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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. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Author: David R. Morrison, Elsa Brunet-Ratnasingham, Marc Afilalo, Nardin Rezk, Michael Hultström, Maik Pietzner, Hugo Zeberg, Tala Abdullah, Nicola D. Kerrison, Daniel Kaufmann, Celia M. T. Greenwood, Tomoko Nakanishi, Guillaume Butler-Laporte, Elin Thysell, Claudia Langenberg, Kaiqiong Zhao, Danielle Henry, Michaël Chassé, Vincenzo Forgetta, Madeleine Durand, Miklos Lipcsey, Clare Paterson, Michael Pollak, Jonathan Afilalo, Yiheng Chen, Vincent Mooser, Xiaoqing Xue, Zaman Afrasiabi, Louis Petitjean, Meriem Bouab, J. Brent Richards, Johan Normark, Branka Vulesevic, Nofar Kimchi, Charlotte Guzman, Noor Almamlouk, Chris Tselios, Sirui Zhou, Robert Frithiof, Olumide Adeleye, and Laetitia Laurent
Subjects: 0301 basic medicine, Innate immune system, business.industry, Confounding, Case-control study, Mendelian Randomization Analysis, General Medicine, Odds ratio, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Severity of illness, Mendelian randomization, Immunology, Medicine, business
Abstract: To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.
Published: 2021

3. A cross-platform approach identifies genetic regulators of human metabolism and health

Author: Kay-Tee Khaw, Angela M. Wood, Julian L. Griffin, Gabi Kastenmüller, Fiona M. Gribble, Adam S. Butterworth, Luca A. Lotta, Verena Zuber, Chen Li, Victoria P W Auyeung, Johannes Raffler, Isobel D. Stewart, Nita G. Forouhi, Jian'an Luan, Nicholas J. Wareham, Claudia Langenberg, Maik Pietzner, Laura B. L. Wittemans, Eleanor Wheeler, Robert A. Scott, Roberto Bonelli, John Danesh, Frank Reimann, Praveen Surendran, Stephen Burgess, Ellie Paige, Clare Oliver-Williams, Albert Koulman, Fumiaki Imamura, Eric B. Fauman, Gregory A. Michelotti, Melanie Bahlo, Eleanor Sanderson, and Emma K. Biggs
Subjects: Nonsynonymous substitution, 0303 health sciences, Mechanism (biology), Genome-wide association study, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Pleiotropy, Mendelian randomization, Genetics, Genetic Pleiotropy, Metabolome, Allelic heterogeneity, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: In cross-platform analyses of 174 metabolites, we identify 499 associations (P
Published: 2021

4. Genetic architecture of host proteins involved in SARS-CoV-2 infection

Author: Eric R. Gamazon, Erin Oerton, Nicola D. Kerrison, Nicholas J. Wareham, Aroon D. Hingorani, Maik Pietzner, Juan P Casas, Chris Finan, Rachel Ostroff, Gabi Kastenmüller, Steve A. Williams, Johannes Raffler, Eleanor Wheeler, Julia Carrasco-Zanini, Jian'an Luan, Markus Ralser, Victoria P W Auyeung, Claudia Langenberg, Wheeler, Eleanor [0000-0002-8616-6444], Raffler, Johannes [0000-0003-2495-4020], Auyeung, Victoria P. W. [0000-0002-0823-3963], Luan, Jian’an [0000-0003-3137-6337], Finan, Chris [0000-0002-3319-1937], Williams, Steve A. [0000-0002-8661-4315], Kastenmüller, Gabi [0000-0002-2368-7322], Gamazon, Eric R. [0000-0003-4204-8734], Wareham, Nicholas J. [0000-0003-1422-2993], Hingorani, Aroon D. [0000-0001-8365-0081], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Pietzner, Maik [0000-0003-3437-9963], Carrasco Zanini Sánchez, Julia [0000-0002-3988-7505], Au Yeung, Victoria [0000-0002-0823-3963], Luan, Jian'an [0000-0003-3137-6337], and Wareham, Nicholas [0000-0003-1422-2993]
Subjects: 0301 basic medicine, Male, 45/61, Science, Quantitative Trait Loci, education, General Physics and Astronomy, Computational biology, Host-Derived Cellular Factors, 030204 cardiovascular system & hematology, Phenome, Quantitative trait locus, Biology, DNA sequencing, General Biochemistry, Genetics and Molecular Biology, ABO Blood-Group System, 82/80, 03 medical and health sciences, 631/208, 0302 clinical medicine, Immune system, Drug Delivery Systems, 692/53, Humans, Blood Coagulation, Repurposing, health care economics and organizations, Regulation of gene expression, Internet, Multidisciplinary, 45, SARS-CoV-2, article, COVID-19, Proteins, General Chemistry, Middle Aged, Genetic architecture, humanities, 030104 developmental biology, Drug development, Gene Expression Regulation, Host-Pathogen Interactions, Female, Aptamers, Peptide
Abstract: Funder: Medical Research Council, Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).
Published: 2020

