212 results on '"Claudia Langenberg"'
Search Results
2. Loci for insulin processing and secretion provide insight into type 2 diabetes risk
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K. Alaine Broadaway, Xianyong Yin, Alice Williamson, Victoria A. Parsons, Emma P. Wilson, Anne H. Moxley, Swarooparani Vadlamudi, Arushi Varshney, Anne U. Jackson, Vasudha Ahuja, Stefan R. Bornstein, Laura J. Corbin, Graciela E. Delgado, Om P. Dwivedi, Lilian Fernandes Silva, Timothy M. Frayling, Harald Grallert, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Christian Herder, Sandra Herrmann, Kurt Højlund, David A. Hughes, Marcus E. Kleber, Cecilia M. Lindgren, Ching-Ti Liu, Jian’an Luan, Anni Malmberg, Angela P. Moissl, Andrew P. Morris, Nikolaos Perakakis, Annette Peters, John R. Petrie, Michael Roden, Peter E.H. Schwarz, Sapna Sharma, Angela Silveira, Rona J. Strawbridge, Tiinamaija Tuomi, Andrew R. Wood, Peitao Wu, Björn Zethelius, Damiano Baldassarre, Johan G. Eriksson, Tove Fall, Jose C. Florez, Andreas Fritsche, Bruna Gigante, Anders Hamsten, Eero Kajantie, Markku Laakso, Jari Lahti, Deborah A. Lawlor, Lars Lind, Winfried März, James B. Meigs, Johan Sundström, Nicholas J. Timpson, Robert Wagner, Mark Walker, Nicholas J. Wareham, Hugh Watkins, Inês Barroso, Stephen O’Rahilly, Niels Grarup, Stephen CJ. Parker, Michael Boehnke, Claudia Langenberg, Eleanor Wheeler, and Karen L. Mohlke
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Genetics ,ALSPAC ,Genetics (clinical) - Abstract
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p-value < 5x10-8), which validated 12 previously reported loci for proinsulin and 10 additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher vs. lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait loci (eQTL) data, suggesting candidate genes including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal, but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms predisposing to disease.
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- 2023
3. 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
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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
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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.
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- 2023
4. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases
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Yiheng Chen, Tianyuan Lu, Ulrika Pettersson-Kymmer, Isobel D. Stewart, Guillaume Butler-Laporte, Tomoko Nakanishi, Agustin Cerani, Kevin Y. H. Liang, Satoshi Yoshiji, Julian Daniel Sunday Willett, Chen-Yang Su, Parminder Raina, Celia M. T. Greenwood, Yossi Farjoun, Vincenzo Forgetta, Claudia Langenberg, Sirui Zhou, Claes Ohlsson, and J. Brent Richards
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Genetics ,Article - Abstract
Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 loci; and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian Randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, alpha-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.
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- 2023
5. Development and validation of a metabolite score for red meat intake: an observational cohort study and randomized controlled dietary intervention
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Chunxiao Li, Fumiaki Imamura, Roland Wedekind, Isobel D Stewart, Maik Pietzner, Eleanor Wheeler, Nita G Forouhi, Claudia Langenberg, Augustin Scalbert, Nicholas J Wareham, Imamura, Fumiaki [0000-0002-6841-8396], Wedekind, Roland [0000-0003-1364-7666], Forouhi, Nita G [0000-0002-5041-248X], Scalbert, Augustin [0000-0001-6651-6710], and Apollo - University of Cambridge Repository
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Nutrition and Dietetics ,diabetes ,food and beverages ,Medicine (miscellaneous) ,prediction ,metabolomics ,Diet ,Cohort Studies ,meat ,Red Meat ,Diabetes Mellitus, Type 2 ,Risk Factors ,biomarker ,Humans ,Prospective Studies - Abstract
BACKGROUND: Self-reported meat consumption is associated with disease risk but objective assessment of different dimensions of this heterogeneous dietary exposure in observational and interventional studies remains challenging. OBJECTIVES: We aimed to derive and validate scores based on plasma metabolites for types of meat consumption. For the most predictive score, we aimed to test whether the included metabolites varied with change in meat consumption, and whether the score was associated with incidence of type 2 diabetes (T2D) and other noncommunicable diseases. METHODS: We derived scores based on 781 plasma metabolites for red meat, processed meat, and poultry consumption assessed with 7-d food records among 11,432 participants in the EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition-Norfolk) cohort. The scores were then tested for internal validity in an independent subset (n = 853) of the same cohort. In focused analysis on the red meat metabolite score, we examined whether the metabolites constituting the score were also associated with meat intake in a randomized crossover dietary intervention trial of meat (n = 12, Lyon, France). In the EPIC-Norfolk study, we assessed the association of the red meat metabolite score with T2D incidence (n = 1478) and other health endpoints. RESULTS: The best-performing score was for red meat, comprising 139 metabolites which accounted for 17% of the explained variance of red meat consumption in the validation set. In the intervention, 11 top-ranked metabolites in the red meat metabolite score increased significantly after red meat consumption. In the EPIC-Norfolk study, the red meat metabolite score was associated with T2D incidence (adjusted HR per SD: 1.17; 95% CI: 1.10, 1.24). CONCLUSIONS: The red meat metabolite score derived and validated in this study contains metabolites directly derived from meat consumption and is associated with T2D risk. These findings suggest the potential for objective assessment of dietary components and their application for understanding diet-disease associations.The trial in Lyon, France, was registered at clinicaltrials.gov as NCT03354130.
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- 2022
6. Genetic architecture and shared mechanisms of common ‘neglected’ diseases
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Maik Pietzner, Spiros Denaxas, Summaira Yasmeen, Maria Wörheide, Hannah E. Schmidt, Burulça Uluvar, Aakash Nepal, Mine Koprulu, Julia Carrasco-Zanini, Matthias Arnold, Annika Vogt, Gabi Kastenmüller, Harry Hemingway, and Claudia Langenberg
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Many diseases with significant health burden and healthcare costs have been neglected in biomedical research, partly due to a lack of data. Here, we systematically harmonized >12 million primary care and hospitalisation health records from ∼440,000 UK Biobank participants into 1445 collated disease terms for genetic analyses. This included ∼200 diseases with >10,000 cases that are predominantly managed in primary care, like skin and non-serious infectious diseases. We quantify the heritability for these common diseases, identify novel loci with extreme effect sizes, and highlight novel roles of poorly characterised genes, e.g.PNLIPRP3as a sebaceous gland cell-specific gene for rosacea. We characterise the substantial regional pleiotropy with more than 300 independent genomic regions associated with multiple, often seemingly unrelated diseases and use these insights to generate a pan-genome disease network of shared disease loci to prioritise potential pathways contributing to multiple diseases and onset of multimorbidity. We demonstrate the value of primary care data to improve and guide genetic approaches for drug selection, repurposing, and adverse event prediction, e.g.,IGFR1as a putative multi-disease target for, among others, gout and atrial fibrillation, through network augmentation and integration of molecular quantitative trait loci. We make all results publicly available via an interactive webserver (https://www.omicscience.org/apps/phecodes). Our results provide new insights for diseases across diverse clinical specialties and provide a resource for drug discovery and mechanistic understanding.
