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

Author

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

Published
2023
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5. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, and Hattersley, Andrew T

Subjects
Clinical Research, Obesity, Genetics, Nutrition, Prevention, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Cardiovascular, Animals, Body Fat Distribution, Body Mass Index, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Male, Proteins, Risk Factors, Waist-Hip Ratio, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF

Published
2019

7. A systematic review of human evidence for the intergenerational effects of exposure to ionizing radiation.

Author

Stephens, Jade, Moorhouse, Alexander J., Craenen, Kai, Schroeder, Ewald, Drenos, Fotios, and Anderson, Rhona

Subjects
ABANDONED children, IONIZING radiation, RADIATION exposure, BOOLEAN searching, HUMAN abnormalities
Abstract

Purpose: To provide a synthesis of the published evidence pertaining to the intergenerational health effects of parental preconceptional exposure to ionizing radiation in humans. Methods: The study populations are the descendants of those who were exposed to ionizing radiation prior to conception. A Boolean search identified publications for review in accordance with Office of Health Assessment and Translation guidelines. Initially, a risk of bias assessment was conducted for each published study and relevant data extracted. Information was organized into adverse health outcome groups and exposure situations. To make an assessment from the body of evidence within each group, an initial confidence rating was assigned, before factors including inconsistencies between studies, magnitude of effect, dose response and confounders were considered. From this, 'an effect', 'no effect' or whether the evidence remained 'inadequate' to determine either effect or no effect, was ascertained. This assessment was based primarily upon the author's conclusions within that evidence-base and, by binomial probability testing of the direction of effect reported. Results: 2441 publications were identified for review which after screening was reduced to 127. For the majority of the adverse health groups, we find there to be inadequate evidence from which to determine whether the health effect was, or was not, associated with parental preconceptional radiation exposure. This was largely due to heterogeneity between individual study's findings and conclusions within each group and, the limited number of studies within each group. We did observe one health grouping (congenital abnormalities) in occupationally exposed populations, where an increase in effect relative to their controls or large magnitude of effects, were reported, although it is noted that the authors of these studies interpreted their findings as most likely not to be associated with parental radiation exposure. Conclusions: We find there to be a lack of evidence to enable the formal assessment of radiation-related adverse effects in offspring of exposed humans. This is not the same as there being no clear evidence that effects may occur but does infer that if adverse health effects do arise in children of exposed parents, then these effects are small and difficult to reproducibly measure. Inconsistencies in designing studies are unavoidable, however we highlight the need for an element of standardization and, more sharing of primary datasets as part of open access initiatives, in order for future reviews to make reasonable conclusions. Overall, there is a need for future work to ensure comparable measures between studies where possible. [ABSTRACT FROM AUTHOR]

Published
2024
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8. No Evidence That Vitamin D Levels or Deficiency Are Associated with the Risk of Open-Angle Glaucoma in Individuals of European Ancestry: A Mendelian Randomisation Analysis.

Author

Kanso, Nour, Hashimi, Munisa, Amin, Hasnat A., Day, Alexander C., and Drenos, Fotios

Subjects
VITAMIN D deficiency, VITAMIN D metabolism, RETINAL ganglion cells, OPEN-angle glaucoma, SINGLE nucleotide polymorphisms
Abstract

Background: Glaucoma is the second leading cause of blindness worldwide, with intraocular pressure as the only known modifiable risk factor. Vitamin D has been proposed to influence intraocular pressure and decrease retinal ganglion cell degeneration. Based on these findings, vitamin D has been suggested to prevent or reduce the severity of primary open-angle glaucoma (POAG), which is the most common form. Methods: We applied two-sample Mendelian randomisation (MR) analyses to data from the SUNLIGHT consortium and the UK Biobank to assess the causal effect of vitamin D levels and vitamin D deficiency on primary open-angle glaucoma (POAG). MR analysis, including sensitivity tests using other GWAS summary statistics from FinnGen, was also performed. We also investigated the association between single nucleotide polymorphisms (SNPs) on genes involved in vitamin D metabolic pathways and POAG. Results: We found no statistical evidence that vitamin D levels (OR = 1.146, 95% CI 0.873 to 1.504, p = 0.326) or vitamin D deficiency (OR = 0.980 (95% CI 0.928 to 1.036, p = 0.471) causally affect the risk of developing POAG. Sensitivity analyses, including the use of a more relaxed p-value threshold, and use of winter-measured samples only, replication in the FinnGen dataset, and exploration of specific genetic markers also showed no evidence of association between SNPs for genes involved in key steps of vitamin D metabolism and POAG. Conclusions: These results indicate that vitamin D may not be a significant factor in modifying POAG risk, challenging the hypothesis that vitamin D supplementation could be effective in reducing POAG risk. Further research should focus on identifying other potential risk factors for POAG prevention strategies. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, and Easton, Douglas F

Subjects
CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Nutrition, Obesity, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

Published
2018

10. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D’Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, and Easton, Douglas F