5. 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

6. 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

7. Plasma protein patterns as comprehensive indicators of health

Author: Tim Bauer, Martin J. Shipley, Mark A. Sarzynski, Leigh Alexander, Yolanda Hagar, Michael A Hinterberg, Aroon D. Hingorani, Stephen A. Williams, Mika Kivimäki, Juan P. Casas, Sophie Weiss, Christian Jonasson, Claudia Langenberg, Nicholas J. Wareham, Rachel Ostroff, Peter Ganz, Gargi Datta, Jessica Chadwick, Jessica A. Ash, Robert Kirk DeLisle, and Claude Bouchard
Subjects: Male, 0301 basic medicine, Diabetes risk, Immunology, Disease, Intra-Abdominal Fat, Cardiovascular, Bioinformatics, Medical and Health Sciences, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Behavioral and Social Science, Health care, Humans, Medicine, Obesity, Precision Medicine, Exercise, Life Style, Metabolic and endocrine, Nutrition, business.industry, Prevention, Blood Proteins, General Medicine, Precision medicine, Blood proteins, Health indicator, Heart Disease, Good Health and Well Being, 030104 developmental biology, Adipose Tissue, Liver, Health assessment, 030220 oncology & carcinogenesis, Body Composition, Lean body mass, Female, Generic health relevance, business
Abstract: Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3–10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12–16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check. Large-scale aptamer-based scanning of plasma proteins coupled with machine learning demonstrates proof-of-concept and feasibility of an individualized health check using a single blood sample.
Published: 2019

8. 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

9. 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

10. 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

11. 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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12. Variants associated with HHIP expression have sex-differential effects on lung function