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- 2023
7. Identifying therapeutic targets for cancer: 2,094 circulating proteins and risk of nine cancers
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Karl Smith-Byrne, Åsa Hedman, Marios Dimitriou, Trishna Desai, Alexandr V. Sokolov, Helgi B. Schioth, Mine Koprulu, Maik Pietzner, Claudia Langenberg, Joshua Atkins, Ricardo Cortez, James McKay, Paul Brennan, Sirui Zhou, Brent J. Richards, James Yarmolinsky, Richard M. Martin, Joana Borlido, Xinmeng J. Mu, Adam Butterworth, Xia Shen, Jim Wilson, Themistocles L. Assimes, Rayjean J. Hung, Christopher Amos, Mark Purdue, Nathaniel Rothman, Stephen Chanock, Ruth C. Travis, Mattias Johansson, and Anders Mälarstig
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BackgroundUnderstanding the role of circulating proteins in cancer risk can reveal key biological pathways and identify novel therapeutic targets for cancer prevention.MethodsWe investigated the associations of 2,094 circulating proteins with risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) usingcispQTL Mendelian randomisation (MR) and colocalization. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalization were replicated using an independent cancer GWAS. Additionally, MR and colocalization phenome-wide association analyses (PHEWAS) were conducted to identify potential adverse side-effects of altering risk proteins. Finally, we mapped cancer risk proteins to drug and ongoing clinical trials targets.ResultsWe identified 40 proteins associated with cancer risk, of which a majority replicated and were novel. Among these were proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment (OR): 2.27, 95% CI: 1.88 to 2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [OR: 0.79, 95% CI: 0.73 to 0.85]. PHEWAS highlighted multiple links between proteins and potential adverse effects of protein-altering interventions. Additionally, 18 proteins associated with cancer risk mapped to existing therapeutic interventions, while 15 were not currently known to be under clinical investigation, such as GAS1 and triple negative breast cancer [OR: 1.88, 95% CI: 1.42 to 2.47].ConclusionOur findings emphasize the importance of proteomics for improving our understanding of cancer aetiology. Additionally, we demonstrate the benefit of in-depth protein PHEWAS analyses on risk proteins to identify potential adverse side-effects of protein-altering interventions. Using these methods, we identify a subset of risk proteins as potential drug targets for the prevention and treatment of cancer as well as opportunities for drug repurposing.
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- 2023
8. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
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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
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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.
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- 2023
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9. COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis
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Satoshi Yoshiji, Tianyuan Lu, Guillaume Butler-Laporte, Julia Carrasco-Zanini-Sanchez, Yiheng Chen, Kevin Liang, Julian Daniel Sunday Willett, Chen-Yang Su, Shidong Wang, Darin Adra, Yann Ilboudo, Takayoshi Sasako, Vincenzo Forgetta, Yossi Farjoun, Hugo Zeberg, Sirui Zhou, Michael Hultström, Mitchell Machiela, Nicholas J. Wareham, Vincent Mooser, Nicholas J. Timpson, Claudia Langenberg, and J. Brent Richards
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Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity has broad effects on circulating protein levels, we investigated circulating proteins that mediate the effects of obesity on coronary artery disease (CAD), stroke, and type 2 diabetes—since doing so may prioritize targets for therapeutic intervention. By integrating proteome-wide Mendelian randomization (MR) screening 4,907 plasma proteins, colocalization, and mediation analyses, we identified seven plasma proteins, including collagen type VI α3 (COL6A3). COL6A3 was strongly increased by body mass index (BMI) (β= 0.32, 95% CI: 0.26–0.38,P= 3.7 × 10-8per s.d. increase in BMI) and increased the risk of CAD (OR = 1.47, 95% CI:1.26–1.70,P= 4.5 × 10-7per s.d. increase in COL6A3). Notably, COL6A3 is cleaved at its C-terminus to produce endotrophin, which was found to mediate this effect on CAD. In single-cell RNA sequencing of adipose tissues and coronary arteries,COL6A3was highly expressed in cell types involved in metabolic dysfunction and fibrosis. Finally, we found that body fat reduction can reduce plasma levels of COL6A3-derived endotrophin, thereby highlighting a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effect of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target.
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- 2023
10. Lowering of circulating sclerostin may increase risk of atherosclerosis and its risk factors: evidence from a genome‐wide association meta‐analysis followed by Mendelian randomization
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Jie Zheng, Eleanor Wheeler, Maik Pietzner, Till F.M. Andlauer, Michelle S. Yau, April E. Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatelj, Kaare M. Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia A Peyser, Maryam Kavousi, Paul S. de Vries, Clint L. Miller, Maxime Bos, Sander W. van der Laan, Rajeev Malhotra, Markus Herrmann, Hubert Scharnagl, Marcus Kleber, George Dedoussis, Eleftheria Zeggini, Maria Nethander, Claes Ohlsson, Mattias Lorentzon, Nick Wareham, Claudia Langenberg, Michael V. Holmes, George Davey Smith, and Jonathan H. Tobias
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Rheumatology ,Immunology ,Immunology and Allergy - Published
- 2023
11. Lowering of circulating sclerostin may increase risk of atherosclerosis and its risk factors: evidence from a genome-wide association meta-analysis followed by Mendelian randomization
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Jie Zheng, Eleanor Wheeler, Maik Pietzner, Till Andlauer, Michelle Yau, April E. Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatel, Kaare M Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia A Peyser, Maryam Kavousi, Paul S. de Vries, Clint L. Miller, Maxime Bos, Sander W. van der Laan, Rajeev Malhotra, Markus Herrmann, Hubert Scharnagl, Marcus Kleber, George Dedoussis, Eleftheria Zeggini, Maria Nethander, Claes Ohlsson, Mattias Lorentzon, Nick Wareham, Claudia Langenberg, Michael V. Holmes, George Davey Smith, Jonathan H. Tobias, Zheng, Jie [0000-0002-6623-6839], Yau, Michelle S [0000-0002-0445-6334], Hartley, April E [0000-0003-4932-1588], Frysz, Monika [0000-0001-5729-778X], Prijatelj, Vid [0000-0002-9463-3962], Scharnagl, Hubert [0000-0002-2750-006X], Zeggini, Eleftheria [0000-0003-4238-659X], and Apollo - University of Cambridge Repository
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3204 Immunology ,2 Aetiology ,Aging ,Heart Disease ,Prevention ,Human Genome ,Genetics ,2.1 Biological and endogenous factors ,32 Biomedical and Clinical Sciences ,Atherosclerosis ,Cardiovascular ,3202 Clinical Sciences ,Heart Disease - Coronary Heart Disease - Abstract
Sclerostin inhibition is a new therapeutic approach for increasing bone mineral density (BMD) but its cardiovascular safety is unclear. We conducted a genome-wide association study (GWAS) meta-analysis of circulating sclerostin in 33,961 Europeans followed by Mendelian randomization (MR) to estimate the causal effects of sclerostin on 15 atherosclerosis-related diseases and risk factors. GWAS meta-analysis identified 18 variants independently associated with sclerostin, which including a novel cis signal in the SOST region and three trans signals in B4GALNT3, RIN3 and SERPINA1 regions that were associated with opposite effects on circulating sclerostin and eBMD. MR combining these four SNPs suggested lower sclerostin increased hypertension risk (odds ratio [OR]=1.09, 95%CI=1.04 to 1.15), whereas bi-directional analyses revealed little evidence for an effect of genetic liability to hypertension on sclerostin levels. MR restricted to cis (SOST) SNPs additionally suggested sclerostin inhibition increased risk of type 2 diabetes (T2DM) (OR=1.26; 95%CI=1.08 to 1.48) and myocardial infarction (MI) (OR=1.31, 95% CI=1.183 to 1.45). Furthermore, these analyses suggested sclerostin inhibition increased coronary artery calcification (CAC) (β=0.74, 95%CI=0.33 to 1.15), levels of apoB (β=0.07; 95%CI=0.04 to 0.10; this result was driven by rs4793023) and triglycerides (β=0.18; 95%CI=0.13 to 0.24), and reduced HDL-C (β=-0.14; 95%CI=-0.17 to -0.10). This study provides genetic evidence to support a causal effect of sclerostin inhibition on increased hypertension risk. Cis-only analyses suggested that sclerostin inhibition additionally increases the risk of T2DM, MI, CAC, and an atherogenic lipid profile. Together, our findings reinforce the requirement for strategies to mitigate against adverse effects of sclerostin inhibitors like romosozumab on atherosclerosis and its related risk factors.
