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

Your search keyword '"Claudia Langenberg"' showing total 166 results

Start Over Author "Claudia Langenberg" Topic female

166 results on '"Claudia Langenberg"'

1. Quantifying the Relationship Between Physical Activity Energy Expenditure and Incident Type 2 Diabetes: A Prospective Cohort Study of Device-Measured Activity in 90,096 Adults

Author: Tessa Strain, Paddy C. Dempsey, Katrien Wijndaele, Stephen J. Sharp, Nicola Kerrison, Tomas I. Gonzales, Chunxiao Li, Eleanor Wheeler, Claudia Langenberg, Søren Brage, Nick Wareham, Strain, Tessa [0000-0002-7086-1047], Dempsey, Paddy C [0000-0002-1714-6087], Wijndaele, Katrien [0000-0003-2199-7981], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Male, Adult, Advanced and Specialized Nursing, Endocrinology, Diabetes and Metabolism, Middle Aged, Diabetes Mellitus, Type 2, Internal Medicine, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, Obesity, Energy Metabolism, Exercise
Abstract: OBJECTIVE To investigate the association between accelerometer-derived physical activity energy expenditure (PAEE) and incident type 2 diabetes (T2D) in a cohort of middle-aged adults and within subgroups. RESEARCH DESIGN AND METHODS Data were from 90,096 UK Biobank participants without prevalent diabetes (mean 62 years of age; 57% women) who wore a wrist accelerometer for 7 days. PAEE was derived from wrist acceleration using a population-specific method validated against doubly labeled water. Logistic regressions were used to assess associations between PAEE, its underlying intensity, and incident T2D, ascertained using hospital episode and mortality data up to November 2020. Models were progressively adjusted for demographic, lifestyle factors, and BMI. RESULTS The association between PAEE and T2D was approximately linear (n = 2,018 events). We observed 19% (95% CI 17–21) lower odds of T2D per 5 kJ · kg−1 · day−1 in PAEE without adjustment for BMI and 11% (9–13) with BMI adjustment. The association was stronger in men than women and weaker in those with obesity and higher genetic susceptibility to obesity. There was no evidence of effect modification by genetic susceptibility to T2D or insulin resistance. For a given level of PAEE, odds of T2D were lower among those engaging in more moderate-to-vigorous activity. CONCLUSIONS There was a strong linear relationship between PAEE and incident T2D. A difference in PAEE equivalent to an additional daily 20-min brisk walk was associated with 19% lower odds of T2D. The association was broadly similar across population subgroups, supporting physical activity for diabetes prevention in the whole population.
Published: 2023

2. Metabolomic profiles predict individual multidisease outcomes

Author: Thore Buergel, Jakob Steinfeldt, Greg Ruyoga, Maik Pietzner, Daniele Bizzarri, Dina Vojinovic, Julius Upmeier zu Belzen, Lukas Loock, Paul Kittner, Lara Christmann, Noah Hollmann, Henrik Strangalies, Jana M. Braunger, Benjamin Wild, Scott T. Chiesa, Joachim Spranger, Fabian Klostermann, Erik B. van den Akker, Stella Trompet, Simon P. Mooijaart, Naveed Sattar, J. Wouter Jukema, Birgit Lavrijssen, Maryam Kavousi, Mohsen Ghanbari, Mohammad A. Ikram, Eline Slagboom, Mika Kivimaki, Claudia Langenberg, John Deanfield, Roland Eils, Ulf Landmesser, Department of Public Health, Clinicum, Buergel, Thore [0000-0003-1159-007X], Bizzarri, Daniele [0000-0002-6881-273X], Upmeier Zu Belzen, Julius [0000-0002-0966-4458], Hollmann, Noah [0000-0001-8556-518X], Wild, Benjamin [0000-0002-7492-8448], Chiesa, Scott T [0000-0003-4323-2189], Spranger, Joachim [0000-0002-8900-4467], van den Akker, Erik B [0000-0002-7693-0728], Trompet, Stella [0000-0001-5006-0528], Sattar, Naveed [0000-0002-1604-2593], Jukema, J Wouter [0000-0002-3246-8359], Ghanbari, Mohsen [0000-0002-9476-7143], Ikram, Mohammad A [0000-0003-0372-8585], Kivimaki, Mika [0000-0002-4699-5627], Eils, Roland [0000-0002-0034-4036], Landmesser, Ulf [0000-0002-0214-3203], Apollo - University of Cambridge Repository, Epidemiology, Surgery, and Radiology & Nuclear Medicine
Subjects: Heart Failure, Magnetic Resonance Spectroscopy, Diabetes Mellitus, Type 2, SDG 3 - Good Health and Well-being, 3121 General medicine, internal medicine and other clinical medicine, Humans, Metabolomics, Female, Breast Neoplasms, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Publisher Copyright: © 2022, The Author(s). Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.
Published: 2022

3. 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
Full Text: View/download PDF

4. MC3R links nutritional state to childhood growth and the timing of puberty

Author: Anthony P. Coll, MN Bedenbaugh, DT Porter, David H. Rowitch, John R. B. Perry, D A van Heel, X Dai, Rachel N. Lippert, Debra Rimmington, A. L. Gonçalves Soares, Felix R. Day, Duckett K, Patrick Sweeney, Zhaoyang Xu, Ahsan Nabi Khan, Hilary C. Martin, John Tadross, Roger D. Cone, Brian Y.H. Lam, Klj Ellacott, Richard B. Simerly, J Rosmaninho-Salgado, Alice E. Williamson, Gkc Dowsett, Sarah Finer, Irene Cimino, Giles S.H. Yeo, Audrey Melvin, Kara Rainbow, Claudia Langenberg, Stephen O'Rahilly, Nicholas J. Wareham, Katherine Ridley, Richard C. Trembath, Staffan Holmqvist, Sophie Buller, N J Timpson, Kaitlin H Wade, Ken K. Ong, and Elena G. Bochukova
Subjects: Male, medicine.medical_specialty, Time Factors, Calorie, Adolescent, media_common.quotation_subject, Hypothalamus, Nutritional Status, Estrous Cycle, Nutrient sensing, Biology, Weight Gain, Article, Mice, Child Development, Central melanocortin system, Internal medicine, medicine, Animals, Humans, Sexual maturity, Obesity, Sexual Maturation, Insulin-Like Growth Factor I, Child, media_common, Aged, 80 and over, Menarche, Multidisciplinary, Homozygote, Puberty, Appetite, Melanocortins, Melanocortin 4 receptor, Phenotype, medicine.anatomical_structure, Endocrinology, Lean body mass, Female, Melanocortin, Receptor, Melanocortin, Type 3
Abstract: The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. MC3R deficiency is associated with a delay in the onset of puberty, and a reduction in growth and lean mass.
Published: 2021

5. Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region

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

6. Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization

Author: Veerle Dam, N Charlotte Onland-Moret, Stephen Burgess, Maria-Dolores Chirlaque, Sanne A E Peters, Ewoud Schuit, Kaja Tikk, Elisabete Weiderpass, Clare Oliver-Williams, Angela M Wood, Anne Tjønneland, Christina C Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Matthias B Schulze, Antonia Trichopoulou, Pietro Ferrari, Giovanna Masala, Vittorio Krogh, Rosario Tumino, Giuseppe Matullo, Salvatore Panico, Jolanda M A Boer, W M Monique Verschuren, Marit Waaseth, Maria José Sánchez Pérez, Pilar Amiano, Liher Imaz, Conchi Moreno-Iribas, Olle Melander, Sophia Harlid, Maria Nordendahl, Patrik Wennberg, Timothy J Key, Elio Riboli, Carmen Santiuste, Rudolf Kaaks, Verena Katzke, Claudia Langenberg, Nicholas J Wareham, Heribert Schunkert, Jeanette Erdmann, Christina Willenborg, Christian Hengstenberg, Marcus E Kleber, Graciela Delgado, Winfried März, Stavroula Kanoni, George Dedoussis, Panos Deloukas, Majid Nikpay, Ruth McPherson, Markus Scholz, Andrej Teren, Adam S Butterworth, Yvonne T van der Schouw, Dam, Veerle [0000-0002-5982-232X], Onland-Moret, N Charlotte [0000-0002-2360-913X], Burgess, Stephen [0000-0001-5365-8760], Chirlaque, Maria-Dolores [0000-0001-9242-3040], Schuit, Ewoud [0000-0002-9548-3214], Weiderpass, Elisabete [0000-0003-2237-0128], Overvad, Kim [0000-0001-6429-7921], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Trichopoulou, Antonia [0000-0002-7204-6396], Ferrari, Pietro [0000-0001-9358-7338], Masala, Giovanna [0000-0002-5758-9069], Krogh, Vittorio [0000-0003-0122-8624], Panico, Salvatore [0000-0002-5498-8312], Harlid, Sophia [0000-0001-8540-6891], Riboli, Elio [0000-0001-6795-6080], Katzke, Verena [0000-0002-6509-6555], Schunkert, Heribert [0000-0001-6428-3001], Hengstenberg, Christian [0000-0002-8284-2994], Kleber, Marcus E [0000-0003-0663-7275], Deloukas, Panos [0000-0001-9251-070X], Nikpay, Majid [0000-0003-0285-6454], McPherson, Ruth [0000-0002-9087-6107], Scholz, Markus [0000-0002-4059-1779], and Apollo - University of Cambridge Repository
Subjects: Male, MENOPAUSE, Aging, IMPACT, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Coronary Disease, VARIANTS, Biochemistry, Polymorphism, Single Nucleotide, AGE, Endocrinology, Mendelian Randomization, Aging/genetics, Reproductive aging, risk factors, Humans, cardiovascular diseases, GENOME-WIDE ASSOCIATION, coronary heart disease, Coronary Disease/epidemiology, RISK, MORTALITY, Biochemistry (medical), Mendelian Randomization Analysis, Coronary heart disease, BIAS, Risk factors, reproductive aging, Genome-Wide Association Study/methods, Female, FASTING GLUCOSE, Genome-Wide Association Study
Abstract: The EPIC-CVD project was supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270, MR/L003120/1), the British Heart Foundation (SP/09/002, RG/08/014, RG13/13/30194), and the UK National Institute of Health Research (to EPIC-CVD). The establishment of the subcohort was supported by the EU Sixth Framework Programme (FP6) (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_ UU_12015/1 and MC_UU_12015/5). The national EPIC cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy) and MIUR "Dipartimenti di Eccellenza"(Project D15D18000410001) to the Department of Medical Sciences; Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); and Cancer Research UK, Medical Research Council (United Kingdom). LIFE-Heart is funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by funds of the Free State of Saxony within the framework of the excellence initiative. This work is supported by the Dutch Heart Foundation (2013T083 to V.D.), by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1 to S.A.E.P.), and by a Sir Henry Dale Fellowship jointly funded by the Welcome Trust and the Royal Society (204623/Z/16/Z to S.B.). None of the funding sources had a role in the collection, analysis, and interpretation of the data, nor in the decision to submit the article for publication., Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men., European Commission HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) G0800270 MR/L003120/1 British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), EU Sixth Framework Programme (FP6) LSHM_CT_2006_037197, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_ UU_12015/1 MC_UU_12015/5, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe Federal Ministry of Education & Research (BMBF) Deutsches Krebsforschungszentrum (Germany), Ministry of Health and Social Solidarity (Greece) Stavros Niarchos Foundation (Greece) Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR) MIUR "Dipartimenti di Eccellenza" D15D18000410001, Dutch Ministry of Public Health, Welfare and Sports, LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF) ERC-2009-AdG 232997, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III, Junta de Andalucia, Principality of Asturias, Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society Swedish Scientific Council (Sweden) Regional Government of Skane and Vasterbotten (Sweden), Cancer Research UK UK Research & Innovation (UKRI) Medical Research Council UK (MRC), Leipzig Research Center for Civilization Diseases (LIFE), European Commission, Free State of Saxony, Netherlands Heart Foundation 2013T083, Medical Research Council UK (MRC) MR/P014550/1, Sir Henry Dale Fellowship - Welcome Trust 204623/Z/16/Z, Sir Henry Dale Fellowship - Royal Society 204623/Z/16/Z
Published: 2022