Author: Carl A. Melbourne, Caroline Hayward, Stefan Karrasch, Dirk Keidel, Katherine A. Fawcett, Susan M. Ring, Yohan Bossé, Carol A. Wang, Ben Michael Brumpton, Claudia Langenberg, Peter K. Joshi, Ke Hao, Igor Rudan, David J. Porteous, Don D. Sin, Raquel Granell, Blair H. Smith, Jian'an Luan, Kristian Hveem, Sarah E. Harris, Sandosh Padmanabhan, Archie Campbell, Sebastian May-Wilson, Veronique Vitart, Nicola Pirastu, Arnulf Langhammer, Craig E. Pennell, John M. Starr, Stefan Weiss, Karina Patasova, Nicholas J. Wareham, James F. Wilson, Deborah Jarvis, Tim D. Spector, Nick Shrine, David P. Strachan, Martin D. Tobin, Beate Stubbe, David M. Evans, Kirsi H. Pietiläinen, Mangino Massimo, Ian P. Hall, Graham L. Hall, Jaakko Kaprio, Ralf Ewert, Rachel E. Foong, Claudia Flexeder, Louise V. Wain, Ma'en Obeidat, Cristen J. Willer, Leo-Pekka Lyytikäinen, Olli T. Raitakari, John Henderson, Konstantin Strauch, Marta R Moksnes, Cosetta Minelli, Nicole Probst-Hensch, Pirro G. Hysi, Anna L. Guyatt, Henry Völzke, Thomas Meitinger, Peter D. Sly, Ozren Polasek, Anne Richmond, Mika Kähönen, Maarten van den Berge, Medea Imboden, Thibaud Boutin, Lucija Klaric, Laura Portas, Terho Lehtimäki, Ian J. Deary, Taina Rantanen, Catherine John, Teemu Palviainen, Fawcett, Katherine A [0000-0002-6675-2112], Obeidat, Ma'en [0000-0002-5443-2752], Shrine, Nick [0000-0003-3641-4371], Weiss, Stefan [0000-0002-3553-4315], May-Wilson, Sebastian [0000-0003-2668-5717], Boutin, Thibaud S [0000-0003-4754-1675], Portas, Laura [0000-0003-1789-1893], Harris, Sarah E [0000-0002-4941-5106], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Palviainen, Teemu [0000-0002-7847-8384], Keidel, Dirk [0000-0003-4706-5728], Minelli, Cosetta [0000-0001-9166-3958], Langenberg, Claudia [0000-0002-5017-7344], Bossé, Yohan [0000-0002-3067-3711], Van den Berge, Maarten [0000-0002-9336-7340], Sin, Don D [0000-0002-0756-6643], Campbell, Archie [0000-0003-0198-5078], Porteous, David [0000-0003-1249-6106], Padmanabhan, Sandosh [0000-0003-3869-5808], Smith, Blair H [0000-0002-5362-9430], Ring, Sue [0000-0003-3103-9330], Rantanen, Taina [0000-0002-1604-1945], Pennell, Craig E [0000-0002-0937-6165], Kaprio, Jaakko [0000-0002-3716-2455], Vitart, Veronique [0000-0002-4991-3797], Hayward, Caroline [0000-0002-9405-9550], Hall, Ian P [0000-0001-9933-3216], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Groningen Research Institute for Asthma and COPD (GRIAC), Technology Centre, University of Helsinki, Institute for Molecular Medicine Finland, Genetic Epidemiology, HUS Abdominal Center, Department of Medicine, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Department of Public Health, Research Programs Unit, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, and Department of Clinical Physiology and Nuclear Medicine
Subjects: 0301 basic medicine, Spirometry, medicine.medical_specialty, HHIP, Medicine (miscellaneous), Expression, Genome-wide Interaction Study, Hhip, Lung Function, Sex, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Genome-wide interaction study, Lung function, Internal medicine, expression, medicine, sex, Allele, Enhancer, Gene, Lung, genome-wide interaction study, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, lung function, ALSPAC, Differential effects, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P-8) interactions with sex on lung function, and 21 showed suggestive interactions (P-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Published: 2021

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. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019

17. 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

18. Prepubertal Dietary and Plasma Phospholipid Fatty Acids Related to Puberty Timing: Longitudinal Cohort and Mendelian Randomization Analyses

Author: Nicholas J. Wareham, Jian'an Luan, Nita G. Forouhi, Ken K. Ong, John R. B. Perry, Claudia Langenberg, Tuck Seng Cheng, Felix R. Day, Cheng, Tuck Seng [0000-0003-4442-7332], Ong, Ken K [0000-0003-4689-7530], Apollo - University of Cambridge Repository, and Ong, Ken K. [0000-0003-4689-7530]
Subjects: Gerontology, Adult, Male, Adolescent, 030209 endocrinology & metabolism, Article, Time, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Mendelian Randomization, Mendelian randomization, Medicine, Humans, TX341-641, 030212 general & internal medicine, Longitudinal Studies, Longitudinal cohort, Prospective cohort study, Child, Phospholipids, Nutrition and Dietetics, business.industry, Nutrition. Foods and food supply, Fatty Acids, Puberty, Age Factors, Mendelian Randomization Analysis, ALSPAC, Diet, Research centre, Child, Preschool, puberty timing, Female, business, Food Science, prospective study
Abstract: Funder: NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014, Dietary intakes of polyunsaturated, monounsaturated and saturated fatty acids (FAs) have been inconsistently associated with puberty timing. We examined longitudinal associations of prepubertal dietary and plasma phospholipid FAs with several puberty timing traits in boys and girls. In the Avon Longitudinal Study of Parents and Children, prepubertal fat intakes at 3-7.5 years and plasma phospholipid FAs at 7.5 years were measured. Timings of Tanner stage 2 genital or breast development and voice breaking or menarche from repeated reports at 8-17 years, and age at peak height velocity (PHV) from repeated height measurements at 5-20 years were estimated. In linear regression models with adjustment for maternal and infant characteristics, dietary substitution of polyunsaturated FAs for saturated FAs, and higher concentrations of dihomo-γ-linolenic acid (20:3n6) and palmitoleic acid (16:1n7) were associated with earlier timing of puberty traits in girls (n = 3872) but not boys (n = 3654). In Mendelian Randomization models, higher genetically predicted circulating dihomo-γ-linolenic acid was associated with earlier menarche in girls. Based on repeated dietary intake data, objectively measured FAs and genetic causal inference, these findings suggest that dietary and endogenous metabolic pathways that increase plasma dihomo-γ-linolenic acid, an intermediate metabolite of n-6 polyunsaturated FAs, may promote earlier puberty timing in girls.
Published: 2021

