, Jian'an Luan, Domenico Palli, Francesca Mancini, Annemieke M.W. Spijkerman, Rosario Tumino, Matthias B. Schulze, Eleni Sofianopoulou, María Dolores Chirlaque, N. Charlotte Onland-Moret, Eleanor Wheeler, Isobel D. Stewart, Paul W. Franks, Stephen J. Sharp, Salvatore Panico, Fumiaki Imamura, Nicholas J. Wareham, Felix R. Day, Zheng, Ju-Sheng [0000-0001-6560-4890], Lotta, Luca A [0000-0002-2619-5956], Fagherazzi, Guy [0000-0001-5033-5966], Franks, Paul W [0000-0002-0520-7604], Rolandsson, Olov [0000-0002-1341-6828], Schulze, Matthias B [0000-0002-0830-5277], Forouhi, Nita G [0000-0002-5041-248X], Wareham, Nicholas J [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, LEVEL, Physiology, 030209 endocrinology & metabolism, Genome-wide association study, Type 2 diabetes, Ascorbic Acid, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, EPIC-NORFOLK, 03 medical and health sciences, VEGETABLE INTAKE, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, DESIGN, Risk Factors, Diabetes mellitus, Mendelian randomization, Internal Medicine, Medicine, Humans, 030212 general & internal medicine, OXIDATIVE STRESS, Epidemiology/Health Services Research, METAANALYSIS, Genetic association, Advanced and Specialized Nursing, Vitamin C, FRUIT, business.industry, GENETIC-VARIATION, Mendelian Randomization Analysis, medicine.disease, 3. Good health, Diabetes Mellitus, Type 2, ASCORBIC-ACID, Endokrinologi och diabetes, Medical genetics, LIFE-STYLE, business, Genome-Wide Association Study
Abstract: OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
Published: 2020

4. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Author: Alison D. Murray, Anna L. Guyatt, Jing Hua Zhao, Eugene R. Bleecker, Matthias Wielscher, Frank Dudbridge, Martin D. Tobin, Veronique Vitart, Ida Surakka, Nadia N. Hansel, Ozren Polasek, Caroline Hayward, David P. Strachan, Per Bakke, Stefan Karrasch, Anubha Mahajan, James F. Wilson, Shona M. Kerr, Ruth Tal-Singer, James D. Crapo, Victoria E. Jackson, Jonathan Marten, Olli T. Raitakari, María Soler Artigas, Medea Imboden, Sungho Won, Beate Stubbe, Ulf Gyllensten, George R. Washko, Eleftheria Zeggini, David A. Lynch, Brian D. Hobbs, Matthew Moll, Mika Kähönen, Rajesh Rawal, Guy Brusselle, Ma'en Obeidat, Nicholas J. Wareham, Claudia Langenberg, Nicole Probst-Hensch, Peter K. Joshi, Blair H. Smith, Stefan Weiss, Woo Jin Kim, Kathleen C. Barnes, Sarah E. Harris, David J. Porteous, Stefan Enroth, Ian P. Hall, Alan L. James, Sina A. Gharib, Paul R. H. J. Timmers, Xingnan Li, Louise V. Wain, John E. Hokanson, Holger Schulz, Ralf Ewert, Ani Manichaikul, Lies Lahousse, Georg Homuth, R. Graham Barr, Scott T. Weiss, Phuwanat Sakornsakolpat, Sara R.A. Wijnant, Edwin K. Silverman, Christian Gieger, Jennie Hui, Andrew P. Morris, James P. Cook, Michael J. McGeachie, Dawn L. DeMeo, Nick Shrine, Traci M. Bartz, Amund Gulsvik, Deborah A. Meyers, Katherine A. Kentistou, Igor Rudan, Jian'an Luan, Ian J. Deary, Catherine John, Michael H. Cho, Lars Lind, Marjo-Riitta Järvelin, Ah Ra Do, Terho Lehtimäki, Stephen S. Rich, Bruce M. Psaty, Tampere University, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Department of Clinical Chemistry, Epidemiology, and Pulmonary Medicine
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, AMERICAN THORACIC SOCIETY, Vital Capacity, LOCI, Genome-wide association study, EMPHYSEMA, Cohort Studies, 03 medical and health sciences, FEV1/FVC ratio, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Risk Factors, Internal medicine, Forced Expiratory Volume, adult, case-control studies, cohort studies, female, forced expiratory volume, genome-wide association study, humans, male, middle aged, phenotype, pulmonary disease, chronic obstructive, risk factors, vital capacity, Medicine and Health Sciences, medicine, COPD, Humans, SMOKING-BEHAVIOR, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, FAMILIAL AGGREGATION, GENETIC EPIDEMIOLOGY, Framingham Risk Score, HERITABILITY, business.industry, Case-control study, Family aggregation, Odds ratio, Articles, Middle Aged, medicine.disease, respiratory tract diseases, LUNG-FUNCTION, Phenotype, 030228 respiratory system, Genetic epidemiology, Case-Control Studies, Female, 3111 Biomedicine, business, Genome-Wide Association Study
Abstract: Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1
Published: 2020

5. Autoimmunity plays a role in the onset of diabetes after 40 years of age

Author: Vittorio Krogh, Rudolf Kaaks, Yvonne T. van der Schouw, Gianluca Severi, Eva Ardanaz, Marc J. Gunter, Tilman Kühn, Nicholas J. Wareham, Timothy J. Key, Francesca Mancini, Carlotta Sacerdote, María José Sánchez, Heiner Boeing, Annemieke M.W. Spijkerman, Peter M. Nilsson, Guy Fagherazzi, Miren Dorronsoro, María Dolores Chirlaque, Kay-Tee Khaw, Olov Rolandsson, Stephen J. Sharp, Salvatore Panico, Domenico Palli, Nita G. Forouhi, Christiane S. Hampe, Claudia Langenberg, Kim Overvad, Rosario Tumino, Elio Riboli, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), LSHM_CT_2006_037197 N∫ 6236 National Institutes of Health, NIH: DK26190 Compagnia di San Paolo Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Medical Research Council, MRC: MC_UU_12015/1, MC_UU_12015/5, MR/N003284/1 Cancer Research UK, CRUK World Cancer Research Fund, WCRF Bundesministerium für Bildung und Forschung, BMBF Västerbotten Läns Landsting Ministerie van Volksgezondheid, Welzijn en Sport, VWS Agentschap NL: IGE05012 Vetenskapsrådet, VR Umeå Universitet Bundesministerium für Forschung und Technologie, BMFT Deutsche Krebshilfe Bundesministerium fÃ¼r Bildung und Frauen, BMBF Stichting Diabetes Onderzoek Nederland NIHR Imperial Biomedical Research Centre, BRC NIHR Cambridge Biomedical Research Centre: IS-BRC-1215-20014, O. Rolandsson: The Västerboten County Council, M. Dorronsoro: We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as to the team of trained nurses who participated in the recruitment, R. Kaaks: German Cancer Aid, German Ministry of Research (BMBF), K. T. Khaw: Medical Research Council UK, Cancer Research UK, T. Kühn: German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF), S. Panico: Compagnia di San Paolo, A. M. W. Spijkerman: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Statistics Netherlands (the Netherlands), EPIC Ragusa acknowledges for their participation blood donors of AVIS-Ragusa (local blood donors association), Y. T. van der Schouw: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Dutch ZON (Zorg Onderzoek Nederland), WCRF, Statistics Netherland, E. Riboli: Imperial College Biomedical Research Centre., Open access funding provided by Umea University. Funding for the InterAct project was provided by the EU FP6 Programme (grant number LSHM_CT_2006_037197). The autoantibody measurement was funded by Västerbotten County Council and Umeå University, Sweden (OR), the National Institutes of Health (DK26190) (CSH) and the Medical Research Council (MC_UU_12015/1) (NJW). OR: the Västerbotten County Council, Umeå University, MDC: Health Research Fund (FIS) of the Spanish Ministry of Health, Murcia Regional Government (N∫ 6236), EA: the Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government, RK: German Cancer Aid, the German Ministry of Research (BMBF), TJK: Cancer Research UK, KTK: the Medical Research Council UK, Cancer Research UK, PMN: the Swedish Research Council, KO: the Danish Cancer Society, SP: Compagnia di San Paolo, AMWS: the Dutch Ministry of Public Health, Welfare and Sports (VWS), the Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands, RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government, AMWS: LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), YTvdS: verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht, LK Research Funds, Dutch Prevention Funds, NGF: MRC core support (MC_UU_12015/5), NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Acknowledgements, We thank all EPIC participants and staff for their contribution to this study. We thank N. Kerrison (MRC Epidemiology Unit, Cambridge, UK) for managing the data and the laboratory team at the MRC Epidemiology Unit, Cambridge for managing the blood samples for the EPIC-InterAct project. We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as the team of trained nurses who participated in the recruitment. O. Rolandsson: The V?sterboten County Council, T. K?hn: German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF), E. Riboli: Imperial College Biomedical Research Centre. Some of the data were presented as an abstract at the 54th EASD Annual Meeting in 2018., Rolandsson, Olov [0000-0002-1341-6828], and Apollo - University of Cambridge Repository
Subjects: Male, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Autoimmunity, Type 2 diabetes, medicine.disease_cause, LADA, Endocrinology, Autoantibody, 0302 clinical medicine, POPULATION, RISK, 0303 health sciences, Glutamate Decarboxylase, ANTIBODY POSITIVITY, GAD, Middle Aged, Phenotype, Genetic risk score, Pathophysiology, 3. Good health, Diabetes and Metabolism, Type 1 diabetes, Endokrinologi och diabetes, Female, Life Sciences & Biomedicine, Adult, 030209 endocrinology & metabolism, Endocrinology and Diabetes, Antibodies, Article, 1117 Public Health and Health Services, Endocrinology & Metabolism, 03 medical and health sciences, GLUTAMIC-ACID DECARBOXYLASE, Insulin resistance, Diabetes mellitus, Internal Medicine, medicine, Humans, TYPE-1, Aged, 030304 developmental biology, Science & Technology, business.industry, RECOGNITION, 1103 Clinical Sciences, ADULTS, medicine.disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Incident diabetes, Case-Control Studies, Immunology, 1114 Paediatrics and Reproductive Medicine, AUTOANTIBODIES, indident diabetes, business
Abstract: Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
Published: 2019

6. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
Published: 2021

7. Identifying adults at high-risk for change in weight and BMI in England: a longitudinal, large-scale, population-based cohort study using electronic health records

Author: Spiros Denaxas, Harry Hemingway, Manuel Gomes, Richard Dobson, Goya Wannamethee, Dimitra Kleio Kipourou, Alvina G. Lai, Laura Pasea, Lan Wen, Gesthimani Misirli, Krishnan Bhaskaran, Amitava Banerjee, Pagona Lagiou, R. Thomas Lumbers, Nicholas J. Wareham, Karla Diaz-Ordaz, Rachel L. Batterham, Kostas Tsilidis, Claudia Langenberg, Michail Katsoulis, Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Lai, Alvina G [0000-0001-8960-8095], and Batterham, Rachel L [0000-0002-5477-8585]
Subjects: Adult, Male, Adolescent, Endocrinology, Diabetes and Metabolism, Population, Overweight, Body Mass Index, 1117 Public Health and Health Services, Cohort Studies, Young Adult, Endocrinology, Risk Factors, Internal Medicine, medicine, Electronic Health Records, Humans, Risk factor, education, Child, Aged, education.field_of_study, business.industry, Absolute risk reduction, Infant, 1103 Clinical Sciences, Odds ratio, medicine.disease, Obesity, humanities, England, 1101 Medical Biochemistry and Metabolomics, Child, Preschool, Female, Underweight, medicine.symptom, business, Demography, Cohort study
Abstract: Funder: Department of Health, Funder: Medical Research Council, BackgroundTargeted obesity prevention policies would benefit from the identification of population groups with the highest risk of weight gain. The relative importance of adult age, sex, ethnicity, geographical region, and degree of social deprivation on weight gain is not known. We aimed to identify high-risk groups for changes in weight and BMI using electronic health records (EHR).MethodsIn this longitudinal, population-based cohort study we used linked EHR data from 400 primary care practices (via the Clinical Practice Research Datalink) in England, accessed via the CALIBER programme. Eligible participants were aged 18-74 years, were registered at a general practice clinic, and had BMI and weight measurements recorded between Jan 1, 1998, and June 30, 2016, during the period when they had eligible linked data with at least 1 year of follow-up time. We calculated longitudinal changes in BMI over 1, 5, and 10 years, and investigated the absolute risk and odds ratios (ORs) of transitioning between BMI categories (underweight, normal weight, overweight, obesity class 1 and 2, and severe obesity [class 3]), as defined by WHO. The associations of demographic factors with BMI transitions were estimated by use of logistic regression analysis, adjusting for baseline BMI, family history of cardiovascular disease, use of diuretics, and prevalent chronic conditions.FindingsWe included 2 092 260 eligible individuals with more than 9 million BMI measurements in our study. Young adult age was the strongest risk factor for weight gain at 1, 5, and 10 years of follow-up. Compared with the oldest age group (65-74 years), adults in the youngest age group (18-24 years) had the highest OR (4·22 [95% CI 3·86-4·62]) and greatest absolute risk (37% vs 24%) of transitioning from normal weight to overweight or obesity at 10 years. Likewise, adults in the youngest age group with overweight or obesity at baseline were also at highest risk to transition to a higher BMI category; OR 4·60 (4·06-5·22) and absolute risk (42% vs 18%) of transitioning from overweight to class 1 and 2 obesity, and OR 5·87 (5·23-6·59) and absolute risk (22% vs 5%) of transitioning from class 1 and 2 obesity to class 3 obesity. Other demographic factors were consistently less strongly associated with these transitions; for example, the OR of transitioning from normal weight to overweight or obesity in people living in the most socially deprived versus least deprived areas was 1·23 (1·18-1·27), for men versus women was 1·12 (1·08-1·16), and for Black individuals versus White individuals was 1·13 (1·04-1·24). We provide an open access online risk calculator, and present high-resolution obesity risk charts over a 1-year, 5-year, and 10-year follow-up period.InterpretationA radical shift in policy is required to focus on individuals at the highest risk of weight gain (ie, young adults aged 18-24 years) for individual-level and population-level prevention of obesity and its long-term consequences for health and health care.FundingThe British Hearth Foundation, Health Data Research UK, the UK Medical Research Council, and the National Institute for Health Research.
Published: 2021

8. The genomics of heart failure: design and rationale of the HERMES consortium

Author: Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, 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 ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine
Subjects: Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract: Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
Published: 2021

9. 586Effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation analysis

Author: Isobel D. Stewart, Claudia Langenberg, Rachel M. Freathy, Luca A. Lotta, Maik Pietzner, Nicole M. Warrington, Maria Carolina Borges, David M. Evans, Debbie A Lawlor, and Jian Zhao
Subjects: Pregnancy, Prenatal nutrition, Epidemiology, Offspring, Birth weight, Physiology, Mendelian Randomization Analysis, Single-nucleotide polymorphism, General Medicine, Biology, medicine.disease, symbols.namesake, Pleiotropism, Mendelian inheritance, symbols, medicine
Abstract: Background It is suggested amino acids are critical for fetal growth, but analyses assessing causality are lacking. Mendelian randomisation (MR) can be used to examine causal effects under instrumental variable (IV) assumptions. Methods We conducted a two-sample MR study utilizing summary data from genome-wide association studies (GWAS) of amino acids (sample 1, n = 86,507) and of offspring birthweight (sample 2, combined UK Biobank and Early Growth Genetics Consortium, n = 406,063). Seventy-five independent single nucleotide polymorphisms (SNPs) robustly associated with 18 amino acids (p Results There was evidence of positive causal effects of maternal alanine (51.9 g birthweight increase per SD increase in amino acid level, 95% CI: 24.2, 79.5), glutamine (51.3 g, 95% CI: 33.5, 69.0), glycine (10.4 g, 95% CI: 1.3, 19.6) and serine (27.1 g, 95% CI: 11.2, 43.0) on birthweight and inverse causal effects of maternal isoleucine (-109.7 g, 95% CI: -194.6, -24.9) and histidine (-41.1 g, 95% CI: -78.5, -3.7) on birthweight. Sensitivity analyses to explore reverse causality and bias due to horizontal pleiotropy supported our findings. Conclusions Some maternal circulating amino acids have causal effects on birthweight. Key messages MR can be extended to probe effects of maternal nutrition on offspring development.
Published: 2021

10. Weight Change and the Onset of Cardiovascular Diseases: Emulating Trials Using Electronic Health Records

Author: Riyaz S. Patel, R. Thomas Lumbers, Konstantinos K. Tsilidis, Rachel L. Batterham, Goya Wannamethee, Michail Katsoulis, Karla Diaz-Ordaz, Spiros Denaxas, Pagona Lagiou, Alvina G. Lai, Claudia Langenberg, Constantinos A. Parisinos, Harry Hemingway, Bianca De Stavola, Amitava Banerjee, Manuel Gomes, Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: medicine.medical_specialty, Epidemiology, Overweight, Lower risk, 1117 Public Health and Health Services, Body Mass Index, Weight loss, Risk Factors, Internal medicine, medicine, Electronic Health Records, Humans, business.industry, 0104 Statistics, Weight change, Absolute risk reduction, medicine.disease, Obesity, Cross-Sectional Studies, Chronic Diseases, Cardiovascular Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine.symptom, business, Weight gain, Body mass index
Abstract: Supplemental Digital Content is available in the text., Background: Cross-sectional measures of body mass index (BMI) are associated with cardiovascular disease (CVD) incidence, but less is known about whether weight change affects the risk of CVD. Methods: We estimated the effect of 2-y weight change interventions on 7-y risk of CVD (CVD death, myocardial infarction, stroke, hospitalization from coronary heart disease, and heart failure) by emulating hypothetical interventions using electronic health records. We identified 138,567 individuals with 45–69 years of age without chronic disease in England from 1998 to 2016. We performed pooled logistic regression, using inverse-probability weighting to adjust for baseline and time-varying confounders. We categorized each individual into a weight loss, maintenance, or gain group. Results: Among those of normal weight, both weight loss [risk difference (RD) vs. weight maintenance = 1.5% (0.3% to 3.0%)] and gain [RD = 1.3% (0.5% to 2.2%)] were associated with increased risk for CVD compared with weight maintenance. Among overweight individuals, we observed moderately higher risk of CVD in both the weight loss [RD = 0.7% (−0.2% to 1.7%)] and the weight gain group [RD = 0.7% (−0.1% to 1.7%)], compared with maintenance. In the obese, those losing weight showed lower risk of coronary heart disease [RD = −1.4% (−2.4% to −0.6%)] but not of stroke. When we assumed that chronic disease occurred 1–3 years before the recorded date, estimates for weight loss and gain were attenuated among overweight individuals; estimates for loss were lower among obese individuals. Conclusion: Among individuals with obesity, the weight-loss group had a lower risk of coronary heart disease but not of stroke. Weight gain was associated with increased risk of CVD across BMI groups. See video abstract at, http://links.lww.com/EDE/B838.
Published: 2021

11. Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Author: Erin Macdonald-Dunlop, Lucija Klarić, Lasse Folkersen, Paul R.H.J. Timmers, Stefan Gustafsson, Jing Hua Zhao, Niclas Eriksson, Anne Richmond, Stefan Enroth, Niklas Mattsson-Carlgren, Daria V. Zhernakova, Anette Kalnapenkis, Martin Magnusson, Eleanor Wheeler, Shih-Jen Hwang, Yan Chen, Andrew P Morris, Bram Prins, Urmo Võsa, Nicholas J. Wareham, John Danesh, Johan Sundstrom, Bruna Gigante, Damiano Baldassarre, Rona J. Strawbridge, Harry Campbell, Ulf Gyllensten, Chen Yao, Daniela Zanetti, Themistocles L. Assimes, Per Eriksson, Daniel Levy, Claudia Langenberg, J. Gustav Smith, Tõnu Esko, Jingyuan Fu, Oskar Hansson, Åsa Johansson, Caroline Hayward, Lars Wallentin, Agneta Siegbahn, Lars Lind, Adam S. Butterworth, Karl Michaëlsson, James E. Peters, Anders Mälarstig, Peter K. Joshi, and James F. Wilson
Subjects: Genetics, medicine.medical_specialty, Genetic epidemiology, Expression quantitative trait loci, DNA methylation, medicine, Medical genetics, Disease, Quantitative trait locus, Biology, medicine.disease, Inflammatory bowel disease, Genetic architecture
Abstract: We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
Published: 2021

12. GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health

Author: Claudia Langenberg, Po-Ru Loh, John R. B. Perry, Yajie Zhao, Maik Pietzner, Felix R. Day, Stasa Stankovic, Mine Koprulu, Eleanor Wheeler, Nicola D. Kerrison, Nicholas J. Wareham, Ken K. Ong, Hana Lango Allen, Zhao, Yajie [0000-0002-2747-0219], Stankovic, Stasa [0000-0002-6602-1379], Wheeler, Eleanor [0000-0002-8616-6444], Day, Felix R [0000-0003-3789-7651], Pietzner, Maik [0000-0003-3437-9963], Loh, Po-Ru [0000-0001-5542-9064], Wareham, Nicholas J [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Ong, Ken K [0000-0003-4689-7530], Perry, John R B [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Perry, John RB [0000-0001-6483-3771], Day, Felix R. [0000-0003-3789-7651], Wareham, Nicholas J. [0000-0003-1422-2993], Ong, Ken K. [0000-0003-4689-7530], and Perry, John R. B. [0000-0001-6483-3771]
Subjects: Male, DNA Mutational Analysis, 45/43, General Physics and Astronomy, Genome-wide association study, Type 2 diabetes, Genome-wide association studies, Whole Exome Sequencing, Receptor, IGF Type 1, 0302 clinical medicine, Loss of Function Mutation, Leukocytes, Insulin, Exome, Exome sequencing, Genetics, 0303 health sciences, Multidisciplinary, Mosaicism, article, Middle Aged, humanities, 631/208/211, Female, Signal Transduction, Genomic instability, Adult, Science, 631/208/205/2138, Biology, General Biochemistry, Genetics and Molecular Biology, 692/163/2743/137/773, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Allele, Loss function, 030304 developmental biology, Genetic association, Aged, Chromosomes, Human, Y, 45, Case-control study, General Chemistry, medicine.disease, Diabetes Mellitus, Type 2, Case-Control Studies, Carrier Proteins, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Funder: Department of Health, Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10-10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10-12), 4 kg higher fat mass (p = 1.3 × 10-4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10-4) and 4.5 kg lower handgrip strength (p = 4.7 × 10-7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
Published: 2021
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13. Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study

Author: Diana Kuh, Aroon D. Hingorani, Maria Carolina Borges, Jian'an Luan, Tina Shah, John C. Chambers, Andrew Wong, Claudia Langenberg, Debbie A Lawlor, Juha Auvinen, Sylvain Sebert, N. Maneka G. De Silva, Weihua Zhang, Jorgen Engmann, Tom R. Gaunt, Marjo-Ritta Jarvelin, and Xiaoshuai Zhang
Subjects: Blood Glucose, 0301 basic medicine, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, digestive system, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Risk Factors, Internal medicine, Diabetes mellitus, Nonalcoholic fatty liver disease, Mendelian randomization, Internal Medicine, medicine, Genetic predisposition, Humans, Aspartate Aminotransferases, business.industry, nutritional and metabolic diseases, Genetics/Genomes/Proteomics/Metabolomics, Alanine Transaminase, Mendelian Randomization Analysis, Fasting, gamma-Glutamyltransferase, medicine.disease, digestive system diseases, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Liver, Liver function, Insulin Resistance, business, human activities
Abstract: Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.
Published: 2019

14. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author: Phuwanat Sakornsakolpat, James F. Wilson, María Soler Artigas, Beate Stubbe, Nicholas J. Wareham, James D. Crapo, Victoria E. Jackson, Eleftheria Zeggini, Olga G. Troyanskaya, Medea Imboden, A. Mesut Erzurumluoglu, Adam S. Butterworth, Carl A. Melbourne, Ian Sayers, Lars Lind, Stefan Weiss, Margaret M. Parker, Timmers Prhj, Edwin K. Silverman, John C. Whittaker, Ian P. Hall, Ozren Polasek, Mika Kähönen, Katherine A. Fawcett, Anna Hansell, Liming Li, David J. Porteous, Louise V. Wain, Robert A. Scott, Richard Packer, Richard J. Allen, Robin G Walters, Anna L. Guyatt, Terho Lehtimäki, Nicole Probst-Hensch, Shona M. Kerr, Christian Gieger, Matthias Wielscher, Rajesh Rawal, Jing Hua Zhao, John E. Hokanson, Holger Schulz, Nicola F. Reeve, Claudia Langenberg, Ke Hao, Corry-Anke Brandsma, Megan L. Paynton, Vitart, Dmitry Prokopenko, Jennie Hui, Eugene R. Bleecker, Ma'en Obeidat, John Danesh, Ralf Ewert, Benjamin B. Sun, Frank Dudbridge, Jian Zhou, Brian D. Hobbs, Blair H. Smith, Don D. Sin, Dawn L. DeMeo, Joseph C. Maranville, Ida Surakka, Alison Catherine Murray, Nicholas Locantore, Katherine A. Kentistou, Terri H. Beaty, Igor Rudan, Kuang Lin, Amund Gulsvik, Ian J. Deary, Ruth Tal-Singer, Kijoung Song, David C. Nickle, Michael H. Cho, Jian'an Luan, Joshua D. Hoffman, Georg Homuth, Zhengming Chen, Dandi Qiao, Heiko Runz, Per Bakke, Chiara Batini, Caroline Hayward, Stefan Karrasch, Alan James, Andrew P. Morris, Prescott G. Woodruff, Laura M Yerges Armstrong, David Sparrow, Ulf Gyllensten, James P. Cook, Jonathan Marten, Olli T. Raitakari, Nick Shrine, Deborah A. Meyers, Tobin, Ruth Boxall, Marjo-Riitta Järvelin, David P. Strachan, Sarah E. Harris, Philippe Joubert, Stefan Enroth, Xingnan Li, van den Berge M, Anubha Mahajan, Yohan Bossé, Peter K. Joshi, Shrine, Nick [0000-0003-3641-4371], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Sakornsakolpat, Phuwanat [0000-0002-4308-0974], Obeidat, Ma'en [0000-0002-5443-2752], Weiss, Stefan [0000-0002-3553-4315], Kentistou, Katherine A [0000-0002-5816-664X], Sun, Benjamin B [0000-0001-6347-2281], Enroth, Stefan [0000-0002-5056-9137], Vitart, Veronique [0000-0002-4991-3797], Allen, Richard J [0000-0002-8450-3056], Beaty, Terri H [0000-0002-7644-1705], Bossé, Yohan [0000-0002-3067-3711], Joshi, Peter K [0000-0002-6361-5059], Mahajan, Anubha [0000-0001-5585-3420], Murray, Alison [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Sayers, Ian [0000-0001-5601-5410], Smith, Blair H [0000-0002-5362-9430], Tal-Singer, Ruth [0000-0002-5275-8062], Timmers, Paul RHJ [0000-0002-5197-1267], Troyanskaya, Olga G [0000-0002-5676-5737], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Zeggini, Eleftheria [0000-0003-4238-659X], Hayward, Caroline [0000-0002-9405-9550], Morris, Andrew P [0000-0002-6805-6014], Butterworth, Adam S [0000-0002-6915-9015], Walters, Robin G [0000-0002-9179-0321], Cho, Michael H [0000-0002-4907-1657], Strachan, David P [0000-0001-7854-1366], Tobin, Martin D [0000-0002-3596-7874], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Groningen Research Institute for Asthma and COPD (GRIAC), UNIVERSITY OF OULU, and Commission of the European Communities
Subjects: Male, Smoking/genetics, LOCI, Genome-wide association study, VARIANTS, Bioinformatics, Genome-wide association studies, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, GWAS, GENOME-WIDE ASSOCIATION, HERITABILITY, COPD, Lung, 11 Medical and Health Sciences, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Genetic Predisposition to Disease/genetics, Smoking, 1184 Genetics, developmental biology, physiology, Middle Aged, Polymorphism, Single Nucleotide/genetics, 3. Good health, medicine.anatomical_structure, Meta-analysis, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Understanding Society Scientific Group, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, Aged, Respiratory tract diseases, Science & Technology, Case-control study, Lung/physiopathology, 06 Biological Sciences, medicine.disease, Pulmonary Disease, Chronic Obstructive/genetics, respiratory tract diseases, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD., Editorial summary: A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.
Published: 2019

15. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium

Author: Panos Deloukas, Christina-Alexandra Schulz, Caren E. Smith, Lu Qi, Mary F. Feitosa, Melissa E. Garcia, Natalia Pervjakova, Denise K. Houston, Michael A. Province, Stavroula Kanoni, Torben Hansen, Jean Shin, Lynda M. Rose, Oscar H. Franco, Yongmei Liu, Trudy Voortman, Marie-Claude Vohl, Luigi Ferrucci, Chloé Sarnowski, Paul S. de Vries, Jose C. Florez, John C. Lieske, Louis Pérusse, Misa Graff, Jian'an Luan, Nicola M. McKeown, Felix R. Day, L. Adrienne Cupples, Qibin Qi, Frank J. A. van Rooij, Robert A. Scott, Josée Dupuis, Stephen S. Rich, Jorma Viikari, Tarunveer S. Ahluwalia, Leo-Pekka Lyytikäinen, Paul M. Ridker, Tomáš Paus, Stephen Turner, Harri Rissanen, Audrey Y. Chu, Albert Hofman, Olli T. Raitakari, Paul Knekt, Daniel I. Chasman, Nita G. Forouhi, Vera Mikkilä, Toshiko Tanaka, Mika Kähönen, George Dedoussis, Minjung Kho, Yun J. Sung, Anne E. Justice, Julius S. Ngwa, Ani Manichaikul, M. Carola Zillikens, Jordi Merino, Dena G. Hernandez, Rozenn N. Lemaitre, Tao Huang, Sharon L.R. Kardia, Jing Hua Zhao, Stefania Bandinelli, Veikko Salomaa, Arne Astrup, Wei Zhao, David S. Siscovick, John Blangero, Zdenka Pausova, Dabeeru C. Rao, Oluf Pedersen, Craig E. Pennell, Wendy H. Oddy, Jose M. Ordovas, Jessica C. Kiefte-de Jong, Marju Orho-Melander, Hassan S. Dashti, Satu Männistö, Tuomo Rankinen, Constantina Papoutsakis, Sherly X. Li, Antti Jula, Kari E. North, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexis C. Frazier-Wood, Nicholas J. Wareham, Ulrika Ericson, Markus Perola, Ioanna P. Kalafati, Renée de Mutsert, Jinyan Huang, Ruifang Li-Gao, Claudia Langenberg, Mike A. Nalls, Olivia Li, Joanne E. Curran, Dennis O. Mook-Kanamori, Niina Eklund, Jerome I. Rotter, Angelo Tremblay, Claude Bouchard, Jennifer A. Smith, Terho Lehtimäki, Mary K. Wojczynski, Carol A. Wang, Epidemiology, Internal Medicine, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Day, Felix [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Forouhi, Nita [0000-0002-5041-248X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Aging, Calorie, Genotype, Heart Diseases, Receptors, Retinoic Acid, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Obesity, Molecular Biology, Aged, 2. Zero hunger, Genetics, Family aggregation, Membrane Proteins, Genomics, Nutrients, Middle Aged, medicine.disease, 3. Good health, Fibroblast Growth Factors, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Meta-analysis, Medical genetics, Female, Energy Intake, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10(−6)) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
Published: 2019

16. Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification

Author: Sara M. Willems, Josée Dupuis, Martina Müller-Nurasyid, Boehnke M, Mark H, Salem, Inês Barroso, Letizia Marullo, Kari Stefansson, C Gieger, Anna Ulrich, Morris J. Brown, González Ksg, Grant W. Montgomery, Anders Hamsten, Emma Ahlqvist, Aaron Isaacs, Kay-Tee Khaw, Amy Hofman, Corrêa Ir, Inger Njølstad, L Zudina, Rona J. Strawbridge, J. Tuomilehto, E Albrecht, Jing Hua Zhao, Patrick M. Sexton, Mark I. McCarthy, Roxana Maria Rujan, Chiara Scapoli, Anne U. Jackson, Ioanna Tzoulaki, van Duijn C, Giuseppe Deganutti, Reedik Mägi, Jose C. Florez, Bernhard O. Boehm, Toby Johnson, Petar Todorov, Jones B, Inga Prokopenko, Leif Groop, Lagou, Hugh Watkins, Balkhiyarova Z, Tomas A, Longda Jiang, Oddgeir L. Holmen, Tan Tm, Barbara Thorand, Andre G. Uitterlinden, Wolfgang Koenig, He Gao, Sodbo Zh Sharapov, Claudia Langenberg, D Rybin, Ayse Demirkan, H Grallert, Christine Meisinger, Eric F, Denise Wootten, Heinz Erich Wichmann, Wolfgang Kratzer, Paul Elliott, Tune H. Pers, Beben Benyamin, Yurii S. Aulchenko, Robert A. Scott, Marika Kaakinen, Alessia David, Tom Wilsgaard, John Whitfield, Patricia B. Munroe, Chen S, Karen L. Mohlke, Alessia Faggian, Evangelos Evangelou, Philippe Froguel, Nicholas J. Wareham, Unnur Thorsteinsdottir, N. G. Martin, Christopher A. Reynolds, Steinthorsdottir, Heather M. Stringham, Mark J. Caulfield, Gudmar Thorleifsson, James B. Meigs, Anuj Goel, Kristian Hveem, Evan L. Brittain, and Julian S
Subjects: Diabetes Complication, 0303 health sciences, business.industry, Glucose Measurement, Genome-wide association study, Type 2 diabetes, medicine.disease, Bioinformatics, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, medicine, Blood sugar regulation, business, 030217 neurology & neurosurgery, Homeostasis, 030304 developmental biology, Genetic association
Abstract: Homeostatic control of blood glucose requires different physiological responses in the fasting and post-prandial states. We reasoned that glucose measurements under non-standardised conditions (random glucose; RG) may capture diverse glucoregulatory processes more effectively than previous genome-wide association studies (GWAS) of fasting glycaemia or after standardised glucose loads. Through GWAS meta-analysis of RG in 493,036 individuals without diabetes of diverse ethnicities we identified 128 associated loci represented by 162 distinct signals, including 14 with sex-dimorphic effects, 9 discovered through trans-ethnic analysis, and 70 novel signals for glycaemic traits. Novel RG loci were particularly enriched in expression in the ileum and colon, indicating a prominent role for the gastrointestinal tract in the control of blood glucose. Functional studies and molecular dynamics simulations of coding variants of GLP1R, a well-established type 2 diabetes treatment target, provided a genetic framework for optimal selection of GLP-1R agonist therapy. We also provided new evidence from Mendelian randomisation that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Thus, our approach based on RG GWAS provided wide-ranging insights into the biology of glucose regulation, diabetes complications and the potential for treatment stratification.
Published: 2021

17. The trans-ancestral genomic architecture of glycemic traits

Author: Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Published: 2021

18. The potential shared role of inflammation in insulin resistance and schizophrenia: a bi-directional two-sample Mendelian randomization study