7. 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

8. Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis

Author: Neil Murphy, Mingyang Song, Nikos Papadimitriou, Robert Carreras-Torres, Claudia Langenberg, Richard M Martin, Konstantinos K Tsilidis, Inês Barroso, Ji Chen, Timothy M Frayling, Caroline J Bull, Emma E Vincent, Michelle Cotterchio, Stephen B Gruber, Rish K Pai, Polly A Newcomb, Aurora Perez-Cornago, Franzel J B van Duijnhoven, Bethany Van Guelpen, Pavel Vodicka, Alicja Wolk, Anna H Wu, Ulrike Peters, Andrew T Chan, Marc J Gunter, Murphy, Neil [0000-0003-3347-8249], Song, Mingyang [0000-0002-1324-0316], Carreras-Torres, Robert [0000-0002-2925-734X], Langenberg, Claudia [0000-0002-5017-7344], Martin, Richard M [0000-0002-7992-7719], Tsilidis, Konstantinos K [0000-0002-8452-8472], Barroso, Inês [0000-0001-5800-4520], Frayling, Timothy M [0000-0001-8362-2603], Bull, Caroline J [0000-0002-2176-5120], Vincent, Emma E [0000-0002-8917-7384], Gruber, Stephen B [0000-0001-8656-7822], Pai, Rish K [0000-0002-2692-221X], Perez-Cornago, Aurora [0000-0002-5652-356X], van Duijnhoven, Franzel JB [0000-0001-8367-2352], Van Guelpen, Bethany [0000-0002-9692-101X], Wolk, Alicja [0000-0001-7387-6845], Chan, Andrew T [0000-0001-7284-6767], Gunter, Marc J [0000-0001-5472-6761], and Apollo - University of Cambridge Repository
Subjects: Blood Glucose, Glycated Hemoglobin, Male, Cancer Research, insulin, Nutrition and Disease, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Oncology, Diabetes Mellitus, Type 2, type-2 diabetes colorectal cancer, Risk Factors, Hyperinsulinism, Voeding en Ziekte, glycemic traits, Mendelian randomization, Humans, Insulin, Life Science, Female, ICEP, glucose, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: Background Glycemic traits—such as hyperinsulinemia, hyperglycemia, and type 2 diabetes—have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. Methods Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). Results In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. Conclusions Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
Published: 2022

9. 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

10. 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

11. 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

12. 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

13. Synergistic insights into human health from aptamer- and antibody-based proteomic profiling

Author: Erin Oerton, Maik Pietzner, Nicholas J. Wareham, Steve A. Williams, Julia Carrasco-Zanini, Nicola D. Kerrison, Eleanor Wheeler, Aroon D. Hingorani, Claudia Langenberg, Mine Koprulu, Jian'an Luan, Pietzner, Maik [0000-0003-3437-9963], Carrasco-Zanini, Julia [0000-0002-3988-7505], Koprulu, Mine [0000-0001-6870-4539], Luan, Jian’an [0000-0003-3137-6337], Hingorani, Aroon D. [0000-0001-8365-0081], Williams, Steve A. [0000-0002-8661-4315], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Luan, Jian'an [0000-0003-3137-6337], Hingorani, Aroon D [0000-0001-8365-0081], Williams, Steve A [0000-0002-8661-4315], Wareham, Nicholas J [0000-0003-1422-2993], Wheeler, Eleanor [0000-0002-8616-6444], and Wareham, Nicholas [0000-0003-1422-2993]
Subjects: Adult, Male, Proteomics, Proteome, Science, Aptamer, Quantitative Trait Loci, 631/208/729/743, 45/43, General Physics and Astronomy, Proteomic analysis, Diseases, Computational biology, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Antibodies, Cohort Studies, Human health, Alzheimer Disease, Protein Interaction Mapping, Humans, Protein Interaction Maps, Biomarker discovery, Receptors, Immunologic, Multidisciplinary, Membrane Glycoproteins, biology, 692/699, Proteomic Profiling, Blood proteins, 82/79, article, General Chemistry, Middle Aged, Phenotype, 631/45/612/1221, biology.protein, Female, Antibody, 631/1647/2067, Aptamers, Peptide
Abstract: Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques-the aptamer-based SomaScan�� v4 assay and the antibody-based Olink assays-to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein-phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer's disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries., The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We are grateful to all the volunteers and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046). Proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and Somalogic. JCZ is supported by a 4-year Wellcome Trust PhD Studentship and the Cambridge Trust, CL, EW, and NJW are funded by the Medical Research Council (MC_UU_12015/1). NJW is a NIHR Senior Investigator. ADH is an NIHR Senior Investigator and supported by the UCL Hospitals NIHR Biomedical Research Centre and the UCL BHF Research Accelerator (AA/18/6/34223). We thank Philippa Pettingill, Ida Grundberg, Klev Diamanti, and Andrea Ballagi for advice and comments on an earlier draft of this manuscript. We thank Vladimir Saudek for generating a 3D-model of variant GDF-15 protein.
Published: 2021

14. Mapping the proteo-genomic convergence of human diseases

Author: Claudia Langenberg, Maik Pietzner, Aroon D. Hingorani, Johannes Raffler, Matthias Arnold, Isobel D. Stewart, Nicholas J. Wareham, James Cook, Maria A. Wörheide, Julia Carrasco-Zanini, Wiebke Arlt, Eleanor Wheeler, Robert A. Scott, Nicola D. Kerrison, Eric R. Gamazon, Adrian Cortes, Erin Oerton, Stephen O'Rahilly, Gabi Kastenmüller, Jian'an Luan, Mine Koprulu, Pietzner, Maik [0000-0003-3437-9963], Wheeler, Eleanor [0000-0002-8616-6444], Carrasco-Zanini, Julia [0000-0002-3988-7505], Cortes, Adrian [0000-0002-3490-007X], Koprulu, Mine [0000-0001-6870-4539], Wörheide, Maria A [0000-0002-9326-7227], Oerton, Erin [0000-0002-7367-4263], Cook, James [0000-0002-2534-8738], Luan, Jian'an [0000-0003-3137-6337], Raffler, Johannes [0000-0003-2495-4020], Arnold, Matthias [0000-0002-4666-0923], Arlt, Wiebke [0000-0001-5106-9719], O'Rahilly, Stephen [0000-0003-2199-4449], Kastenmüller, Gabi [0000-0002-2368-7322], Gamazon, Eric R [0000-0003-4204-8734], Hingorani, Aroon D [0000-0001-8365-0081], Wareham, Nicholas J [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Male, Aging, Proteome, Quantitative Trait Loci, Genomics, Genome-wide association study, Computational biology, Disease, Gallstones, Quantitative trait locus, Biology, Article, Drug Development, Genetic variation, Humans, Connective Tissue Diseases, Genetic Association Studies, Internet, Sex Characteristics, Multidisciplinary, Genome, Human, Alternative splicing, COVID-19, Genetic Variation, Proteins, Blood Proteins, Alternative Splicing, Phenotype, Human genome, Female, Genome-Wide Association Study
Abstract: Detangling gene-disease connections Many diseases are at least partially due to genetic causes that are not always understood or targetable with specific treatments. To provide insight into the biology of various human diseases as well as potential leads for therapeutic development, Pietzner et al . undertook detailed, genome-wide proteogenomic mapping. The authors analyzed thousands of connections between potential disease-associated mutations, specific proteins, and medical conditions, thereby providing a detailed map for use by future researchers. They also supplied some examples in which they applied their approach to medical contexts as varied as connective tissue disorders, gallstones, and COVID-19 infections, sometimes even identifying single genes that play roles in multiple clinical scenarios. —YN
Published: 2021

15. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study

Author: Helen McShane, A Alamoudi, D Parekh, G Burns, R. Gisli Jenkins, Marco Sereno, R Djukanovic, Onn Min Kon, N I Lone, David M. Evans, L Daines, N A Hanley, Z. Omar, William Greenhalf, Nicola Williams, K Storton, Asaf David, T Wallis, E Pacpaco, H McCauley, L. O'Brien, K Hainey, P. Novotny, C Tong, L Ingram, S Gurram, C Avram, C Coleman, Edward T. Bullmore, Richard G. Brown, R Aul, K A Tripp, D. Cristiano, A Michael, Michael C Steiner, Padmasayee Papineni, A Howell, Gail Carson, Peter J. M. Openshaw, Simon Heller, G Madzamba, K Paradowski, S Singh, K Bramham, Teresa Light, David Price, V Shaw, A Yousuf, T Dong, T Hiwot, G Simons, Philip L. Molyneaux, A Ashworth, Ashley C. Brown, N Magee, A L Tan, R A Evans, Mark Toshner, Robert Sykes, W Saxon, S Finney, A Mohamed, P Cairns, Christos P Kotanidis, J D Chalmers, O Adeyemi, L Knibbs, A J Moss, S L Rowland-Jones, O M Kon, L P Ho, A Martineau, B Zhao, M G Crooks, J Meiring, Ewen M Harrison, Louise V. Wain, S Wright, E Robertson, David A. Lomas, H Lamlum, David E. Newby, P Chowdhury, K Mangion, Toby Hillman, E Turner, H McAllister-Williams, S West, J McGinness, B Whittam, T. Gorsuch, K Dempsey, L Mcgarvey, K Poinasamy, K Shevket, Emma Baldry, M Buch, N French, Olivia C. Leavy, Stephen C. J. Parker, H Newell, Louise M. Howard, O. Zongo, P Beirne, C Sharpe, N Mills, C David, M Bayley, Carmine M. Pariante, P Haldar, Z Kausar, A Dipper, I Hall, P McArdle, G Ogg, Rachael A. Evans, A.J. Buttress, M Pareek, Paul E Pfeffer, Denise Anderson, James D. Chalmers, P Kar, Caroline J. Jolley, S Plein, Nigel J. Brunskill, C Oliver, John R. Hurst, Clive Ballard, F Barrett, D Baguley, Nick P. Talbot, N Chaudhuri, A Young, Jonathan P. Busby, H Dobson, K Holmes, Liam G Heaney, Ruth E Barker, Anthony N. Price, David J. Stensel, L Brear, Louise Sigfrid, Marcia Soares, Patrice Carter, J R Hurst, John R. Geddes, Donghyung Lee, L Watson, J M Lord, H Parfrey, N Odell, J Glossop, K. Liyanage, Bryan Williams, S Neubauer, O Elneima, David R Baldwin, G Mallison, C Francis, A Te, D Foote, F Woodhead, A De Soyza, A Atkins, M Stern, A Morley, E Bright, N Basu, Simon E. Brill, D Southern, D Forton, L G Heaney, B Raman, Malcolm G Semple, M Mariveles, Charalambos Antoniades, Nawar Diar Bakerly, Swapna Mandal, Aroon D. Hingorani, E K Sage, Ania Korszun, A Hosseini, Louise Allan, M Toshner, Fergus V. Gleeson, Cherie Armour, J Quigley, S Drain, Thomas Kabir, M Havinden-Williams, Ben G. Marshall, S Patale, C Bourne, L Wright, Rachel L. Batterham, S Jones, S Linford, Salman Siddiqui, C Laing, A Horsley, S Greenwood, A Lingford-Hughes, S. Jose, Stefan Neubauer, S L Dobson, M Rahman, Alex D. McMahon, S Young, A Frankel, Joe Dennis, Claire M. Nolan, J Fuld, J Mayet, Nayia Petousi, Brij Patel, A Fairman, F Speranza, A Bularga, Colin Berry, Charlotte L. Edwardson, A Lloyd, H Jones, N Mairs, H Assefa-Kebede, L Gilmour, D Jones, Siobhan Kelly, I Cruz, Tim Rees, A Haggar, R. Wolf-Roberts, R Flockton, R Dowling, Geraldine Landers, C. Price, P Neill, John B. Cole, A L Key, Elaine Hardy, P Kitterick, Elodie Murali, Carly Welch, P Crisp, Rachel C. Chambers, L Carr, P C Calder, A McQueen, S Defres, A Dewar, F Adeyemi, Avan Aihie Sayer, D W Connell, M Halling-Brown, Neil J. Greening, M Andrews, Linda MacLiver, Kevin A. Davies, E Wade, Elizabeth M. Tunnicliffe, H Jarvis, Kathryn M. Abel, N Hart, A J Yousuf, Nicholas Easom, Alexander Richards, Lee B. Smith, P Dulawan, Janet T Scott, Amisha Singapuri, E Sapey, G Willis, P M George, S Bain, H. Tench, S S Kon, N Window, M J Rowland, A. J. Shah, B Card, A Knighton, P Chowienczyk, Luke Daines, Cathie Sudlow, Joseph Jacob, J Rossdale, S Paddick, Ifan Jones, A Storrie, Sonia Johnson, Huzaifa Adamali, Gail Davies, R G Jenkins, J Murira, Kamlesh Khunti, W Y James, Ajay M. Shah, A B Docherty, Donna J. Menzies, R Morriss, K Piper Hanley, James J Furniss, C Overton, P Mansoori, Phil Harrison, P Greenhaff, A Humphries, H. McGuinness, Gerome Breen, Hayley Hardwick, Davies Adeloye, P Pfeffer, H Lota, Daniel G. Wootton, William Monteiro, A Holbourn, R Hamil, Y Ellis, Traolach S. Brugha, A Alli, D Wraith, Jennifer K Quint, H Atkins, I Peralta, David C. Thomas, A Bolger, J Rodgers, S Portukhay, David Wilson, Michael Sharpe, Steven Kerr, T Plekhanova, J Lewis, S. Quaid, O Olaosebikan, L Lim, K Roy, A Checkley, A Newton Cox, A Dougherty, Bill Deakin, R Pius, A Hoare, N. Dormand, T Craig, Dhruv Parekh, Betty Raman, K E Lewis, Christopher E. Brightling, L G Spencer, Z Suleiman, E R Chilvers, Keith M. Channon, A Saratzis, R Lenagh, N Diar Bakerly, I Macharia, G Kaltsakas, L Morrison, M Ralser, K Fallon, C J Tee, JM Watson, J Nunag, R Gregory, J E Pearl, C Wright, K Regan, D Johnston, P Hogarth, Najib M. Rahman, G P McCann, Julie Evans, N Easom, Joseph Hughes, J Skeemer, H Baxendale, E Hufton, B Elliott, L V Wain, Ardythe L. Morrow, Meenal Patel, S Glover, C Xie, M Harvie, Alan Hughes, David B. Thomas, N Choudhury, Mark J. Tobin, Elizabeta B. Mukaetova-Ladinska, Richard W. Francis, J L Heeney, Shyam Madathil, Ellen Guthrie, S Yasmin, H Turton, M Marks, I Koychev, Melanie J. Davies, John P Greenwood, Daniel Peckham, E Lee, Iain B. McInnes, K Hadley, Charlotte Summers, J Chen, A Prickett, Timothy R Nicholson, K Lewis, A Cross, Jamie Brown, G Ross, H Wheeler, Manu Sharma, Igor Rudan, A Routen, M J Noonan, J Wild, K Jiwa, B. Welsh, Jonathan Pimm, J Kwan, A Lucey, C Favager, K Brindle, Nazir I Lone, Naveed Sattar, C Christie, James E. Mitchell, M Wilkins, C Coupland, T Thornton, Christian P Subbe, Alex Horsley, J Blaikely, G F Toingson, S Walsh, A Lea, Jennifer A. Smith, Margot W. Parkes, M Dixon, Luke Howard, N Majeed, A Hayday, Jack A. Sargeant, Michael Pavlides, K Leitch, J. Pendlebury, Andrew Donaldson, T Peto, Thomas A Jackson, N Rahman, M Gibbons, J Phipps, S Logan, D Wilkinson, J Breeze, D Holgate, R Osbourne, M Hoare, M Malim, Ryan S Thwaites, Stephen R Knight, W Ibrahim, J Rowland, Andrew M. Taylor, B Al-Sheklly, R. Loosley, S Megson, C Summersgill, Z Coburn, R Evans, I Wilson, B Pathmanathan, Jeremy George, A Angyal, S Betts, A Deans, C E Brightling, S Kerr, N Selby, L Price, A Ramos, S N Diwanji, P Kurupati, J S Brown, K Scott, A Sheikh, Krisnah Poinasamy, R Ugwuoke, Teresa Thompson, K Chong-James, Gerry P McCann, John R. Petrie, R Hughes, E. Watson, K McIvor, Trudie Chalder, Melissa Heightman, B Gooptu, H Evans, Thomas Yates, R Ahmed, Nicholas Hart, R Allen, W Schwaeble, J Simpson, Sara Clohisey, Janet M. Lord, R Bell, R Baggott, Clare J Taylor, Keir Lewis, Lynda Connor, F Thaivalappil, Kathryn J Saunders, Lynsey S. Hall, Richard Kevin Stone, Aliki Thomas, L Turtle, H Tedd, L Matthews, J Bambrough, S Stanel, M J McMahon, L Chetham, Enya Daynes, R Hurst, Angela Cook, M Aljaroof, Ling-Pei Ho, Paul Moss, H Arnold, S Fairbairn, Anthony J. Rostron, L Garner, Kyle Harrington, Douglas Grieve, B Connolly, Khalida Ismail, Craig Johnson, E. Russell, T Hussell, S Kon, Claudia Langenberg, E Wall, A Rowland, Miriam Harvey, N Powell, Catherine Pennington, N Armstrong, J C Porter, A Ient, Matthew Hotopf, R Parvin, M Richardson, I Smith, L Lightstone, J. Dasgin, Lynne Armstrong, A Charalambou, J R Geddes, C. Clark, E Gourlay, A Botkai, G Choudhury, J Bonnington, Matthew A. Brown, Paul Dark, S Thackray-Nocera, J Woods, E Stringer, R Free, Aarti Shikotra, J Jacob, P Clift, W Man, Sally J Singh, B King, Nikki Gautam, A Zawia, K McCafferty, L Milligan, S Whittaker, A Elmer, H Chinoy, H Welch, J Haworth, A Shikotra, Matthew J. Rowland, A Singapuri, M McNarry, F. Davies, F Khan, T Mcnally, Alfred A.R. Thompson, A McArdle, V Brown, Helen L. Fisher, M Spears, Peter Jezzard, Morag Henderson, D Thickett, U Munawar, M Broome, Graeme Jones, M. Gummadi, S Marciniak, L Poll, E Calvelo, J Hawkes, D Saralaya, S Walder, Omer Elneima, E M Harrison, C E Bolton, S J Singh, Khalid Shah, S Diver, M Willicombe, M Ainsworth, H Nassa, O C Leavy, D C Thomas, R Upthegrove, C Singh, C Echevarria, Sebastian Edwards, N Lewis-Burke, C Bloomfield, D L Sykes, J Parmar, Sam M. Janes, Simon Wessely, Shaney L Barratt, Judith Clarke, S McAdoo, G MacGowan, Hamish McAuley, L O Wajero, C Dobson, David J. Burn, Daniel Lasserson, Gill Arbane, Matthew Richardson, D McAulay, Rhian M. Touyz, Miles D. Witham, E Major, J Whitney, C J Jolley, Michael Beadsworth, N Goodman, S Walmsley, Daniel F. McAuley, Kath Chapman, Paul Cullinan, Margaret Jones, K P Yip, Nilesh J. Samani, M Bourne, Jeremy S. Brown, A Bloss, Alison M. Lawrie, Timothy Felton, L Bishop, T Sass, Oliver Polgar, M Bakali, N Hawkings, T Chalder, Mujtaba Husain, B Jayaraman, Hannah Bayes, Vicky Kamwa, B Hargadon, Y Peng, C Jolley, D Matila, Clare E. Mackay, J Worsley, R Dharmagunawardena, R Samuel, L Fabbri, R Russell, K Bhui, David W. Clark, S Heller, Anne Dell, J Nyaboko, N Huneke, Michael Marks, L Hesselden, A Greenhalgh, L Broad, M Bakau, Susan P. Walker, Marlies Ostermann, Smitaa Patel, E Fraser, R I Evans, V Whitehead, S Ahmad, C King, B Young, David T Arnold, Paul Klenerman, S Dunn, H McAuley, D Faluyi, B Holroyd-Hind, H Qureshi, E Bradley, Brendan G Cooper, P Shah, L Houchen, Shelley Fletcher, Todd Evans, Andrew Smith, Jill Walsh, Amanda F. Elliott, V Harris, L Holdsworth, A Ford, R Saunders, K Vellore, Jonathan Finch, A McGovern, D Nicoll, A Briggs, J Oxton, G A Davies, Milton Ashworth, T I de Silva, V Lewis, James Stockley, S Byrne, Alison G. Harvey, M Sereno, Marc Lipman, S Terry, A Moss, L. McMorrow, Nick A Maskell, Annemarie B Docherty, R Sabit, J Kenneth Baillie, Jennifer M. Short, Louise Stadon, Aziz Sheikh, S A Williams-Howard, Atul Gupta, D Altmann, J Cavanagh, S Francis, E. Perkins, E McIvor, P Atkin, Julie Williams, D Sutherland, J Rangeley, Derek Bell, J Valabhji, J K Baillie, Isobel D. Stewart, P McCourt, P Rivera-Ortega, N J Greening, Anthony De Soyza, M Dalton, Group, PHOSP-COVID Collaborative, Apollo - University of Cambridge Repository, Baguley, David, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, and UK Research and Innovation
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Health Status, medicine.medical_treatment, MEDLINE, Comorbidity, Disease, Logistic regression, PHOSP-COVID Collaborative Group, 1117 Public Health and Health Services, Cognition, SDG 3 - Good Health and Well-being, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Mechanical ventilation, United Kingdom/epidemiology, business.industry, COVID-19, 1103 Clinical Sciences, Articles, Middle Aged, Mental health, United Kingdom, Middle age, Hospitalization, Mental Health, Acute Disease, COVID-19/complications, Female, business, 1199 Other Medical and Health Sciences, Follow-Up Studies
Abstract: Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.
Published: 2021

16. Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment

Author: George Thanassoulis, James C. Engert, Haoyu Wu, Claudia Langenberg, Vincent Mooser, Vincenzo Forgetta, Nicholas J. Wareham, J. Brent Richards, and Jian'an Luan
Subjects: Male, A lipoprotein, medicine.medical_specialty, Apolipoprotein B, Risk Assessment, Internal medicine, Humans, Medicine, Prospective Studies, Aged, biology, Atherosclerotic cardiovascular disease, business.industry, General Medicine, Middle Aged, Atherosclerosis, Endocrinology, Apolipoprotein B-100, biology.protein, Female, lipids (amino acids, peptides, and proteins), Polygenic risk score, business, Risk assessment, Lipoprotein(a), Lipoprotein
Abstract: Background: Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing. Methods: PRSs were developed using least absolute shrinkage and selection operator regression among 273 222 and 356 958 UK Biobank participants of white British ancestry for Lp(a) and ApoB, respectively, and validated in separate sets of 60 771 UK Biobank and 15 050 European Prospective Investigation into Cancer and Nutrition-Norfolk participants. We then assessed the proportion of participants who, based on these PRSs, were unlikely to benefit from Lp(a) or ApoB measurements, according to current lipid guidelines. Results: In the UK Biobank and European Prospective Investigation into Cancer and Nutrition-Norfolk cohorts, the area under the receiver operating curve for the PRS-predicted Lp(a) and ApoB to identify individuals with elevated Lp(a) and ApoB was at least 0.91 (95% CI, 0.90–0.92) and 0.74 (95% CI, 0.73–0.75), respectively. The Lp(a) PRS and measured Lp(a) showed comparable association with atherosclerotic cardiovascular disease incidence, whereas the ApoB PRS was in general less predictive of atherosclerotic cardiovascular disease risk than measured ApoB. In the context of the European Society of Cardiology/European Atherosclerosis Society lipid guidelines, at a 95% sensitivity to identify individuals with elevated Lp(a) and ApoB levels, at least 54% of Lp(a) and 24% of ApoB testing could be reduced by prescreening with a PRS while maintaining a low false-negative rate. Conclusions: A substantial proportion of suggested testing for elevated Lp(a) and a modest proportion of testing for elevated ApoB could potentially be reduced by prescreening individuals with PRSs.
Published: 2021

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

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

18. 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

19. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021

20. 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
Full Text: View/download PDF

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

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. 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

29. 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

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

Author: Maik, Pietzner, Eleanor, Wheeler, Julia, Carrasco-Zanini, Johannes, Raffler, Nicola D, Kerrison, Erin, Oerton, Victoria P W, Auyeung, Jian'an, Luan, Chris, Finan, Juan P, Casas, Rachel, Ostroff, Steve A, Williams, Gabi, Kastenmüller, Markus, Ralser, Eric R, Gamazon, Nicholas J, Wareham, Aroon D, Hingorani, and Claudia, Langenberg
Subjects: Male, Internet, SARS-CoV-2, Quantitative Trait Loci, COVID-19, Proteins, Host-Derived Cellular Factors, Middle Aged, ABO Blood-Group System, Drug Delivery Systems, Gene Expression Regulation, Host-Pathogen Interactions, Genetics, Humans, Female, Author Correction, Blood Coagulation, Aptamers, Peptide, Biomarkers
Abstract: 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

31. 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

32. 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
Full Text: View/download PDF

33. 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

34. 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

35. 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

36. 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

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

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

38. Longitudinal Trends in Childhood Insulin Levels and Body Mass Index and Associations With Risks of Psychosis and Depression in Young Adults

Author: Benjamin Ian Perry, Stanley Zammit, Rachel Upthegrove, Eleanor Winpenny, Peter G. Jones, David B. Dunger, Gulam Khandaker, Nicholas J. Wareham, Jan Stochl, Claudia Langenberg, Perry, Ben [0000-0002-1533-026X], Stochl, Jan [0000-0002-9693-9930], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Winpenny, Eleanor [0000-0003-1933-0168], Dunger, David [0000-0002-2566-9304], Jones, Peter [0000-0002-0387-880X], Khandaker, Golam [0000-0002-4935-9220], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Psychosis, medicine.medical_specialty, Longitudinal study, Adolescent, Risk Assessment, Body Mass Index, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Insulin, Longitudinal Studies, Risk factor, Child, Psychiatry, Depression (differential diagnoses), Depressive Disorder, business.industry, Correction, Cardiometabolic Risk Factors, Infant, medicine.disease, Comorbidity, United Kingdom, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Child, Preschool, Cohort, Female, business, Body mass index, 030217 neurology & neurosurgery, Cohort study
Abstract: Importance: Cardiometabolic disorders often occur concomitantly with psychosis and depression, contribute to high mortality rates, and are detectable from the onset of the psychiatric disorders. However, it is unclear whether longitudinal trends in cardiometabolic traits from childhood are associated with risks for adult psychosis and depression.Objective: To examine whether specific developmental trajectories of fasting insulin (FI) levels and body mass index (BMI) from early childhood were longitudinally associated with psychosis and depression in young adults.Design, Setting, and Participants: A cohort study from the Avon Longitudinal Study of Parents and Children, a prospective study including a population-representative British cohort of 14 975 individuals, was conducted using data from participants aged 1 to 24 years. Body mass index and FI level data were used for growth mixture modeling to delineate developmental trajectories, and associations with psychosis and depression were assessed. The study was conducted between July 15, 2019, and March 24, 2020.Exposures: Fasting insulin levels were measured at 9, 15, 18, and 24 years, and BMI was measured at 1, 2, 3, 4, 7, 9, 10, 11, 12, 15, 18, and 24 years. Data on sex, race/ethnicity, paternal social class, childhood emotional and behavioral problems, and cumulative scores of sleep problems, average calorie intake, physical activity, smoking, and alcohol and substance use in childhood and adolescence were examined as potential confounders.Main Outcomes and Measures: Psychosis risk (definite psychotic experiences, psychotic disorder, at-risk mental state status, and negative symptom score) depression risk (measured using the computerized Clinical Interview Schedule-Revised) were assessed at 24 years.Results: From data available on 5790 participants (3132 [54.1%] female) for FI levels and data available on 10 463 participants (5336 [51.0%] female) for BMI, 3 distinct trajectories for FI levels and 5 distinct trajectories for BMI were noted, all of which were differentiated by mid-childhood. The persistently high FI level trajectory was associated with a psychosis at-risk mental state (adjusted odds ratio [aOR], 5.01; 95% CI, 1.76-13.19) and psychotic disorder (aOR, 3.22; 95% CI, 1.11-9.90) but not depression (aOR, 1.38; 95% CI, 0.75-2.54). A puberty-onset major increase in BMI was associated with depression (aOR, 4.46; 95% CI, 2.38-9.87) but not psychosis (aOR, 1.98; 95% CI, 0.56-7.79).Conclusions and Relevance: The cardiometabolic comorbidity of psychosis and depression may have distinct, disorder-specific early-life origins. Disrupted insulin sensitivity could be a shared risk factor for comorbid cardiometabolic disorders and psychosis. A puberty-onset major increase in BMI could be a risk factor or risk indicator for adult depression. These markers may represent targets for prevention and treatment of cardiometabolic disorders in individuals with psychosis and depression.
Published: 2021