19. 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

20. 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

21. 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

22. 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

23. Plasma metabolites to profile pathways in noncommunicable disease multimorbidity

Author: Maik Pietzner, Gabi Kastenmüller, Kay-Tee Khaw, Nicholas J. Wareham, Isobel D. Stewart, Claudia Langenberg, Johannes Raffler, Gregory A. Michelotti, Raffler, Johannes [0000-0003-2495-4020], Michelotti, Gregory A [0000-0002-3936-4675], Kastenmüller, Gabi [0000-0002-2368-7322], Wareham, Nicholas J [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, Plasma, 0302 clinical medicine, Metabolomics, Global health, Metabolome, Medicine, Multimorbidity, Humans, Noncommunicable Diseases, Aged, business.industry, General Medicine, Middle Aged, Cancer registry, 030104 developmental biology, Noncommunicable disease, 030220 oncology & carcinogenesis, Female, Multiple Chronic Conditions, business, Cohort study
Abstract: Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses., We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. MP was supported by a fellowship of the German Research Foundation (DFG 1446/2-1). JR is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant no. 01ZX1912D).
Published: 2021

24. 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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25. 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

26. 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

27. 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

28. 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

29. Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases

Author: Rachael A Lawson, Adam S. Butterworth, Emanuele Di Angelantonio, Klaudia Walter, Joanna M M Howson, Lixin Li, Caroline H. Williams-Gray, Ekaterina Yonova-Doing, Zoe J. Golder, Marta Camacho, Aurora Gomez-Duran, Peter M. Rothwell, Kousik Kundu, Na Cai, Maik Pietzner, Nicholas J. Wareham, John Danesh, Annette I. Burgess, Willem H. Ouwehand, Oliver Stegle, Marc Jan Bonder, Claudia Calabrese, Claudia Langenberg, Nicole Soranzo, Nicholas A. Watkins, Patrick F. Chinnery, David J. Roberts, Isobel D. Stewart, Medical Research Council (UK), Engineering and Physical Sciences Research Council (UK), Economic and Social Research Council (UK), Department of Health & Social Care (UK), Wellcome Trust, University of Cambridge, European Commission, NIHR Biomedical Research Centre (UK), Cai, Na, Gómez-Durán, Aurora, Kundu, Kousik, Burgess, Annette I., Calabrese, Claudia, Camacho, Marta, Lawson, Rachael A., Williams-Gray, Caroline H., Di Angelantonio, Emanuele, Butterworth, Adam S., Pietzner, Maik, Wareham, Nicholas J., Langenberg, Claudia, Danesh, John, Walter, Klaudia, Rothwell, Peter M., Howson, Joanna M. M., Stegle, Oliver, Chinnery, Patrick F., Soranzo, Nicole, Cai, Na [0000-0001-7496-2075], Gómez-Durán, Aurora [0000-0002-5895-6860], Kundu, Kousik [0000-0002-1019-8351], Burgess, Annette I. [0000-0003-3442-8083], Calabrese, Claudia [0000-0002-8941-2620], Camacho, Marta [0000-0002-1490-5703], Lawson, Rachael A. [0000-0003-2608-8285], Williams-Gray, Caroline H. [0000-0002-2648-9743], Di Angelantonio, Emanuele [0000-0001-8776-6719], Butterworth, Adam S. [0000-0002-6915-9015], Pietzner, Maik [0000-0003-3437-9963], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Danesh, John [0000-0003-1158-6791], Walter, Klaudia [0000-0003-4448-0301], Rothwell, Peter M. [0000-0001-9739-9211], Howson, Joanna M. M. [0000-0001-7618-0050], Stegle, Oliver [0000-0002-8818-7193], Chinnery, Patrick F. [0000-0002-7065-6617], Soranzo, Nicole [0000-0003-1095-3852], Burgess, Annette I [0000-0003-3442-8083], Lawson, Rachael A [0000-0003-2608-8285], Butterworth, Adam S [0000-0002-6915-9015], Wareham, Nick J [0000-0003-1422-2993], Howson, Joanna MM [0000-0001-7618-0050], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
Subjects: Male, Mitochondrial DNA, education, Cell, Blood Donors, Disease, Biology, Cytoplasmic hybrid, DNA, Mitochondrial, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Risk Factors, medicine, Humans, Age of Onset, health care economics and organizations, 030304 developmental biology, Genetics, 0303 health sciences, N-Formylmethionine, General Medicine, Middle Aged, United Kingdom, 3. Good health, Mitochondria, Cytosol, Proteostasis, medicine.anatomical_structure, Haplotypes, Cardiovascular Diseases, Female, 030217 neurology & neurosurgery, Biomarkers, Human mitochondrial DNA haplogroup, Follow-Up Studies
Abstract: 47 p.-11 fig., Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis., This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. N.C. is supported by an EBI–Sanger Postdoctoral Fellowship. A.G.-D. receives funding from the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust. E.Y.-D. was funded by the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme. J.M.M.H. was funded by the NIHR Cambridge BRC (BRC-1215-20014)*. P.F.C.is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Evelyn Trust and the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. C.H.W.-G. is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1) and by the Cambridge Centre for Parkinson-Plus. N.S. is supported by the Wellcome Trust(grant number 098051 until 30 September 2016 and 206194 from 1 October 2016),the Cambridge BHF Centre of Research Excellence (RE/18/1/34212) and the NIHR Cambridge Biomedical Research Centre Biomedical Resources Grant, University of Cambridge, Cardiovascular Theme (RG64226). J.D. holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award*. R.A.L. is supported by grants from Parkinson’s UK. Sequencing of INTERVAL samples was supported by the Wellcome Trust (grant number 206194). Metabolon metabolomics assays were funded by the NIHR BioResource, the Wellcome Trust (grant number 206194) and the NIHR Cambridge BRC (BRC-1215-20014)*. Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). SomaLogic assays were funded by Merck and the NIHR Cambridge BRC (BRC-1215-20014)*. ICICLE-PD was funded by Parkinson’s UK (J-0802, G-1301, G-1507) and the Lockhart Parkinson’s Disease Research Fund and supported by the NIHR Newcastle Biomedical Research Unit and the NIHR Cambridge Biomedical Research Centre (146281). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). Genetic work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372.
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. 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

32. 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

33. 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

34. 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

35. 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

36. 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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37. SARS-CoV-2 (COVID-19): What Do We Know About Children? A Systematic Review

Author: Catherine Falconer, Orla Murphy, Oliver T Mytton, Edward Mullins, Wikum Jayatunga, Tom Fowler, Danielle H Eddy, Claudia Langenberg, Nisha Mehta, Jonathan S. Nguyen-Van-Tam, Mytton, Oliver [0000-0003-3218-9912], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Male, Pediatrics, editorial, Attack rate, coronavirus, medicine.disease_cause, 0302 clinical medicine, Epidemiology, 030212 general & internal medicine, Child, Asymptomatic Infections, 11 Medical and Health Sciences, Coronavirus, Transmission (medicine), transmission, Editorial Commentary, AcademicSubjects/MED00290, Infectious Diseases, Radiological weapon, Child, Preschool, Female, medicine.symptom, Coronavirus Infections, pharmacokinetics, Life Sciences & Biomedicine, Hydroxychloroquine, Adult, Microbiology (medical), medicine.medical_specialty, Adolescent, Pneumonia, Viral, Immunology, MEDLINE, Asymptomatic, Microbiology, 03 medical and health sciences, children, 030225 pediatrics, Major Article, medicine, Humans, Pandemics, Science & Technology, business.industry, SARS-CoV-2, Public health, Infant, Newborn, COVID-19, Infant, 06 Biological Sciences, infection, business, ACUTE RESPIRATORY SYNDROME
Abstract: Background Few pediatric cases of coronavirus disease 2019 (COVID-19) have been reported and we know little about the epidemiology in children, although more is known about other coronaviruses. We aimed to understand the infection rate, clinical presentation, clinical outcomes, and transmission dynamics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in order to inform clinical and public health measures. Methods We undertook a rapid systematic review and narrative synthesis of all literature relating to SARS-CoV-2 in pediatric populations. The search terms also included SARS-CoV and MERS-CoV. We searched 3 databases and the COVID-19 resource centers of 11 major journals and publishers. English abstracts of Chinese-language papers were included. Data were extracted and narrative syntheses conducted. Results Twenty-four studies relating to COVID-19 were included in the review. Children appear to be less affected by COVID-19 than adults by observed rate of cases in large epidemiological studies. Limited data on attack rate indicate that children are just as susceptible to infection. Data on clinical outcomes are scarce but include several reports of asymptomatic infection and a milder course of disease in young children, although radiological abnormalities are noted. Severe cases are not reported in detail and there are few data relating to transmission. Conclusions Children appear to have a low observed case rate of COVID-19 but may have rates similar to adults of infection with SARS-CoV-2. This discrepancy may be because children are asymptomatic or too mildly infected to draw medical attention and be tested and counted in observed cases of COVID-19.
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. Clinical classifiers of COVID-19 infection from novel ultra-high-throughput proteomics