Subjects
Genetics, Biotechnology, Nutrition, Obesity, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Cancer, Stroke, Metabolic and endocrine, Cardiovascular, Oral and gastrointestinal, Adult, Animals, Body Mass Index, Drosophila, Energy Intake, Energy Metabolism, Female, Gene Frequency, Genetic Variation, Humans, Male, Proteins, Syndrome, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018

12. Rare and low-frequency coding variants alter human adult height

Author

Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R, Kjaer, Troels R, Fine, Rebecca S, Lu, Yingchang, Schurmann, Claudia, Highland, Heather M, Rüeger, Sina, Thorleifsson, Gudmar, Justice, Anne E, Lamparter, David, Stirrups, Kathleen E, Turcot, Valérie, Young, Kristin L, Winkler, Thomas W, Esko, Tõnu, Karaderi, Tugce, Locke, Adam E, Masca, Nicholas GD, Ng, Maggie CY, Mudgal, Poorva, Rivas, Manuel A, Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K, Adair, Linda S, Alam, Dewan S, Albrecht, Eva, Allin, Kristine H, Allison, Matthew, Amouyel, Philippe, Appel, Emil V, Arveiler, Dominique, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Banas, Bernhard, Bang, Lia E, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bonnycastle, Lori L, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Carey, David J, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J, Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul IW, de Borst, Gert J, de Denus, Simon, de Groot, Mark CH, de Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, den Hollander, Anneke I, Dennis, Joe G, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M, Easton, Douglas F, Ebeling, Tapani, Edwards, Todd L, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, and Faul, Jessica D

Subjects
Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, ADAMTS Proteins, Adult, Alleles, Body Height, Cell Adhesion Molecules, Female, Gene Frequency, Genetic Variation, Genome, Human, Glycoproteins, Glycosaminoglycans, Hedgehog Proteins, Humans, Intercellular Signaling Peptides and Proteins, Interferon Regulatory Factors, Interleukin-11 Receptor alpha Subunit, Male, Multifactorial Inheritance, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Pregnancy-Associated Plasma Protein-A, Procollagen N-Endopeptidase, Proteoglycans, Proteolysis, Receptors, Androgen, Somatomedins, EPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators, General Science & Technology
Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Published
2017

13. Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study

Author

Zagkos, Loukas, Dib, Marie-Joe, Pinto, Rui, Gill, Dipender, Koskeridis, Fotios, Drenos, Fotios, Markozannes, Georgios, Elliott, Paul, Zuber, Verena, Tsilidis, Kostas, Dehghan, Abbas, and Tzoulaki, Ioanna

Subjects
Obesity -- Prevention, Gallstones -- Prevention, Omega-3 fatty acids -- Health aspects -- Genetic aspects, Biological sciences
Abstract

Background Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. Methods and findings The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed. Conclusions Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention., Author(s): Loukas Zagkos 1,*, Marie-Joe Dib 1, Rui Pinto 1,2, Dipender Gill 1,3,4, Fotios Koskeridis 5, Fotios Drenos 6,7, Georgios Markozannes 5, Paul Elliott 1,2,8, Verena Zuber 1,2, Kostas Tsilidis [...]

Published
2022
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14. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author

Liu, Chunyu, Kraja, Aldi T, Smith, Jennifer A, Brody, Jennifer A, Franceschini, Nora, Bis, Joshua C, Rice, Kenneth, Morrison, Alanna C, Lu, Yingchang, Weiss, Stefan, Guo, Xiuqing, Palmas, Walter, Martin, Lisa W, Chen, Yii-Der Ida, Surendran, Praveen, Drenos, Fotios, Cook, James P, Auer, Paul L, Chu, Audrey Y, Giri, Ayush, Zhao, Wei, Jakobsdottir, Johanna, Lin, Li-An, Stafford, Jeanette M, Amin, Najaf, Mei, Hao, Yao, Jie, Voorman, Arend, Larson, Martin G, Grove, Megan L, Smith, Albert V, Hwang, Shih-Jen, Chen, Han, Huan, Tianxiao, Kosova, Gulum, Stitziel, Nathan O, Kathiresan, Sekar, Samani, Nilesh, Schunkert, Heribert, Deloukas, Panos, Li, Man, Fuchsberger, Christian, Pattaro, Cristian, Gorski, Mathias, Kooperberg, Charles, Papanicolaou, George J, Rossouw, Jacques E, Faul, Jessica D, Kardia, Sharon LR, Bouchard, Claude, Raffel, Leslie J, Uitterlinden, André G, Franco, Oscar H, Vasan, Ramachandran S, O'Donnell, Christopher J, Taylor, Kent D, Liu, Kiang, Bottinger, Erwin P, Gottesman, Omri, Daw, E Warwick, Giulianini, Franco, Ganesh, Santhi, Salfati, Elias, Harris, Tamara B, Launer, Lenore J, Dörr, Marcus, Felix, Stephan B, Rettig, Rainer, Völzke, Henry, Kim, Eric, Lee, Wen-Jane, Lee, I-Te, Sheu, Wayne H-H, Tsosie, Krystal S, Edwards, Digna R Velez, Liu, Yongmei, Correa, Adolfo, Weir, David R, Völker, Uwe, Ridker, Paul M, Boerwinkle, Eric, Gudnason, Vilmundur, Reiner, Alexander P, van Duijn, Cornelia M, Borecki, Ingrid B, Edwards, Todd L, Chakravarti, Aravinda, Rotter, Jerome I, Psaty, Bruce M, Loos, Ruth JF, Fornage, Myriam, Ehret, Georg B, Newton-Cheh, Christopher, Levy, Daniel, and Chasman, Daniel I