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

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

40. Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study

Author: Michael M. Mendelson, Nita G. Forouhi, Nicola D. Kerrison, Marie-France Hivert, Kay-Tee Khaw, Allan Vaag, Jaspal S. Kooner, Alexander Perfilyev, Felix R. Day, James B. Meigs, Jussi Pihlajamäki, John R. B. Perry, Ken K. Ong, Alexia Cardona, Daniel Levy, Isobel D. Stewart, Marie Loh, Nicholas J. Wareham, Chunyu Liu, Charlotte Ling, Luca A. Lotta, Audrey Y. Chu, Claudia Langenberg, R. David Leslie, Josée Dupuis, Stephan Beck, Dirk S. Paul, Robert A. Scott, Benjamin Lehne, John C. Chambers, Cardona, Alexia [0000-0002-7877-5565], Lotta, Luca A [0000-0002-2619-5956], Khaw, Kay-Tee [0000-0002-8802-2903], Forouhi, Nita G [0000-0002-5041-248X], Leslie, R David [0000-0002-1786-1531], Ling, Charlotte [0000-0003-0587-7154], Hivert, Marie-France [0000-0001-7752-2585], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Blood Glucose, Epigenomics, Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Quantitative trait locus, Biology, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Internal Medicine, Humans, Epigenetics, education, Genetic Association Studies, Genetic association, Aged, Genetics, education.field_of_study, Incidence, nutritional and metabolic diseases, Genetics/Genomes/Proteomics/Metabolomics, DNA Methylation, Middle Aged, European Prospective Investigation into Cancer and Nutrition, 030104 developmental biology, Diabetes Mellitus, Type 2, England, DNA methylation, Female
Abstract: Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.
Published: 2019
Full Text: View/download PDF

41. Quality of dietary fat and genetic risk of type 2 diabetes:individual participant data meta-analysis

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

42. The Consortium of Metabolomics Studies (COMETS):Metabolomics in 47 Prospective Cohort Studies

Author: Jackie F. Price, Marc J. Gunter, Lorelei A. Mucci, Therese Tillin, Qibin Qi, Loic Le Marchand, Tamara B. Harris, Luca A. Lotta, Clara Barrios Barrera, Yoav Ben-Shlomo, Rachael Z. Stolzenberg-Solomon, Kathryn M. Rexrode, Massimo Mangino, Svati H. Shah, Sei Harada, Toru Takebayashi, David M. Herrington, A. Heather Eliassen, Clary B. Clish, Debbie A Lawlor, Cornelia M. Ulrich, Mika Kivimäki, Deron R. Herr, Juan P. Casas, Naji Younes, Cristina Menni, Joshua N. Sampson, Jessica Lasky-Su, Ioanna Tzoulaki, Gordon C. S. Smith, Ying Wang, Ulla Sovio, Wei Jie Seow, Nathan Appel, Andriy Derkach, Chin Meng Khoo, Matej Orešič, Bing Yu, Andrew Wong, Bruce S. Kristal, Lucilla Poston, Eric Boerwinkle, Charles E. Matthews, Xiao-Ou Shu, Paul Elliott, C Gieger, Howard D. Sesso, Mary C. Playdon, Wei Zheng, Adam Risch, Victoria L. Stevens, Mattias Johansson, Ewy Mathé, Jennifer Ose, Nicholas J. Wareham, Marinella Temprosa, Alexandre C. Pereira, Ruth C. Travis, Steven C. Moore, Krista A. Zanetti, Eoin Fahy, Hua Zhao, Ramachandran S. Vasan, Claudia Langenberg, Rachel S. Kelly, Caroline Dale, Ann W. Hsing, Joel N. Hirschhorn, Mukesh Verma, Abbas Dehghan, Eric S. Orwoll, Rachel A. Murphy, Elise Hoover, Demetrius Albanes, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, Medical Research Council (MRC), UK DRI Ltd, Langenberg, Claudia [0000-0002-5017-7344], Smith, Gordon [0000-0003-2124-0997], Sovio, Ulla [0000-0002-0799-1105], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: Gerontology, Male, Epidemiology, Health Behavior, Disease, heart disease, Global Health, Body Mass Index, COLORECTAL-CANCER, 0302 clinical medicine, Interquartile range, genetics, NATIONAL DEATH INDEX, 030212 general & internal medicine, Longitudinal Studies, Prospective Studies, Prospective cohort study, Child, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, Cancer, Aged, 80 and over, Hematologic Tests, diabetes, Diabetes, Cohort, cohort, Middle Aged, metabolomics, Prospective, Heart Disease, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Bristol Population Health Science Institute, Adult, medicine.medical_specialty, Adolescent, PROSTATE-CANCER RISK, ATHEROSCLEROSIS RISK, National Death Index, 03 medical and health sciences, Young Adult, Metabolomics, OSTEOPOROTIC FRACTURES, MALE MEAT-EATERS, Metabolome, medicine, Genetics, Humans, cancer, BREAST-CANCER, 01 Mathematical Sciences, Aged, Study Design, Science & Technology, business.industry, BETA-CAROTENE, prospective, BODY-MASS INDEX, Socioeconomic Factors, METABOLITE PROFILES, business, Epidemiologic Methods, Biomarkers
Abstract: The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).
Published: 2019

43. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author: David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.
Published: 2019

44. Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis

Author: Sara Grioni, Giuseppe Matullo, Heiner Boeing, Ioanna Tzoulaki, J. Ramón Quirós, Yvonne T. van der Schouw, Concepción Moreno-Iribas, Jolanda M. A. Boer, Elio Riboli, Michail Katsoulis, Larraitz Arriola, Guri Skeie, Pietro Ferrari, Emanuele Di Angelantonio, Timothy J. Key, Adam S. Butterworth, Matthias Johansson, Gunnar Engström, Antonia Trichopoulou, Patrik Wennberg, Verena Katzke, Fabrice Bonnet, Calogero Saieva, Elisabete Weiderpass, Heinz Freisling, W M Monique Verschuren, Anne Kirstine Eriksen, Laura Johnson, Annika Steffen, Kim Overvad, John Danesh, Karel G.M. Moons, Magdalena Stepien, Margareta Norberg, Michael J. Sweeting, Vassiliki Benetou, Nicholas J. Wareham, Olle Melander, Elena Molina-Portillo, Claudia Agnoli, Rudolf Kaaks, Camille Lassale, Salvatore Panico, Claudia Langenberg, Rosario Tumino, Anne Tjønneland, José María Huerta, Sandra Colorado-Yohar, Daphne L. van der A, Lassale, Camille, Tzoulaki, Ioanna, Moons, Karel G. M, Sweeting, Michael, Boer, Jolanda, Johnson, Laura, Huerta, José María, Agnoli, Claudia, Freisling, Heinz, Weiderpass, Elisabete, Wennberg, Patrik, Van Der A, Daphne L, Arriola, Larraitz, Benetou, Vassiliki, Boeing, Heiner, Bonnet, Fabrice, Colorado yohar, Sandra M, Engström, Gunnar, Eriksen, Anne K, Ferrari, Pietro, Grioni, Sara, Johansson, Matthia, Kaaks, Rudolf, Katsoulis, Michail, Katzke, Verena, Key, Timothy J, Matullo, Giuseppe, Melander, Olle, Molina portillo, Elena, Moreno iribas, Concepción, Norberg, Margareta, Overvad, Kim, Panico, Salvatore, Quirós, J. Ramón, Saieva, Calogero, Skeie, Guri, Steffen, Annika, Stepien, Magdalena, Tjønneland, Anne, Trichopoulou, Antonia, Tumino, Rosario, Van Der Schouw, Yvonne T, Verschuren, W. M. Monique, Langenberg, Claudia, Di Angelantonio, Emanuele, Riboli, Elio, Wareham, Nicholas J, Danesh, John, Butterworth, Adam S., Imperial College Trust, and Commission of the European Communities
Subjects: Gerontology, Male, obesity, Cardiac & Cardiovascular Systems, Epidemiology, CARDIOMETABOLIC TRAITS, physical activity, Coronary Disease, 030204 cardiovascular system & hematology, Body Mass Index, German, 0302 clinical medicine, 030212 general & internal medicine, ALL-CAUSE MORTALITY, media_common, Adiposity, 2. Zero hunger, Coronary heart disease, Metabolic syndrome, Obesity, METABOLICALLY HEALTHY, Middle Aged, waist circumference, 3. Good health, Europe, MENDELIAN RANDOMIZATION, language, Female, body mass index procedure, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Cohort study, medicine.medical_specialty, 1102 Cardiovascular Medicine And Haematology, smoking, POOLED ANALYSIS, 03 medical and health sciences, medicine, Journal Article, media_common.cataloged_instance, Humans, overweight, European union, coronary heart disease, Metabolic health, INCIDENT CARDIOVASCULAR-DISEASE, Government, Science & Technology, business.industry, FAT DISTRIBUTION, coronary heart disease risk, medicine.disease, language.human_language, BODY-MASS INDEX, PHYSICAL-ACTIVITY, Cardiovascular System & Hematology, Family medicine, Case-Control Studies, Cardiovascular System & Cardiology, RISK-FACTORS, business
Abstract: Aims: The hypothesis of ‘metabolically healthy obesity’ implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We tested this hypothesis in a large pan-European prospective study. Methods and results: We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study (‘EPIC-CVD’). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction (‘unhealthy’) as >_ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses. Conclusion: Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of ‘metabolically healthy obesity’, encouraging population-wide strategies to tackle obesity., European Union (EU) HEALTH-F2-2012-279233, European Research Council (ERC) 268834, Medical Research Council UK (MRC) G0800270 MR/L003120/1 MR/M012190/1, British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), Regional Government of Asturias, Hellenic Health Foundation, German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research, Cancer Research UK 570/A16491, Regione Sicilia, Associazione Iblea per la Ricerca Epidemiologica (A.I.R.E.) - ONLUS Ragusa, Associazione Volontari Italiani Sangue AVIS Ragusa, Compagnia di San Paolo, Human Genetics Foundation-Torino (HuGeF), British Heart Foundation RG/13/13/30194 RG/08/014/24067, Cancer Research UK 16491, Medical Research Council UK (MRC) MR/L003120/1 G0800270 MC_UU_12015/1, National Institute for Health Research (NIHR) NF-SI-0512-10135 NF-SI-0512-10165, Novo Nordisk Foundation NNF17OC0026936
Published: 2019