Author: Anna-Sophia Egger, Archie Campbell, Leif E. Sander, Laura Michalick, Anja Freiwald, Caroline Hayward, Matthew White, Christoph B. Messner, Riccardo E. Marioni, Christof von Kalle, Kathrin Textoris-Taube, David J. Porteous, Christiane Kilian, Michael Muelleder, Aleksej Zelezniak, Kathryn S. Lilley, Martin Witzenrath, Stefan Hippenstiel, Wolfgang M. Kuebler, Charlotte Thibeault, Federica Agostini, Spyros I. Vernardis, Vadim Demichev, Markus Ralser, Daniela Ludwig, Florian Kurth, Andreas C. Hocke, Marco Kreidl, Christian Drosten, Claudia Langenberg, Moritz Pfeiffer, and Daniel Wendisch
Subjects: 0303 health sciences, Plasma samples, Coronavirus disease 2019 (COVID-19), Computer science, High throughput proteomics, Computational biology, Proteomics, 3. Good health, Rapid assessment, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Coagulation system, Throughput (business), 030304 developmental biology
Abstract: SummaryThe COVID-19 pandemic is an unprecedented global challenge. Highly variable in its presentation, spread and clinical outcome, novel point-of-care diagnostic classifiers are urgently required. Here, we describe a set of COVID-19 clinical classifiers discovered using a newly designed low-cost high-throughput mass spectrometry-based platform. Introducing a new sample preparation pipeline coupled with short-gradient high-flow liquid chromatography and mass spectrometry, our methodology facilitates clinical implementation and increases sample throughput and quantification precision. Providing a rapid assessment of serum or plasma samples at scale, we report 27 biomarkers that distinguish mild and severe forms of COVID-19, of which some may have potential as therapeutic targets. These proteins highlight the role of complement factors, the coagulation system, inflammation modulators as well as pro-inflammatory signalling upstream and downstream of Interleukin 6. Application of novel methodologies hence transforms proteomics from a research tool into a rapid-response, clinically actionable technology adaptable to infectious outbreaks.Highlights-A completely redesigned clinical proteomics platform increases throughput and precision while reducing costs.-27 biomarkers are differentially expressed between WHO severity grades for COVID-19.-The study highlights potential therapeutic targets that include complement factors, the coagulation system, inflammation modulators as well as pro-inflammatory signalling both upstream and downstream of interleukin 6.
Published: 2020

40. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study

Author: Amitava Banerjee, Harry Hemingway, Ana Torralbo, Deenan Pillay, Claudia Langenberg, Steve Harris, Wai Keong Wong, Mahdad Noursadeghi, Spiros Denaxas, Laura Pasea, Bryan Williams, Christina Pagel, Arturo Gonzalez-Izquierdo, Neil J. Sebire, Christopher Holmes, Laura Shallcross, Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, medicine.medical_specialty, Pneumonia, Viral, Population, 030204 cardiovascular system & hematology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pandemic, Humans, Medicine, 030212 general & internal medicine, Mortality, education, Pandemics, Aged, Aged, 80 and over, Estimation, education.field_of_study, Models, Statistical, business.industry, Incidence (epidemiology), Public health, COVID-19, Multimorbidity, General Medicine, Middle Aged, United Kingdom, 3. Good health, Relative risk, Population study, Female, Coronavirus Infections, business, Cohort study, Demography
Abstract: Summary Background The medical, societal, and economic impact of the coronavirus disease 2019 (COVID-19) pandemic 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 thus far have underlying conditions. Models have not incorporated information on high-risk conditions or their longer-term baseline (pre-COVID-19) mortality. We estimated the excess number of deaths over 1 year under different COVID-19 incidence scenarios based on varying levels of transmission suppression and differing mortality impacts based on different relative risks for the disease. Methods In this population-based cohort study, we used linked primary and secondary care electronic health records from England (Health Data Research UK–CALIBER). We report prevalence of underlying conditions defined by Public Health England guidelines (from March 16, 2020) in individuals aged 30 years or older registered with a practice between 1997 and 2017, using validated, openly available phenotypes for each condition. We estimated 1-year mortality in each condition, developing simple models (and a tool for calculation) of excess COVID-19-related deaths, assuming relative impact (as relative risks [RRs]) of the COVID-19 pandemic (compared with background mortality) of 1·5, 2·0, and 3·0 at differing infection rate scenarios, including full suppression (0·001%), partial suppression (1%), mitigation (10%), and do nothing (80%). We also developed an online, public, prototype risk calculator for excess death estimation. Findings We included 3 862 012 individuals (1 957 935 [50·7%] women and 1 904 077 [49·3%] men). We estimated that more than 20% of the study population are in the high-risk category, of whom 13·7% were older than 70 years and 6·3% were aged 70 years or younger with at least one underlying condition. 1-year mortality in the high-risk population was estimated to be 4·46% (95% CI 4·41–4·51). Age and underlying conditions combined to influence background risk, varying markedly across conditions. In a full suppression scenario in the UK population, we estimated that there would be two excess deaths (vs baseline deaths) with an RR of 1·5, four with an RR of 2·0, and seven with an RR of 3·0. In a mitigation scenario, we estimated 18 374 excess deaths with an RR of 1·5, 36 749 with an RR of 2·0, and 73 498 with an RR of 3·0. In a do nothing scenario, we estimated 146 996 excess deaths with an RR of 1·5, 293 991 with an RR of 2·0, and 587 982 with an RR of 3·0. Interpretation We provide policy makers, researchers, and the public a simple model and an online tool for understanding excess mortality over 1 year from the COVID-19 pandemic, based on age, sex, and underlying condition-specific estimates. These results signal the need for sustained stringent suppression measures as well as sustained efforts to target those at highest risk because of underlying conditions with a range of preventive interventions. Countries should assess the overall (direct and indirect) effects of the pandemic on excess mortality. Funding National Institute for Health Research University College London Hospitals Biomedical Research Centre, Health Data Research UK.
Published: 2020

41. Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection

Author: Moritz Pfeiffer, Aleksej Zelezniak, Charlotte Thibeault, Florian Kurth, Federica Agostini, Vadim Demichev, Leif E. Sander, Daniel Wendisch, Christian Drosten, Wolfgang M. Kuebler, Christoph B. Messner, Riccardo E. Marioni, Markus Ralser, Claudia Langenberg, David J. Porteous, Christof von Kalle, Laura Michalick, Matthew White, Anna Sophia Egger, Kathrin Textoris-Taube, Christiane Kilian, Spyros I. Vernardis, Michael Mülleder, Stefan Hippenstiel, Kathryn S. Lilley, Martin Witzenrath, Anja Freiwald, Norbert Suttorp, Caroline Hayward, Andreas C. Hocke, Archie Campbell, Marco Kreidl, Daniela Ludwig, Langenberg, Claudia [0000-0002-5017-7344], Lilley, Kathryn [0000-0003-0594-6543], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Proteomics, Histology, Standardization, Coronavirus disease 2019 (COVID-19), Computer science, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Computational biology, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Betacoronavirus, Young Adult, 0302 clinical medicine, Humans, Throughput (business), Pandemics, mass spectrometry, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, SARS-CoV-2, COVID-19, Cell Biology, Blood Proteins, Middle Aged, clinical classifiers, COVID-19 infection, 3. Good health, Workflow, high-throughput proteomics, Potential biomarkers, SWATH-MS, Female, Plasma proteomics, antiviral immune response, Coronavirus Infections, 030217 neurology & neurosurgery, Biomarkers
Abstract: Summary The COVID-19 pandemic is an unprecedented global challenge and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high throughput serum and plasma proteomics that builds on ISO13485 standardisation and high-flow liquid chromatography to facilitate implementation in clinical laboratories. Our low-cost workflow quantifies 180 proteomes per day per mass spectrometer, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, our platform supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets., Graphical Abstract, Highlights - A standardized, ultra-highthroughput clinical platform for serum and plasma proteomics - Platform enables high precision quantification of 180 patient samples/day at low cost - 27 biomarkers are differentially expressed between WHO severity grades for COVID-19 - Biomarkers include proteins not previously associated with COVID-19 infection, Messner and Demichev et al. present a standardized, low cost, ultra-highthroughput platform for serum and plasma proteomics designed for clinical use and apply it to a cohort of hospitalized COVID-19 patients. They identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19.
Published: 2020