Subjects
Biological Sciences, Genetics, Cardiovascular, Hypertension, Prevention, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Blood Pressure, Exome, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, CHD Exome+ Consortium, ExomeBP Consortium, GoT2DGenes Consortium, T2D-GENES Consortium, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, CKDGen Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Published
2016

15. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

Author

Ehret, Georg B, Ferreira, Teresa, Chasman, Daniel I, Jackson, Anne U, Schmidt, Ellen M, Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Lousie A, Kanoni, Stavroula, Petersen, Ann-Kristin, Pihur, Vasyl, Strawbridge, Rona J, Shungin, Dmitry, Hughes, Maria F, Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M, Magnusson, Patrik K, Salfati, Elias L, Rallidis, Loukianos S, Theusch, Elizabeth, Smith, Andrew JP, Folkersen, Lasse, Witkowska, Kate, Pers, Tune H, Joehanes, Roby, Kim, Stuart K, Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D, Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O, Bochud, Murielle, CHARGE-EchoGen consortium, CHARGE-HF consortium, Wellcome Trust Case Control Consortium, Absher, Devin, Adair, Linda S, Amin, Najaf, Arking, Dan E, Axelsson, Tomas, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R, Barroso, Inês, Bevan, Stephen, Bis, Joshua C, Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L, Boomsma, Dorret I, Bornstein, Stefan R, Brown, Morris J, Burnier, Michel, Cabrera, Claudia P, Chambers, John C, Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S, Chung, Ren-Hua, Collins, Francis S, Connell, John M, Döring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F, Doney, Alex SF, Drenos, Fotios, Edkins, Sarah, Eicher, John D, Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farrall, Martin, Felix, Janine F, Ferrières, Jean, Ferrucci, Luigi, Fornage, Myriam, and Forrester, Terrence

Subjects
CHARGE-EchoGen consortium, CHARGE-HF consortium, Wellcome Trust Case Control Consortium, Cells, Cultured, Humans, Hypertension, Microarray Analysis, Blood Pressure, Polymorphism, Single Nucleotide, African Continental Ancestry Group, Asian Continental Ancestry Group, Genome-Wide Association Study, Cells, Cultured, Polymorphism, Single Nucleotide, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Published
2016

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

Author

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

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

Author

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

Published
2021
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19. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials

Author

Swerdlow, Daniel I, Preiss, David, Kuchenbaecker, Karoline B, Holmes, Michael V, Engmann, Jorgen EL, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul CD, Scott, Robert A, Leusink, Maarten, Verweij, Niek, Sharp, Stephen J, Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A, Drenos, Fotios, Li, Yun R, Lowe, Gordon, Gallacher, John, Stewart, Marlene CW, Tzoulaki, Ioanna, Buxbaum, Sarah G, van der A, Daphne L, Forouhi, Nita G, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Schnabel, Renate B, Hubacek, Jaroslav A, Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Romanvan, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, de Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J Wouter, Westendorp, Rudi GJ, de Borst, Gert Jan, de Jong, Pim A, Algra, Ale, Spiering, Wilko, der Zee, Anke H Maitland-van, Klungel, Olaf H, de Boer, Anthonius, Doevendans, Pieter A, Eaton, Charles B, Robinson, Jennifer G, Duggan, David, DIAGRAM Consortium, MAGIC Consortium, Kjekshus, John, Downs, John R, Gotto, Antonio M, Keech, Anthony C, Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S, Poulter, Neil R, Waters, David D, Pedersen, Terje R, Amarenco, Pierre, Nakamura, Haruo, McMurray, John JV, Lewsey, James D, Chasman, Daniel I, Ridker, Paul M, Maggioni, Aldo P, Tavazzi, Luigi, Ray, Kausik K, Seshasai, Sreenivasa Rao Kondapally, Manson, JoAnn E, Price, Jackie F, Whincup, Peter H, Morris, Richard W, Lawlor, Debbie A, Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J, Fornage, Myriam, Siscovick, David S, Cushman, Mary, Kumari, Meena, Wareham, Nick J, Verschuren, WM Monique, Redline, Susan, Patel, Sanjay R, Whittaker, John C, and Hamsten, Anders

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Clinical Trials and Supportive Activities, Clinical Research, Genetics, Nutrition, Diabetes, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundStatins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.MethodsWe used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.FindingsData were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).InterpretationThe increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.FundingThe funding sources are cited at the end of the paper.