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- 2023
12. Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites
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Lorenzo Bomba, Klaudia Walter, Qi Guo, Praveen Surendran, Kousik Kundu, Suraj Nongmaithem, Mohd Anisul Karim, Isobel D. Stewart, Claudia Langenberg, John Danesh, Emanuele Di Angelantonio, David J. Roberts, Willem H. Ouwehand, Ian Dunham, Adam S. Butterworth, and Nicole Soranzo
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Gene Frequency ,Whole Genome Sequencing ,Exome Sequencing ,Genetics ,Humans ,Exome ,Prospective Studies ,Genetics (clinical) - Abstract
Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.
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- 2022
13. Physical activity attenuates but does not eliminate coronary heart disease risk amongst adults with risk factors: EPIC-CVD case-cohort study
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Melony C Fortuin-de Smidt, Maquins Odhiambo Sewe, Camille Lassale, Elisabete Weiderpass, Jonas Andersson, José María Huerta, Ulf Ekelund, Krasimira Aleksandrova, Tammy YN Tong, Christina C Dahm, Anne Tjønneland, Cecilie Kyrø, Karen Steindorf, Matthias B Schulze, Verena Katzke, Carlotta Sacerdote, Claudia Agnoli, Giovanna Masala, Rosario Tumino, Salvatore Panico, Jolanda MA Boer, N Charlotte Onland-Moret, GC Wanda Wendel-Vos, Yvonne T van der Schouw, Kristin Benjaminsen Borch, Antonio Agudo, Dafina Petrova, María Dolores Chirlaque, Moreno Iribas Conchi, Pilar Amiano, Olle Melander, Alicia K Heath, Dagfinn Aune, Nita G Forouhi, Claudia Langenberg, Soren Brage, Elio Riboli, Nicholas J Wareham, John Danesh, Adam S Butterworth, Patrik Wennberg, Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Brage, Soren [0000-0002-1265-7355], Wareham, Nicholas [0000-0003-1422-2993], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
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Adult ,Cardiac & Cardiovascular Systems ,population preventable fraction ,Epidemiology ,Hypercholesterolemia ,QUESTIONNAIRE ,physical activity ,BLOOD-PRESSURE ,EXERCISE ,Coronary Disease ,ALL-CAUSE ,Cohort Studies ,Risk Factors ,Humans ,risk factors ,Obesity ,Prospective Studies ,coronary heart disease ,Exercise ,POPULATION ,Science & Technology ,Physical activity ,MORTALITY ,Incidence ,Public Health, Global Health, Social Medicine and Epidemiology ,ASSOCIATION ,PREVENTION ,case-cohort study ,Coronary heart disease ,Population preventable fraction ,Risk factors ,Case-cohort study ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,CARDIOVASCULAR-DISEASE ,Hypertension ,Cardiovascular System & Cardiology ,LIFE-STYLE ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine - Abstract
Aims This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. Methods and results EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal). Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32–64%] and 21% (95%CI 2–44%), with hypercholesterolaemia were 80% (95%CI 55–108%) and 48% (95%CI 22–81%), with hypertension were 80% (95%CI 65–96%) and 49% (95%CI 28–74%), with diabetes were 142% (95%CI 63–260%), and 100% (95%CI 32–204%), and amongst smokers were 152% (95%CI 122–186%) and 109% (95%CI 74–150%). Conclusions In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.
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- 2022
14. Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders
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Linda Repetto, Jiantao Chen, Zhijian Yang, Ranran Zhai, Paul Timmers, Ting Li, Emma Twait, Sebastian May-Wilson, Marisa Muckian, Bram Prins, Grace Png, Charles Kooperberg, Åsa Johansson, Robert Hillary, Eleanor Wheeler, Lu Pan, Yazhou He, Sofia Klasson, Shahzad Ahmad, James Peters, Arthur Gilly, Maria Karaleftheri, Emmanouil Tsafantakis, Jeffrey Haessler, Ulf Gyllensten, Sarah Harris, Nicholas Wareham, Andreas Göteson, Cecilia Lagging, M. Arfan Ikram, Cornelia van Duijn, Christina Jern, Mikael Landén, Claudia Langenberg, Ian Deary, Riccardo Marioni, Stefan Enroth, Alexander Reiner, George Dedoussis, Eleftheria Zeggini, Adam Butterworth, Anders Mälarstig, James Wilson, Pau Navarro, and Xia Shen
- Abstract
Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
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- 2023
15. Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases
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Corinne Carland, Grace Png, Anders Malarstig, Pik Fang Kho, Stefan Gustafsson, Karl Michaelsson, Lars Lind, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Anna Ramisch, Erin Macdonald-Dunlop, Lucija Klaric, Peter K. Joshi, Yan Chen, Hanna M. Björck, Per Eriksson, Julia Carrasco-Zanini, Eleanor Wheeler, Karsten Suhre, Arthur Gilly, Eleftheria Zeggini, Ana Viñuela, Emmanouil T. Dermitzakis, James F. Wilson, Claudia Langenberg, Gaurav Thareja, Anna Halama, Frank Schmidt, SCALLOP Consortium, Daniela Zanetti, and Themistocles Assimes
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Background: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. Methods: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. Results: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). Conclusion: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.
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- 2023
16. Genetic mechanisms of 184 neuro-related proteins in human plasma
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Linda Repetto, Jiantao Chen, Zhijian Yang, Ranran Zhai, Paul R. H. J. Timmers, Ting Li, Emma L. Twait, Sebastian May-Wilson, Marisa D. Muckian, Bram P. Prins, Grace Png, Charles Kooperberg, Åsa Johansson, Robert F. Hillary, Eleanor Wheeler, Lu Pan, Yazhou He, Sofia Klasson, Shahzad Ahmad, James E. Peters, Arthur Gilly, Maria Karaleftheri, Emmanouil Tsafantakis, Jeffrey Haessler, Ulf Gyllensten, Sarah E. Harris, Nicholas J. Wareham, Andreas Göteson, Cecilia Lagging, Mohammad Arfan Ikram, Cornelia M. van Duijn, Christina Jern, Mikael Landén, Claudia Langenberg, Ian J. Deary, Riccardo E. Marioni, Stefan Enroth, Alexander P. Reiner, George Dedoussis, Eleftheria Zeggini, Adam S. Butterworth, Anders Mälarstig, James F. Wilson, Pau Navarro, and Xia Shen
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Article - Abstract
Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein’s heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.
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- 2023
17. The impact of acute nutritional interventions on the plasma proteome
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Spyros I Vernardis, Vadim Demichev, Oliver Lemke, Nana-Maria Grüning, Christoph Messner, Matt White, Maik Pietzner, Alina Peluso, Tinh-Hai Collet, Elana Henning, Christoph Gille, Archie Campbell, Caroline Hayward, David J Porteous, Riccardo E Marioni, Michael Mülleder, Aleksej Zelezniak, Nicholas J Wareham, Claudia Langenberg, I Sadaf Farooqi, and Markus Ralser
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Chemical Biology & High Throughput ,Endocrinology ,Metabolism ,Ecology,Evolution & Ethology ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Synthetic Biology ,Biochemistry ,Computational & Systems Biology - Abstract
ContextHumans respond profoundly to changes in diet, while nutrition and environment have a great impact on population health. It is therefore important to deeply characterize the human nutritional responses.ObjectiveEndocrine parameters and the metabolome of human plasma are rapidly responding to acute nutritional interventions such as caloric restriction or a glucose challenge. It is less well understood whether the plasma proteome would be equally dynamic, and whether it could be a source of corresponding biomarkers.MethodsWe used high-throughput mass spectrometry to determine changes in the plasma proteome of i) 10 healthy, young, male individuals in response to 2 days of acute caloric restriction followed by refeeding; ii) 200 individuals of the Ely epidemiological study before and after a glucose tolerance test at 4 time points (0, 30, 60, 120 minutes); and iii) 200 random individuals from the Generation Scotland study. We compared the proteomic changes detected with metabolome data and endocrine parameters.ResultsBoth caloric restriction and the glucose challenge substantially impacted the plasma proteome. Proteins responded across individuals or in an individual-specific manner. We identified nutrient-responsive plasma proteins that correlate with changes in the metabolome, as well as with endocrine parameters. In particular, our study highlights the role of apolipoprotein C1 (APOC1), a small, understudied apolipoprotein that was affected by caloric restriction and dominated the response to glucose consumption and differed in abundance between individuals with and without type 2 diabetes.ConclusionOur study identifies APOC1 as a dominant nutritional responder in humans and highlights the interdependency of acute nutritional response proteins and the endocrine system.