45. Generalizability of a diabetes-associated country-specific exploratory dietary pattern is feasible across European populations

Author: Domenico Palli, Stephen J. Sharp, Salvatore Panico, Aurelio Barricarte, Olatz Mokoroa, Anne Tjønneland, Nicola D. Kerrison, Peter M. Nilsson, Elio Riboli, Olov Rolandsson, Courtney Dow, Kay-Tee Khaw, Claudia Langenberg, Guy Fagherazzi, Claudia Agnoli, Ruth Schübel, Nicholas J. Wareham, Francesca Mancini, Heinz Freisling, Annemieke M.W. Spijkerman, Janine Kröger, Tammy Y.N. Tong, Matthias B. Schulze, Nita G. Forouhi, Valerie Cayssials, Jose Ramon Quiros Garcia, Heiner Boeing, Kim Overvad, Cecilie Kyrø, Sandra Colorado-Yohar, Timothy J. Key, Ivonne Sluijs, Tilman Kühn, Franziska Jannasch, Rosario Tumino, Carlotta Sacerdote, Paul W. Franks, Mohammad Sediq Sahrai, Christina C. Dahm, María José Sánchez, Marc J. Gunter, Langenberg, Claudia [0000-0002-5017-7344], Sharp, Stephen [0000-0003-2375-1440], Forouhi, Nita [0000-0002-5041-248X], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: Male, principal component analysis, type 2 diabetes mellitus, Medicine (miscellaneous), Type 2 diabetes, Cohort Studies, Food group, 0302 clinical medicine, Risk Factors, Nutritional Epidemiology, Medicine, 030212 general & internal medicine, 2. Zero hunger, Principal Component Analysis, Diabetis, diet-disease association, Nutrition and Dietetics, Incidence, Incidence (epidemiology), Diabetes, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, Näringslära, Meta-analysis, Population study, Female, Disease Susceptibility, Cohort study, Adult, replication, dietary patterns, 030209 endocrinology & metabolism, 03 medical and health sciences, Environmental health, Humans, ddc:610, Nutrició, Aged, Nutrition, business.industry, Case-control study, medicine.disease, Diet, meta-analysis, Diabetes Mellitus, Type 2, Case-Control Studies, Feasibility Studies, Institut für Ernährungswissenschaft, business
Abstract: Background Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence. Objective The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries. Methods Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association. Results Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea. Conclusions Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.
Published: 2019

46. A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Author: Bamidele O. Tayo, RJ Waken, Mario Sims, Diane M. Becker, Tõnu Esko, Yingchang Lu, Pamela J. Schreiner, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Archie Campbell, Ozren Polasek, Salman M. Tajuddin, Jing Hua Zhao, Barbara V. Howard, Saima Afaq, Vilmundur Gudnason, Lynda M. Rose, Francis S. Collins, Massimiliano Cocca, Ruth J. F. Loos, Yii-Der Ida Chen, W. James Gauderman, Jaspal S. Kooner, Lawrence F. Bielak, Ulrich Broeckel, Anuradhani Kasturiratne, Melissa A. Richard, Tomohiro Katsuya, Nicola D. Kerrison, Tin Aung, Lisa de las Fuentes, Lynne E. Wagenknecht, Oscar H. Franco, Yongmei Liu, Eric Boerwinkle, Nana Matoba, Saskia P. Hagenaars, Rob M. van Dam, Tibor V. Varga, Nilesh J. Samani, Tangchun Wu, Thomas H. Mosley, Caroline Hayward, Joseph H. Lee, Frida Renström, Tamara B. Harris, Alena Stančáková, Adesola Ogunniyi, Wen Bin Wei, Lenore J. Launer, Marcus Dörr, Xiuqing Guo, Jennifer A. Smith, Terho Lehtimäki, Dan E. Arking, Fang-Chi Hsu, Karin Leander, Martin Farrall, Konstantin Strauch, Albert V. Smith, Richard S. Cooper, Chiea Chuen Khor, Changwei Li, James E. Hixson, Sami Heikkinen, David R. Weir, Pirjo Komulainen, Renée de Mutsert, Raymond Noordam, Ubaydah Nasri, Paul M. Ridker, C. Charles Gu, Tamuno Alfred, Jerome I. Rotter, Nora Franceschini, Nita G. Forouhi, Lihua Wang, Alanna C. Morrison, Jian-Min Yuan, Ching-Yu Cheng, Peter S. Braund, Paul Elliott, Gregory P. Wilson, Jianjun Liu, Xiaofeng Zhu, Markku Laakso, Christian Gieger, Yukihide Momozawa, Rainer Rettig, Carsten Oliver Schmidt, Amy R. Bentley, Wei Zhao, Ioanna Ntalla, Kenneth Rice, Yoichiro Kamatani, Andres Metspalu, Helen R. Warren, Yechiel Friedlander, Susan Redline, Kurt Lohman, Cornelia M. van Duijn, Aravinda Chakravarti, Traci M. Bartz, Sarah E. Harris, Yih Chung Tham, He Gao, Mike A. Nalls, Mathilde Boissel, Donna K. Arnett, Harold Snieder, James S. Pankow, Babatunde L. Salako, Laura J. Bierut, Tin Louie, Albertine J. Oldehinkel, Xueling Sim, Thomas Meitinger, Maris Alver, Claudia Langenberg, Stephen B. Kritchevsky, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Alexandre C. Pereira, Michael R. Brown, Karen Schwander, Charles Kooperberg, Blair H. Smith, Annette Peters, Fernando Pires Hartwig, Yanhua Zhou, Jie Yao, Alisa K. Manning, Keng-Hung Lin, Dennis O. Mook-Kanamori, Ervin R. Fox, Tuomo Rankinen, Timo A. Lakka, Charles N. Rotimi, Nicholette D. Palmer, Jiang He, Nicholas J. Wareham, Jingmin Liu, Yun Ju Sung, Cathy C. Laurie, Donald W. Bowden, Yong-Bing Xiang, Lisa R. Yanek, B. Kuhnel, Nancy L. Pedersen, Yajuan Wang, Ananda R. Wickremasinghe, Jonathan Marten, Yi-Jen Hung, Dabeeru C. Rao, Bernardo L. Horta, Joel D. Kaufman, Barry I. Freedman, Chuan Gao, Olli T. Raitakari, Reedik Mägi, Solomon K. Musani, Albert Hofman, Wanqing Wen, Heming Wang, Xiao-Ou Shu, Y Liu, Mark J. Caulfield, Meian He, Daniel I. Chasman, Carl D. Langefeld, Charumathi Sabanayagam, Bruce M. Psaty, Jasmin Divers, R. Graham Barr, Chew-Kiat Heng, Stella Aslibekyan, John M. Starr, Stefan Weiss, Anuj Goel, Tuomas O. Kilpeläinen, Terrence Forrester, Mary F. Feitosa, Jost B. Jonas, Kae-Woei Liang, Colleen M. Sitlani, Daniel Levy, Marie Loh, Qing Duan, Aldi T. Kraja, Tien Yin Wong, Myriam Fornage, Andrea R. V. R. Horimoto, Michele K. Evans, David J. Porteous, Dina Vojinovic, Hua Tang, Michael A. Province, Ching-Ti Liu, Rainer Rauramaa, William R. Scott, Cora E. Lewis, Charles B. Eaton, Sharon L.R. Kardia, Michael Boehnke, James Scott, Colin A McKenzie, Jin-Fang Chai, Woon-Puay Koh, Yucheng Jia, Claude Bouchard, Peter S. Sever, Koichi Matsuda, Najaf Amin, Ulf de Faire, Walter Palmas, André G. Uitterlinden, Thomas T. Perls, Erin B. Ware, Wayne Huey-Herng Sheu, Michiaki Kubo, Ya Xing Wang, Hugh Watkins, Steven C. Hunt, Weihua Zhang, Johanna Kuusisto, Lili Milani, Rajkumar Dorajoo, Georg Ehret, L. Adrienne Cupples, Franco Giulianini, Zoltán Kutalik, Jose E Krieger, Kevin Sandow, Bruna Gigante, Alexander P. Reiner, Preeti Gupta, Heikki A. Koistinen, Treva Rice, Patricia B. Munroe, Wen-Jane Lee, Jennifer A. Brody, Paolo Gasparini, Paul W. Franks, Yik Ying Teo, Leo-Pekka Lyytikäinen, Thomas W. Winkler, Patricia A. Peyser, Ian J. Deary, Jessica D. Faul, Sing Hui Lim, Fumihiko Takeuchi, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, E. Shyong Tai, Candace M Kammerer, Mary K. Wojczynski, Pim van der Harst, Marzyeh Amini, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Benjamin Lehne, M. Waldenberger, Jeffrey R. O'Connell, Hugues Aschard, Ilaria Gandin, Kent D. Taylor, Igor Rudan, Christopher P. Nelson, John M. C. Connell, Jian'an Luan, Mickaël Canouil, Robert A. Scott, Yize Li, Marguerite R. Irvin, Sung, Yun Ju, de Las Fuentes, Lisa, Winkler, Thomas W, Chasman, Daniel I, Bentley, Amy R, Kraja, Aldi T, Ntalla, Ioanna, Warren, Helen R, Guo, Xiuqing, Schwander, Karen, Manning, Alisa K, Brown, Michael R, Aschard, Hugue, Feitosa, Mary F, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Kilpeläinen, Tuomas O, Richard, Melissa A, Aslibekyan, Stella, Bartz, Traci M, Dorajoo, Rajkumar, Li, Changwei, Liu, Yongmei, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kammerer, Candace M, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Mckenzie, Colin A, Nelson, Christopher P, Noordam, Raymond, Scott, Robert A, Sheu, Wayne H H, Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J, Varga, Tibor V, Waken, Robert J, Wang, Heming, Wang, Yajuan, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan E, Aung, Tin, Barr, R Graham, Bielak, Lawrence F, Boerwinkle, Eric, Bottinger, Erwin P, Braund, Peter S, Brody, Jennifer A, Broeckel, Ulrich, Cade, Brian, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Cocca, Massimiliano, Collins, Francis S, Connell, John M, de Mutsert, Renée, de Silva, H Janaka, Dörr, Marcu, Duan, Qing, Eaton, Charles B, Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D, Forouhi, Nita G, Franco, Oscar H, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Gu, C Charle, Gupta, Preeti, Hagenaars, Saskia P, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hofman, Albert, Howard, Barbara V, Hunt, Steven C, Irvin, Marguerite R, Jia, Yucheng, Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D, Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A, Kooperberg, Charles B, Krieger, Jose E, Kubo, Michiaki, Kutalik, Zoltan, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Joseph H, Lehne, Benjamin, Levy, Daniel, Lewis, Cora E, Li, Yize, Lim, Sing Hui, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Yeheng, Loh, Marie, Lohman, Kurt K, Louie, Tin, Mägi, Reedik, Matsuda, Koichi, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Mosley, Thomas H, Nalls, Mike A, Nasri, Ubaydah, O'Connell, Jeff R, Ogunniyi, Adesola, Palmas, Walter R, Palmer, Nicholette D, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Porteous, David, Raitakari, Olli T, Renström, Frida, Rice, Treva K, Ridker, Paul M, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L, Sandow, Kevin, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Sims, Mario, Sitlani, Colleen M, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tang, Hua, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Wojczynski, Mary K, Xiang, Yong-Bing, Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Chen, Yii-Der Ida, Weir, David R, de Faire, Ulf, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost Bruno, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K E, Oldehinkel, Albertine J, Pereira, Alexandre C, Perls, Thoma, Rauramaa, Rainer, Redline, Susan, Rettig, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wareham, Nicholas J, Watkins, Hugh, Wickremasinghe, Ananda R, Wu, Tangchun, Kamatani, Yoichiro, Laurie, Cathy C, Bouchard, Claude, Cooper, Richard S, Evans, Michele K, Gudnason, Vilmundur, Hixson, Jame, Kardia, Sharon L R, Kritchevsky, Stephen B, Psaty, Bruce M, van Dam, Rob M, Arnett, Donna K, Mook-Kanamori, Dennis O, Fornage, Myriam, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Loos, Ruth J F, Reiner, Alex P, Rotimi, Charles N, Bierut, Laura J, Zhu, Xiaofeng, Cupples, L Adrienne, Province, Michael A, Rotter, Jerome I, Franks, Paul W, Rice, Kenneth, Elliott, Paul, Caulfield, Mark J, Gauderman, W Jame, Munroe, Patricia B, Rao, Dabeeru C, Morrison, Alanna C, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.), National Institutes of Health (R01HL118305), We thank anonymous reviewers for critical reading and providing constructive and insightful comments, which substantially improved the article. This project, like several other projects, was carried out as part of the CHARGE Gene–Lifestyle Interactions Working Group., Conflict of Interest statement. The authors declare no competing financial interests except for the following: B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson, O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health), L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction, P.S. has received research awards from Pfizer Inc, J.B.J. is a consultant for Mundipharma Co. (Cambridge, UK), Patent holder with Biocompatibles UK Ltd (Franham, Surrey, UK) (title: treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor, Patent number: 20120263794) and Patent application with University of Heidelberg (Heidelberg, Germany) (title: agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia, Europäische Patentanmeldung 15000771.4), P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative project, M.A.N.'s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, M.A.N. also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and M.J. C. is chief scientist for Genomics England, a UK government company., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), 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), Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), University Management, Department of Medicine, University of Helsinki, HUS Abdominal Center, Endokrinologian yksikkö, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)
Subjects: Male, Receptors, Vasopressin, multi-ancestry, Genome-wide association study, Blood Pressure, HYDROCARBON RECEPTOR AHR, 030204 cardiovascular system & hematology, Antiporters, gene-smoking interaction, 0302 clinical medicine, Polymorphism (computer science), genome-wide study, Ethnicity, OXIDATIVE STRESS, Association Studies Article, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Genetics, ddc:616, Aged, 80 and over, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], DEPENDENT HYPERTENSION, CARDIOVASCULAR RISK, Smoking, 1184 Genetics, developmental biology, physiology, General Medicine, ASSOCIATION, Middle Aged, Caspase 9, 3. Good health, Pulse pressure, ENVIRONMENT INTERACTION, Sulfate Transporters, T-CADHERIN, Hypertension, Female, Life Sciences & Biomedicine, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Biochemistry & Molecular Biology, Mean arterial pressure, Adolescent, Diastole, Biology, elevated blood pressure, gene-smoking interactions, 03 medical and health sciences, Young Adult, Insulin resistance, Lifelines Cohort Study, medicine, Humans, Arterial Pressure, Molecular Biology, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, Polymorphism, Genetic, Tumor Suppressor Proteins, Racial Groups, Membrane Proteins, 06 Biological Sciences, SYSTOLIC BLOOD-PRESSURE, BODY-MASS INDEX, medicine.disease, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Heart failure, 1182 Biochemistry, cell and molecular biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Gene-Environment Interaction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome-Wide Association Study
Abstract: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P
Published: 2019