Author: Felix R. Day, Peter B. Jones, Stephen Burgess, Benjamin Ian Perry, Stan Zammit, Rachel Upthegrove, Claudia Langenberg, Gulam Khandaker, Nicholas J. Wareham, Amy M. Mason, Hannah J. Jones, Perry, Benjamin I. [0000-0002-1533-026X], Burgess, Stephen [0000-0001-5365-8760], Mason, Amy M. [0000-0002-8019-0777], Day, Felix R. [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas J. [0000-0003-1422-2993], Jones, Peter B. [0000-0002-0387-880X], Khandaker, Golam M. [0000-0002-4935-9220], Apollo - University of Cambridge Repository, Perry, Benjamin I [0000-0002-1533-026X], Mason, Amy M [0000-0002-8019-0777], Day, Felix R [0000-0003-3789-7651], Wareham, Nicholas J [0000-0003-1422-2993], Jones, Peter B [0000-0002-0387-880X], and Khandaker, Golam M [0000-0002-4935-9220]
Subjects: 0301 basic medicine, Physiology, Single Nucleotide Polymorphisms, medicine.medical_treatment, Genome-wide association study, Type 2 diabetes, Bioinformatics, Biochemistry, Endocrinology, Medical Conditions, 0302 clinical medicine, Insulin, Immune Response, Aged, 80 and over, 2. Zero hunger, Genomics, General Medicine, Middle Aged, 16. Peace & justice, 3. Good health, Europe, Phenotype, Schizophrenia, Medicine, Inflammation, Single nucleotide polymorphisms, Inflammatory diseases, Insulin resistance, Genome-wide association studies, Genetics, Research Article, Adult, Inflammatory Diseases, Immunology, Young Adult, 03 medical and health sciences, Signs and Symptoms, Diabetes mellitus, Mental Health and Psychiatry, Mendelian randomization, Genome-Wide Association Studies, medicine, Humans, Aged, Genetic association, Diabetic Endocrinology, Medicine and health sciences, Endocrine Physiology, Biology and life sciences, business.industry, Cardiometabolic Risk Factors, Computational Biology, Human Genetics, Mendelian Randomization Analysis, Genome Analysis, medicine.disease, Hormones, 030104 developmental biology, Insulin Resistance, Clinical Medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. Methods and findings We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. Conclusions Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance., In a Mendelian randomization study, Benjamin Perry and colleagues investigate the genetic evidence supporting relationships between inflammation, insulin resistance, and schizophrenia., Author summary Why was this study done? Cardiometabolic disorders such as diabetes are up to 30% more common in people with schizophrenia than in the general population, and are among the predominant causes of a 10- to 15-year shortened life expectancy in people with schizophrenia. Insulin resistance, a precursor to diabetes, is sometimes detectable in young adults suffering their first episode of psychosis, which suggests that chronic lifestyle and clinical factors, such as smoking, physical inactivity, and medication side effects may not fully explain the comorbidity. Inflammation has been consistently associated with schizophrenia and cardiometabolic disorders, and so could be a common mechanism for schizophrenia and cardiometabolic disorders. This could help to at least in part explain why people who have schizophrenia also have higher rates of cardiometabolic disorders, over and above the commonly attributed lifestyle/clinical factors. What did the researchers do and find? To examine whether insulin resistance and 7 related cardiometabolic traits causally influence schizophrenia risk or vice versa, we conducted bidirectional, two-sample, uni- and multivariable mendelian randomizsation (MR) analyses. The MR approach uses genetic variants as proxies for modifiable exposures to untangle the problems of reverse causation and unmeasured confounding. To test a hypothesis that inflammation may be a common mechanism for schizophrenia and cardiometabolic disorders, we also examined a subset of genetic variants which were associated with inflammation as well as the cardiometabolic trait. We also used multivariable MR (MVMR) as a sensitivity analysis to adjust for C-reactive protein (CRP), an archetypal inflammatory marker, as a general downstream marker of systemic inflammation. After correction for multiple testing, overall, there was no significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we found evidence that supports a causal relationship of an inflammation-related insulin resistance phenotype with schizophrenia. Evidence for the association of an inflammation-related insulin resistance phenotype with schizophrenia attenuated fully in MVMR analysis after adjusting for CRP, suggesting that these associations may be underpinned by inflammation. What do these findings mean? These results suggest that cardiometabolic traits are unlikely to have a causal role in the pathogenesis of schizophrenia or vice versa. However, our results suggest that inflammation is related to the risk of both schizophrenia and insulin resistance, which may at least partly explain why they commonly occur in clinical practice. Treating or preventing inflammation may be a putative therapeutic option for prevention and/or treatment of both schizophrenia and comorbid insulin resistance. In the future, more research is needed to understand the biological mechanisms underpinning how inflammation may increase the risk of schizophrenia and insulin resistance.
Published: 2021

19. Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression

Author: Tunde Peto, Alan C. Bird, Ferenc B Sallo, Brendan R E Ansell, Roberto Bonelli, Claudia Langenberg, Thomas S. Scerri, Traci E Clemons, Irene Leung, Luca A. Lotta, Melanie Bahlo, Bahlo, Melanie [0000-0001-5132-0774], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, lcsh:Medicine, Genome-wide association study, Disease, 0302 clinical medicine, Serine, GWAS, Mendelian randomisation, Genetics (clinical), Macular telangiectasia, Genetics, 0303 health sciences, 3. Good health, Statistical genetics, Disease Progression, Metabolome, Molecular Medicine, Retinal Disorder, lcsh:QH426-470, Endophenotypes, Genomics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Metabolomics, Humans, Genetic Predisposition to Disease, Molecular Biology, 030304 developmental biology, Genetic association, Research, lcsh:R, Retinal Vessels, medicine.disease, Human genetics, Biosynthetic Pathways, lcsh:Genetics, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Endophenotype, Retinal disease, 030221 ophthalmology & optometry, Retinal Telangiectasis, Genome-Wide Association Study
Abstract: Background Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. Methods We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. Results Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Conclusions Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
Published: 2021

20. Estimating the Population Benefits of Blood Pressure Lowering: A Wide-Angled Mendelian Randomization Study in UK Biobank

Author: Claudia Langenberg, Susanna C. Larsson, Amy M. Mason, Dipender Gill, Hannah Higgins, Stephen Burgess, Higgins, Hannah [0000-0001-9115-0992], Mason, Amy M [0000-0002-8019-0777], Larsson, Susanna C [0000-0003-0118-0341], Gill, Dipender [0000-0001-7312-7078], Langenberg, Claudia [0000-0002-5017-7344], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository
Subjects: Cardiac & Cardiovascular Systems, Heart disease, Epidemiology, Population impact, Blood Pressure, Disease, cardiovascular disease, Risk Factors, Medicine, Cardiac and Cardiovascular Systems, 1102 Cardiorespiratory Medicine and Haematology, Biological Specimen Banks, education.field_of_study, Kardiologi, Middle Aged, Biobank, Causality, Cardiovascular Diseases, Cohort, Cardiology, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, genetic epidemiology, hypertension, Population, Brief Communication, Polymorphism, Single Nucleotide, Elevated blood, Internal medicine, Mendelian randomization, Diseases of the circulatory (Cardiovascular) system, Humans, Intensive care medicine, education, Aged, Science & Technology, business.industry, Vascular disease, Mendelian Randomization Analysis, medicine.disease, United Kingdom, Confidence interval, Blood pressure, Genetic epidemiology, RC666-701, Cardiovascular System & Cardiology, Blood pressure lowering, business, high blood pressure, Genome-Wide Association Study
Abstract: Background The causal relevance of elevated blood pressure for several cardiovascular diseases (CVDs) is uncertain, as is the population impact of blood pressure lowering. This study systematically assesses evidence of causality for various CVDs in a 2‐sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long‐term population shifts in the distribution of systolic blood pressure (SBP). Methods and Results We investigated associations of genetically predicted SBP as predicted by 256 genetic variants with 21 CVDs in UK Biobank, a population‐based cohort of UK residents. The sample consisted of 376 703 participants of European ancestry, aged 40 to 69 years at recruitment. Genetically predicted SBP was positively associated with 14 of the outcomes ( P Conclusions Risk of many CVDs is influenced by long‐term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long‐term population‐wide reductions in the distribution of blood pressure.
Published: 2021

21. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Author: Kamil Sicinski, B. Gwen Windham, Nathalie van der Velde, Luigi Ferrucci, Jian'an Luan, Fernando Rivadeneira, Thuy Vy Duong, Ryan Cvejkus, David A. Bennett, José A. Carnicero, Megan L. Grove, Stefan Walter, Cheryl L. Ackert-Bicknell, Joshua R. Lewis, Adam J. Santanasto, David Melzer, Aron S. Buchman, Janice L. Atkins, Garan Jones, Joanne M. Murabito, Shengjun Hong, Stefania Bandinelli, Michelle C. Odden, Leocadio Rodríguez-Mañas, Magnus Karlsson, Erika Kague, Najada Stringa, Francisco J. Garcia, Chia-Ling Kuo, Dominik Spira, Maria Nethander, André G. Uitterlinden, Claes Ohlsson, Jingyun Yang, Sahar Ghasemi, George A. Kuchel, Dan Mellström, Eric Boerwinkle, Pamela Herd, Lisette C. P. G. M. de Groot, Alexander Teumer, M. Carola Zillikens, Alison E. Fohner, Dan E. Arking, Douglas P. Kiel, Kathryn L. Lunetta, Claudia Langenberg, Toshiko Tanaka, David Karasik, Natasja M. van Schoor, Thomas Kocher, Luke C. Pilling, Lars Bertram, Bruce M. Psaty, Philip L. De Jager, Katerina Trajanoska, Martijn Huisman, Joseph M. Zmuda, Mary L. Biggs, Misa Graff, Qihua Tan, Ilja Demuth, Mary K. Wojczynski, Nicholas J. Wareham, Uwe Völker, Chloé Sarnowski, Jones, Garan [0000-0002-8917-3930], Trajanoska, Katerina [0000-0002-3792-4296], Santanasto, Adam J. [0000-0002-6912-2909], Stringa, Najada [0000-0001-6350-452X], Atkins, Janice L. [0000-0003-4919-9068], Lewis, Joshua R. [0000-0003-1003-8443], Luan, Jian’an [0000-0003-3137-6337], Sarnowski, Chloe [0000-0002-6090-7099], Lunetta, Kathryn L. [0000-0002-9268-810X], Cvejkus, Ryan [0000-0001-5287-5341], Nethander, Maria [0000-0003-3688-906X], Yang, Jingyun [0000-0002-3495-3710], Walter, Stefan [0000-0002-6010-7550], Kague, Erika [0000-0002-0266-9424], Graff, Misa [0000-0001-6380-1735], de Groot, Lisette C. P. G. M. [0000-0003-2778-2789], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas J. [0000-0003-1422-2993], Tan, Qihua [0000-0003-3194-0030], Buchman, Aron S. [0000-0002-6426-2742], De Jager, Philip L. [0000-0002-8057-2505], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Kocher, Thomas [0000-0001-9605-2822], Teumer, Alexander [0000-0002-8309-094X], Bertram, Lars [0000-0002-0108-124X], Melzer, David [0000-0002-0170-3838], Kuchel, George A. [0000-0001-8387-7040], Ferrucci, Luigi [0000-0002-6273-1613], Karasik, David [0000-0002-8826-0530], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P. [0000-0001-8474-0310], Pilling, Luke C. [0000-0002-3332-8454], Apollo - University of Cambridge Repository, Epidemiology, Internal Medicine, VU University medical center, General practice, Epidemiology and Data Science, APH - Aging & Later Life, APH - Personalized Medicine, APH - Societal Participation & Health, Geriatrics, AMS - Ageing & Vitality, Santanasto, Adam J [0000-0002-6912-2909], Atkins, Janice L [0000-0003-4919-9068], Lewis, Joshua R [0000-0003-1003-8443], Luan, Jian'an [0000-0003-3137-6337], Lunetta, Kathryn L [0000-0002-9268-810X], de Groot, Lisette CPGM [0000-0003-2778-2789], Wareham, Nicholas J [0000-0003-1422-2993], Buchman, Aron S [0000-0002-6426-2742], De Jager, Philip L [0000-0002-8057-2505], Uitterlinden, Andre G [0000-0002-7276-3387], Kuchel, George A [0000-0001-8387-7040], Kiel, Douglas P [0000-0001-8474-0310], and Pilling, Luke C [0000-0002-3332-8454]
Subjects: Male, 0301 basic medicine, Aging, Sarcopenia, 45/43, General Physics and Astronomy, Arthritis, Bioinformatics, Cohort Studies, Grip strength, 0302 clinical medicine, Growth Differentiation Factor 5, Genetics research, Aged, 80 and over, Geriatrics, Muscle Weakness, Multidisciplinary, article, Genomics, 631/208/205, Middle Aged, Nutritional Biology, Europe, Meta-analysis, 631/208/212, Medical genetics, Female, medicine.symptom, Cohort study, medicine.medical_specialty, Science, Predictive markers, Polymorphism, Single Nucleotide, HLA-DQ alpha-Chains, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, 692/53/2423, Mendelian randomization, medicine, Life Science, Humans, Genetic Predisposition to Disease, Muscle Strength, Genetic association study, Aged, VLAG, Autoimmune disease, 45, business.industry, 692/308/2056, Muscle weakness, General Chemistry, medicine.disease, 030104 developmental biology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.
Published: 2021

22. Identifying high-risk groups for change in weight and body mass index: population cohort of 11 million measurements in 2.3 million adults

Author: Alvina G. Lai, Richard Dobson, Krishnan Bhaskaran, Pagona Lagiou, Rachel L. Batterham, Spiros Denaxas, Manuel Gomes, Kostas Tsilidis, Goya Wannamethee, Claudia Langenberg, R. T. Lumbers, Michail Katsoulis, Karla Diaz-Ordaz, Dimitra Kleio Kipourou, Harry Hemingway, Nicholas J. Wareham, Laura Pasea, Ami Banerjee, and Gesthimani Misirli
Subjects: education.field_of_study, business.industry, Population, Odds ratio, Overweight, medicine.disease, Obesity, Confidence interval, Social deprivation, Medicine, medicine.symptom, business, education, Body mass index, Weight gain, Demography
Abstract: BackgroundAdult obesity prevention policies, which are largely untargeted, have met with limited success globally. Population groups with the highest risk of weight gain, if they could be reliably identified using readily available information, might benefit from targeted policy. The relative importance of age, sex, ethnicity, geographical region and social deprivation for weight gain is unknown.MethodsWe calculated longitudinal changes in BMI over one, five and ten years and investigated transition between BMI categories using 11,187,383 clinically recorded, repeated measures of BMI from population-based electronic health records of 2,328,477 adults in England (1998-2016). The influence of risk factors was tested using logistic regression.FindingsThe youngest adult age group (18-24 years) was more strongly associated with risk of weight gain than older age, male sex, socioeconomic deprivation, ethnicity or geographic region. Among the youngest adults, the top quartile gained 15.9kg in men and 12kg in women at 10 years. The odds of transitioning to a higher BMI category over 10 years were 4-6 times higher in the youngest (18-24 years) compared to oldest (65-74 years) individuals; odds ratio (95% confidence interval) 4.22 (3.85-4.62)) from normal weight to overweight or obesity, 4.60 (4.06-5.22) for overweight to obesity, and 5.87 (5.23-6.59) from obesity to severe obesity in multiple adjusted analyses. Among the youngest adults, socially deprived men were at greater risk of transitioning from normal weight to overweight (72%) and from overweight to obesity (68%) over 10 years. We provide an open access online risk calculator (https://pasea.shinyapps.io/bmi_shiny_app/) and present high resolution obesity risk charts over a 1-, 5- and 10-year follow-up.InterpretationA radical shift in policy is required to focus on those at highest risk of weight gain-young adults-for individual and population level prevention of obesity and its long-term consequences for health and health care.FundingBHF, HDR-UK, MRC
Published: 2021

23. Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality : observational and Mendelian randomisation analyses

Author: Eleni Sofianopoulou, Stephen K Kaptoge, Shoaib Afzal, Tao Jiang, Dipender Gill, Thomas E Gundersen, Thomas R Bolton, Elias Allara, Matthew G Arnold, Amy M Mason, Ryan Chung, Lisa A M Pennells, Fanchao Shi, Luanluan Sun, Peter Willeit, Nita G Forouhi, Claudia Langenberg, Stephen J Sharp, Salvatore Panico, Gunnar Engström, Olle Melander, Tammy Y N Tong, Aurora Perez-Cornago, Margareta Norberg, Ingegerd Johansson, Verena Katzke, Bernard Srour, María José Sánchez, Daniel Redondo-Sánchez, Anja Olsen, Christina C Dahm, Kim Overvad, Magritt Brustad, Guri Skeie, Conchi Moreno-Iribas, N Charlotte Onland-Moret, Yvonne T van der Schouw, Konstantinos K Tsilidis, Alicia K Heath, Claudia Agnoli, Vittorio Krogh, Ian H de Boer, Camilla Jannie Kobylecki, Yunus Çolak, Armin Zittermann, Johan Sundström, Paul Welsh, Elisabete Weiderpass, Elom K Aglago, Pietro Ferrari, Robert Clarke, Marie-Christine Boutron, Gianluca Severi, Conor MacDonald, Rui Providencia, Giovanna Masala, Raul Zamora Ros, Jolanda Boer, WM Monique Verschuren, Peggy Cawthon, Louise L Schierbeck, Cyrus Cooper, Matthias B Schulze, Manuela M Bergmann, Anke Hannemann, Stefan Kiechl, Hermann Brenner, Natasja M van Schoor, Juan R Albertorio, Carlotta Sacerdote, Allan Linneberg, Line L Kårhus, José María Huerta, Liher Imaz, Christel Joergensen, Yoav Ben-Shlomo, Annamari Lundqvist, John Gallacher, Naveed Sattar, Angela M Wood, Nicholas J Wareham, Børge G Nordestgaard, Emanuele Di Angelantonio, John Danesh, Adam S Butterworth, Stephen Burgess, Epidemiology and Data Science, APH - Aging & Later Life, APH - Personalized Medicine, and Collaboration, Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Myocardial Infarction, Coronary Disease, Disease, Endocrinology and Diabetes, vitamin D deficiency, 1117 Public Health and Health Services, Endocrinology, Risk Factors, Internal medicine, Internal Medicine, Vitamin D and neurology, Medicine, Humans, Cardiac and Cardiovascular Systems, Myocardial infarction, Prospective Studies, Vitamin D, Prospective cohort study, education, Stroke, education.field_of_study, Kardiologi, Nutrition and Dietetics, business.industry, 1103 Clinical Sciences, Articles, Vitamins, Mendelian Randomization Analysis, Middle Aged, medicine.disease, Vitamin D Deficiency, Näringslära, 1101 Medical Biochemistry and Metabolomics, Dietary Supplements, Endokrinologi och diabetes, business, Cohort study
Abstract: Background Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Methods Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Findings Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration Interpretation Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies. Funding British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.
Published: 2021

24. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Stavroula Kanoni, Bakker Sjl., Winkelmann Br, Wieland Kiess, Josée Dupuis, Palmer Cna., James F. Wilson, Schwarz Peh., Maria Dimitriou, Joop Jukema, Sara M. Willems, J L Min, R. Rauramaa, Perry Jrb., Momoko Horikoshi, Timo A. Lakka, Nicole Soranzo, J Kaprio, Niek Verweij, Martina Müller-Nurasyid, Jaana Lindström, Toby Johnson, Olga D. Carlson, Nita G. Forouhi, George Dedoussis, Johnson Pcd., Patrick K.E. Magnusson, Gonçalo R. Abecasis, Ozren Polasek, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Nancy L. Pedersen, Beate St Pourcain, Erik P A Van Iperen, Iva Miljkovic, Stefania Bandinelli, M. A. Province, Veikko Salomaa, Andrew A. Hicks, Evelin Mihailov, Rick Jansen, James B. Meigs, D Rybin, Peter Kovacs, George Davey Smith, Rona J. Strawbridge, Gudmar Thorleifsson, Meena Kumari, Chiara Scapoli, Christopher J. Groves, Barbara Thorand, T.B. Harris, Ulf de Faire, Inga Prokopenko, Stela McLachlan, Ping An, Anubha Mahajan, L.F. Bielak, Rebecca J. Webster, David Altshuler, Susan Campbell, Bernhard O. Boehm, A. Metspalu, Perttu Salo, D.I. Boomsma, Ilja M. Nolte, Andrea Ganna, Timothy M. Frayling, Pau Navarro, N J Timpson, Kardia Slr., Jeanette M. Stafford, Tõnu Esko, Ulrika Krus, Richa Saxena, Per Eriksson, Peter P. Pramstaller, Anne U. Jackson, V Lagou, Anders Franco-Cereceda, David S. Siscovick, Josephine M. Egan, Loos Rjf., C Gieger, Amanda J. Bennett, Anna Ulrich, Satu Männistö, Mika Kivimäki, Loic Yengo, Caroline Hayward, George Nicholson, C M van Duijn, Anke Tönjes, Nigel W. Rayner, Jose C. Florez, Leif Groop, Valeri Lyssenko, Lyle J. Palmer, Vilmantas Giedraitis, Maria G. Stathopoulou, B. Balkau, Anneli Pouta, Anuj Goel, Pierre Meneton, Serena Sanna, Jesper R. Gådin, Claudia Langenberg, Alessia Faggian, H Grallert, Karen Kapur, Marcus E. Kleber, Philippe Froguel, Boehnke M, Harry Campbell, Anders Hamsten, T. Saaristo, Antigone S. Dimas, Jarvelin M-R., F Karpe, A. Körner, Leena Kinnunen, Markus Perola, Joanne M. Meyer, May E. Montasser, Erik Ingelsson, Naveed Sattar, Yvonne Boettcher, Sirkka Keinänen-Kiukaanniemi, Aaron Isaacs, Gerjan Navis, Ian Ford, Amélie Bonnefond, Reedik Mägi, Tove Fall, Dmitry Shungin, Jenna Price, Igor Rudan, Richard M. Watanabe, Luigi Ferrucci, Jian'an Luan, Harst Pvd., Marika Kaakinen, Tatijana Zemunik, Christian Herder, Shin S-Y., Veronique Vitart, Ross M. Fraser, Alan R. Shuldiner, Panagiotis Deloukas, C. Lecoeur, Letizia Marullo, Kari Stefansson, Lars Lind, Winfried März, L Zudina, Aroon D. Hingorani, Gonneke Willemsen, de Geus Ejcn., Albert V. Smith, Jeffery R. O'Connell, Yongmei Liu, James S. Pankow, Sarah H. Wild, Patricia B. Munroe, Patricia A. Peyser, Nicholas J. Wareham, Tiinamaija Tuomi, Nicholas D. Hastie, Markku Laakso, Albert Hofman, J. Tuomilehto, Emmanouil T. Dermitzakis, Thomas Illig, Tomohiro Tanaka, Cecilia M. Lindgren, Sarin A-P., Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Andrew P. Morris, Richard N. Bergman, Mark I. McCarthy, Nabila Bouatia-Naji, Günther Silbernagel, João Fadista, Harold Snieder, Ins Barroso, Michael Stumvoll, B.W.J.H. Penninx, M Blüher, Stefan R Bornstein, Laura J. Rasmussen-Torvik, Alan F. Wright, Peter Vollenweider, G K Hovingh, Heikki A. Koistinen, Sophie Visvikis-Siest, Vilmundur Gudnason, Eric Boerwinkle, Hottenga J-J., Guo Li, Paul W. Franks, Université de Lille, Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Genetics, Multidisciplinary, Science, Insulin, medicine.medical_treatment, General Physics and Astronomy, Diagnostic marker, Genome-wide association study, General Chemistry, Type 2 diabetes, Quantitative trait locus, Biology, medicine.disease, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Fasting glucose, Sexual dimorphism, Pre diabetes, [SDU]Sciences of the Universe [physics], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine
Abstract: The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.
Published: 2021

25. Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study

Author: Eric L. Harshfield, Claudia Langenberg, Marios K. Georgakis, Rainer Malik, Nora Franceschini, Hugh S. Markus, Nicholas J. Wareham, Martin Dichgans, Georgakis, Marios K [0000-0003-3507-3659], Harshfield, Eric L [0000-0001-8767-0928], Malik, Rainer [0000-0001-9212-2520], Franceschini, Nora [0000-0001-9755-2175], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas J [0000-0003-1422-2993], Markus, Hugh S [0000-0002-9794-5996], Dichgans, Martin [0000-0002-0654-387X], and Apollo - University of Cambridge Repository
Subjects: Carotid Artery Diseases, Blood Glucose, 0301 basic medicine, epidemiology [Atrophy], metabolism [Diabetes Mellitus, Type 2], Glycated Hemoglobin A, endocrine system diseases, genetics [Cerebrovascular Disorders], epidemiology [Cerebral Hemorrhage], Type 2 diabetes, 030204 cardiovascular system & hematology, 0302 clinical medicine, pathology [Brain], Insulin-Secreting Cells, metabolism [Glycated Hemoglobin], genetics [Insulin Resistance], epidemiology [Ischemic Stroke], Stroke, metabolism [Blood Glucose], 0303 health sciences, epidemiology [Diabetes Mellitus, Type 2], Brain, Mendelian Randomization Analysis, epidemiology [Hyperglycemia], White Matter, genetics [Carotid Artery Diseases], 3. Good health, Cardiology, genetics [Atrophy], medicine.medical_specialty, genetics [Cerebral Hemorrhage], metabolism [Glycated Hemoglobin A], genetics [Diabetes Mellitus, Type 2], diagnostic imaging [White Matter], 03 medical and health sciences, Insulin resistance, Internal medicine, Diabetes mellitus, Mendelian randomization, epidemiology [Carotid Artery Diseases], medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, cardiovascular diseases, ddc:610, Risk factor, diagnostic imaging [Brain], Cerebral Hemorrhage, Ischemic Stroke, 030304 developmental biology, Glycated Hemoglobin, Intracerebral hemorrhage, business.industry, Type 2 Diabetes Mellitus, genetics [Ischemic Stroke], medicine.disease, Cerebrovascular Disorders, genetics [Hyperglycemia], metabolism [Hyperglycemia], epidemiology [Cerebrovascular Disorders], 030104 developmental biology, Diabetes Mellitus, Type 2, Hyperglycemia, hemoglobin A1c protein, human, Neurology (clinical), Atrophy, Insulin Resistance, business
Abstract: RationaleType 2 diabetes mellitus (T2D) is an established risk factor for cerebrovascular disease but the mechanisms underlying this association remain elusive. Disentangling the causal effects of T2D, hyperglycemia, and pre-diabetic phenotypes (insulin resistance, β-cell dysfunction) on major etiological stroke subtypes (ischemic stroke, intracerebral hemorrhage, ischemic stroke subtypes) could inform the development of preventive strategies.ObjectiveWe employed Mendelian randomization (MR) to explore the effects of genetic predisposition to T2D, hyperglycemia, insulin resistance, and β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.Methods and ResultsWe selected instruments for genetic predisposition to T2D, HbA1c levels, fasting glucose levels, insulin resistance, and β-cell dysfunction (proxied by pro-insulin levels) based on published genome-wide association studies (up to 898,130 individuals). Applying two-sample MR, we examined associations with ischemic stroke, intracerebral hemorrhage, and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke; up to 60,341 cases and 454,450 controls). We further explored associations with the related phenotypes of carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy. Genetic predisposition to T2D and elevated HbA1c levels in the pre-diabetic range were associated with higher risk of any ischemic stroke, large artery stroke, carotid plaque and small vessel stroke. Independently of HbA1c levels, we further found genetic predisposition to insulin resistance to be associated with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke. Predisposition to β-cell dysfunction was further associated with intracerebral hemorrhage, lower grey matter volume, and total brain volume.ConclusionsThis study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show differential effects of genetically determined insulin resistance and β-cell dysfunction on large artery and small vessel stroke that might have implications for anti-diabetic treatments targeting these mechanisms.
Published: 2021
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26. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author: Daniel I. Chasman, Torben Hansen, Rebecca S. Fine, Kari E. North, Harald Grallert, Jeffrey Haesser, Jie Yao, Arund D. Pradhan, Peter Kovacs, Mariaelisa Graff, Rebecca D. Jackson, Zoltán Kutalik, James G. Wilson, Neil Robertson, Mika Kähönen, Linda S. Adair, Jennifer Kriebel, Ruth J. F. Loos, Massimo Mangino, Jayne F. Martin Carli, Yiying Zhang, M. Arfan Ikram, Paraskevi Christofidou, Linda Broer, Paul M. Ridker, Barbara McKnight, Satu Männistö, Sophia Metz, Tea Skaaby, Jette Bork-Jensen, Craig E. Pennell, Sophie Molnos, Michael A. Province, Xiuqing Guo, Laura B. L. Wittemans, Stephen J. Lye, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Tim Kacprowski, America A. Sandoval-Zárate, Hermina Jakupović, Tuomas O. Kilpeläinen, Michael Preuss, Jaeyoung Hong, Cristina Venturini, Ying Wu, Germán D. Carrasquilla, Ivana Prokic, Mary F. Feitosa, Melissa E. Garcia, Paul L. Auer, Leslie A. Lange, Leo-Pekka Lyytikäinen, Kristin L. Young, Tugce Karaderi, Alexander P. Reiner, Tim D. Spector, Anubha Mahajan, Claudia Schurmann, Jerome I. Rotter, Rudolph L. Leibel, Georg Homuth, Claudia A. Doege, Hakon Hakonarson, Nicholas J. Wareham, Najaf Amin, Shuai Wang, Matthias Blüher, Ayse Demirkan, Andrew P. Morris, Charles A. LeDuc, Claudia Langenberg, Hanieh Yaghootkar, Mike A. Nalls, Erik Ingelsson, Dennis O. Mook-Kanamori, Jorge R. Kizer, Carolina Medina-Gomez, Timothy M. Frayling, Colleen M. Sitlani, David A. Mackey, Bruce M. Psaty, Matthias Nauck, Struan F.A. Grant, Konstantin Strauch, Olli T. Raitakari, Alexander Teumer, Mark Walker, Jonathan P. Bradfield, Judith B. Borja, Karen L. Mohlke, Lars Lind, André G. Uitterlinden, Renée de Mutsert, Ruifang Li-Gao, Cassandra N. Spracklen, Jin Li, Anne E. Justice, Cecilia M. Lindgren, Kaiying Guo, Terho Lehtimäki, Pekka Jousilahti, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, Tamara B. Harris, Matthew A. Allison, Carol A. Wang, Niels Grarup, Lam Opal Huang, Veikko Salomaa, Jian'an Luan, Robert A. Scott, Kent D. Taylor, James B. Meigs, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Department of Organisation and Personnel Management, Health Services Management & Organisation (HSMO), Yaghootkar, Hanieh [0000-0001-9672-9477], Kilpeläinen, Tuomas O [0000-0002-8349-3028], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Leptin, Models, Molecular, medicine.medical_specialty, Genotype, Protein Conformation, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, KLF14, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Missense mutation, Humans, Allele, Exome, Adiposity, 2. Zero hunger, Racial Groups, digestive, oral, and skin physiology, Gene Expression Regulation, Developmental, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, Obesity, 030104 developmental biology, Endocrinology, hormones, hormone substitutes, and hormone antagonists
Abstract: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
Published: 2020

27. Genome-wide association analysis of type 2 diabetes in the EPIC-InterAct study

Author: Peter M. Nilsson, Olov Rolandsson, Eleanor Wheeler, Nicholas J. Wareham, Nita G. Forouhi, Matthias B. Schulze, Kim Overvad, Claudia Langenberg, Nicola D. Kerrison, Pilar Amiano, Catalina Bonet, Mark I. McCarthy, Inês Barroso, Yvonne T. van der Schouw, Lina Cai, Giovanna Masala, José María Huerta, Eva Ardanaz, Anne Tjønneland, Miguel Rodríguez-Barranco, Panos Deloukas, Leif Groop, Guy Fagherazzi, Jian'an Luan, Valeria Pala, Elio Riboli, Carlotta Sacerdote, Rosario Tumino, Paul W. Franks, Annemieke M.W. Spijkerman, Stephen J. Sharp, Salvatore Panico, Rudolf Kaaks, Cai, Lina [0000-0003-2598-8388], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Deloukas, Panos [0000-0001-9251-070X], Groop, Leif C [0000-0002-0187-3263], Huerta, José María [0000-0002-9637-3869], Masala, Giovanna [0000-0002-5758-9069], Nilsson, Peter M [0000-0002-5652-8459], Overvad, Kim [0000-0001-6429-7921], Schulze, Matthias B [0000-0002-0830-5277], Tumino, Rosario [0000-0003-2666-414X], van der Schouw, Yvonne T [0000-0002-4605-435X], Forouhi, Nita G [0000-0002-5041-248X], Barroso, Inês [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Luan, Jian’an [0000-0003-3137-6337], Groop, Leif C. [0000-0002-0187-3263], Nilsson, Peter M. [0000-0002-5652-8459], Schulze, Matthias B. [0000-0002-0830-5277], van der Schouw, Yvonne T. [0000-0002-4605-435X], and Forouhi, Nita G. [0000-0002-5041-248X]
Subjects: Gerontology, Data Descriptor, endocrine system diseases, Epidemiology, Type 2 diabetes, 0302 clinical medicine, Risk Factors, Genetics research, 692/699/2743/137/773, 692/308/174, Prospective Studies, lcsh:Science, Prospective cohort study, 0303 health sciences, Diabetis, Diabetes, Computer Science Applications, Europe, Cardiovascular diseases, Endokrinologi och diabetes, Cohort, Statistics, Probability and Uncertainty, data-descriptor, Information Systems, Statistics and Probability, medicine.medical_specialty, MEDLINE, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Endocrinology and Diabetes, Library and Information Sciences, Education, 03 medical and health sciences, medicine, Mortalitat, Humans, Mortality, Life Style, 030304 developmental biology, Genetic association, business.industry, Malalties cardiovasculars, Public health, 692/308/2056, nutritional and metabolic diseases, medicine.disease, Summary statistics, Diabetes Mellitus, Type 2, lcsh:Q, business, Genome-Wide Association Study
Abstract: Funder: European Union FP6 programme grant number LSHM_CT_2006_037197, Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.
Published: 2020

28. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis

Author: Nita G. Forouhi, Kim Overvad, Ivonne Sluijs, Tammy Y.N. Tong, Christina C. Dahm, Kay-Tee Khaw, Thomas E. Gundersen, José María Huerta, Peter M. Nilsson, Miguel Rodríguez-Barranco, Nasser Laouali, Adam S. Butterworth, Giovanna Masala, Sara Grioni, Rosario Tumino, Anja Olsen, Stephen J. Sharp, Salvatore Panico, J. Ramón Quirós, Yvonne T. van der Schouw, Eleanor Wheeler, Rudolf Kaaks, Alicia K Heath, Eva Ardanaz, Felix R. Day, Eleni Sofianopoulou, Konstantinos K. Tsilidis, Luca A. Lotta, Nicholas J. Wareham, Douae El-Fatouhi, Claudia Langenberg, Heiner Boeing, Guy Fagherazzi, Paula Jakszyn, Olov Rolandsson, Rupal L. Shah, Mazda Jenab, Miren Dorronsoro, Ju-Sheng Zheng, Fumiaki Imamura, Isobel D. Stewart, Elio Riboli, Paul W. Franks, Louise Hansen, John Danesh, Carlotta Sacerdote, Jian'an Luan, Niki Dimou, Annemieke M.W. Spijkerman, Tilman Kühn, Zheng, Ju-Sheng [0000-0001-6560-4890], Sharp, Stephen J [0000-0003-2375-1440], Day, Felix R [0000-0003-3789-7651], Sluijs, Ivonne [0000-0001-7758-4911], Shah, Rupal L [0000-0001-8789-8869], van der Schouw, Yvonne T [0000-0002-4605-435X], Dahm, Christina C [0000-0003-0481-2893], Dimou, Niki [0000-0003-1678-9328], Franks, Paul W [0000-0002-0520-7604], Fagherazzi, Guy [0000-0001-5033-5966], Huerta, José María [0000-0002-9637-3869], Heath, Alicia K [0000-0001-6517-1300], Hansen, Louise [0000-0002-7109-8864], Jenab, Mazda [0000-0002-0573-1852], Kühn, Tilman [0000-0001-7702-317X], Laouali, Nasser [0000-0002-8532-456X], Masala, Giovanna [0000-0002-5758-9069], Olsen, Anja [0000-0003-4788-503X], Rodríguez-Barranco, Miguel [0000-0002-9972-9779], Sacerdote, Carlotta [0000-0002-8008-5096], Tong, Tammy YN [0000-0002-0284-8959], Tumino, Rosario [0000-0003-2666-414X], Tsilidis, Konstantinos K [0000-0002-8452-8472], Riboli, Elio [0000-0001-6795-6080], Langenberg, Claudia [0000-0002-5017-7344], Forouhi, Nita G [0000-0002-5041-248X], Wareham, Nicholas J [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Sharp, Stephen J. [0000-0003-2375-1440], Day, Felix R. [0000-0003-3789-7651], Shah, Rupal L. [0000-0001-8789-8869], van der Schouw, Yvonne T. [0000-0002-4605-435X], Dahm, Christina C. [0000-0003-0481-2893], Franks, Paul W. [0000-0002-0520-7604], Heath, Alicia K. [0000-0001-6517-1300], Tong, Tammy Y. N. [0000-0002-0284-8959], Tsilidis, Konstantinos K. [0000-0002-8452-8472], Forouhi, Nita G. [0000-0002-5041-248X], and Wareham, Nicholas J. [0000-0003-1422-2993]
Subjects: Male, Single Nucleotide Polymorphisms, Organic chemistry, Genome-wide association study, Type 2 diabetes, VARIANTS, 030204 cardiovascular system & hematology, Biochemistry, Endocrinology, Medical Conditions, Mathematical and Statistical Techniques, 0302 clinical medicine, DESIGN, Risk Factors, Medicine and Health Sciences, Metabolites, VITAMIN-D SUPPLEMENTATION, 030212 general & internal medicine, Prospective Studies, Vitamin D, 11 Medical and Health Sciences, RISK, Diabetis, Statistics, Diabetes, Genomics, Vitamins, General Medicine, Metaanalysis, Middle Aged, Type 2 Diabetes, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Physical sciences, Chemistry, OBESITY, Endokrinologi och diabetes, Medicine, LIFE-STYLE, Female, Life Sciences & Biomedicine, Research Article, Adult, medicine.medical_specialty, Endocrine Disorders, DATABASE, Vitamina D, European Continental Ancestry Group, Single-nucleotide polymorphism, Endocrinology and Diabetes, Research and Analysis Methods, Lower risk, White People, Chemical compounds, 03 medical and health sciences, Medicine, General & Internal, General & Internal Medicine, Internal medicine, Organic compounds, Diabetes Mellitus, Genome-Wide Association Studies, medicine, Vitamin D and neurology, Genetics, Humans, Statistical Methods, Science & Technology, business.industry, Biology and Life Sciences, Computational Biology, Human Genetics, Odds ratio, Mendelian Randomization Analysis, Genome Analysis, medicine.disease, Metabolism, Diabetes Mellitus, Type 2, Genetic Loci, Metabolic Disorders, Relative risk, Dietary Supplements, GENETIC-DETERMINANTS, business, Mathematics, Genètica, Genome-Wide Association Study
Abstract: Background Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D., Using both observational and genetic analyses, Ju-Sheng Zheng and colleagues investigate the relationship between vitamin D metabolites and type 2 diabetes among European individuals., Author summary Why was this study done? There is ongoing uncertainty on whether the body’s vitamin D status indicated by blood 25-hydroxyvitamin D (25(OH)D) is relevant to the prevention of type 2 diabetes. There are conflicting findings from observational studies and a limited number of randomised controlled trials. Prior research did not distinguish between different metabolites of total 25(OH)D, including 25(OH)D3 and C3-epi-25(OH)D3, an isomer of 25(OH)D3. It is not clear whether the associations of 25(OH)D metabolites with type 2 diabetes are causal, with conflicting findings from prior Mendelian randomisation studies of total 25(OH)D and no previous Mendelian randomisation studies appraising 25(OH)D metabolites. What did the researchers do and find? The current research compared observational estimates of the association between 25(OH)D metabolites and incident type 2 diabetes with Mendelian randomisation estimates based on genetic instruments. Using multiple data sources, we performed genome-wide association studies among 120,618 individuals for total 25(OH)D, and among 40,562 individuals for the other vitamin D metabolites. Among participants of European descent, 10 genetic loci were identified for total 25(OH)D, 7 loci for 25(OH)D3 and 3 loci for C3-epi-25(OH)D3. In meta-analysis of observational studies, we found that each 1–standard deviation higher level of total 25(OH)D was associated with 20% lower risk of type 2 diabetes. The result was similar for 25(OH)D3, but for C3-epi-25(OH)D3, a positive association with type 2 diabetes was found. With up to 80,983 type 2 diabetes cases and 842,909 controls, we assessed the association of genetically predicted differences in total 25(OH)D and its metabolites with type 2 diabetes. Neither genetically predicted higher total 25(OH)D level nor genetically predicted higher levels of 25(OH)D metabolites were significantly associated with type 2 diabetes. What do these findings mean? There were conflicting findings for a link with type 2 diabetes for the observational analysis of biochemically measured 25(OH)D metabolites versus the genetically predicted levels of these metabolites. The null findings based on Mendelian randomisation analysis indicate that blood levels of 25(OH)D or its metabolites are not likely to be causal factors for the development of type 2 diabetes. The current findings together with other evidence from randomised controlled trials do not support the use of vitamin D supplementation for the prevention of type 2 diabetes.
Published: 2020

29. Meta-analysis investigating the role of interleukin-6 mediated inflammation in type 2 diabetes

Author: Jian'an Luan, Nicholas Bowker, Stephen J. Sharp, Claudia Langenberg, Aris Baras, Luca A. Lotta, Eleanor Wheeler, Nicholas J. Wareham, Manuel A. R. Ferreira, Rupal L. Shah, Isobel D. Stewart, Bowker, Nicholas [0000-0002-8794-894X], Shah, Rupal [0000-0001-8789-8869], Sharp, Stephen [0000-0003-2375-1440], Luan, Jian'an [0000-0003-3137-6337], Wheeler, Eleanor [0000-0002-8616-6444], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Blood Glucose, lcsh:Medicine, Type 2 diabetes, 0302 clinical medicine, Risk Factors, Epidemiology, Odds Ratio, Prospective cohort study, Adiposity, education.field_of_study, lcsh:R5-920, biology, General Medicine, 030220 oncology & carcinogenesis, Meta-analysis, Cytokines, Disease Susceptibility, Inflammation Mediators, lcsh:Medicine (General), Research Paper, Signal Transduction, medicine.medical_specialty, Trans-ethnic, Population, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Genetic, Internal medicine, medicine, Humans, Body Weights and Measures, Genetic Predisposition to Disease, Interleukin 6, education, Inflammation, business.industry, Interleukin-6, lcsh:R, medicine.disease, Receptors, Interleukin-6, 030104 developmental biology, Diabetes Mellitus, Type 2, biology.protein, Etiology, business, Body mass index, Biomarkers
Abstract: Background Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated inflammation is implicated in the pathophysiology of T2D. Methods We performed a meta-analysis of 15 prospective studies to investigate associations between IL-6 levels and incident T2D including 5,421 cases and 31,562 non-cases. We also estimated the association of a loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R), previously shown to mimic the effects of IL-6R inhibition, in a large trans-ethnic meta-analysis of six T2D case-control studies including 260,614 cases and 1,350,640 controls. Findings In a meta-analysis of 15 prospective studies, higher levels of IL-6 (per log pg/mL) were significantly associated with a higher risk of incident T2D (1·24 95% CI, 1·17, 1·32; P = 1 × 10−12). In a trans-ethnic meta-analysis of 260,614 cases and 1,350,640 controls, the IL6R Asp358Ala missense variant was associated with lower odds of T2D (OR, 0·98; 95% CI, 0·97, 0·99; P = 2 × 10−7). This association was not due to diagnostic misclassification and was consistent across ethnic groups. IL-6 levels mediated up to 5% of the association between higher body mass index and T2D. Interpretation Large-scale human prospective and genetic data provide evidence that IL-6 mediated inflammation is implicated in the etiology of T2D but suggest that the impact of this pathway on disease risk in the general population is likely to be small. Funding The EPIC Norfolk study has received funding from the Medical Research Council (MRC) (MR/N003284/1, MC-UU_12015/1 and MC_PC_13048) and Cancer Research UK (C864/A14136). The Fenland Study is funded by the MRC (MC_UU_12015/1 and MC_PC_13046).
Published: 2020

30. Integrating Genetics and the Plasma Proteome to Predict the Risk of Type 2 Diabetes

Author: Maik Pietzner, Julia Carrasco Zanini, Claudia Langenberg, Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Proteomics, 0301 basic medicine, Future studies, Proteome, Endocrinology, Diabetes and Metabolism, Genetics (AP Morris, Section Editor), 030209 endocrinology & metabolism, Type 2 diabetes, Computational biology, Phenome, Genome, Causal risk factors, Plasma, 03 medical and health sciences, 0302 clinical medicine, Topical Collection on Genetics, Internal Medicine, medicine, Genetic predisposition, Genetics, Humans, Biomarker discovery, ComputingMilieux_MISCELLANEOUS, Central layer, business.industry, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 2, Pharmaceutical Preparations, Plasma proteome, FOS: Biological sciences, business, Prediction
Abstract: Funder: University of Cambridge, Purpose of the Review: Proteins are the central layer of information transfer from genome to phenome and represent the largest class of drug targets. We review recent advances in high-throughput technologies that provide comprehensive, scalable profiling of the plasma proteome with the potential to improve prediction and mechanistic understanding of type 2 diabetes (T2D). Recent Findings: Technological and analytical advancements have enabled identification of novel protein biomarkers and signatures that help to address challenges of existing approaches to predict and screen for T2D. Genetic studies have so far revealed putative causal roles for only few of the proteins that have been linked to T2D, but ongoing large-scale genetic studies of the plasma proteome will help to address this and increase our understanding of aetiological pathways and mechanisms leading to diabetes. Summary: Studies of the human plasma proteome have started to elucidate its potential for T2D prediction and biomarker discovery. Future studies integrating genomic and proteomic data will provide opportunities to prioritise drug targets and identify pathways linking genetic predisposition to T2D development.
Published: 2020

31. Body mass index and heart failure risk: a cohort study in 1.5 million individuals and Mendelian randomisation analysis

Author: Chim C. Lang, Albert Henry, Michael V. Holmes, Claudia Langenberg, Thomas R. Lumbers, Harry Hemingway, Ify R. Mordi, Naveed Sattar, and Michail Katsoulis
Subjects: medicine.medical_specialty, Proportional hazards model, business.industry, Hazard ratio, Absolute risk reduction, Odds ratio, medicine.disease, Heart failure, Internal medicine, medicine, Risk factor, business, Body mass index, Cohort study
Abstract: AimsElevated body mass index (BMI) is a known risk factor for heart failure (HF), however, the underlying mechanisms are incompletely understood. The aim of this study was to investigate the role of common HF risk factors as potential mediators.Methods and ResultsElectronic health record data from primary care, hospital admissions and death registrations in England were used to perform an observational analysis. Data for 1.5 million individuals aged 18 years or older, with BMI measurements and free from heart failure at baseline, were included between 1998 and 2016. Cox models were used to estimate the association between BMI and HF with and without adjustment for atrial fibrillation (AF), diabetes mellitus (DM), coronary heart disease (CHD), and hypertension (HTN). Univariable and multivariable two-sample Mendelian randomisation was performed to estimate causal effects.Among non-underweight individuals, BMI was positively associated with HF with a 1-SD (∼ 4.8kg/m2) higher BMI associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI] 1.30, 1.32). Genetically predicted BMI yielded a causal odds ratio (OR) of 1.64 per 4.8 kg/m2BMI (95% CI 1.58, 1.70) which attenuated by 41% (to OR of 1.38 (95% CI 1.31 - 1.45), when simultaneously accounting for AF, DM, CHD and SBP.ConclusionAbout 40% of the excess risk of HF due to adiposity is driven by SBP, AF, DM and CHD. These findings highlight the importance of the prevention and treatment of excess adiposity and downstream HF risk factors to prevent HF, even in people in whom the above risk factors are well managed.One-sentence summaryThis study of the role of excess adiposity as a risk factor for HF, including an observational analysis of measured BMI 1.5 million individuals and multivariable MR analysis of genetically elevated BMI, provides evidence that adiposity is causally associated with HF, with approximately 40% of the effect being mediated by conventional risk pathways.Graphical abstract
Published: 2020

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

Author: Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris
Subjects: 0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.
Published: 2020

33. A genome-wide association study of asthma-COPD overlap syndrome (ACOS)

Author: Victor E. Ortega, Anna L. Guyatt, Ann Chen Wu, Eugene R. Bleecker, Nick Shrine, Jessica Lasky-Su, Jukka Koskela, Thorunn Asta Olafsdottir, Traci M. Bartz, Samuli Ripatti, Deborah A. Meyers, Ian P. Hall, Caroline Hayward, Natalie Terzikhan, Sina A. Gharib, Lystra P. Hayden, Ben Michael Brumpton, Lies Lahousse, Louise V. Wain, Shuguang Leng, Kari Stefansson, Catherine John, Michael H. Cho, Carlos Iribarren, Josée Dupuis, Yohannes Tesfaigzi, Tarja Laitinen, Hanfei Xu, Claudia Langenberg, Hans Petersen, Su H. Chu, Ian Sayers, Martin D. Tobin, Gudmar Thorleifsson, Xingnan Li, Ingileif Jonsdottir, Arnulf Langhammer, Jian'an Luan, Jiangyuan Liu, and Lori C. Sakoda
Subjects: COPD, medicine.medical_specialty, business.industry, Genetic variants, Genome-wide association study, Overlap syndrome, medicine.disease, Biobank, respiratory tract diseases, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, medicine, 030212 general & internal medicine, Asthma copd overlap, business, Lung function, Asthma
Abstract: Individuals with characteristics of both asthma and COPD (asthma-COPD overlap syndrome, ACOS) experience significantly worse outcomes than those with asthma or COPD alone. Despite hundreds of genetic associations with asthma, COPD and lung function, no genetic variants have specifically been associated with ACOS. We hypothesized that there are genetic determinants of ACOS and sought to identify these in a genome-wide association study. We defined ACOS based on self-reported doctor-diagnosed asthma and spirometric GOLD2+ airflow limitation. We tested 7693381 genetic variants for association with ACOS in 8068 cases and 40360 healthy controls from UK Biobank (stage 1). We identified signals where P Thirty-one genetic variants met criteria for inclusion in stage 2. Of these, eight were associated at genome-wide significance (P Whilst our results suggest that many genetic variants associated with ACOS are shared with asthma and/or COPD, we identify a new, distinct signal that may implicate cellular pathways characteristic of ACOS.
Published: 2020

34. The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Author: Hugoline G. de Haan, Andrew A. Hicks, Achilleas Pitsilides, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Anders Hamsten, Dennis O. Mook-Kanamori, Zorayr Arzumanyan, Betina H. Thuesen, Karin Leander, Fernando Rivideneira, Lynne E. Wagenknecht, Andrew R. Wood, Annique Claringbould, Ele Ferranni, Sölve Elmståhl, Eleanor Wheeler, Sharon L.R. Kardia, Richa Saxena, Tatijana Zemunik, Cassandra N. Spracklen, Ken K. Ong, Xiao-Ou Shu, Johannes Waage, Blair H. Smith, Rozenn N. Lemaitre, Torben Hansen, Peter K. Joshi, Lisa R. Yanek, Neil R. Robertson, Sven Bergmann, Mila Desi Anasanti, Inger Njølstad, Ananda R. Wickremasinghe, Xu Lin, Harold Snieder, Wanqing Wen, Veronique Vitart, Paul R. H. J. Timmers, Timo Saaristo, James F. Wilson, Tian Xie, Tao Huang, Rainer Rauramaa, Kei Hang, Rebecca Rohde, Li-Ching Chang, Jing Hua Zhao, Kazuya Setoh, Yasuharu Tabara, Michael Stumvoll, Mark O. Goodarzi, Igor Rudan, James B. Meigs, Jaakko Tuomilehto, Richard M. Watanabe, Ruth J. F. Loos, Reedik Mägi, Jouke-Jan Hottenga, Ozren Polasek, Michael Y. Tsai, Donald W. Bowden, Diana Kuh, Erik B. van den Akker, Yii-Der Ida Chen, Daniel I. Chasman, Weihua Zhang, Nicholette D. Palmer, Marcus E. Kleber, Anny H. Xiang, Chang-Hsun Hsieh, Alan B. Zonderman, Stefan Gustafsson, Timo A. Lakka, Brian H. Chen, Dermot F. Reilly, Francis S. Collins, Oluf Pedersen, Corri Black, Yang Hai, Zoltán Kutalik, Yoriko Heianza, Willa A. Hsueh, Vilmundur Gudnason, Robert C. Kaplan, Jun Liu, Michael A. Province, Aliki-Eleni Farmaki, Stephen S. Rich, Jian'an Luan, Erik Ingelsson, Marie Loh, Michael Preuss, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Colin N. A. Palmer, Fumihiko Matsuda, Takahisa Kawaguchi, Sohee Han, Ching-Ti Liu, Young-Jin Kim, L. Southam, Sara M. Willems, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Stephan J. L. Bakker, Momoko Horikoshi, Tarunveer S. Ahluwalia, Annette Schürmann, Graciela E. Delgado, Thibaud S. Boutin, Thomas Sparsø, Sandosh Padmanabhan, Fouad Kandeel, Eco J. C. de Geus, Anubha Mahajan, Claudia Schurmann, Klaus Bønnelykke, Leslie A. Lange, Qing Duan, Rona J. Strawbridge, Dennis Raven, Gonçalo R. Abecasis, Mitsuhiro Yokota, Jani Heikkinen, Elizabeth Selvin, Audrey Y. Chu, Anke Tönjes, Marta E. Alarcón-Riquelme, Hans Bisgaard, P. Eline Slagboom, Eric Boerwinkle, Massimo Mangino, Catharina A. Hartman, Geltrude Mingrone, Lenore J. Launer, Michael Boehnke, Emil V. R. Appel, Niels Grarup, Arushi Varshney, Archie Campbell, Kari E. North, W. Craig Johnson, Inês Barroso, Ya X. Wang, Carola Marzi, Anuj Goel, Eleftheria Zeggini, Lu Qi, Yasumasa Ohyagi, Tien Yin Wong, Tanja G. M. Vrijkotte, Gudny Eiriksdottir, Harald Grallert, Ishminder K. Kooner, Trevor A. Mori, Jagadish Vangipurapu, Laura J Corbin, Tomohiro Katsuya, Wen B. Wei, Segun Fatumo, Debashree Ray, Annette Peters, Lori L. Bonnycastle, Ilja M. Nolte, M. Arfan Ikram, Manjinder S. Sandhu, Marit E. Jørgensen, Christian Herder, Damia Noce, Sarah C. Nelson, Chien-Hsiun Chen, Heather M. Stringham, Yong-Bing Xiang, Bruce M. Psaty, Alain G. Bertoni, Gaëlle Marenne, Timothy M. Frayling, Jose C. Florez, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Damiano Baldassarre, J. Wouter Jukema, Wei Huang, Yi-Cheng Chang, Albertine J. Oldehinkel, Xiaoshuai Zhang, Yujie Wang, Shaofeng Huo, Xueling Sim, Norihiro Kato, Bernhard O. Böhm, Lorraine Southam, Mari Nelis, Gonneke Willemsen, Laura J. Rasmussen-Torvik, Philippe Froguel, Charumathi Sabanayagam, Leif Groop, Loic Yengo, Shi Jinxiu, Adolfo Correa, Serena Sanna, Arne Astrup, Teemu Kuulasmaa, Symen Ligthart, Shih-Yi Lin, David J. Porteous, Harry Campbell, Peter Vollenweider, Mark J. Caulfield, Kristi Läll, Anne Ndungu, Carl D. Langefeld, Tanya M. Teslovich, Heikki A. Koistinen, Ying Wu, Mattias Frånberg, D.I. Boomsma, Lawrence F. Bielak, Diana van Heemst, Peter Kovacs, Markku Laakso, Leslie J. Raffel, Katharina E. Schraut, Noël P. Burtt, Michiya Igase, Craig E. Pennell, Claudia Langenberg, Huaixing Li, Teresa Tusie, Laura M. Raffield, Jorgen Engmann, Stephen C. J. Parker, Michele K. Evans, Chaolong Wang, Rico Rueedi, Jianjun Liu, Pankow S. James, Hortensia Moreno-Macías, Fumihiko Takeuchi, Cornelia M. van Duijn, Sanghoon Moon, Susan R. Heckbert, Thomas A. Buchanan, Ko Willems van Dijk, Toru Nabika, May E. Montasser, Caroline Hayward, Jie Yao, Aaron Leong, Antje Körner, Jouko Saramies, Jost B. Jonas, Pim van der Harst, Naveed Sattar, Helen R. Warren, Alice Stanton, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Mi Yeong Hwang, Jin Fang Chai, Alicia Huerta-Chagoya, Anette P. Gjesing, Ching-Yu Cheng, Debbie A Lawlor, Simin Liu, Man Li, Ivana Kolcic, Erwin P. Bottinger, Andrew Wong, Stella Trompet, Heming Wang, Jirong Long, Xiuqing Guo, Jeffrey R. O'Connell, Meena Kumari, Sirkka Keinänen-Kiukaanniemi, Rita R. Kalyani, Bengt Sennblad, Mohammad Hadi Zafarmand, Kent D. Taylor, Katherine A. Kentistou, Carol A. Wang, Shuiqing Lai, Patricia B. Munroe, Patricia A. Peyser, Lawrence J. Beilin, Niek Verweij, Inga Prokopenko, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Ping An, Matthias Blüher, Isobel D. Stewart, Alexander P. Reiner, Anna L. Gloyn, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, Wei Zhao, Andres Metspalu, Wieland Kiess, Kathleen A. Ryan, Astrid van Hylckama Vlieg, Jaana Lindström, Wei Zheng, E. Shyong Tai, Josée Dupuis, Nanette R. Lee, Laura J. Scott, Nicholas J. Timpson, George Dedoussis, Mark I. McCarthy, Tatsuaki Matsubara, Carlos Lorenzo, Denis Rybin, Luigi Ferruci, Chelsea K. Raulerson, Mika Kivimäki, Paul M. Ridker, Jer-Yuarn Wu, Shufa Du, Jaeyoung Hong, Linda S. Adair, Tin Louie, Valeriya Lyssenko, Susan Redline, Kelvin Lam, Qibin Qi, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Sahoko Ichihara, Nicholas J. Wareham, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Rob M. van Dam, Claire J. Steves, Liang Sun, Albert V. Smith, Raymond Noordam, Tom Wilsgaard, Winfried März, Jung Ho Gong, Matt J. Neville, Jerry L. Nadler, Giorgio Pistis, Karen L. Mohlke, Bruna Gigante, Jennifer A. Brody, Andrew P. Morris, Marie Lauzon, Peter E. H. Schwarz, Bernardo L. Horta, Xiaoran Chai, Ji Chen, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Javier Gayán, Elena Tremoli, Girish N. Nadkarni, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Jingyi Tan, Sameline Grimsgaard, Bong-Jo Kim, Kerrin S. Small, Jill M. Norris, Cecilia M. Lindgren, Richard N. Bergman, Mark Walker, Henrik Vestergaard, Larissa Aviles-Santa, Jing He, Masahiro Nakatochi, Peter P. Pramstaller, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Kevin Sandow, Jaspal S. Kooner, Carlos A. Aguilar-Salinas, Peitao Wu, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Nan Wang, Franco Giulianini, Tao Wang, Honglan Li, Abbas Dehghan, Christian Fuchsberger, and Pontiano Kaleebu
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Type 2 diabetes, medicine.disease, Fasting insulin, Fasting glucose, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, medicine, Genomic architecture, business, Glycated haemoglobin, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.
Published: 2020