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- 2023
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18. MC3R links nutritional state to childhood growth and the timing of puberty
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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
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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.
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- 2021
19. Identifying and visualising multimorbidity and comorbidity patterns in patients in the English National Health Service: a population-based study
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Valerie Kuan, Spiros Denaxas, Praveetha Patalay, Dorothea Nitsch, Rohini Mathur, Arturo Gonzalez-Izquierdo, Reecha Sofat, Linda Partridge, Amanda Roberts, Ian C K Wong, Melanie Hingorani, Nishi Chaturvedi, Harry Hemingway, Aroon D Hingorani, Daniel C Alexander, Innocent G Asiimwe, Simon Ball, Frances Bennett, Maria Carolina Borges, Adam Butterworth, Sandesh Chopade, Christopher Clarkson, Martin Cox, Caroline Dale, Diana Dunca, Jorgen E Engmann, Alba Fernandez-Sanles, Chris Finan, Natalie Fitzpatrick, Jean Gallagher, Jasmine Gratton, Christian Gross, Albert Henry, Mira Hidajat, Aroon Hingorani, Nikita Hukerikar, Andrea Jorgensen, Roshni Joshi, Michail Katsoulis, Rashmi Kumar, Alvina G Lai, Claudia Langenberg, Deborah Lawlor, Mary Mancini, Diane Miller, Margaret Ogden, Eda B Ozyigit, Shilpa Patel, Munir Pirmohamed, David Ryan, Amand F Schmidt, Anoop D Shah, Tina Shah, Rohan Takhar, Ana Torralbo, Ayath Ullah, Lauren E Walker, Alasdair Warwick, Eleanor Wheeler, Victoria L Wright, Honghan Wu, and Magdalena Zwierzyna
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Health Information Management ,Medicine (miscellaneous) ,Decision Sciences (miscellaneous) ,Health Informatics - Abstract
BACKGROUND: Globally, there is a paucity of multimorbidity and comorbidity data, especially for minority ethnic groups and younger people. We estimated the frequency of common disease combinations and identified non-random disease associations for all ages in a multiethnic population. METHODS: In this population-based study, we examined multimorbidity and comorbidity patterns stratified by ethnicity or race, sex, and age for 308 health conditions using electronic health records from individuals included on the Clinical Practice Research Datalink linked with the Hospital Episode Statistics admitted patient care dataset in England. We included individuals who were older than 1 year and who had been registered for at least 1 year in a participating general practice during the study period (between April 1, 2010, and March 31, 2015). We identified the most common combinations of conditions and comorbidities for index conditions. We defined comorbidity as the accumulation of additional conditions to an index condition over an individual's lifetime. We used network analysis to identify conditions that co-occurred more often than expected by chance. We developed online interactive tools to explore multimorbidity and comorbidity patterns overall and by subgroup based on ethnicity, sex, and age. FINDINGS: We collected data for 3 872 451 eligible patients, of whom 1 955 700 (50.5%) were women and girls, 1 916 751 (49.5%) were men and boys, 2 666 234 (68.9%) were White, 155 435 (4.0%) were south Asian, and 98 815 (2.6%) were Black. We found that a higher proportion of boys aged 1-9 years (132 506 [47.8%] of 277 158) had two or more diagnosed conditions than did girls in the same age group (106 982 [40.3%] of 265 179), but more women and girls were diagnosed with multimorbidity than were boys aged 10 years and older and men (1 361 232 [80.5%] of 1 690 521 vs 1 161 308 [70.8%] of 1 639 593). White individuals (2 097 536 [78.7%] of 2 666 234) were more likely to be diagnosed with two or more conditions than were Black (59 339 [60.1%] of 98 815) or south Asian individuals (93 617 [60.2%] of 155 435). Depression commonly co-occurred with anxiety, migraine, obesity, atopic conditions, deafness, soft-tissue disorders, and gastrointestinal disorders across all subgroups. Heart failure often co-occurred with hypertension, atrial fibrillation, osteoarthritis, stable angina, myocardial infarction, chronic kidney disease, type 2 diabetes, and chronic obstructive pulmonary disease. Spinal fractures were most strongly non-randomly associated with malignancy in Black individuals, but with osteoporosis in White individuals. Hypertension was most strongly associated with kidney disorders in those aged 20-29 years, but with dyslipidaemia, obesity, and type 2 diabetes in individuals aged 40 years and older. Breast cancer was associated with different comorbidities in individuals from different ethnic groups. Asthma was associated with different comorbidities between males and females. Bipolar disorder was associated with different comorbidities in younger age groups compared with older age groups. INTERPRETATION: Our findings and interactive online tools are a resource for: patients and their clinicians, to prevent and detect comorbid conditions; research funders and policy makers, to redesign service provision, training priorities, and guideline development; and biomedical researchers and manufacturers of medicines, to provide leads for research into common or sequential pathways of disease and inform the design of clinical trials. FUNDING: UK Research and Innovation, Medical Research Council, National Institute for Health and Care Research, Department of Health and Social Care, Wellcome Trust, British Heart Foundation, and The Alan Turing Institute.
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- 2022
20. Correction: The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals
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Maik Pietzner, Manishkumar Patel, Claudia Langenberg, and Nardin Rezk
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Clinical Biochemistry ,Molecular Medicine ,General Medicine ,Molecular Biology - Published
- 2022
21. Genome-wide association study identifiesADRA2AandIRX1as novel risk genes for Raynaud’s phenomenon
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Sylvia Hartmann, Summaira Yasmeen, Spiros Denaxas, Harry Hemingway, Maik Pietzner, and Claudia Langenberg
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BackgroundRaynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers in fingers and toes triggered by cold or emotional stress. Despite its high reported heritability, no causal genes have been robustly identified, limiting mechanistic understanding and treatment options.AimTo investigate the genetic architecture of RP to better understand its aetiology and identify new potential therapeutic targets.MethodsWe conducted a genome-wide association study including 9,084 RP cases and 435,357 controls, based on diagnoses from electronic health records, among participants of the UK Biobank study. We identified candidate causal variants and genes using Bayesian fine-mapping and colocalization with gene expression across 49 tissues. We performed phenome-wide association analyses for all significant RP loci and computed genetic correlations followed by latent causal variable analyses between RP and a total of 205 selected phenotypes.ResultsWe identified eight unreported genomic regions associated with the risk of RP atp<5×10−8and assignedADRA2A(rs7090046, odds ratio (OR) per allele: 1.27; 95%-CI: 1.23-1.31; p−47) andIRX1(rs11748327, OR: 1.20; 95%-CI: 1.16-1.23, p−28) as the candidate causal genes at the two strongest loci. Higher expression ofADRA2Ain tibial artery andIRX1in skeletal muscle was thereby associated with a higher RP risk. We identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG=-0.12; p-value=0.01), while significant positive genetic correlations with reported comorbidities like migraine, depression, or peripheral artery disease are likely explained by shared risk factors.ConclusionOur results provide the first robust evidence for a strong genetic contribution to RP, highlighting a so far underrated role of α2A-adrenoreceptor signalling, encoded atADRA2A, as an important mechanism for hypersensitivity to catecholamine-induced vasospasms even at thermoneutral conditions.