Published
2015

21. Severe obesity may be an oligogenic condition: evidence from 1,714 adults seeking treatment in the UK National Health Service

Author

Almansoori, Sumaya, primary, Amin, Hasnat, additional, Alsters, Suzanne, additional, Handley, Dale KM, additional, Yiorkas, Andrianos M, additional, Hashim, Nikman Adli Nor, additional, Ramzi, Nurul Hanis, additional, Bonaomi, Gianluca, additional, Ahmed, Javed, additional, Agrawal, Sanjay, additional, Small, Peter, additional, Purkayastha, Sanjay, additional, Haelst, Mieke Van, additional, Walters, Robin G, additional, Roux, Carel W le, additional, Chahal, Harvinder S, additional, Drenos, Fotios, additional, and Blakemore, Alexandra I, additional

Published
2023
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22. Gene-Centric Meta-Analysis of Lipid Traits in African, East Asian and Hispanic Populations

Author

Elbers, Clara C, Guo, Yiran, Tragante, Vinicius, van Iperen, Erik PA, Lanktree, Matthew B, Castillo, Berta Almoguera, Chen, Fang, Yanek, Lisa R, Wojczynski, Mary K, Li, Yun R, Ferwerda, Bart, Ballantyne, Christie M, Buxbaum, Sarah G, Chen, Yii-Der Ida, Chen, Wei-Min, Cupples, L Adrienne, Cushman, Mary, Duan, Yanan, Duggan, David, Evans, Michele K, Fernandes, Jyotika K, Fornage, Myriam, Garcia, Melissa, Garvey, W Timothy, Glazer, Nicole, Gomez, Felicia, Harris, Tamara B, Halder, Indrani, Howard, Virginia J, Keller, Margaux F, Kamboh, M Ilyas, Kooperberg, Charles, Kritchevsky, Stephen B, LaCroix, Andrea, Liu, Kiang, Liu, Yongmei, Musunuru, Kiran, Newman, Anne B, Onland-Moret, N Charlotte, Ordovas, Jose, Peter, Inga, Post, Wendy, Redline, Susan, Reis, Steven E, Saxena, Richa, Schreiner, Pamela J, Volcik, Kelly A, Wang, Xingbin, Yusuf, Salim, Zonderland, Alan B, Anand, Sonia S, Becker, Diane M, Psaty, Bruce, Rader, Daniel J, Reiner, Alex P, Rich, Stephen S, Rotter, Jerome I, Sale, Michèle M, Tsai, Michael Y, Borecki, Ingrid B, Hegele, Robert A, Kathiresan, Sekar, Nalls, Michael A, Taylor, Herman A, Hakonarson, Hakon, Sivapalaratnam, Suthesh, Asselbergs, Folkert W, Drenos, Fotios, Wilson, James G, and Keating, Brendan J

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Clinical Research, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Alleles, Asian People, Black People, Cholesterol, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Hispanic or Latino, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Polymorphism, Single Nucleotide, Triglycerides, genetic variants, loci, lipid, genotyping, CD36 deficiency, General Science & Technology
Abstract

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

Published
2012

23. Lived Experiences of Newly Diagnosed Type 1 Diabetes Mellitus Children and Adolescents in Uganda

Author

Nsamba,Jonathan, Nabirye,Gloria, Hense,Sibasis, Drenos,Fotios, and Mathews,Elezebeth

Subjects
lived experiences, perceptions, children, diabetes, Journal of Multidisciplinary Healthcare, Uganda, General Medicine, General Nursing
Abstract

Jonathan Nsamba,1,2 Gloria Nabirye,3 Sibasis Hense,1 Fotios Drenos,2 Elezebeth Mathews1 1Department of Public Health & Community Medicine, Central University of Kerala, Kasaragod, Kerala, India; 2Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, London, UB8 3PH UK; 3Department of Nursing Sciences, Faculty of Health Sciences, Busitema University, Mbale, UgandaCorrespondence: Elezebeth Mathews; Fotios Drenos, Email dr.elezebethmathews@cukerala.ac.in; Fotios.Drenos@brunel.ac.ukIntroduction: The first-year post-diagnosis is the most challenging and stressful period in the lifetime of a young child and adolescent living with diabetes, given the adjustments that are meant to be adopted. Therefore, psychosocial factors affecting newly diagnosed children and adolescents need to be well understood and children supported to improve treatment adherence. However, evidence concerning psychosocial experiences among young patients with diabetes is scant in Uganda. This study explores the perceptions and experiences of newly diagnosed children and adolescents in Uganda.Methods: A qualitative exploratory design was employed. We recruited participants aged 6 to < 18 years diagnosed within twelve months from three study sites: Mulago National Referral Hospital, Wakiso HCIV, and St Francis Nsambya Hospital. Twenty in-depth interviews were conducted, and textual data were analysed thematically using a framework approach.Results: We identified five themes: battling with symptoms, emotions at diagnosis, challenges in coping with diabetes management, changes I have made, and positive outcomes registered. The analysis found that young people living with diabetes experience a new world of adjustments, including insulin therapy, routine blood glucose monitoring, and dietary changes that are often difficult to deal with, especially in the first year after diagnosis.Discussion: Continuous psychosocial support to newly diagnosed young children and adolescents with T1DM is vital. Addressing psychosocial challenges may improve adherence to treatment regimens.Conclusion: Our findings have demonstrated the mixed experiences of newly diagnosed young children and adolescents living with diabetes, from anxiety and stigmatization to independence.Keywords: children, diabetes, perceptions, lived experiences, Uganda