42. 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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43. 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

44. Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci

Author: Tom Dudding, Nicholas J. Timpson, Jian'an Luan, Ruth E. Mitchell, Vincenzo Forgetta, J. Brent Richards, Simon Haworth, Rupal L. Shah, Despoina Manousaki, Adil Harroud, Claudia Langenberg, Shah, Rupal [0000-0001-8789-8869], Luan, Jian'an [0000-0003-3137-6337], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Genome-wide association study, Single-nucleotide polymorphism, vitamin D, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Vitamin D and neurology, SNP, Humans, Genetics (clinical), 2. Zero hunger, rare variants, Heritability, genetic correlation, gene-environment interaction, pathway analysis, Minor allele frequency, 030104 developmental biology, genome-wide association studies, partitioned heritability, Female, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract: We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide as- sociation study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrich- ment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared herita- bility with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 3 109) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architec- ture of 25OHD.
Published: 2020

45. 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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46. Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes

Author: Fumiaki Imamura, Maik Pietzner, Fiona M. Gribble, Robert A. Scott, John Danesh, Clare Oliver-Williams, Julian L. Griffin, Roberto Bonelli, Frank Reimann, Isobel D. Stewart, Stephen Burgess, Kay-Tee Khaw, Luca A. Lotta, Adam S. Butterworth, Eric B. Fauman, Melanie Bahlo, Angela M. Wood, Nita G. Forouhi, Emma K. Biggs, Gabi Kastenm uumlller, Johannes Raffler, Praveen Surendran, Chen Li, Victoria P W Auyeung, Verena Zuber, Nicholas J. Wareham, Eleanor Sanderson, Gregory A. Michelotti, Laura B. L. Wittemans, Claudia Langenberg, and Albert Koulman
Subjects: 2. Zero hunger, 0303 health sciences, Metabolite, Metabolism, Computational biology, Biology, Small molecule, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, Human health, 0302 clinical medicine, chemistry, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p-10) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10-30)]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.
Published: 2020
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47. 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

48. 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

49. 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

50. Genomic insights into the causes of type 2 diabetes

Author: Luca A. Lotta, Claudia Langenberg, Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, education.field_of_study, Population, Drug Repositioning, Genomics, Genome-wide association study, General Medicine, Disease, Computational biology, Biology, Biobank, 03 medical and health sciences, Phenotype, 030104 developmental biology, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Genetic Predisposition to Disease, Molecular Targeted Therapy, Allele, education, Exome, Genome-Wide Association Study, Genetic association
Abstract: Summary Genome-wide association studies have implicated around 250 genomic regions in predisposition to type 2 diabetes, with evidence for causal variants and genes emerging for several of these regions. Understanding of the underlying mechanisms, including the interplay between β-cell failure, insulin sensitivity, appetite regulation, and adipose storage has been facilitated by the integration of multidimensional data for diabetes-related intermediate phenotypes, detailed genomic annotations, functional experiments, and now multiomic molecular features. Studies in diverse ethnic groups and examples from population isolates have shown the value and need for a broad genomic approach to this global disease. Transethnic discovery efforts and large-scale biobanks in diverse populations and ancestries could help to address some of the Eurocentric bias. Despite rapid progress in the discovery of the highly polygenic architecture of type 2 diabetes, dominated by common alleles with small, cumulative effects on disease risk, these insights have been of little clinical use in terms of disease prediction or prevention, and have made only small contributions to subtype classification or stratified approaches to treatment. Successful development of academia–industry partnerships for exome or genome sequencing in large biobanks could help to deliver economies of scale, with implications for the future of genomics-focused research.
Published: 2018

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