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- 2022
22. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes
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Eugene J. Gardner, Katherine A. Kentistou, Stasa Stankovic, Samuel Lockhart, Eleanor Wheeler, Felix R. Day, Nicola D. Kerrison, Nicholas J. Wareham, Claudia Langenberg, Stephen O'Rahilly, Ken K. Ong, John R.B. Perry, Gardner, EJ [0000-0001-9671-1533], and Apollo - University of Cambridge Repository
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UK Biobank ,IGF1 ,Genetics ,Mendelian randomization ,exome-wide association study ,type 2 diabetes ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Abstract
Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency < 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (GCK, GIGYF1, HNF1A) in addition to missense variants in ZEB2 (n = 31 carriers; odds ratio [OR] = 5.5 [95% confidence interval = 2.5-12.0]; p = 6.4 × 10-7), MLXIPL (n = 245; OR = 2.3 [1.6-3.2]; p = 3.2 × 10-7), and IGF1R (n = 394; OR = 2.4 [1.8-3.2]; p = 1.3 × 10-10). Carriers of damaging missense variants within IGF1R were also shorter (-2.2 cm [-1.8 to -2.7]; p = 1.2 × 10-19) and had higher circulating insulin-like growth factor-1 (IGF-1) protein levels (2.3 nmol/L [1.7-2.9]; p = 2.8 × 10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance was supported by Mendelian randomization analyses using common variants. These results increase understanding of the genetic architecture of T2D and highlight the growth hormone/IGF-1 axis as a potential therapeutic target.
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- 2022
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23. Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region
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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
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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.
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- 2021
24. Detection and characterization of male sex chromosome abnormalities in the UK Biobank study
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Yajie Zhao, Eugene J. Gardner, Marcus A. Tuke, Huairen Zhang, Maik Pietzner, Mine Koprulu, Raina Y. Jia, Katherine S. Ruth, Andrew R. Wood, Robin N. Beaumont, Jessica Tyrrell, Samuel E. Jones, Hana Lango Allen, Felix R. Day, Claudia Langenberg, Timothy M. Frayling, Michael N. Weedon, John R.B. Perry, Ken K. Ong, Anna Murray, Zhao, Yajie [0000-0002-2747-0219], Lango Allen, Hana [0000-0002-7803-8688], Langenberg, Claudia [0000-0002-5017-7344], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Joint Activities, and University of Helsinki
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Male ,Disorders of sexual development ,1184 Genetics, developmental biology, physiology ,Thrombosis ,Type 2 diabetes ,XYY ,KLINEFELTER-SYNDROME ,United Kingdom ,Endocrinology ,Klinefelter Syndrome ,Diabetes Mellitus, Type 2 ,XYY Karyotype ,47,XYY ,Humans ,3111 Biomedicine ,Genetics (clinical) ,Sex Chromosome Aberrations ,Biological Specimen Banks - Abstract
Purpose: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. Methods: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. Results: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 x 10(-8)), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P Conclusion: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
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- 2022
25. ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19
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Maik Pietzner, Robert Lorenz Chua, Eleanor Wheeler, Katharina Jechow, Julian D. S. Willett, Helena Radbruch, Saskia Trump, Bettina Heidecker, Hugo Zeberg, Frank L. Heppner, Roland Eils, Marcus A. Mall, J. Brent Richards, Leif-Erik Sander, Irina Lehmann, Sören Lukassen, Nicholas J. Wareham, Christian Conrad, Claudia Langenberg, Pietzner, Maik [0000-0003-3437-9963], Wheeler, Eleanor [0000-0002-8616-6444], Radbruch, Helena [0000-0001-6941-3397], Zeberg, Hugo [0000-0001-7118-1249], Heppner, Frank L [0000-0001-9816-8917], Mall, Marcus A [0000-0002-4057-2199], Richards, J Brent [0000-0002-3746-9086], Sander, Leif-Erik [0000-0002-0476-9947], Lukassen, Sören [0000-0001-7045-6327], Wareham, Nicholas J [0000-0003-1422-2993], Conrad, Christian [0000-0001-7036-342X], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
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Respiratory System ,45/43 ,General Physics and Astronomy ,genetics [DNA-Binding Proteins] ,Peptidyl-Dipeptidase A ,General Biochemistry, Genetics and Molecular Biology ,82/80 ,692/699/255/2514 ,ELF5 protein, human ,Humans ,genetics [COVID-19] ,metabolism [Peptidyl-Dipeptidase A] ,metabolism [Epithelial Cells] ,49/91 ,genetics [Angiotensin-Converting Enzyme 2] ,Multidisciplinary ,SARS-CoV-2 ,article ,COVID-19 ,Epithelial Cells ,General Chemistry ,631/208/205 ,genetics [Transcription Factors] ,692/4017 ,DNA-Binding Proteins ,ddc:500 ,Angiotensin-Converting Enzyme 2 ,692/499 ,Transcription Factors - Abstract
Funder: Wellcome Trust, Funder: National Institute for Health Research (NIHR), Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.
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- 2022
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26. Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization
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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
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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
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- 2022
27. Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease
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Nick Shrine, Abril G Izquierdo, Jing Chen, Richard Packer, Robert J Hall, Anna L Guyatt, Chiara Batini, Rebecca J Thompson, Chandan Pavuluri, Vidhi Malik, Brian D Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y Millwood, Zhengming Chen, Liming Li, Sara RA Wielscher, Lies Lahousse, Guy Brusselle, Andre G Uitterlinden, Ani Manichaikul, Elizabeth C Oelsner, Stephen S Rich, R. Graham Barr, Shona M Kerr, Veronique Vitart, Michael R Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M Bartz, Sina A Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E Ortega, Deborah A Meyers, Eugene R Bleecker, Stacey B Gabriel, Namrata Gupta, Albert Vernon Smith, Jian’an Luan, Jing-Hua Zhao, Ailin F Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T O’Connor, Gaurav Thareja, Omar M E., Hamdi Mbarek, Karsten Suhre, Raquel Granell, Tariq O Faquih, Pieter S Hiemstra, Annelies M Slats, Benjamin H Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T Koskela, Annah B Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A Kentistou, Peter K Joshi, Paul RHJ Timmers, Alexander T Williams, Robert C Free, Xueyang Wang, John L Morrison, Frank D Gilliland, Zhanghua Chen, Carol A Wang, Rachel E Foong, Sarah E Harris, Adele Taylor, Paul Redmond, James P Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H Pietiläinen, Simon R Cox, Craig E Pennell, Graham L Hall, W. James Gauderman, Chris Brightling, James F Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O Mook-Kanamori, Nicholas J Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo-Riitta Jarvelin, Alanna C Morrison, Ozren Polasek, Igor Rudan, Joo-Hyeon Lee, Ian Sayers, Emma L Rawlins, Frank Dudbridge, Edwin K Silverman, David P Strachan, Robin G Walters, Andrew P Morris, Stephanie J London, Michael H Cho, Louise V Wain, Ian P Hall, and Martin D Tobin
- Abstract
Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
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- 2022
28. MO048: Genome-wide studies reveal factors associated with circulating uromodulin and its relations with complex diseases
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Yong LI, Yurong Cheng, Francesco Consolato, Guglielmo Schiano, Michael Chong, Maik Pietzner, Ngoc Quynh Nguyen, Nora Scherer, Mary Biggs, Marcus E Kleber, Stefan Haug, Burulça Göçmen, Marie Pigeyre, Peggy Sekula, Inga Steinbrenner, Pascal Schlosser, Christina Joseph, Jennifer Brody, Morgan Grams, Caroline Hayward, Ulla T Schultheiß, Bernhard Kraemer, Florian Kronenberg, Annette Peters, Jochen Seissler, Dominik Steubl, Cornelia Then, Matthias Wuttke, Winfried Maerz, Kai-Uwe Eckardt, Christian Gieger, Eric Boerwinkle, Bruce Psaty, Josef Coresh, Peter Oefner, Guillaume Pare, Claudia Langenberg, Juergen E Scherberich, Bing Yu, Shreeram Akilesh, Olivier Devuyst, Luca Rampoldi, and Anna Köttgen
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Transplantation ,Nephrology - Abstract
BACKGROUND AND AIMS UMOD is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is the most abundant protein in urine and related to chronic kidney disease, hypertension and pathogen defense. Through basolateral release from kidney epithelial cells, uromodulin also reaches the blood, where its function is largely unknown. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin in seven cohorts using two complementary assays. METHOD Separate genome-wide association study meta-analyses for circulating uromodulin were conducted for the antibody-based assay (five cohorts, N = 13 985) and the aptamer-based SOMAscan assay (two cohorts, N = 18 070). Genome-wide significant loci were placed into their functional genomic context using RNA-seq, ATAC-seq and Hi-C data generated from primary human kidney tissue. An array of downstream genetic analyses was then performed for significant loci, including fine-mapping, colocalization analyses and gene-by-gene interaction analyses. The B4GALNT2 p.Cys466Arg allele was expressed in MDCK cells and studied by immunofluorescence and Western blotting analyses. RESULTS We detected and replicated 13 genome-wide significant loci (P CONCLUSION This study provides human genetic evidence of new pathway members of uromodulin and delivers novel insights into its determinants and systemic role in the circulation.