Published
2022

24. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Author

Lanktree, Matthew B, Guo, Yiran, Murtaza, Muhammed, Glessner, Joseph T, Bailey, Swneke D, Onland-Moret, N Charlotte, Lettre, Guillaume, Ongen, Halit, Rajagopalan, Ramakrishnan, Johnson, Toby, Shen, Haiqing, Nelson, Christopher P, Klopp, Norman, Baumert, Jens, Padmanabhan, Sandosh, Pankratz, Nathan, Pankow, James S, Shah, Sonia, Taylor, Kira, Barnard, John, Peters, Bas J, Maloney, Cliona M, Lobmeyer, Maximilian T, Stanton, Alice, Zafarmand, M Hadi, Romaine, Simon PR, Mehta, Amar, van Iperen, Erik PA, Gong, Yan, Price, Tom S, Smith, Erin N, Kim, Cecilia E, Li, Yun R, Asselbergs, Folkert W, Atwood, Larry D, Bailey, Kristian M, Bhatt, Deepak, Bauer, Florianne, Behr, Elijah R, Bhangale, Tushar, Boer, Jolanda MA, Boehm, Bernhard O, Bradfield, Jonathan P, Brown, Morris, Braund, Peter S, Burton, Paul R, Carty, Cara, Chandrupatla, Hareesh R, Chen, Wei, Connell, John, Dalgeorgou, Chrysoula, de Boer, Anthonius, Drenos, Fotios, Elbers, Clara C, Fang, James C, Fox, Caroline S, Frackelton, Edward C, Fuchs, Barry, Furlong, Clement E, Gibson, Quince, Gieger, Christian, Goel, Anuj, Grobbee, Diederik E, Hastie, Claire, Howard, Philip J, Huang, Guan-Hua, Johnson, W Craig, Li, Qing, Kleber, Marcus E, Klein, Barbara EK, Klein, Ronald, Kooperberg, Charles, Ky, Bonnie, LaCroix, Andrea, Lanken, Paul, Lathrop, Mark, Li, Mingyao, Marshall, Vanessa, Melander, Olle, Mentch, Frank D, Meyer, Nuala J, Monda, Keri L, Montpetit, Alexandre, Murugesan, Gurunathan, Nakayama, Karen, Nondahl, Dave, Onipinla, Abiodun, Rafelt, Suzanne, Newhouse, Stephen J, Otieno, F George, Patel, Sanjey R, Putt, Mary E, Rodriguez, Santiago, Safa, Radwan N, Sawyer, Douglas B, Schreiner, Pamela J, Simpson, Claire, Sivapalaratnam, Suthesh, Srinivasan, Sathanur R, and Suver, Christine

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Black or African American, Asian People, Body Height, Cardiovascular System, Female, Gene Frequency, Genetic Heterogeneity, Genetic Loci, Genome-Wide Association Study, Hispanic or Latino, Humans, Interleukin-11, Male, Polymorphism, Single Nucleotide, Smad3 Protein, White People, Hugh Watkins on behalf of PROCARDIS, Meena Kumari on behalf of the Whitehall II Study and the WHII 50K Group, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Published
2011

25. Rare variants of the glucagon-like peptide-1 receptor (GLP1R) gene are overrepresented in a severe obesity cohort and associated with type 2 diabetes in the UK Biobank

Author

Handley, Dale, primary, Almansoori, Sumaya, additional, Sato, Mitra, additional, Amin, Hasnat, additional, Alsters, Suzanne, additional, Chahal, Harvinder, additional, Purkayastha, Sanjay, additional, Murphy, Kevin G, additional, van Haelst, Mieke, additional, le Roux, Carel, additional, Tan, Tricia, additional, Walters, Robin, additional, Drenos, Fotios, additional, and Blakemore, Alexandra IF, additional

Published
2023
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26. Models of genetic and non-genetic factors in human longevity

Author

Drenos, Fotios

Subjects
612.68
Abstract

There is little doubt today that ageing is a partially inherited characteristic with the environment playing an equally important role. In this project our aim was to elucidate the gene-gene and gene-environment interactions relevant to ageing through the use of theoretical models and the evolutionary theories of ageing. With our first model we establish for the first time the plausibility of an immunogenetic trade-off between reproduction and survival under infection pressure from the environment while making detailed predictions for the expected point of balance in two different countries, one developing and the other developed, together with predictions about the surprising speed with which an evolutionary transition between the two states can occur. In our second model we develop a detailed simulation program based on epidemiological studies to account for the action of the apolipoprotein gene in western populations, its association with lifestyle parameters, and its evolution over the last 2 million years. We suggest a two-stage history for evolution of Apo E where the establishment of the E3 allele took place during the shift of humanoids to a meat-based diet and the £2 allele started to appear slowly as a rare mutation. Later, with the spread of agriculture and the increasing longevity of humans, the alleles began to be selected more and more towards their current frequencies. Finally, we show how a combination of socioeconomic factors and the stochasticity of mortality can be the driving forces behind the heterogeneity seen in human populations today and reveal the key factors generating this heterogeneity.

Published
2004

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

Author

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

Published
2016
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30. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals

Author

Deelen, Joris, Kettunen, Johannes, Fischer, Krista, van der Spek, Ashley, Trompet, Stella, Kastenmüller, Gabi, Boyd, Andy, Zierer, Jonas, van den Akker, Erik B., Ala-Korpela, Mika, Amin, Najaf, Demirkan, Ayse, Ghanbari, Mohsen, van Heemst, Diana, Ikram, M. Arfan, van Klinken, Jan Bert, Mooijaart, Simon P., Peters, Annette, Salomaa, Veikko, Sattar, Naveed, Spector, Tim D., Tiemeier, Henning, Verhoeven, Aswin, Waldenberger, Melanie, Würtz, Peter, Davey Smith, George, Metspalu, Andres, Perola, Markus, Menni, Cristina, Geleijnse, Johanna M., Drenos, Fotios, Beekman, Marian, Jukema, J. Wouter, van Duijn, Cornelia M., and Slagboom, P. Eline

Published
2019
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31. Genetic Evidence Strongly Supports Managing Weight and Blood Pressure in Addition to Glycemic Control in Preventing Vascular Complications in People With Type 2 Diabetes.

Author

Ahmed, Altayeb, Amin, Hasnat, Drenos, Fotios, Sattar, Naveed, and Yaghootkar, Hanieh

Subjects
GLYCEMIC control, TYPE 2 diabetes, BLOOD pressure, SYSTOLIC blood pressure, AMBULATORY blood pressure monitoring, GENOME-wide association studies, TRAFFIC accidents
Abstract

OBJECTIVE: To investigate the causal association of type 2 diabetes and its components with risk of vascular complications independent of shared risk factors obesity and hypertension and to identify the main driver of this risk. RESEARCH DESIGN AND METHODS: We conducted Mendelian randomization (MR) using independent genetic variants previously associated with type 2 diabetes, fasting glucose, HbA1c, fasting insulin, BMI, and systolic blood pressure as instrumental variables. We obtained summary-level data for 18 vascular diseases (15 for type 2 diabetes) from FinnGen and publicly available genome-wide association studies as our outcomes. We conducted univariable and multivariable MR, in addition to sensitivity tests to detect and minimize pleiotropic effects. RESULTS: Univariable MR analysis showed that type 2 diabetes was associated with 9 of 15 outcomes; BMI and systolic blood pressure were associated with 13 and 15 of 18 vascular outcomes, respectively; and fasting insulin was associated with 4 and fasting glucose with 2. No robust association was found for HbA1c instruments. With adjustment for correlated traits in the multivariable test, BMI and systolic blood pressure, consistent causal effects were maintained, while five associations with type 2 diabetes (chronic kidney disease, ischemic heart disease, heart failure, subarachnoid hemorrhage, and intracerebral hemorrhage) were attenuated to null. CONCLUSIONS: Our findings add strong evidence to support the importance of BMI and systolic blood pressure in the development of vascular complications in people with type 2 diabetes. Such findings strongly support the need for better weight and blood pressure management in type 2 diabetes, independent of glucose lowering, to limit important complications. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Identifying gene–gene interactions that are highly associated with four quantitative lipid traits across multiple cohorts

Author

De, Rishika, Verma, Shefali S., Holzinger, Emily, Hall, Molly, Burt, Amber, Carrell, David S., Crosslin, David R., Jarvik, Gail P., Kuivaniemi, Helena, Kullo, Iftikhar J., Lange, Leslie A., Lanktree, Matthew B., Larson, Eric B., North, Kari E., Reiner, Alex P., Tragante, Vinicius, Tromp, Gerard, Wilson, James G., Asselbergs, Folkert W., Drenos, Fotios, Moore, Jason H., Ritchie, Marylyn D., Keating, Brendan, and Gilbert-Diamond, Diane

Published
2017
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34. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D’Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmantas, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathias, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niels, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charles, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian’an, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., McCarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O’Connel, Jeffrey R., O’Donoghue, Michelle L., Loohuis, Loes M. Olde, Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Markus, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H.-H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Edwards, Digna R. Velez, Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Understanding Society Scientific Group, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Panos, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., and Loos, Ruth J. F.