35. Appetite disinhibition rather than hunger explains genetic effects on adult BMI trajectory

Author: Archana Singh-Manoux, Koutatsu Maruyama, Adam G. Tabak, David Boniface, Noriko Cable, Daryth Stallone, Hiroyasu Iso, Ayako Hiyoshi, Meena Kumari, Aroon D. Hingorani, Claudia Langenberg, Eric J. Brunner, Nicholas J. Wareham, Mika Kivimäki, Martin J. Shipley, Clare H. Llewellyn, John Wilson, Brunner, Eric J. [0000-0002-0595-4474], Tabak, Adam [0000-0002-6234-3936], Singh-Manoux, Archana [0000-0002-1244-5037], Hingorani, Aroon [0000-0001-8365-0081], Kivimäki, Mika [0000-0002-4699-5627], Llewellyn, Clare [0000-0002-0066-2827], Apollo - University of Cambridge Repository, and Brunner, Eric J [0000-0002-0595-4474]
Subjects: Male, Lifestyle modification, Longitudinal study, Hunger, Epidemiology, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, Population, Medicine (miscellaneous), Appetite, 030209 endocrinology & metabolism, Weight Gain, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, 692/308/174, 030212 general & internal medicine, Longitudinal Studies, Obesity, Overeating, education, media_common, Aged, education.field_of_study, Nutrition and Dietetics, business.industry, 692/700/459/284, article, Correction, Feeding Behavior, Middle Aged, medicine.disease, Inhibition, Psychological, Disinhibition, Linear Models, Female, medicine.symptom, business, Weight gain, Demography
Abstract: Background/objectives The mediating role of eating behaviors in genetic susceptibility to weight gain during mid-adult life is not fully understood. This longitudinal study aims to help us understand contributions of genetic susceptibility and appetite to weight gain. Subjects/methods We followed the body-mass index (BMI) trajectories of 2464 adults from 45 to 65 years of age by measuring weight and height on four occasions at 5-year intervals. Genetic risk of obesity (gene risk score: GRS) was ascertained, comprising 92 BMI-associated single-nucleotide polymorphisms and split at a median (=high and low risk). At the baseline, the Eating Inventory was used to assess appetite-related traits of ‘disinhibition’, indicative of opportunistic eating or overeating and ‘hunger’ which is susceptibility to/ability to cope with the sensation of hunger. Roles of the GRS and two appetite-related scores for BMI trajectories were examined using a mixed model adjusted for the cohort effect and sex. Results Disinhibition was associated with higher BMI (β = 2.96; 95% CI: 2.66–3.25 kg/m2), and accounted for 34% of the genetically-linked BMI difference at age 45. Hunger was also associated with higher BMI (β = 1.20; 0.82–1.59 kg/m2) during mid-life and slightly steeper weight gain, but did not attenuate the effect of disinhibition. Conclusions Appetite disinhibition is most likely to be a defining characteristic of genetic susceptibility to obesity. High levels of appetite disinhibition, rather than hunger, may underlie genetic vulnerability to obesogenic environments in two-thirds of the population of European ancestry.
Published: 2020

36. Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription

Author: Rebecca Bounds, Inês Barroso, Eleftheria Zeggini, Felicity Payne, Nicholas J. Wareham, Caroline Hayward, Elana Henning, Stephen O'Rahilly, Gaëlle Marenne, Elena G. Bochukova, Audrey E. Hendricks, Sofie Ashford, Allan Daly, Julia M. Keogh, I. Sadaf Farooqi, Saad Pathan, Aliki Perdikari, Eleanor Wheeler, Vanisha Mistry, Christopher J. Lelliott, Claudia Langenberg, The Wellcome Trust Sanger Institute [Cambridge], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), University of Colorado [Denver], Metabolic Research Laboratories [Cambridge, UK] (University of Cambridge), Wellcome Trust - MRC Cambridge-Addenbrooke’s Hospital [Cambridge, UK], MRC Human Genetics Unit, University of Edinburgh-Western General Hospital, Generation Scotland [Edinburgh, UK] (Centre for Genomic and Experimental Medicine), University of Edinburgh-Institute of Genetics and Molecular Medicine [Edinburgh, UK], MRC Epidemiology Unit [Cambridge, UK] (Wellcome Trust-MRC Institute of Metabolic Science), University of Cambridge [UK] (CAM)-Addenbrooke’s Hospital [Cambridge, UK]-Wellcome Trust-MRC Institute of Metabolic Science (IMS), MRC Metabolic Diseases Unit [Cambridge, UK] (Metabolic Research Laboratories), University of Cambridge [UK] (CAM), Helmholtz Zentrum München = German Research Center for Environmental Health, marenne, gaelle, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Helmholtz-Zentrum München (HZM)
Subjects: Male, 0301 basic medicine, Pediatric Obesity, Pro-Opiomelanocortin, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Bioinformatics, Mice, 0302 clinical medicine, Endocrinology, Missing heritability problem, Chlorocebus aethiops, Transcriptional regulation, Medicine, Exome, genetics, Child, Cells, Cultured, Exome sequencing, Genetics, Intracellular Signaling Peptides and Proteins, Imidazoles, POMC, Middle Aged, Penetrance, Obesity, Morbid, [SDV] Life Sciences [q-bio], Female, Adult, MEDLINE, Biology, Article, Childhood obesity, 03 medical and health sciences, gene set, Animals, Humans, severe childhood obesity, Molecular Biology, Gene, Genetic association, function, Genetic heterogeneity, business.industry, association, Genetic Variation, Cell Biology, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, business, 030217 neurology & neurosurgery
Abstract: Summary Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability., Graphical Abstract, Highlights • Three genes (PHIP, DGKI, and ZMYM4) are linked to severe childhood obesity • Wild-type PHIP enhances POMC transcription, but variants in PHIP repress POMC • Rare variants in BMI-associated loci from GWAS are enriched in severe obesity • Genetic architecture of severe childhood obesity reveals a continuum of causality, Childhood obesity can be caused by penetrant mutations in a number of genes controlling appetite and body weight. Marenne et al. identify three genes with mutations with variable penetrance in a continuum of causality in childhood obesity, and demonstrate that variants in PHIP repress POMC transcription.
Published: 2020

37. Weight change and the incidence of cardiovascular diseases in adults with normal weight, overweight and obesity without chronic diseases; emulating trials using electronic health records

Author: Constantinos A. Parisinos, Alvina G. Lai, Manuel Gomes, KD Ordaz, Bianca De Stavola, Harry Hemingway, Claudia Langenberg, P Lagiou, Spiros Denaxas, K Tsilidis, Ami Banerjee, Michail Katsoulis, Rachel L. Batterham, R T Lumbers, and Goya Wannamethee
Subjects: 2. Zero hunger, medicine.medical_specialty, business.industry, Incidence (epidemiology), Weight change, 030204 cardiovascular system & hematology, Overweight, Lower risk, medicine.disease, Obesity, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Internal medicine, medicine, 030212 general & internal medicine, medicine.symptom, business, Body mass index, Weight gain
Abstract: BackgroundCross sectional measures of body mass index (BMI) are associated with cardiovascular disease (CVD) incidence, but less is known about whether weight change affects the risk of CVD.MethodsWe estimated the effect of 2-year weight change interventions on 7-year risk of CVD, by emulating hypothetical target trials using electronic health records. We identified 138.567 individuals in England between 1998 and 2016, aged 45-69 years old, free of chronic diseases at baseline. We performed pooled logistic regression, using inverse-probability weighting to adjust for baseline and time-varying variables. Each individual was classified into a weight loss, maintenance, or gain group.FindingsIn the normal weight, both weight loss and gain were associated with increased risk for CVD [HR vs weight maintenance=1.53 (1.18-1.98) and 1.43 (1.19-1.71 respectively)]. Among overweight individuals, both weight loss and gain groups, compared to weight maintenance, had a moderately higher risk of CVD [HR=1.20 (0.99–1.44) and 1.17 (0.99–1.38), respectively]. In the obese, weight loss had a lower risk lower risk of CHD [HR =0.66 (0.49–0.89)] and a moderately lower risk of CVD [HR =0.90 (0.72–1.13)]. When we assumed that a chronic disease occurred 1-3 years before the recorded date, estimates for weight loss and gain were attenuated among overweight individuals and estimates for weight loss were stronger among individuals with obesity.InterpretationAmong individuals with obesity, the weight loss group had a lower risk of CHD and moderately lower risk of CVD. Weight gain increased the risk of CVD across BMI groups.
Published: 2020
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38. Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

Author: Fumiaki Imamura, George Davey Smith, Chanwook Lee, Nicholas J. Wareham, M. Arfan Ikram, George McMahon, Aysu Okbay, Frank J. A. van Rooij, Peter Bowers, Carson C. Chow, Patrick Turley, Ronald de Vlaming, Jian'an Luan, Oscar H. Franco, Trudy Voortman, Daniel J. Benjamin, André G. Uitterlinden, Casper A.P. Burik, Nita G. Forouhi, K. Paige Harden, Pauline M Emmett, Cornelius A. Rietveld, Juan R. González, Bruce H. R. Wolffenbuttel, Philipp Koellinger, Mark Alan Fontana, James J. Lee, David Cesarini, Harold Snieder, Kim Valeska Emilie Braun, Emma L Anderson, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Richard Karlsson Linnér, Susan M. Ring, Claudia Langenberg, Tonũ Esko, Fernando Rivadeneira, Kaitlin H Wade, Jessica C. Kiefte-de Jong, Taulant Muka, Mohsen Ghanbari, S. Fleur W. Meddens, Linnér, Richard Karlsson [0000-0001-7839-2858], Okbay, Aysu [0000-0002-5170-7781], Rietveld, Cornelius A [0000-0003-4053-1861], Ghanbari, Mohsen [0000-0002-9476-7143], Imamura, Fumiaki [0000-0002-6841-8396], van der Most, Peter J [0000-0001-8450-3518], Voortman, Trudy [0000-0003-2830-6813], Wade, Kaitlin H [0000-0003-3362-6280], Braun, Kim VE [0000-0001-8738-4139], Gonzalez, Juan R [0000-0003-3267-2146], Kiefte-de Jong, Jessica C [0000-0002-8136-0918], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Ring, Susan [0000-0003-3103-9330], Rivadeneira, Fernando [0000-0001-9435-9441], Snieder, Harold [0000-0003-1949-2298], van Rooij, Frank JA [0000-0002-8600-9852], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G [0000-0002-5041-248X], Ikram, M Arfan [0000-0003-0372-8585], Uitterlinden, Andre G [0000-0002-7276-3387], van Vliet-Ostaptchouk, Jana V [0000-0002-7943-3153], Lee, James J [0000-0001-6547-5128], Benjamin, Daniel J [0000-0002-2642-5416], Apollo - University of Cambridge Repository, Rietveld, Cornelius A. [0000-0003-4053-1861], van der Most, Peter J. [0000-0001-8450-3518], Wade, Kaitlin H. [0000-0003-3362-6280], Braun, Kim V. E. [0000-0001-8738-4139], Gonzalez, Juan R. [0000-0003-3267-2146], Kiefte-de Jong, Jessica C. [0000-0002-8136-0918], Luan, Jian’an [0000-0003-3137-6337], van Rooij, Frank J. A. [0000-0002-8600-9852], Forouhi, Nita G. [0000-0002-5041-248X], Ikram, M. Arfan [0000-0003-0372-8585], Uitterlinden, Andre G. [0000-0002-7276-3387], van Vliet-Ostaptchouk, Jana V. [0000-0002-7943-3153], Lee, James J. [0000-0001-6547-5128], Benjamin, Daniel J. [0000-0002-2642-5416], Applied Economics, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Economics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: 0301 basic medicine, BETA-KLOTHO, PROTEIN-INTAKE, LD SCORE REGRESSION, Diseases, Genome-wide association study, Type 2 diabetes, METABOLIC-ACTIVITY, OBESITY RISK, Cardiovascular, Medical and Health Sciences, CHAIN AMINO-ACIDS, Body Mass Index, 631/208, 0302 clinical medicine, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, SOCIOECONOMIC-STATUS, 030212 general & internal medicine, Aetiology, Psychiatry, 2. Zero hunger, Genetics, 692/699, Diabetes, article, Genomics, Biological Sciences, SDG 11 - Sustainable Cities and Communities, 3. Good health, Psychiatry and Mental health, SDG 1 - No Poverty, Type 2, WEIGHT-LOSS, Single-nucleotide polymorphism, Biology, 23andMe Research Team, Genetic correlation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, Behavioral and Social Science, Diabetes Mellitus, medicine, Humans, Obesity, Molecular Biology, Life Style, Metabolic and endocrine, Nutrition, Genetic association, EPIC- InterAct Consortium, Prevention, Human Genome, Psychology and Cognitive Sciences, medicine.disease, Genetic architecture, Diet, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Body mass index, Genome-Wide Association Study
Abstract: We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10-8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10-5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1-0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction. This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC, https://www.thessgac.org/). The research has also been conducted using the UK Biobank Resource under Application Number 11425. The study was supported by funding from the Ragnar Söderberg Foundation (E9/11 and E42/15), the Swedish Research Council (421-2013-1061), The Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant to Philipp Koellinger (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, The Open Philanthropy Project (2016-152872, 010623-00001), and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to NBER, and R01-AG042568-02 and R56-AG042568-04 to the University of Southern California. CCC was supported by the Intramural Research Program of the NIH/NIDDK and thanks Kevin Hall for informative discussions. PME was funded by Nestlé Nutrition. We thank the DietGen and CHARGE consortia for sharing diet-composition GWAS summary statistics, and we thank 23andMe, Inc., for sharing physical activity GWAS summary statistics. A full list of acknowledgements is provided in Supplementary Information 13.
Published: 2020

39. Estimating excess 1- year mortality from COVID-19 according to underlying conditions and age in England: a rapid analysis using NHS health records in 3.8 million adults

Author: Wai Keong Wong, Deenan Pillay, Arturo Gonzalez-Izquierdo, Harry Hemingway, Spiros Denaxas, Laura Pasea, Ana Torralbo, Bryan Williams, Amitava Banerjee, Christina Pagel, Laura Shallcross, Steve Harris, Claudia Langenberg, and Mahdad Noursadeghi
Subjects: COPD, medicine.medical_specialty, education.field_of_study, Coronavirus disease 2019 (COVID-19), business.industry, Public health, Population, Disease, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Relative risk, Diabetes mellitus, Medicine, 030212 general & internal medicine, business, education, Kidney disease, Demography
Abstract: BackgroundThe medical, health service, societal and economic impact of the COVID-19 emergency has unknown effects on overall population mortality. Previous models of population mortality are based on death over days among infected people, nearly all of whom (to date at least) have underlying conditions. Models have not incorporated information on high risk conditions or their longer term background (pre-COVID-19) mortality. We estimated the excess number of deaths over 1 year under different COVID-19 incidence rates and differing mortality impacts.MethodsUsing population based linked primary and secondary care electronic health records in England (HDR UK - CALIBER), we report the prevalence of underlying conditions defined by UK Public Health England COVID-19 guidelines (16 March 2020) in 3,862,012 individuals aged ≥30 years from 1997-2017. We used previously validated phenotypes, openly available (https://caliberresearch.org/portal), for each condition using ICD-10 diagnosis, Read, procedure and medication codes. We estimated the 1-year mortality in each condition, and developed simple models of excess COVID-19-related deaths assuming relative risk (RR) of the impact of the emergency (compared to background mortality) of 1.2, 1.5 and 2.0.Findings20.0% of the population are at risk according to current PHE guidelines, of which; 13.7% were age>70 years and 6.3% aged ≤70 years with ≥1 underlying condition (cardiovascular disease (2.3%), diabetes (2.2%), steroid therapy (1.9%), severe obesity (0.9%), chronic kidney disease (0.6%) and chronic obstructive pulmonary disease, COPD (0.5%). Multimorbidity (co-occurrence of ≥2 conditions in an individual) was common (10.1%). The 1-year mortality in the at-risk population was 4.46%, and age and underlying conditions combine to influence background risk, varying markedly across conditions (5.9% in age>70 years, 8.6% for COPD and 13.1% in those with ≥3 or more conditions). In a suppression scenario (at SARS CoV2 rates of 0.001% of the UK population), there would be minimal excess deaths (3 and 7 excess deaths at relative risk, RR, 1.5 and 2.0 respectively). At SARS CoV2 rates of 10% of the UK population (mitigation) the model estimates the numbers of excess deaths as: 13791, 34479 and 68957 (at RR 1.2, 1.5 and 2.0 respectively). At SARS CoV2 rates of 80% in the UK population (“do-nothing”), the model estimates the number of excess deaths as 110332, 275,830 and 551,659 (at RR 1.2, 1.5 and 2.0) respectively.InterpretationWe provide the public, researchers and policy makers a simple model to estimate the excess mortality over 1 year from COVID-19, based on underlying conditions at different ages. If the relative mortality impact of COVID-19 were to be about 20% (similar magnitude as the established winter vs summer mortality excess), then the excess deaths would be 0 when 1 in 100 000 (suppression), 13791 when 1 in 10 (mitigation) and 110332 when 8 in 10 are infected (“do nothing”) scenario. However, the relative impact of COVID-19 is unknown. If the emergency were to double the mortality risk, then we estimate 7, 68957 and 551,659 excess deaths in the same scenarios. These results may inform the need for more stringent suppression measures as well as efforts to target those at highest risk for a range of preventive interventions.
Published: 2020
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40. Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes

Author: Harriet McKinney, Leong L. Ng, Maik Pietzner, Simona D'Amore, Julian L. Griffin, Bekir Erguener, Michael Allison, John J Lambourne, Mattia Frontini, Matthew C Sims, Paul D. W. Kirk, Adrian Park, Denis Seyres, Kate Downes, Carly Kempster, Claudia Langenberg, Luigi Grassi, Luca Stefanucci, Frances Burden, Paulenne Quinn, Claire Adams, Albert Koulman, Karola Rehnström, Gabriele Mocciaro, Christoph Bock, Thong Huy Cao, Amy Frary, Samantha Farrow, Roman Kreuzhuber, Michele Vacca, David B. Savage, Oliver Slingsby, Alessandra Cabassi, and Joana Batista
Subjects: 0303 health sciences, education.field_of_study, business.industry, Population, Bioinformatics, medicine.disease, Phenotype, Pathophysiology, 3. Good health, Pathogenesis, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Epigenetics, Lipodystrophy, business, education, 030304 developmental biology, Epigenomics
Abstract: Improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis are ongoing healthcare challenges. Using plasma biomarkers analysis coupled with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (obese and lipodystrophy) and comparing these to lean individuals and blood donors, the present study identifies the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells and shows that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery shows the loss of the patterns of abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurs via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Taken together, by integrating across data layers, the observed molecular and metabolic differences form a disease signature that is able to discriminate, amongst the blood donors, those individuals with a higher likelihood of having cardiometabolic syndrome, even when not presenting with the classic features.
Published: 2020

41. High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease

Author: Dipender Gill, Verena Zuber, Stephen Burgess, Leonardo Bottolo, Mika Ala-Korpela, Claudia Langenberg, Adam S. Butterworth, Zuber, Verena [0000-0001-9827-1877], Gill, Dipender [0000-0001-7312-7078], Ala-Korpela, Mika [0000-0001-5905-1206], Langenberg, Claudia [0000-0002-5017-7344], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository
Subjects: False discovery rate, 0301 basic medicine, Apolipoprotein B, Epidemiology, CAD, Coronary Artery Disease, 030204 cardiovascular system & hematology, VARIANTS, Bioinformatics, risk factor selection, Coronary artery disease, chemistry.chemical_compound, Bayes' theorem, 0302 clinical medicine, Risk Factors, Medicine, apolipoprotein B, Public, Environmental & Occupational Health, 0303 health sciences, biology, CHOLESTEROL, 0104 Statistics, Mendelian Randomization Analysis, General Medicine, ASSOCIATION, Lipids, metabolomics, 3. Good health, FALSE DISCOVERY RATE, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, coronary artery disease, Lipoproteins, 1117 Public Health and Health Services, 03 medical and health sciences, TARGETS, Mendelian randomization, Humans, AcademicSubjects/MED00860, Risk factor, METAANALYSIS, 030304 developmental biology, Apolipoproteins B, Science & Technology, Cardiovascular Risks, blood lipids, Cholesterol, business.industry, Bayes Theorem, Cholesterol, LDL, APO-B, medicine.disease, lipoproteins, 030104 developmental biology, chemistry, biology.protein, business
Abstract: BackgroundGenetic variants can be used to prioritize risk factors as potential therapeutic targets via Mendelian randomization (MR). An agnostic statistical framework using Bayesian model averaging (MR-BMA) can disentangle the causal role of correlated risk factors with shared genetic predictors. Here, our objective is to identify lipoprotein measures as mediators between lipid-associated genetic variants and coronary artery disease (CAD) for the purpose of detecting therapeutic targets for CAD.MethodsAs risk factors we consider 30 lipoprotein measures and metabolites derived from a high-throughput metabolomics study including 24,925 participants. We fit multivariable MR models of genetic associations with CAD estimated in 453,595 participants (including 113,937 cases) regressed on genetic associations with the risk factors. MR-BMA assigns to each combination of risk factors a model score quantifying how well the genetic associations with CAD are explained. Risk factors are ranked by their marginal score and selected using false discovery rate (FDR) criteria. We perform sensitivity and replication analyses varying the dataset for genetic associations with CAD.ResultsIn the main analysis, the top combination of risk factors ranked by the model score contains apolipoprotein B (ApoB) only. ApoB is also the highest ranked risk factor with respect to the marginal score (FDR< 0.005). Additionally, ApoB is selected in all replication analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise.ConclusionsOur agnostic genetic investigation prioritizes ApoB across all datasets considered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD.Key messagesIt is a common consensus that lipoproteins increase cardiovascular disease risk, yet little is known about the exact mechanisms.We use genetic associations with high-throughput metabolomics features to draw a detailed picture of lipid traits and characteristics allowing for an unprecedented resolution when considering lipids as risk factors for cardiovascular disease.This study integrates genetic data from a large scale metabolomics study including 25,000 samples and the largest study on cardiovascular disease risk including 113,937 cases and 339,658 controls.MR-BMA, a novel algorithm for multivariable MR (Zuber and Burgess, Nature Communications 2020; 11(1):29) is used to identify the most likely causal lipid determinants of cardiovascular disease from a large set of candidate risk factors with shared genetic predictors.Our agnostic genetic investigation prioritizes apolipoprotein B across all datasets considered, suggesting that apolipoprotein B, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of cardiovascular disease risk.
Published: 2020
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42. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Joris Deelen, Antonia Trichopoulou, Sara Hägg, Kim Overvad, Elisabete Weiderpass, Iryna O. Fedko, Rudolf Kaaks, Nicola D. Kerrison, Kirsi H. Pietiläinen, Ida Surakka, Veikko Salomaa, Svetlana Stoma, Jaakko Kaprio, Alessandra Allione, Cornelia M. van Duijn, Nicholas G. Martin, Veryan Codd, Olle Melander, Nilesh J. Samani, Josine E. Verhoeven, Anne Tjønneland, Natalia Pervjakova, Domenico Palli, Adam S. Butterworth, Nicholas J. Wareham, María Dolores Chirlaque, P. Eline Slagboom, Massimo Mangino, Pascal P. Arp, Christopher P. Nelson, Brenda W.J.H. Penninx, Jessica L. Buxton, Pietro Ferrari, Tao Jiang, Iiris Hovatta, Taylor K. Loe, N. Charlotte Onland-Moret, Salvatore Panico, Peter Jones, Heiner Boeing, Timothy J. Key, Luca A. Lotta, Miguel Rodríguez-Barranco, Diana van Heemst, Chen Li, Robert A. Scott, Sarah E. Medland, Giuseppe Matullo, Alexessander Couto Alves, Rosario Tumino, Jouke-Jan Hottenga, Ken K. Ong, Vittorio Krogh, Gonneke Willemsen, Andres Metspalu, Eva Albrecht, Elina Sillanpää, Johan G. Eriksson, Najaf Amin, Dale R. Nyholt, Reedik Mägi, Eros Lazzerini Denchi, Peter M. Nilsson, André G. Uitterlinden, Antonio Agudo, Yuri Milaneschi, Ashley van der Spek, Alessia Russo, Linda Broer, Federico Canzian, Marian Beekman, Grant W. Montgomery, Sophie C Warner, Guy Fagherazzi, Markus Perola, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Robert Karlsson, Tim D. Spector, Paul W. Franks, H. Eka D. Suchiman, Claudia Langenberg, Liher Imaz, Nancy L. Pedersen, Scott D. Gordon, Stephen E. Hamby, J. Ramón Quirós, Yvonne T. van der Schouw, Concha Moreno, Christian Gieger, Pekka Jousilahti, Dorret I. Boomsma, Marc J. Gunter, Benjamin Miraglio, Gianluca Severi, John Danesh, UNIVERSITY OF OULU, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Sociology and Social Gerontology, Li, Chen [0000-0002-6423-6325], Ong, Kenneth [0000-0003-4689-7530], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Abdominal Center, Department of Medicine, Endokrinologian yksikkö, Clinicum, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, HUS Helsinki and Uusimaa Hospital District, Department of Psychology and Logopedics, Genetics, SLEEPWELL Research Program, Department of Public Health, Mind and Matter, Internal Medicine, and Epidemiology
Subjects: Netherlands Twin Register (NTR), Limfomes, LOCI, Genome-wide association study, Disease, VARIANTS, DISEASE, 0302 clinical medicine, Leukocytes, telomere length, GWAS, Genetics(clinical), Càncer, Mendelian randomisation, Thyroid cancer, Genetics (clinical), 11 Medical and Health Sciences, Cancer, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Telòmer, age-related disease, biological aging, Humans, Nucleotides, Genome-Wide Association Study, Telomere, meta-analyysi, genomiikka, Genomics, CANCER, 3. Good health, 030220 oncology & carcinogenesis, MENDELIAN RANDOMIZATION, Medical genetics, Biomarker (medicine), HEART, Lymphomas, Life Sciences & Biomedicine, Medical Genetics, medicine.medical_specialty, GENES, DATABASE, Age-related Disease, Biological Aging, Mendelian Randomisation, Telomere Length, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Journal Article, 030304 developmental biology, Medicinsk genetik, Science & Technology, 06 Biological Sciences, medicine.disease, Genòmica, ikääntyminen, 1182 Biochemistry, cell and molecular biology, telomeerit, biological
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Published: 2020

43. rs641738C>T near MBOAT7 is positively associated with liver fat, ALT, and histological severity of NAFLD: a meta-analysis

Author: Jesus M. Banales, Jerome I. Rotter, Connor A. Emdin, Leon A. Adams, Sreekumar G. Pillai, Stephan Buch, Yu Ri Im, Thomas Berg, Claudia Langenberg, Kendra A. Young, Felix Stickel, Elizabeth K. Speliotes, Julia Kozlitina, Sonia Caprio, Madison Fairey, Kevin Teo, Hanieh Yaghootkar, Abhijit Chowdhury, Eu-Pnafld Investigators, Yii-Der Ida Chen, Harriet Hunter, Faiza Qayyum, Pavel Strnad, Matthias C. Reichert, Elmar Aigner, Marcin Krawczyk, Dana de Gracia Hahn, Lin Li, Matthew Hickman, Nicholette D. Palmer, Panu K. Luukkonen, Jiawen Dong, Christian Datz, Ali Canbay, Kent D. Taylor, Joel E. Lavine, Philip E. Melton, Nicola Santoro, Richard M. Watanabe, Xiuqing Guo, Giuseppina Rosaria Umano, Lynne E. Wagenknecht, Amedine Duret, Pallav Bhatnagar, Trevor A. Mori, Johanna K. DiStefano, Anne Tybjærg-Hansen, Stefano Romeo, Julia Wattacheril, Jake P. Mann, Luca Valenti, Ankita Chatterjee, Stefan Stender, Jochen Hampe, Rajarshi Banerjee, Glenn S. Gerhard, Frank Lammert, Rohit Loomba, Christian A. Hudert, Kushala W M Abeysekera, L Heintz, Constantinos A. Parisinos, Hong Kai Lim, Christopher D. Still, Matt Kelly, Mrudula Utukuri, Priyadarshi Basu, Nicholas J. Wareham, Hannele Yki-Järvinen, and Clemens Schafmayer
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Insulin, medicine.medical_treatment, Fatty liver, Genome-wide association study, medicine.disease, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Internal medicine, Genetic model, medicine, Steatosis, Risk factor, business, 030304 developmental biology
Abstract: Background & AimsA common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis.MethodsWe performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models.ResultsData from 1,047,265 participants (8,303 with liver biopsies) across 42 studies was included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05]) and diagnosis of NAFLD (OR 1.22 [95% CI 1.08 - 1.39]) in Caucasian adults. The variant was also positively associated with presence of severe steatosis, NASH, and advanced fibrosis (OR: 1.32 [95% CI: 1.06 - 1.63]) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (Pz=0.002) and lower serum triglycerides (Pz=1.5×10−4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.ConclusionOur study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.
Published: 2019

44. Estimated substitution of tea or coffee for sugar-sweetened beverages was associated with lower type 2 diabetes incidence in case-cohort analysis across 8 European countries in the EPIC-InterAct study

Author: Larraitz Arriola, Nicholas J. Wareham, Kay-Tee Khaw, Peter M. Nilsson, Nita G. Forouhi, Tilman Kühn, Elio Riboli, Dagfinn Aune, Kim Overvad, Anne Tjønneland, Paul W. Franks, Giovanna Masala, Eva Ardanaz, Miguel Rodríguez-Barranco, Maria Dolores Chirlaque, Aurora Perez-Cornago, Heather Ward, Paula Jakszyn, Annemieke M.W. Spijkerman, Matthias B. Schulze, Rudolf Kaaks, Marcela Guevara, Magdalena Stepien, Olov Rolandsson, Valeria Pala, Ivonne Sluijs, Francesca Romana Mancini, José Ramón Quirós, Stephen J. Sharp, Salvatore Panico, Guy Fagherazzi, Heiner Boeing, Fumiaki Imamura, Claudia Langenberg, Benedetta Bendinelli, Heinz Freisling, Dora Romaguera, Rosario Tumino, Linda E.T. Vissers, Elena Salamanca-Fernández, Fulvio Ricceri, Tammy Y.N. Tong, Courtney Dow, Imamura, Fumiaki [0000-0002-6841-8396], Sharp, Stephen [0000-0003-2375-1440], Langenberg, Claudia [0000-0002-5017-7344], Forouhi, Nita [0000-0002-5041-248X], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: Male, humanos, Medicine (miscellaneous), Type 2 diabetes, EPIC, Coffee, Cohort Studies, CONSUMPTION PATTERNS, MELLITUS, 0302 clinical medicine, DESIGN, Risk Factors, estudios prospectivos, WATER, Nutritional Epidemiology, 030212 general & internal medicine, Original Research Article, Prospective Studies, estudios de cohortes, mediana edad, RISK, Sugar-Sweetened Beverages, Nutrition and Dietetics, diabetes, Incidence (epidemiology), Incidence, café, Middle Aged, CANCER, 3. Good health, Näringslära, Europe, beverages, dietary guidelines, epidemiology, sugar-sweetened beverages, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Humans, Tea, té, Life Sciences & Biomedicine, PROJECT, Type 2, Cohort study, estudios de casos y controles, 030209 endocrinology & metabolism, incidencia, 03 medical and health sciences, Environmental health, 0702 Animal Production, medicine, Diabetes Mellitus, factores de riesgo, VALIDITY, METAANALYSIS, Science & Technology, Nutrition & Dietetics, business.industry, NUTRITION&DIETETICS, medicine.disease, PREVENTION, 1111 Nutrition and Dietetics, business, 0908 Food Sciences
Abstract: Introduction: Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another. Objective: The aim of this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992-2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D. Results: Mean +/- SD of estimated consumption of SSB was 55 +/- 105 g/d. Means +/- SDs for the other beverages were as follows: fruit juice, 59 +/- 101 g/d; milk, 209 +/- 203 g/d; coffee, 381 +/- 372 g/d; and tea, 152 +/- 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was -12.0 (95% CI: -20.0, -5.0) per 10,000 person-years among adults consuming SSBs >= 250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or -11.0 (95% CI:-20.0, -2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly. Conclusions: These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations., The InterAct project was funded by the EU FP6 program (LSHM_CT_2006_037197). InterAct investigators acknowledge funding from the following agencies: Medical Research Council Epidemiology Unit Core Support (MC_UU_12015/1, MC_UU_12015/5); National Institute for Health Research, Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014); the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the State of Brandenburg, Germany; Netherlands Agency grant IGE05012 and an Incentive Grant from the Board of the University Medical Center Utrecht (Netherlands); Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, and Statistics Netherlands; Swedish Research Council, Novo Nordisk, Swedish Heart Lung Foundation, and Swedish Diabetes Association; Danish Cancer Society; Deutsche Krebshilfe; Associazione Italiana per la Ricerca sul Cancro; Asturias Regional Government; Navarra Regional Government, Health Research Fund of the Spanish Ministry of Health; CIBER Epidemiologia y Salud Publica, Spain; Murcia Regional Government (grant 6236); and AIRE-ONLUS Ragusa, AVIS-Ragusa, and Sicilian Regional Government.
Published: 2019

45. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author: Angela M Wood, Stephen Kaptoge, Adam S Butterworth, Peter Willeit, Samantha Warnakula, Thomas Bolton, Ellie Paige, Dirk S Paul, Michael Sweeting, Stephen Burgess, Steven Bell, William Astle, David Stevens, Albert Koulman, Randi M Selmer, W M Monique Verschuren, Shinichi Sato, Inger Njølstad, Mark Woodward, Veikko Salomaa, Børge G Nordestgaard, Bu B Yeap, Astrid Fletcher, Olle Melander, Lewis H Kuller, Beverley Balkau, Michael Marmot, Wolfgang Koenig, Edoardo Casiglia, Cyrus Cooper, Volker Arndt, Oscar H Franco, Patrik Wennberg, John Gallacher, Agustín Gómez de la Cámara, Henry Völzke, Christina C Dahm, Caroline E Dale, Manuela M Bergmann, Carlos J Crespo, Yvonne T van der Schouw, Rudolf Kaaks, Leon A Simons, Pagona Lagiou, Josje D Schoufour, Jolanda M A Boer, Timothy J Key, Beatriz Rodriguez, Conchi Moreno-Iribas, Karina W Davidson, James O Taylor, Carlotta Sacerdote, Robert B Wallace, J Ramon Quiros, Rosario Tumino, Dan G Blazer, Allan Linneberg, Makoto Daimon, Salvatore Panico, Barbara Howard, Guri Skeie, Timo Strandberg, Elisabete Weiderpass, Paul J Nietert, Bruce M Psaty, Daan Kromhout, Elena Salamanca-Fernandez, Stefan Kiechl, Harlan M Krumholz, Sara Grioni, Domenico Palli, José M Huerta, Jackie Price, Johan Sundström, Larraitz Arriola, Hisatomi Arima, Ruth C Travis, Demosthenes B Panagiotakos, Anna Karakatsani, Antonia Trichopoulou, Tilman Kühn, Diederick E Grobbee, Elizabeth Barrett-Connor, Natasja van Schoor, Heiner Boeing, Kim Overvad, Jussi Kauhanen, Nick Wareham, Claudia Langenberg, Nita Forouhi, Maria Wennberg, Jean-Pierre Després, Mary Cushman, Jackie A Cooper, Carlos J Rodriguez, Masaru Sakurai, Jonathan E Shaw, Matthew Knuiman, Trudy Voortman, Christa Meisinger, Anne Tjønneland, Hermann Brenner, Luigi Palmieri, Jean Dallongeville, Eric J Brunner, Gerd Assmann, Maurizio Trevisan, Richard F Gillum, Ian Ford, Naveed Sattar, Mariana Lazo, Simon G Thompson, Pietro Ferrari, David A Leon, George Davey Smith, Richard Peto, Rod Jackson, Emily Banks, Emanuele Di Angelantonio, John Danesh, Adam Butterworth, Monique Verschuren, Salomaa Veikko, Astrid Flecther, Manuela Bergmann, Carlos Crespo, Jolanda M.A Boer, J. Ramon Quiros, Eric B Rimm, Dan G Blazer III, Jean-Pierre Dallongeville, Richard F Gillumn, Ian Ford Ford, Simon Thompson, Epidemiology, Wood, Angela M, Kaptoge, Stephen, Butterworth, Adam S, Willeit, Peter, Warnakula, Samantha, Bolton, Thoma, Paige, Ellie, Paul, Dirk S, Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi M, Verschuren, W M Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G, Yeap, Bu B, Fletcher, Astrid, Melander, Olle, Kuller, Lewis H, Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyru, Arndt, Volker, Franco, Oscar H, Wennberg, Patrik, Gallacher, John, de la Cámara, Agustín Gómez, Völzke, Henry, Dahm, Christina C, Dale, Caroline E, Bergmann, Manuela M, Crespo, Carlos J, van der Schouw, Yvonne T, Kaaks, Rudolf, Simons, Leon A, Lagiou, Pagona, Schoufour, Josje D, Boer, Jolanda M A, Key, Timothy J, Rodriguez, Beatriz, Moreno-Iribas, Conchi, Davidson, Karina W, Taylor, James O, Sacerdote, Carlotta, Wallace, Robert B, Quiros, J Ramon, Tumino, Rosario, Blazer, Dan G, Linneberg, Allan, Daimon, Makoto, Panico, Salvatore, Howard, Barbara, Skeie, Guri, Strandberg, Timo, Weiderpass, Elisabete, Nietert, Paul J, Psaty, Bruce M, Kromhout, Daan, Salamanca-Fernandez, Elena, Kiechl, Stefan, Krumholz, Harlan M, Grioni, Sara, Palli, Domenico, Huerta, José M, Price, Jackie, Sundström, Johan, Arriola, Larraitz, Arima, Hisatomi, Travis, Ruth C, Panagiotakos, Demosthenes B, Karakatsani, Anna, Trichopoulou, Antonia, Kühn, Tilman, Grobbee, Diederick E, Barrett-Connor, Elizabeth, van Schoor, Natasja, Boeing, Heiner, Overvad, Kim, Kauhanen, Jussi, Wareham, Nick, Langenberg, Claudia, Forouhi, Nita, Wennberg, Maria, Després, Jean-Pierre, Cushman, Mary, Cooper, Jackie A, Rodriguez, Carlos J, Sakurai, Masaru, Shaw, Jonathan E, Knuiman, Matthew, Voortman, Trudy, Meisinger, Christa, Tjønneland, Anne, Brenner, Hermann, Palmieri, Luigi, Dallongeville, Jean, Brunner, Eric J, Assmann, Gerd, Trevisan, Maurizio, Gillum, Richard F, Ford, Ian, Sattar, Naveed, Lazo, Mariana, Thompson, Simon G, Ferrari, Pietro, Leon, David A, Smith, George Davey, Peto, Richard, Jackson, Rod, Banks, Emily, Di Angelantonio, Emanuele, Danesh, John, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Internal Medicine and Rehabilitation, APH - Personalized Medicine, APH - Aging & Later Life, and Epidemiology and Data Science
Subjects: Male, FLOATING ABSOLUTE RISK, Alcohol abuse, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, Alcohol Drinking/adverse effects, 0302 clinical medicine, Cardiovascular Disease, Prospective Studies, 030212 general & internal medicine, Myocardial infarction, Prospective cohort study, Human Nutrition & Health, media_common, Medicine(all), VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Research Support, Non-U.S. Gov't, Humane Voeding & Gezondheid, Hazard ratio, Substance Abuse, Public Health, Global Health, Social Medicine and Epidemiology, ASSOCIATION, General Medicine, Middle Aged, ddc, 3. Good health, Substance abuse, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, MENDELIAN RANDOMIZATION, Female, Risk assessment, STROKE, Human, Alcohol Drinking, Lower risk, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, US ADULTS, medicine, Journal Article, Life Science, Humans, media_common.cataloged_instance, CORONARY-HEART-DISEASE, ddc:610, Cardiovascular Diseases/etiology, European union, Beroendelära, METAANALYSIS, business.industry, MORTALITY, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 3121 General medicine, internal medicine and other clinical medicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Demography
Abstract: BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.
Published: 2018

46. Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes

Author: Marju Orho-Melander, Claudia Langenberg, Robert A. Scott, Matthew Traylor, Susanna C. Larsson, George Hindy, Nicholas J. Wareham, Olle Melander, Hugh S. Markus, and Sudha Seshadri
Subjects: Blood Glucose, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Type 2 diabetes, Polymorphism, Single Nucleotide, Article, Body Mass Index, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Diabetes mellitus, Internal medicine, Mendelian randomization, Odds Ratio, Humans, Insulin, Medicine, Stroke, business.industry, Fasting, Odds ratio, Mendelian Randomization Analysis, medicine.disease, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Cardiology, Regression Analysis, Neurology (clinical), business, Body mass index, Biomarkers, 030217 neurology & neurosurgery
Abstract: Objective:To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes.Methods:MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNP-stroke associations were derived from METASTROKE and the Stroke Genetics Network (n = 18,476 ischemic stroke cases and 37,296 controls).Results:Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16–1.40, p = 3.3 × 10−7) and small vessel stroke (OR 1.21, 95% CI 1.10–1.33, p = 8.9 × 10−5) but not cardioembolic stroke (OR 1.06, 95% CI 0.97–1.15, p = 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype.Conclusions:This study provides support that T2D may be causally associated with large artery stroke.
Published: 2017

47. Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation

Author: Scott Wilson, Suzanne J. Brown, Jing Hua Zhao, John P. Walsh, Jian'an Luan, Robert A. Scott, Hou-Feng Zheng, Frank Dudbridge, John R. B. Perry, J. Brent Richards, Nicholas J. Wareham, Claudia Langenberg, Benjamin H. Mullin, and Tim D. Spector
Subjects: Adult, Male, musculoskeletal diseases, 0301 basic medicine, Bone disease, Bone density, Osteoporosis, Population, 030209 endocrinology & metabolism, Genome-wide association study, Locus (genetics), Computational biology, Biology, Fractures, Bone, 03 medical and health sciences, Absorptiometry, Photon, 0302 clinical medicine, Bone Density, Genetics, medicine, Humans, education, Molecular Biology, Allele frequency, Genetics (clinical), Aged, Ultrasonography, Aged, 80 and over, Bone mineral, education.field_of_study, Association Studies Articles, General Medicine, Middle Aged, medicine.disease, Calcaneus, 030104 developmental biology, Female, Genome-Wide Association Study
Abstract: Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive genome-wide association study (GWAS) including low-frequency variants (minor allele frequency ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n = 1268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n = 1610 and 13 749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10−8 to 1.6 × 10−9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS after correction for multiple testing, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10−6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10−6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10−4, respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA.
Published: 2017

48. Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

Author: Stefan Gross, Honghuang Lin, Diane T. Smelser, März W, Niek Verweij, Alexander Niessner, Peter M. Visscher, Ruth C. Lovering, Erik Ingelsson, Nicholas L. Smith, Lars Lind, Jerome I. Rotter, Anna Helgadottir, David J. Stott, Michelle L. O'Donoghue, Daniel I. Chasman, Karoline Kuchenbaecker, Morris Ad, Michael W. Nagle, Morris Ap, Steven A. Lubitz, Giedraitis, Abirami Veluchamy, Paul M. Ridker, David J. Carey, Benoit Tyl, Carolina Roselli, Laura M. Yerges-Armstrong, Michael R. Brown, Faiez Zannad, Aroon D. Hingorani, Åsa K. Hedman, Nilesh J. Samani, Daníel F. Guðbjartsson, Maris Teder-Laving, Stephan B. Felix, Christopher Newton-Cheh, Marcus Dörr, Thomas P. Cappola, Daniel I. Swerdlow, Leonard Buckbinder, Xiaosong Wang, Alex S. F. Doney, C. Andersson, Jonathan H. Chung, Joshua D. Backman, Tõnu Esko, Mohsen Ghanbari, Joop Jukema, Ian Ford, Gunnar Engström, Kent D. Taylor, Johan Ärnlöv, P.E Weeke, Kenneth B. Margulies, Peter Svensson, Folkert W. Asselbergs, Lars Køber, Michael V. Holmes, Anders Mälarstig, Chim C. Lang, Krishna G. Aragam, Samuel C. Dudley, Christian Torp-Pedersen, Bruce M. Psaty, Alexander Teumer, John J.V. McMurray, Raul Weiss, Smith Jg, Patrick T. Ellinor, Anjali T. Owens, Ify R. Mordi, G Sveinbjörnsson, Luca A. Lotta, John S. Gottdiener, Christopher M. Haggerty, Christopher P. Nelson, C M Lindgren, Hilma Holm, Michael E. Dunn, Albert Henry, Helen M. Parry, Salomaa, Huilin Xing, Kenneth Rice, Marcus E. Kleber, Spiros Denaxas, Chris Finan, Xu Chen, Unnur Thorsteinsdottir, Naveed Sattar, Bing Yu, Kerri L. Wiggins, Alaa Shalaby, Romaine Spr., Patrik K. E. Magnusson, Adriaan A. Voors, Lumbers Rt, Stella Trompet, Maryam Kavousi, Kari Stefansson, Jian'an Luan, Harry Hemingway, van Setten J, Anubha Mahajan, Olle Melander, Uwe Völker, Peter Almgren, Chaffin, Palmer Cna., Eliana Portilla-Fernandez, Stefan Stender, Markus Perola, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Teemu J. Niiranen, Nicholas J. Wareham, Andrea Koekemoer, James P. Cook, Jeff Brandimarto, Jian Yang, Mary L. Biggs, Claudia Langenberg, Perttu Salo, Sonia Shah, A.G. Uitterlinden, Mari-Liis Tammesoo, Jemma B. Wilk, Craig L. Hyde, Graciela E. Delgado, van der Harst P, Alanna C. Morrison, Kay-Tee Khaw, Barry London, Rebecca Gutmann, Thomas M. Morgan, Franco Giulianini, Abbas Dehghan, Heather L. Bloom, William A. Chutkow, Dawn M. Waterworth, Ramachandran S. Vasan, Jing Hua Zhao, Morley Mp, and Sahar Ghasemi
Subjects: 2. Zero hunger, 0303 health sciences, business.industry, Atrial fibrillation, Genome-wide association study, 030204 cardiovascular system & hematology, Quantitative trait locus, medicine.disease, Bioinformatics, Genetic architecture, 3. Good health, Coronary artery disease, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Heart failure, medicine, Mendelian inheritance, symbols, business, 030304 developmental biology, Genetic association
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. 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 unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.
Published: 2019
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49. Quality of dietary fat and genetic risk of type 2 diabetes:individual participant data meta-analysis

Author: Christina Ellervik, Toshiko Tanaka, Paul M. Ridker, Julie E. Buring, Yuvaraj Mahendran, Rebecca Rohde, Oscar H. Franco, Trudy Voortman, Yii-Der Ida Chen, Kristin L. Young, Kenneth J. Mukamal, K. Saaksjarvi, Peitao Wu, Jerome I. Rotter, Elizabeth Selvin, Audrey Y. Chu, Niels Grarup, Torben Hansen, Lydia A. Bazzano, Meir J. Stampfer, Kari E. North, George Hindy, Nita G. Forouhi, Peter Kraft, Kim Overvad, Camilla H. Sandholt, Paul W. Franks, Ulla Toft, Majken K. Jensen, Veikko Salomaa, Chloé Sarnowski, Bruce M. Psaty, Thorkild I. A. Sørensen, Rozenn N. Lemaitre, Satu Männistö, Jordi Merino, Anne Tjønneland, Alexis C. Frazier-Wood, James B. Meigs, Frank B. Hu, Anne E. Justice, Oluf Pedersen, Marta Guasch-Ferré, Christina-Alexandra Schulz, Caren E. Smith, Jose C. Florez, Dariush Mozaffarian, Claudia Langenberg, Tuomas O. Kilpeläinen, Jaeyoung Hong, Ching-Ti Liu, Mikko Kuokkanen, Annamari Lundqvist, Nicholas J. Wareham, Jian'an Luan, Markus Perola, Josée Dupuis, Hassan S. Dashti, Marju Orho-Melander, Ulrika Ericson, Lu Qi, Stephen J. Sharp, Ming Ding, Jose M. Ordovas, Fumiaki Imamura, Daniel I. Chasman, Kim V.E. Braun, Dianjianyi Sun, Epidemiology, Merino, Jordi [0000-0001-8312-1438], and Apollo - University of Cambridge Repository
Subjects: Male, PREDICTION, Type 2 diabetes, 030204 cardiovascular system & hematology, Corrections, Polyunsaturated fat, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, 2. Zero hunger, ARCHITECTURE, Nutrition and Dietetics, Incidence, Hazard ratio, ASSOCIATION, General Medicine, Middle Aged, 3. Good health, Näringslära, CARDIOVASCULAR-DISEASE, Meta-analysis, NUTRITION, Female, Cohort study, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Lower risk, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diet/adverse effects, Internal medicine, MANAGEMENT, medicine, Humans, CORONARY-HEART-DISEASE, Alleles, Proportional Hazards Models, business.industry, MORTALITY, Research, medicine.disease, Dietary Fats, PREVENTION, PREDISPOSITION, Confidence interval, Diet, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/epidemiology, Dietary Fats/adverse effects, business, Genome-Wide Association Study
Abstract: Objective To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. Design Individual participant data meta-analysis. Data sources Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. Review methods Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. Results Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I 2 =7.1%, τ 2 =0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I 2 =18.0%, τ 2 =0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I 2 =58.8%, τ 2 =0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I 2 =25.9%, τ 2 =0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. Conclusions These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.
Published: 2019

50. Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study

Author: Luke Devey, Lon R. Cardon, Sirui Zhou, Dawn Waterworth, Cong Guo, George Davey Smith, Robert A. Scott, Claudia Langenberg, Lauren E. Mokry, J. Brent Richards, Philippe Sanseau, Nicholas J. Wareham, Richards, J. Brent [0000-0002-3746-9086], Apollo - University of Cambridge Repository, and Richards, J Brent [0000-0002-3746-9086]
Subjects: 0301 basic medicine, Oncology, Epidemiology, 45/43, lcsh:Medicine, Type 2 diabetes, Severity of Illness Index, Inflammatory bowel disease, law.invention, 631/208, 0302 clinical medicine, Randomized controlled trial, law, Odds Ratio, 692/308/174, lcsh:Science, Enterocolitis, Receptors, Interleukin-18, Multidisciplinary, Drug discovery, Anti-Inflammatory Agents, Non-Steroidal, Confounding, Interleukin-18, article, 3. Good health, Drug repositioning, Treatment Outcome, 692/4020/1503/257, medicine.symptom, medicine.medical_specialty, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, business.industry, lcsh:R, Drug Repositioning, 631/154, Mendelian Randomization Analysis, Inflammatory Bowel Diseases, medicine.disease, 030104 developmental biology, lcsh:Q, business, Biomarkers, 030217 neurology & neurosurgery
Abstract: Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11–1.34, P-value = 6 × 10−5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05–1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.
Published: 2019

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