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- 2022
29. Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study
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Jian Zhao, Isobel D Stewart, Denis Baird, Dan Mason, John Wright, Jie Zheng, Tom R Gaunt, David M Evans, Rachel M Freathy, Claudia Langenberg, Nicole M Warrington, Deborah A Lawlor, and Maria Carolina Borges
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Abstract
Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomization and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms (SNPs) robustly associated with 19 amino acids (p < 4.9 × 10−10) were used as genetic instrumental variables. Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per SD increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (−59 g, 95% CI: -106, -11) and phenylalanine (−25 g, 95% CI: -47, -4) lower offspring birthweight. Our findings strengthen evidence for key roles of maternal circulating amino acids in healthy fetal growth.
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- 2022
30. Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
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Nicole Kosik, Nay Aung, Brian Ferolito, John Whittaker, Claudia Langenberg, Andrew Leach, and Gina Peloso
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We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D,PRKD1,PRKD3,MAPK3,TNFSF12,APOC3andNAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.
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- 2022
31. An atlas of genetic scores to predict multi-omic traits
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Yu Xu, Scott C. Ritchie, Yujian Liang, Paul R. H. J. Timmers, Maik Pietzner, Loïc Lannelongue, Samuel A. Lambert, Usman A. Tahir, Sebastian May-Wilson, Åsa Johansson, Praveen Surendran, Artika P Nath, Elodie Persyn, James E. Peters, Clare Oliver-Williams, Shuliang Deng, Bram Prins, Carles Foguet, Jian’an Luan, Lorenzo Bomba, Nicole Soranzo, Emanuele Di Angelantonio, Nicola Pirastu, E Shyong Tai, Rob M van Dam, Emma E Davenport, Dirk S. Paul, Christopher Yau, Robert E. Gerszten, Anders Mälarstig, John Danesh, Xueling Sim, Claudia Langenberg, James F. Wilson, Adam S. Butterworth, and Michael Inouye
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Genetically predicted levels of multi-omic traits can uncover the molecular underpinnings of common phenotypes in a highly efficient manner. Here, we utilised a large cohort (INTERVAL; N=50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, N=3,175; Olink, N=4,822), plasma metabolomics (Metabolon HD4, N=8,153), serum metabolomics (Nightingale, N=37,359), and whole blood Illumina RNA sequencing (N=4,136). We used machine learning to train genetic scores for 17,227 molecular traits, including 10,521 which reached Bonferroni-adjusted significance. We evaluated genetic score performances in external validation across European, Asian and African American ancestries, and assessed their longitudinal stability within diverse individuals. We demonstrated the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of UK Biobank to identify disease associations using a phenome-wide scan. Finally, we developed a portal (OmicsPred.org) to facilitate public access to all genetic scores and validation results as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
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- 2022
32. Damaging missense variants in
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Eugene J, Gardner, Katherine A, Kentistou, Stasa, Stankovic, Samuel, Lockhart, Eleanor, Wheeler, Felix R, Day, Nicola D, Kerrison, Nicholas J, Wareham, Claudia, Langenberg, Stephen, O'Rahilly, Ken K, Ong, and John R B, Perry
- Abstract
Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (
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- 2022
33. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma
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Priyadarshini Kachroo, Isobel D. Stewart, Rachel S. Kelly, Meryl Stav, Kevin Mendez, Amber Dahlin, Djøra I. Soeteman, Su H. Chu, Mengna Huang, Margaret Cote, Hanna M. Knihtilä, Kathleen Lee-Sarwar, Michael McGeachie, Alberta Wang, Ann Chen Wu, Yamini Virkud, Pei Zhang, Nicholas J. Wareham, Elizabeth W. Karlson, Craig E. Wheelock, Clary Clish, Scott T. Weiss, Claudia Langenberg, Jessica A. Lasky-Su, Kachroo, Priyadarshini [0000-0002-5807-1333], Kelly, Rachel S [0000-0003-3023-1822], Stav, Meryl [0000-0001-6565-3617], Cote, Margaret [0000-0001-8079-7221], Lee-Sarwar, Kathleen [0000-0003-0550-1640], Wareham, Nicholas J [0000-0003-1422-2993], Clish, Clary [0000-0001-8259-9245], Langenberg, Claudia [0000-0002-5017-7344], Lasky-Su, Jessica A [0000-0001-6236-4705], and Apollo - University of Cambridge Repository
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Adrenal Cortex Hormones ,Administration, Inhalation ,Humans ,General Medicine ,General Economics, Econometrics and Finance ,General Biochemistry, Genetics and Molecular Biology ,health care economics and organizations ,Asthma - Abstract
The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.
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- 2022
34. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
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David R. Morrison, Elsa Brunet-Ratnasingham, Marc Afilalo, Nardin Rezk, Michael Hultström, Maik Pietzner, Hugo Zeberg, Tala Abdullah, Nicola D. Kerrison, Daniel Kaufmann, Celia M. T. Greenwood, Tomoko Nakanishi, Guillaume Butler-Laporte, Elin Thysell, Claudia Langenberg, Kaiqiong Zhao, Danielle Henry, Michaël Chassé, Vincenzo Forgetta, Madeleine Durand, Miklos Lipcsey, Clare Paterson, Michael Pollak, Jonathan Afilalo, Yiheng Chen, Vincent Mooser, Xiaoqing Xue, Zaman Afrasiabi, Louis Petitjean, Meriem Bouab, J. Brent Richards, Johan Normark, Branka Vulesevic, Nofar Kimchi, Charlotte Guzman, Noor Almamlouk, Chris Tselios, Sirui Zhou, Robert Frithiof, Olumide Adeleye, and Laetitia Laurent
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0301 basic medicine ,Innate immune system ,business.industry ,Confounding ,Case-control study ,Mendelian Randomization Analysis ,General Medicine ,Odds ratio ,Quantitative trait locus ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Severity of illness ,Mendelian randomization ,Immunology ,Medicine ,business - Abstract
To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.
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- 2021
35. A cross-platform approach identifies genetic regulators of human metabolism and health
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Kay-Tee Khaw, Angela M. Wood, Julian L. Griffin, Gabi Kastenmüller, Fiona M. Gribble, Adam S. Butterworth, Luca A. Lotta, Verena Zuber, Chen Li, Victoria P W Auyeung, Johannes Raffler, Isobel D. Stewart, Nita G. Forouhi, Jian'an Luan, Nicholas J. Wareham, Claudia Langenberg, Maik Pietzner, Laura B. L. Wittemans, Eleanor Wheeler, Robert A. Scott, Roberto Bonelli, John Danesh, Frank Reimann, Praveen Surendran, Stephen Burgess, Ellie Paige, Clare Oliver-Williams, Albert Koulman, Fumiaki Imamura, Eric B. Fauman, Gregory A. Michelotti, Melanie Bahlo, Eleanor Sanderson, and Emma K. Biggs
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Nonsynonymous substitution ,0303 health sciences ,Mechanism (biology) ,Genome-wide association study ,Computational biology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Pleiotropy ,Mendelian randomization ,Genetics ,Genetic Pleiotropy ,Metabolome ,Allelic heterogeneity ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
In cross-platform analyses of 174 metabolites, we identify 499 associations (P
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- 2021
36. Author Correction: Proteogenomic links to human metabolic diseases
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Mine Koprulu, Julia Carrasco-Zanini, Eleanor Wheeler, Sam Lockhart, Nicola D. Kerrison, Nicholas J. Wareham, Maik Pietzner, and Claudia Langenberg
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Physiology (medical) ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Cell Biology - Published
- 2023
37. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes
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Eugene J. Gardner, Katherine A. Kentistou, Stasa Stankovic, Samuel Lockhart, Eleanor Wheeler, Felix R. Day, Nicola D. Kerrison, Nicholas J. Wareham, Claudia Langenberg, Stephen O’Rahilly, Ken K. Ong, and John R. B. Perry
- Abstract
Type 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9×10-7) with rare, damaging variants within previously identified genes including GCK, GIGYF1, HNF1A, and TNRC6B. In addition, individuals with rare, damaging missense variants in the genes ZEB2 (N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4×10-7), MLXIPL (N=245; OR=2.3 [1.6-3.2]; p=3.2×10-7), and IGF1R (N=394; OR=2.4 [1.8-3.2]; p=1.3×10-10) have higher risk of T2D. Carriers of damaging missense variants within IGF1R were also shorter (-2.2cm [-1.8-2.7]; p=1.2×10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8×10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis.
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- 2022
38. Genome-wide analysis in over 1 million individuals reveals over 2,000 independent genetic signals for blood pressure
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Helen Warren, Todd Edwards, Ahmad Vaez, Jacob Keaton, Zoha Kamali, Tian Xie, Alireza Ani, Evangelos Evangelou, Jacklyn Hellwege, Loïc Yengo, William Young, Matthew Traylor, Ayush Giri, Peter Visscher, Daniel Chasman, Andrew Morris, Mark Caulfield, Shih-Jen Hwang, Jaspal Kooner, David Conen, John Attia, Alanna Morrison, Ruth Loos, Kati Kristiansson, Reinhold Schmidt, Andrew Hicks, Peter Pramstaller, Christopher Nelson, Nilesh Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriëtte Riese, James Wilson, Harry Campbell, Bruce Psaty, Yingchang Lu, Jerome Rotter, Xiuqing Guo, Kenneth Rice, Peter Vollenweider, Johan Sundstrom, Claudia Langenberg, Martin Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim van der Harst, Paul Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah Harris, Ian Deary, Peter van der Most, Albertine Oldehinkel, Bernard Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Jarvelin, Annette Peters, Christian Gieger, Edward Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin de Borst, Ozren Polasek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli Raitakari, Andrew Johnson, Christopher Newton-Cheh, Morris Brown, Anna Dominiczak, Peter Sever, Neil Poulter, John Chambers, Roberto Elosua, David Siscovick, Tōnu Esko, Andres Metspalu, Rona Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco de Geus, Colin Palmer, Ilja Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna Howson, Christopher O'Donnell, Tim Spector, Mike Nalls, Eleanor Simonsick, Yongmei Liu, Cornelia van Duijn, Adam Butterworth, John Danesh, Cristina Menni, Nick Wareham, Kay Khaw, Joshua Denny, Daniel Levy, Patricia Munroe, and Harold Snieder
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Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P − 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
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- 2022
39. The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses
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Kurt Taylor, Nancy McBride, Jian Zhao, Sam Oddie, Rafaq Azad, John Wright, Ole A. Andreassen, Isobel D Stewart, Claudia Langenberg, Maria Magnus, Maria Carolina Borges, Massimo Caputo, Deborah A Lawlor, Taylor, Kurt [0000-0003-4690-063X], Oddie, Sam [0000-0001-8701-4912], Andreassen, Ole A [0000-0002-4461-3568], and Apollo - University of Cambridge Repository
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Born in Bradford ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics ,ALSPAC ,MoBa ,congenital heart disease ,metabolites - Abstract
BackgroundIt is plausible that maternal pregnancy metabolism influences risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data.MethodsWe undertook multivariable logistic regression of the odds of CHD for 923 Mass Spectrometry (MS)-derived metabolites in a sub-sample of a UK birth cohort (Born in Bradford (BiB); N = 2,605, 46 CHD cases). We considered metabolites reaching a p-value threshold ResultsIn the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. MR analyses were possible for 27/44 metabolites and for 11 there was consistency with multivariable regression results.ConclusionsIn summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that amino acid metabolism during pregnancy, several lipids (more specifically androgenic steroids), and levels of succinylcarnitine could be important contributing factors for CHD.
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- 2022
40. A Saturated Map of Common Genetic Variants Associated with Human Height from 5.4 Million Individuals of Diverse Ancestries
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Rajkumar Dorajoo, Ozren Polasek, Stefania Bandinelli, Jette Bork-Jensen, Maria Knol, Claudia Langenberg, Stavroula Kanoni, Mika Kähönen, Bernhard Banas, Katherine Kentistou, Sailaja Vedantam, Gregory Marcus, Alicia Huerta-Chagoya, Yvonne Golightly, Deborah Malden, Claes Ohlsson, Loic Yengo, Petra Elders, Dharambir Sanghera, Masato Akiyama, Saori Sakaue, Eirini Marouli, Zi-Bing Jin, and Maria Sabater Lleal
- Abstract
Common SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here we show, using GWAS data from 5.4 million individuals of diverse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants.
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- 2022
41. Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases
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Yong Li, Yurong Cheng, Francesco Consolato, Guglielmo Schiano, Michael R. Chong, Maik Pietzner, Ngoc Quynh H. Nguyen, Nora Scherer, Mary L. Biggs, Marcus E. Kleber, Stefan Haug, Burulça Göçmen, Marie Pigeyre, Peggy Sekula, Inga Steinbrenner, Pascal Schlosser, Christina B. Joseph, Jennifer A. Brody, Morgan E. Grams, Caroline Hayward, Ulla T. Schultheiss, Bernhard K. Krämer, Florian Kronenberg, Annette Peters, Jochen Seissler, Dominik Steubl, Cornelia Then, Matthias Wuttke, Winfried März, Kai-Uwe Eckardt, Christian Gieger, Eric Boerwinkle, Bruce M. Psaty, Josef Coresh, Peter J. Oefner, Guillaume Pare, Claudia Langenberg, Jürgen E. Scherberich, Bing Yu, Shreeram Akilesh, Olivier Devuyst, Luca Rampoldi, Anna Köttgen, Pietzner, Maik [0000-0003-3437-9963], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
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ddc:610 ,Population genetics ,Chronic kidney disease ,Genetics ,Nephrology ,610 Medizin ,Blood Pressure ,General Medicine ,FOS: Biological sciences ,Hypertension ,Uromodulin ,Humans ,Renal Insufficiency, Chronic ,Genome-Wide Association Study - Abstract
UMOD is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based (N=13,985) and aptamer-based (N=18,070) assays. We detected 3 and 10 distinct significant (p
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- 2022
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42. Plasma protein patterns as comprehensive indicators of health
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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
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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.
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- 2019
43. Autoimmunity plays a role in the onset of diabetes after 40 years of age
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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 für 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
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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.
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- 2019
44. Physical activity and sedentary behavior; mechanistic insights and role in disease prevention
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Marcel den Hoed, Zhe Wang, Andrew Emmerich, Nicolas Pillon, Timothy Moore, Daiane Hemerich, Marilyn Cornelis, Eugenia Mazzaferro, Siacia Broos, Adam Ameur, Stefania Bandinelli, Joshua Bis, Michael Boehnke, Claude Bouchard, Daniel Chasman, Eco de Geus, Louise Deldicque, Marcus Dörr, Michele Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo Horta, Elina Hypponen, W. Craig Johnson, Sharon Kardia, Lambertus Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik Magnusson, Nicholas Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari North, Claes Ohlsson, Albertine Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda Penninx, Tune Pers, Ozren Polasek, Inga Prokopenko, Charles Rotimi, Nilesh Samani, Xueling Sim, George Davey Smith, Harold Snieder, Thorkild Sorensen, Tim Spector, Nicholas Timpson, Rob van Dam, Nathalie van der Velde, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gerard Waeber, Nick Wareham, David Weir, Erich Wichmann, James Wilson, Andrea Hevener, Anna Krook, Juleen Zierath, Martine Thomis, and Ruth Loos
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Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 individuals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA); leisure screen time (LST); sedentary commuting; and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type IIA muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.
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- 2021
45. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
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Rajkumar Dorajoo, Ozren Polasek, Stefania Bandinelli, Joline Beulens, Jun Takayama, Jette Bork-Jensen, Blair Smith, Colin Palmer, Claudia Langenberg, Stavroula Kanoni, Mika Kähönen, Bernhard Banas, Katherine Kentistou, Alicia Huerta-Chagoya, Shweta Ramdas, Yvonne Golightly, Niek Verweij, Christian Fuchsberger, Claes Ohlsson, Petra Elders, Julia Ramírez, Masato Akiyama, Ida Surakka, Jun Liu, and Zi-Bing Jin
- Abstract
A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.
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- 2021
46. Synergistic insights into human health from aptamer- and antibody-based proteomic profiling
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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]
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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.
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- 2021
47. Mapping the proteo-genomic convergence of human diseases
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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
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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
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- 2021
48. Circulating proteins to predict adverse COVID-19 outcomes
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Edgar Gonzalez-Kozlova, David R. Morrison, Branka Vulesevic, Nofar Kimchi, Robert Marvin, Maik Pietzner, Zaman Afrasiabi, Kimberly Argueta, Louis Petitjean, Naomi Duggan, Ryan Thompson, Meriem Bouab, Manishkumar Patel, Kevin Tuballes, Ieisha Scott, J. Brent Richards, Mario A. Cedillo, Nicole W. Simons, Jocelyn Harris, Tala Abdullah, Claudia Langenberg, Danielle Henry, Vincenzo Forgetta, Daniel Kaufmann, Madeleine Durand, Chen-Yang Su Mr., Michael A Hinterberg, Elsa Brunet-Ratnasingham, Celia M. T. Greenwood, Miriam Merad, Wonseok Jeon, Alexander W. Charney, Sacha Gnjatic, Noam D. Beckmann, Xiaoqing Xue, Nicolas Zaki, Julia Carrasco-Zanini, Diane Marie Del Valle, Joelle Pineau, Esther Cheng, Tomoko Nakanishi, Olumide Adeleye, Kai Nie, Chantal DeLuca, Konstantinos Mouskas, Thomas U. Marron, Marc Afilalo, Guillaume Butler-Laporte, Yiheng Chen, Yossi Farjoun, Yara Moussa, Vincent Mooser, Eric E. Schadt, Clare Paterson, Noor Almamlouk, Chris Tselios, Nathalie Brassard, Sirui Zhou, Hui Xie, Ephraim Kenigsberg, Nardin Rezk, Seunghee Kim-Schulze, Laetitia Laurent, Charlotte Guzman, Erwin Schurr, and Joanthan Afilalo
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Oncology ,medicine.medical_specialty ,Receiver operating characteristic ,Coronavirus disease 2019 (COVID-19) ,business.industry ,medicine.medical_treatment ,Disease progression ,Age and sex ,Cytokine ,Internal medicine ,Cohort ,Medicine ,Generalizability theory ,business ,Predictive modelling - Abstract
Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.
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- 2021
49. Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment
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George Thanassoulis, James C. Engert, Haoyu Wu, Claudia Langenberg, Vincent Mooser, Vincenzo Forgetta, Nicholas J. Wareham, J. Brent Richards, and Jian'an Luan
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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.
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- 2021
50. Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution
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Mine Koprulu, Yajie Zhao, Eleanor Wheeler, Liang Dong, Nuno Rocha, Chen Li, John D Griffin, Satish Patel, Marcel Van de Streek, Craig A Glastonbury, Isobel D Stewart, Felix R Day, Jian’an Luan, Nicholas Bowker, Laura B L Wittemans, Nicola D Kerrison, Lina Cai, Debora M E Lucarelli, Inês Barroso, Mark I McCarthy, Robert A Scott, Vladimir Saudek, Kerrin S Small, Nicholas J Wareham, Robert K Semple, John R B Perry, Stephen O’Rahilly, Luca A Lotta, Claudia Langenberg, David B Savage, Koprulu, Mine [0000-0001-6870-4539], Langenberg, Claudia [0000-0002-5017-7344], Savage, David B [0000-0002-7857-7032], and Apollo - University of Cambridge Repository
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UK Biobank ,Endocrinology, Diabetes and Metabolism ,genetic variants ,Biochemistry (medical) ,Clinical Biochemistry ,Genetic Variation ,Biochemistry ,Endocrinology ,loss of function ,Diabetes Mellitus, Type 2 ,fat distribution ,cardiometabolic risk ,Body Fat Distribution ,Humans ,Exome ,Activin Receptors, Type I ,Genome-Wide Association Study - Abstract
Context Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly noncoding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function (LoF) would be of most therapeutic benefit. Objective This work aimed to identify genes/proteins involved in determining fat distribution. Methods We combined the power of genome-wide analysis of array-based rare, nonsynonymous variants in 450 562 individuals in the UK Biobank with exome-sequence-based rare LoF gene burden testing in 184 246 individuals. Results The data indicate that the LoF of 4 genes (PLIN1 [LoF variants, P = 5.86 × 10–7], INSR [LoF variants, P = 6.21 × 10–7], ACVR1C [LoF + moderate impact variants, P = 1.68 × 10–7; moderate impact variants, P = 4.57 × 10–7], and PDE3B [LoF variants, P = 1.41 × 10–6]) is associated with a beneficial effect on body mass index–adjusted waist-to-hip ratio and increased gluteofemoral fat mass, whereas LoF of PLIN4 (LoF variants, P = 5.86 × 10–7 adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B, and ACVR1C favorably affects metabolic phenotypes (eg, triglycerides [TGs] and high-density lipoprotein [HDL] cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes. Conclusion This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counterintuitive insight into the potential consequences of targeting these molecules therapeutically.
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- 2021
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