Published
2019
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35. Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins

Author

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

Published
2022
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39. New Blood Pressure–Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Author

Kraja, Aldi T., Cook, James P., Warren, Helen R., Surendran, Praveen, Liu, Chunyu, Evangelou, Evangelos, Manning, Alisa K., Grarup, Niels, Drenos, Fotios, Sim, Xueling, Smith, Albert Vernon, Amin, Najaf, Blakemore, Alexandra I.F., Bork-Jensen, Jette, Brandslund, Ivan, Farmaki, Aliki-Eleni, Fava, Cristiano, Ferreira, Teresa, Herzig, Karl-Heinz, Giri, Ayush, Giulianini, Franco, Grove, Megan L., Guo, Xiuqing, Harris, Sarah E., Have, Christian T., Havulinna, Aki S., Zhang, He, Jørgensen, Marit E., Käräjämäki, AnneMari, Kooperberg, Charles, Linneberg, Allan, Little, Louis, Liu, Yongmei, Bonnycastle, Lori L., Lu, Yingchang, Mägi, Reedik, Mahajan, Anubha, Malerba, Giovanni, Marioni, Riccardo E., Mei, Hao, Menni, Cristina, Morrison, Alanna C., Padmanabhan, Sandosh, Palmas, Walter, Poveda, Alaitz, Rauramaa, Rainer, Rayner, Nigel William, Riaz, Muhammad, Rice, Ken, Richard, Melissa A., Smith, Jennifer A., Southam, Lorraine, Stančáková, Alena, Stirrups, Kathleen E., Tragante, Vinicius, Tuomi, Tiinamaija, Tzoulaki, Ioanna, Varga, Tibor V., Weiss, Stefan, Yiorkas, Andrianos M., Young, Robin, Zhang, Weihua, Barnes, Michael R., Cabrera, Claudia P., Gao, He, Boehnke, Michael, Boerwinkle, Eric, Chambers, John C., Connell, John M., Christensen, Cramer K., de Boer, Rudolf A., Deary, Ian J., Dedoussis, George, Deloukas, Panos, Dominiczak, Anna F., Dörr, Marcus, Joehanes, Roby, Edwards, Todd L., Esko, Tõnu, Fornage, Myriam, Franceschini, Nora, Franks, Paul W., Gambaro, Giovanni, Groop, Leif, Hallmans, Göran, Hansen, Torben, Hayward, Caroline, Heikki, Oksa, Ingelsson, Erik, Tuomilehto, Jaakko, Jarvelin, Marjo-Riitta, Kardia, Sharon L.R., Karpe, Fredrik, Kooner, Jaspal S., Lakka, Timo A., Langenberg, Claudia, Lind, Lars, Loos, Ruth J.F., Laakso, Markku, McCarthy, Mark I., Melander, Olle, Mohlke, Karen L., Morris, Andrew P., Palmer, Colin N.A., Pedersen, Oluf, Polasek, Ozren, Poulter, Neil R., Province, Michael A., Psaty, Bruce M., Ridker, Paul M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sever, Peter J., Skaaby, Tea, Stafford, Jeanette M., Starr, John M., van der Harst, Pim, van der Meer, Peter, van Duijn, Cornelia M., Vergnaud, Anne-Claire, Gudnason, Vilmundur, Wareham, Nicholas J., Wilson, James G., Willer, Cristen J., Witte, Daniel R., Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S., Danesh, John, Asselbergs, Folkert W., Wain, Louise V., Ehret, Georg B., Chasman, Daniel I., Caulfield, Mark J., Elliott, Paul, Lindgren, Cecilia M., Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B., and Howson, Joanna M.M.

Published
2017
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43. Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins

Author

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

Published
2022
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46. Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study

Author

Roa-Díaz, Zayne M., primary, Asllanaj, Eralda, additional, Amin, Hasnat A., additional, Rojas, Lyda Z., additional, Nano, Jana, additional, Ikram, Mohammad Arfan, additional, Drenos, Fotios, additional, Franco, Oscar H., additional, Pazoki, Raha, additional, Marques-Vidal, Pedro, additional, Voortman, Trudy, additional, and Muka, Taulant, additional

Published
2021
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47. Sixty-Five Common Genetic Variants and Prediction of Type 2 Diabetes

Author

Talmud, Philippa J., Cooper, Jackie A., Morris, Richard W., Dudbridge, Frank, Shah, Tina, Engmann, Jorgen, Dale, Caroline, White, Jon, McLachlan, Stela, Zabaneh, Delilah, Wong, Andrew, Ong, Ken K., Gaunt, Tom, Holmes, Michael V., Lawlor, Debbie A., Richards, Marcus, Hardy, Rebecca, Kuh, Diana, Wareham, Nicholas, Langenberg, Claudia, Ben-Shlomo, Yoav, Wannamethee, S. Goya, Strachan, Mark W.J., Kumari, Meena, Whittaker, John C., Drenos, Fotios, Kivimaki, Mika, Hingorani, Aroon D., Price, Jacqueline F., and Humphries, Steve E.

Published
2015
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48. Mendelian randomization of blood lipids for coronary heart disease

Author

Holmes, Michael V., Asselbergs, Folkert W., Palmer, Tom M., Drenos, Fotios, Lanktree, Matthew B., Nelson, Christopher P., Dale, Caroline E., Padmanabhan, Sandosh, Finan, Chris, Swerdlow, Daniel I., Tragante, Vinicius, van Iperen, Erik P.A., Sivapalaratnam, Suthesh, Shah, Sonia, Elbers, Clara C., Shah, Tina, Engmann, Jorgen, Giambartolomei, Claudia, White, Jon, Zabaneh, Delilah, Sofat, Reecha, McLachlan, Stela, Doevendans, Pieter A., Balmforth, Anthony J., Hall, Alistair S., North, Kari E., Almoguera, Berta, Hoogeveen, Ron C., Cushman, Mary, Fornage, Myriam, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Karczewski, Konrad J., Hofker, Marten H., Verschuren, W. Monique, Bots, Michiel L., van der Schouw, Yvonne T., Melander, Olle, Dominiczak, Anna F., Morris, Richard, Ben-Shlomo, Yoav, Price, Jackie, Kumari, Meena, Baumert, Jens, Peters, Annette, Thorand, Barbara, Koenig, Wolfgang, Gaunt, Tom R., Humphries, Steve E., Clarke, Robert, Watkins, Hugh, Farrall, Martin, Wilson, James G., Rich, Stephen S., de Bakker, Paul I.W., Lange, Leslie A., Davey Smith, George, Reiner, Alex P., Talmud, Philippa J., Kivimäki, Mika, Lawlor, Debbie A., Dudbridge, Frank, Samani, Nilesh J., Keating, Brendan J., Hingorani, Aroon D., and Casas, Juan P.

Published
2015
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50. No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: a Mendelian randomisation study of open data

Author

Amin, Hasnat A and Drenos, Fotios

Subjects
0301 basic medicine, medicine.medical_specialty, Health (social science), Coronavirus disease 2019 (COVID-19), infectious disease, Medicine (miscellaneous), Affect (psychology), vitamin D deficiency, Health(social science), 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, Vitamin D and neurology, Medicine, 030212 general & internal medicine, nutritional treatment, lcsh:RC620-627, Genetic association, Original Research, pulmonary disease, Nutrition and Dietetics, Respiratory tract infections, business.industry, medicine.disease, Open data, lcsh:Nutritional diseases. Deficiency diseases, 030104 developmental biology, Mendelian inheritance, symbols, nutrient deficiencies, business
Abstract

Data availability statement Data from the COVID-19 Host Genetics Initiative are available in a public, open access repository. UK Biobank data may be obtained from a third party and are not publicly available. The data from the COVID-19 Host Genetics Initiative that were used in this study are available here: https://www.covid19hg.org/results/. UK Biobank data are available to all bona fide researchers for all types of health-related research which is in the public interest. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Copyright © Author(s) (or their employer(s)) 2021. Background Upper respiratory tract infections are reportedly more frequent and more severe in individuals with lower vitamin D levels. Based on these findings, it has been suggested that vitamin D can prevent or reduce the severity of COVID-19. Methods We used two-sample Mendelian randomisation (MR) to assess the causal effect of vitamin D levels on SARS-CoV-2 infection risk and COVID-19 severity using publicly available data. We also carried out a genome-wide association analysis (GWA) of vitamin D deficiency in the UK Biobank (UKB) and used these results and two-sample MR to assess the causal effect of vitamin D deficiency on SARS-CoV-2 infection risk and COVID-19 severity. Results We found no evidence that vitamin D levels causally affect the risk of SARS-CoV-2 infection (ln(OR)=0.17 (95% CI −0.22 to 0.57, p=0.39)) nor did we find evidence that vitamin D levels causally affect COVID-19 severity (ln(OR)=0.36 (95% CI −0.89 to 1.61, p=0.57)). Based on our GWA analysis, we found that 17 independent variants are associated with vitamin D deficiency in the UKB. Using these variants as instruments for our two-sample MR analyses, we found no evidence that vitamin D deficiency causally affects the risk of SARS-CoV-2 infection (ln(OR)=−0.04 (95% CI −0.1 to 0.03, p=0.25)) nor did we find evidence that vitamin D deficiency causally affects COVID-19 severity (ln(OR)=−0.24 (95% CI −0.55 to 0.08, p=0.14)). Conclusions In conclusion, we found no evidence that vitamin D is protective against SARS-CoV-2 infection or COVID-19 severity. Our data support the recent statement by the National Institute for Health and Care Excellence that the use of vitamin D supplementation to mitigate COVID-19 is not supported by the available data. Brunel University London Research Initiative and Enterprise Fund.

Published
2021

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