47. Dairy Product Intake and Risk of Type 2 Diabetes in EPIC-InterAct : A Mendelian Randomization Study

Author: Nita G. Forouhi, Kim Overvad, Aurelio Barricarte, Rudolf Kaaks, Kay-Tee Khaw, J. Ramón Quirós, Yvonne T. van der Schouw, Guy Fagherazzi, Elio Riboli, Olatz Mokoroa, Peter M. Nilsson, Valeria Pala, Claudia Langenberg, Heinz Freisling, Tilman Kühn, Timothy J. Key, Maria Dolores Chirlaque, Paul W. Franks, Domenico Palli, Nicholas J. Wareham, Annemieke M.W. Spijkerman, Catalina Bonet, Miguel Rodríguez-Barranco, Olov Rolandsson, Stephen Burgess, Ivonne Sluijs, Carlotta Sacerdote, Heiner Boeing, Anne Tjønneland, Stephen J. Sharp, Salvatore Panico, Marc J. Gunter, Daniel B Ibsen, Fumiaki Imamura, Rosario Tumino, Linda E.T. Vissers, Vissers, Linda ET [0000-0001-9044-0744], Sluijs, Ivonne [0000-0001-7758-4911], Forouhi, Nita G [0000-0002-5041-248X], Fagherazzi, Guy [0000-0001-5033-5966], Franks, Paul W [0000-0002-0520-7604], Khaw, Kay T [0000-0002-8802-2903], Apollo - University of Cambridge Repository, and Commission of the European Communities
Subjects: Male, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, LACTASE PERSISTENCE, Cohort Studies, Eating, 0302 clinical medicine, Endocrinology, Risk Factors, Neoplasms, Medicine, 030212 general & internal medicine, Advanced and Specialised Nursing, Lactase, Incidence, Mendelian Randomization Analysis, 11 Medical And Health Sciences, Middle Aged, PROSTATE-CANCER, Diabetes and Metabolism, Milk, NUTRITION, Female, HEALTH, Cohort study, Adult, Genotype, GENETIC VARIANT, QUESTIONNAIRE, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Endocrinology & Metabolism, 03 medical and health sciences, Diabetes mellitus, Environmental health, Mendelian randomization, Internal Medicine, Journal Article, Animals, Humans, Product (category theory), VALIDITY, Advanced and Specialized Nursing, business.industry, Case-control study, CONSUMPTION, medicine.disease, Nutrition Assessment, Diabetes Mellitus, Type 2, Case-Control Studies, Gene-Environment Interaction, Dairy Products, business
Abstract: OBJECTIVE To estimate the causal association between intake of dairy products and incident type 2 diabetes. RESEARCH DESIGN AND METHODS The analysis included 21,820 European individuals (9,686 diabetes cases) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study. Participants were genotyped, and rs4988235 (LCT-12910C>T), a single nucleotide polymorphism (SNP) for lactase persistence (LP) that enables digestion of dairy sugar, i.e., lactose, was imputed. Baseline dietary intakes were assessed with diet questionnaires. We investigated the associations between imputed SNP dosage for rs4988235 and intake of dairy products and other foods through linear regression. Mendelian randomization (MR) estimates for the milk-diabetes relationship were obtained through a two-stage least squares regression. RESULTS Each additional LP allele was associated with a higher intake of milk (β 17.1 g/day, 95% CI 10.6–23.6) and milk beverages (β 2.8 g/day, 95% CI 1.0–4.5) but not with intake of other dairy products. Other dietary intakes associated with rs4988235 included fruits (β −7.0 g/day, 95% CI −12.4 to −1.7 per additional LP allele), nonalcoholic beverages (β −18.0 g/day, 95% CI −34.4 to −1.6), and wine (β −4.8 g/day, 95% CI −9.1 to −0.6). In instrumental variable analysis, LP-associated milk intake was not associated with diabetes (hazard ratioper 15 g/day 0.99, 95% CI 0.93–1.05). CONCLUSIONS rs4988235 was associated with milk intake but not with intake of other dairy products. This MR study does not suggest that milk intake is associated with diabetes, which is consistent with previous observational and genetic associations. LP may be associated with intake of other foods as well, but owing to the modest associations, we consider it unlikely that this caused the observed null result.
Published: 2019

48. Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis

Author: Giuseppe Matullo, Kaja Tikk, Stephen Burgess, Elena Salamanca-Fernández, Emanuele Di Angelantonio, María Dolores Chirlaque, Clare Oliver-Williams, Elio Riboli, Conchi Moreno-Iribas, Larraitz Arriola, Renée T. Fortner, N. Charlotte Onland-Moret, Elisabete Weiderpass, Salvatore Panico, Patrik Wennberg, Anna Karakatsani, Adam S. Butterworth, Veerle Dam, Françoise Clavel-Chapelon, Gunnar Engström, Sandra Colorado-Yohar, W M Monique Verschuren, Marianne Holm, Maria Nordendahl, Karel G.M. Moons, Michael J. Sweeting, Rolf H.H. Groenwold, Carlo La Vecchia, Sanne A.E. Peters, Jolanda M. A. Boer, Nicholas J. Wareham, Sabina Sieri, Pietro Ferrari, Kim Overvad, Tilman Kühn, Antonia Trichopoulou, Angela M. Wood, Ewoud Schuit, Rosario Tumino, Timothy J. Key, J. Ramón Quirós, Giovanna Masala, Yvonne T. van der Schouw, John Danesh, Marc J. Gunter, Olle Melander, Anne Tjønneland, Claudia Langenberg, Heiner Boeing, Burgess, Stephen [0000-0001-5365-8760], Wood, Angela [0000-0002-7937-304X], Oliver-Williams, Clare [0000-0002-3573-2426], Di Angelantonio, Emanuele [0000-0001-8776-6719], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Adult, medicine.medical_specialty, Epidemiology, Ovariectomy, 030204 cardiovascular system & hematology, coronary disease, Menopause and Heart Disease, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pan european, Internal medicine, Journal Article, Medicine, Humans, risk factors, VDP::Medisinske Fag: 700, 030212 general & internal medicine, Proportional Hazards Models, Proportional hazards model, business.industry, Age Factors, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Middle Aged, medicine.disease, Coronary heart disease, Menopause, VDP::Medical disciplines: 700, Europe, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Postsurgical menopause, ageing, Female, women, business, Cohort study
Abstract: Background Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors. Methods We used data from EPIC-CVD, a case–cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders. Results After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01–1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10–1.42, p Conclusions Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.
Published: 2019

49. Association of plasma vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study

Author: Courtney Dow, Olatz Mokoroa, Catalina Bonet, Claudia Langenberg, Tilman Kühn, Ivonne Sluijs, Anne Tjønneland, Elena Salamanca-Fernández, Cristina Lasheras, Olov Rolandsson, Jesús Humberto Gómez, Timothy J. Key, Domenico Palli, Rosario Tumino, Nicholas J. Wareham, Ju-Sheng Zheng, Francesca Mancini, Annemieke M.W. Spijkerman, Kay-Tee Khaw, Nita G. Forouhi, Kim Overvad, Peter M. Nilsson, John Danesh, Carlotta Sacerdote, Thomas E. Gundersen, Sabina Sieri, Stephen J. Sharp, Salvatore Panico, Yvonne T. van der Schouw, Eva Ardanaz, Fumiaki Imamura, Magdalena Stepien, Guy Fagherazzi, Mazda Jenab, Adam S. Butterworth, Elio Riboli, Rudolf Kaaks, Paul W. Franks, Heiner Boeing, Zheng, Ju-Sheng, Imamura, Fumiaki, Sharp, Stephen J, van der Schouw, Yvonne T, Sluijs, Ivonne, Gundersen, Thomas E, Ardanaz, Eva, Boeing, Heiner, Bonet, Catalina, Gómez, Jesus Humberto, Dow, Courtney, Fagherazzi, Guy, Franks, Paul W, Jenab, Mazda, Kühn, Tilman, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Lasheras, Cristina, Mokoroa, Olatz, Mancini, Francesca Romana, Nilsson, Peter M, Overvad, Kim, Panico, Salvatore, Palli, Domenico, Rolandsson, Olov, Sieri, Sabina, Salamanca-Fernández, Elena, Sacerdote, Carlotta, Spijkerman, Annemieke Mw, Stepien, Magdalena, Tjonneland, Anne, Tumino, Rosario, Butterworth, Adam S, Riboli, Elio, Danesh, John, Langenberg, Claudia, Forouhi, Nita G, Wareham, Nicholas J, Zheng, Jusheng [0000-0001-6560-4890], Imamura, Fumiaki [0000-0002-6841-8396], Sharp, Stephen [0000-0003-2375-1440], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], 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, Metabolite, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Type 2 diabetes, DETERMINANTS, Biochemistry, medical, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Risk Factors, 030212 general & internal medicine, Prospective Studies, Vitamin D, Prospective cohort study, POPULATION, RISK, education.field_of_study, Nutrition and Dietetics, Incidence, Stereoisomerism, Middle Aged, CANCER, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Näringslära, Europe, Diabetes and Metabolism, Vitamin D/blood, Endokrinologi och diabetes, LIFE-STYLE, NUTRITION, Female, C-3 EPIMER, Diabetes Mellitus, Type 2/blood, Life Sciences & Biomedicine, Cohort study, Adult, medicine.medical_specialty, Diabetes, Pancreatic and Gastrointestinal Hormones, Population, 030209 endocrinology & metabolism, Endocrinology and Diabetes, Europe/epidemiology, 03 medical and health sciences, Endocrinology & Metabolism, Internal medicine, Diabetes mellitus, medicine, Vitamin D and neurology, Humans, education, Clinical Research Articles, METAANALYSIS, Biochemistry, medical, Science & Technology, D-3, Biochemistry (medical), 1103 Clinical Sciences, medicine.disease, chemistry, Diabetes Mellitus, Type 2, 1114 Paediatrics and Reproductive Medicine, SERUM 25-HYDROXYVITAMIN D, Biomarkers/blood, Biomarkers
Abstract: Background Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)–InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography–mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. Results The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. Conclusions Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology., We examined the prospective association of plasma vitamin D metabolites with type 2 diabetes and found that the epimeric form of plasma 25(OH)D3 was positively associated with type 2 diabetes risk.
Published: 2019

50. Exome-derived adiponectin-associated variants implicate obesity and lipid biology

Author: Peter Kovacs, Judith B. Borja, Karen L. Mohlke, Jennifer Kriebel, Kent D. Taylor, Stuart MacGregor, Ruth J. F. Loos, Carol A. Wang, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Jaeyoung Hong, Yingchang Lu, Leslie A. Lange, Terho Lehtimäki, Matthias Blüher, Cassandra N. Spracklen, Michael A. Province, Craig E. Pennell, Laura B. L. Wittemans, Yii-Der Ida Chen, Alex P. Reiner, Nicholas J. Wareham, Massimo Mangino, Kristin L. Young, Tuomas O. Kilpeläinen, David A. Mackey, Michael Preuss, Mika Kähönen, Sara M. Willems, Paraskevi Chirstofidou, Tamara B. Harris, Matthew A. Allison, Michael Boehnke, Jian'an Luan, Cristina Venturini, Kari E. North, Chelsea K. Raulerson, Linda Broer, Paul M. Ridker, Colleen M. Sitlani, Xiuqing Guo, Leo-Pekka Lyytikäinen, Neil Roberston, Pekka Jousilahti, Barbara McKnight, M. Arfan Ikram, Heather M. Highland, Torben Hansen, Niels Grarup, Satu Männistö, James G. Wilson, Konstantin Strauch, Mariaelisa Graff, Ayse Demirkan, Rebecca S. Fine, Tugce Karaderi, Linda S. Adair, Jie Yao, Olli T. Raitakari, Zoltán Kutalik, Jeffrey Haesser, Veikko Salomaa, Sophie Molnos, Rebecca D. Jackson, Renée de Mutsert, Markku Laakso, Mark I. McCarthy, Carolina Medina-Gomez, America A. Sandoval-Zárate, Anke Tönjes, Daniel I. Chasman, Shuai Wang, Michael Stumvoll, Jette Bork-Jensen, Claudia Langenberg, Paul L. Auer, Anubha Mahajan, Claudia Schurmann, Mary F. Feitosa, Melissa E. Garcia, Tim D. Spector, Aruna D. Pradhan, Jorge R. Kizer, Timothy M. Frayling, Ying Wu, James B. Meigs, Andrew P. Morris, Harald Grallert, André G. Uitterlinden, Cecilia M. Lindgren, Traci M. Bartz, Mike A. Nalls, Erik Ingelsson, Jerome I. Rotter, Mark Walker, Ruifang Li-Gao, Ivana Nedeljkovic, Najaf Amin, Hanieh Yaghootkar, Dennis O. Mook-Kanamori, Betina H. Thuesen, Lars Lind, Jin Li, Epidemiology, Internal Medicine, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, University Management, Biostatistics Helsinki, University of Helsinki, Institute for Molecular Medicine Finland, Complex Disease Genetics, and Medical and Clinical Psychology
Subjects: Male, 0301 basic medicine, Candidate gene, Adipose tissue, Genome-wide association study, DISEASE, CANDIDATE GENES, 0302 clinical medicine, Cqardio metabolic traits, RARE, Exome, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, 1184 Genetics, developmental biology, physiology, Hispanic or Latino, Middle Aged, Lipids, Phenotype, ADIPOSE-TISSUE, Adipose Tissue, 030220 oncology & carcinogenesis, Medical genetics, Female, CIRCULATING ADIPONECTIN, Adiponectin, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, Article, White People, Young Adult, 03 medical and health sciences, Cardio Metabolic Traits, Genome-wide Association Study, Obesity, SDG 3 - Good Health and Well-being, medicine, GLYCEMIC TRAITS, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, METAANALYSIS, 030304 developmental biology, Aged, PLASMA ADIPONECTIN, Correction, medicine.disease, Human genetics, Black or African American, 030104 developmental biology, Expression quantitative trait loci, 3111 Biomedicine
Abstract: Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p -7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p -4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
Published: 2019

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

166 results on '"Claudia Langenberg"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources