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1. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R., Torres, Jason M., Rayner, N. William, Payne, Anthony J., Steinthorsdottir, Valgerdur, Scott, Robert A., Grarup, Niels, Cook, James P., Schmidt, Ellen M., Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H., Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F., Below, Jennifer E., Bowden, Donald W., Chambers, John Campbell, Kim, Young Jin, Ng, Maggie C. Y., Petty, Lauren E., Sim, Xueling, Zhang, Weihua, Bennett, Amanda J., Bork-Jensen, Jette, Brummett, Chad M., Canouil, Mickaël, Ec kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon L. R., Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E., Luan, Jian’an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P., Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C., Ford, Ian, Franco, Oscar H., Frayling, Timothy M., Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T., Herder, Christian, Ikram, M. Arfan, Ingelsson, Martin, Jørgensen, Marit E., Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L., Morris, Andrew D., Nadkarni, Girish, Pankow, James S., Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D., Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R., Dupuis, Josée, Peyser, Patricia A., Zeggini, Eleftheria, Loos, Ruth J. F., Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S., Jukema, J. Wouter, Palmer, Colin N. A., Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R., Meigs, James B., Rotter, Jerome I., Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J., Stefansson, Kari, Gloyn, Anna L., Morris, Andrew P., Boehnke, Michael, and McCarthy, Mark I.

Published
2018
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2. Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

Author

Viñuela, Ana, Varshney, Arushi, van de Bunt, Martijn, Prasad, Rashmi B., Asplund, Olof, Bennett, Amanda, Boehnke, Michael, Brown, Andrew A., Erdos, Michael R., Fadista, João, Hansson, Ola, Hatem, Gad, Howald, Cédric, Iyengar, Apoorva K., Johnson, Paul, Krus, Ulrika, MacDonald, Patrick E., Mahajan, Anubha, Manning Fox, Jocelyn E., Narisu, Narisu, Nylander, Vibe, Orchard, Peter, Oskolkov, Nikolay, Panousis, Nikolaos I., Payne, Anthony, Stitzel, Michael L., Vadlamudi, Swarooparani, Welch, Ryan, Collins, Francis S., Mohlke, Karen L., Gloyn, Anna L., Scott, Laura J., Dermitzakis, Emmanouil T., Groop, Leif, Parker, Stephen C. J., and McCarthy, Mark I.

Published
2020
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7. TIGER: The gene expression regulatory variation landscape of human pancreatic islets

Author

Alonso, Lorena, primary, Piron, Anthony, additional, Morán, Ignasi, additional, Guindo-Martínez, Marta, additional, Bonàs-Guarch, Sílvia, additional, Atla, Goutham, additional, Miguel-Escalada, Irene, additional, Royo, Romina, additional, Puiggròs, Montserrat, additional, Garcia-Hurtado, Xavier, additional, Suleiman, Mara, additional, Marselli, Lorella, additional, Esguerra, Jonathan L.S., additional, Turatsinze, Jean-Valéry, additional, Torres, Jason M., additional, Nylander, Vibe, additional, Chen, Ji, additional, Eliasson, Lena, additional, Defrance, Matthieu, additional, Amela, Ramon, additional, Mulder, Hindrik, additional, Gloyn, Anna L., additional, Groop, Leif, additional, Marchetti, Piero, additional, Eizirik, Decio L., additional, Ferrer, Jorge, additional, Mercader, Josep M., additional, Cnop, Miriam, additional, and Torrents, David, additional

Published
2021
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8. TIGER: The gene expression regulatory variation landscape of human pancreatic islets

Author

Alonso, Lorena, Piron, Anthony, Morán, Ignasi, Guindo-Martínez, Marta, Bonàs-Guarch, Sílvia, Atla, Goutham, Miguel-Escalada, Irene, Royo, Romina, Puiggròs, Montserrat, Garcia-Hurtado, Xavier, Suleiman, Mara, Marselli, Lorella, Esguerra, Jonathan L S, Turatsinze, Jean Valéry, Torres, Jason M, Nylander, Vibe, Chen, Ji, Eliasson, Lena, Defrance, Matthieu, Amela, Ramon, MAGIC, Mulder, Hindrik, Gloyn, Anna L, Groop, Leif, Marchetti, Piero, Eizirik, Decio L., Ferrer, Jorge, Mercader, Josep JM, Cnop, Miriam, Torrents, David, Barcelona Supercomputing Center, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, and Leif Groop Research Group

Subjects
CHROMATIN, Epigenomics, endocrine system diseases, PANCREATECTOMIZED PATIENTS, RNA-Seq, Genome-wide association study, VARIANTS, Epigenome, 0302 clinical medicine, DESIGN, Gene Frequency, Allele-specific expression, Databases, Genetic, Cyclin D2, expression quantitative trait locus (eQTL), Genòmica -- Informàtica, RISK, 0303 health sciences, geography.geographical_feature_category, Diabetis, Genome-wide association study (GWAS), Type 2 diabetes, Genomics, Sciences bio-médicales et agricoles, Islet, READ ALIGNMENT, 3. Good health, Europe, Beta cell, Phenotype, SECRETION, type 2 diabetes, Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], endocrine system, Quantitative Trait Loci, Pancreatic islets, PROVIDES INSIGHTS, allele-specific expression, Computational biology, Zinc Transporter 8, Biology, BIOBANK, General Biochemistry, Genetics and Molecular Biology, Regulatory variation, 03 medical and health sciences, Islets of Langerhans, Pàncrees -- Malalties, Genetic variation, Humans, Genetic Predisposition to Disease, Expression quantitative trait locus (eQTL), GENOME-WIDE ASSOCIATION, Allele, 030304 developmental biology, Genetic association, geography, pancreatic islets, regulatory variation, beta cell, epigenomics, genome-wide association study (GWAS), RNA-seq, transcriptome, Genetic Variation, Gene expression, Diabetes Mellitus, Type 2, Expression quantitative trait loci, 1182 Biochemistry, cell and molecular biology, Transcriptome, 030217 neurology & neurosurgery, Genètica, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D., info:eu-repo/semantics/published

Published
2021
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10. Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma

Author

Chung, Katherine Minjee, primary, Singh, Jaffarguriqbal, additional, Lawres, Lauren, additional, Dorans, Kimberly Judith, additional, Garcia, Cathy, additional, Burkhardt, Daniel B., additional, Robbins, Rebecca, additional, Bhutkar, Arjun, additional, Cardone, Rebecca, additional, Zhao, Xiaojian, additional, Babic, Ana, additional, Vayrynen, Sara A., additional, Dias Costa, Andressa, additional, Nowak, Jonathan A., additional, Chang, Daniel T., additional, Dunne, Richard F., additional, Hezel, Aram F., additional, Koong, Albert C., additional, Wilhelm, Joshua J., additional, Bellin, Melena D., additional, Nylander, Vibe, additional, Gloyn, Anna L., additional, McCarthy, Mark I., additional, Kibbey, Richard G., additional, Krishnaswamy, Smita, additional, Wolpin, Brian M., additional, Jacks, Tyler, additional, Fuchs, Charles S., additional, and Muzumdar, Mandar Deepak, additional

Published
2020
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13. Analysis of Differentiation Protocols Defines a Common Pancreatic Progenitor Molecular Signature and Guides Refinement of Endocrine Differentiation

Author

Wesolowska-Andersen, Agata, primary, Jensen, Rikke Rejnholdt, additional, Alcántara, Marta Pérez, additional, Beer, Nicola L., additional, Duff, Claire, additional, Nylander, Vibe, additional, Gosden, Matthew, additional, Witty, Lorna, additional, Bowden, Rory, additional, McCarthy, Mark I., additional, Hansson, Mattias, additional, Gloyn, Anna L., additional, and Honore, Christian, additional

Published
2020
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14. Abstract A35: Microenvironmental adaptations drive obesity-associated pancreatic cancer

Author

Chung, Katherine Minjee, primary, Singh, Jaffarguribal, additional, Lawres, Lauren, additional, Dorans, Kimberly Judith, additional, Robbins, Rebecca, additional, Bhutkar, Arjun, additional, Babic, Ana, additional, Vayrynen, Sara A., additional, Costa, Andressa D., additional, Nowak, Jonathan A., additional, Chang, Daniel T., additional, Dunne, Richard F., additional, Hezel, Aram F., additional, Koong, Albert C., additional, Wilhelm, Joshua J., additional, Bellin, Melena D., additional, Nylander, Vibe, additional, Gloyn, Anna L., additional, McCarthy, Mark I., additional, Wolpin, Brian M., additional, Jacks, Tyler, additional, Fuchs, Charles S., additional, and Muzumdar, Mandar Deepak, additional

Published
2019
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15. Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels, Cook, James P, Schmidt, Ellen M, Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H, Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F, Below, Jennifer E, Bowden, Donald W, Chambers, John Campbell, Kim, Young Jin, Ng, Maggie C Y, Petty, Lauren E, Sim, Xueling, Zhang, Weihua, Bennett, Amanda J, Bork-Jensen, Jette, Brummett, Chad M, Canouil, Mickaël, Ec Kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon L R, Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E, Luan, Jian'an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P, Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C, Ford, Ian, Franco, Oscar H, Frayling, Timothy M, Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T, Herder, Christian, Ikram, M Arfan, Ingelsson, Martin, Jørgensen, Marit E, Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L, Morris, Andrew D, Nadkarni, Girish, Pankow, James S, Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R, Dupuis, Josée, Peyser, Patricia A, Zeggini, Eleftheria, Loos, Ruth J F, Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S, Jukema, J Wouter, Palmer, Colin N A, Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R, Meigs, James B, Rotter, Jerome I, Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J, Stefansson, Kari, Gloyn, Anna L, Morris, Andrew P, Boehnke, Michael, and McCarthy, Mark I

Subjects
endocrine system diseases
Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

Published
2018

17. Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma

Author

Chung, Katherine Minjee, primary, Singh, Jaffarguriqbal, additional, Lawres, Lauren, additional, Dorans, Kimberly Judith, additional, Garcia, Cathy, additional, Burkhardt, Daniel B., additional, Robbins, Rebecca, additional, Bhutkar, Arjun, additional, Cardone, Rebecca, additional, Zhao, Xiaojian, additional, Babic, Ana, additional, Vayrynen, Sara A., additional, Costa, Andressa Dias, additional, Nowak, Jonathan A., additional, Chang, Daniel T., additional, Dunne, Richard F., additional, Hezel, Aram F., additional, Koong, Albert C., additional, Wilhelm, Joshua J., additional, Bellin, Melena D., additional, Nylander, Vibe, additional, Gloyn, Anna L., additional, McCarthy, Mark I., additional, Kibbey, Richard G., additional, Krishnaswamy, Smita, additional, Wolpin, Brian M., additional, Jacks, Tyler, additional, Fuchs, Charles S., additional, and Muzumdar, Mandar Deepak, additional

Published
2019
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18. Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

Author

Viñuela, Ana, primary, Varshney, Arushi, additional, van de Bunt, Martijn, additional, Prasad, Rashmi B., additional, Asplund, Olof, additional, Bennett, Amanda, additional, Boehnke, Michael, additional, Brown, Andrew, additional, Erdos, Michael R., additional, Fadista, João, additional, Hansson, Ola, additional, Hatem, Gad, additional, Howald, Cédric, additional, Iyengar, Apoorva K., additional, Johnson, Paul, additional, Krus, Ulrika, additional, MacDonald, Patrick E., additional, Mahajan, Anubha, additional, Manning Fox, Jocelyn E., additional, Narisu, Narisu, additional, Nylander, Vibe, additional, Orchard, Peter, additional, Oskolkov, Nikolay, additional, Panousis, Nikolaos I., additional, Payne, Anthony, additional, Stitzel, Michael L., additional, Vadlamudi, Swarooparani, additional, Welch, Ryan, additional, Collins, Francis S., additional, Mohlke, Karen L., additional, Gloyn, Anna L., additional, Scott, Laura J., additional, Dermitzakis, Emmanouil T., additional, Groop, Leif, additional, Parker, Stephen C.J., additional, and McCarthy, Mark I., additional

Published
2019
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19. Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

Author

Thurner, Matthias, primary, van de Bunt, Martijn, additional, Torres, Jason M, additional, Mahajan, Anubha, additional, Nylander, Vibe, additional, Bennett, Amanda J, additional, Gaulton, Kyle J, additional, Barrett, Amy, additional, Burrows, Carla, additional, Bell, Christopher G, additional, Lowe, Robert, additional, Beck, Stephan, additional, Rakyan, Vardhman K, additional, Gloyn, Anna L, additional, and McCarthy, Mark I, additional

Published
2018
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20. Author response: Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

Author

Thurner, Matthias, primary, van de Bunt, Martijn, additional, Torres, Jason M, additional, Mahajan, Anubha, additional, Nylander, Vibe, additional, Bennett, Amanda J, additional, Gaulton, Kyle J, additional, Barrett, Amy, additional, Burrows, Carla, additional, Bell, Christopher G, additional, Lowe, Robert, additional, Beck, Stephan, additional, Rakyan, Vardhman K, additional, Gloyn, Anna L, additional, and McCarthy, Mark I, additional

Published
2018
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21. Electrophysiological properties of human β-cell lines EndoC-βH1 and -βH2 conform with human β-cells

Author

Hastoy, Benoît, primary, Godazgar, Mahdieh, additional, Clark, Anne, additional, Nylander, Vibe, additional, Spiliotis, Ioannis, additional, van de Bunt, Martijn, additional, Chibalina, Margarita, additional, Barrett, Amy, additional, Burrows, Carla, additional, Tarasov, Andrei, additional, Scharfmann, Raphael, additional, Gloyn, Anna L., additional, and Rorsman, Patrik, additional

Published
2017
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22. Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

Author

Thurner, Matthias, primary, Bunt, Martijn van de, additional, Torres, Jason M, additional, Mahajan, Anubha, additional, Nylander, Vibe, additional, Bennett, Amanda J, additional, Gaulton, Kyle, additional, Barrett, Amy, additional, Burrows, Carla, additional, Bell, Christopher G, additional, Lowe, Robert, additional, Beck, Stephan, additional, Rakyan, Vardhman K, additional, Gloyn, Anna L, additional, and McCarthy, Mark I, additional

Published
2017
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24. Ionizing Radiation Potentiates High-Fat Diet–Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells

Author

Nylander, Vibe, primary, Ingerslev, Lars R., additional, Andersen, Emil, additional, Fabre, Odile, additional, Garde, Christian, additional, Rasmussen, Morten, additional, Citirikkaya, Kiymet, additional, Bæk, Josephine, additional, Christensen, Gitte L., additional, Aznar, Marianne, additional, Specht, Lena, additional, Simar, David, additional, and Barrès, Romain, additional

Published
2016
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25. 309-OR: Deep Learning Model of Pancreatic Islet Epigenome Refines Association Signals at Type 2 Diabetes Susceptibility Loci.

Author

WESOLOWSKA-ANDERSEN, AGATA, THURNER, MATTHIAS, MAHAJAN, ANUBHA, ABAITUA, FERNANDO, TORRES, JASON, NYLANDER, VIBE, GLOYN, ANNA L., and MCCARTHY, MARK

Abstract

Translation of genome-wide association study findings is hampered by challenges in pinpointing the causal variant and interpretation of the biological significance of noncoding variation. Recently, deep learning models have been successfully applied to study variant effects on DNA accessibility. Here we collected 30 islet-specific publicly available epigenomic datasets, including measures of DNA accessibility, methylation, histone marks, and transcription factor (TF) binding, and used them to train a convolutional neural network (CNN). The resulting model of pancreatic islet epigenome achieved mean AUC of 0.847 per predicted feature (range: 0.713-0.976), with best predictive power for features marking promoters, DNA accessibility and TF binding. Convolution filters in the first CNN layer discovered binding motifs of several TFs with known islet functions, including FOXA2, HNF1A and RFX6. We used this model to predict islet regulatory effects of variants from a recent T2D GWAS study reporting 403 T2D-risk signals in ~900,000 individuals of European ancestry. We observed overall convergence of three complementary approaches to prioritize functional variants: genetic fine-mapping, regulatory annotation enrichment and islet CNN model predictions. We demonstrate the value of integrating deep learning approaches with fine-mapping to identify causal variants by highlighting an association signal at the PROX1 locus, fine-mapped to two nearby plausible variants. Both variants sit in an islet strong open enhancer, and both exhibit strong open chromatin allelic imbalance, but the CNN model predicts only rs17712208 to have regulatory impact in islets (p=1.69e-160), with the A allele disrupting an HNF1B binding motif, resulting in loss of the H3K27ac mark, indicative of an active regulatory element. These predictions will facilitate further functional follow-up studies to fully elucidate the underlying disease mechanisms at prioritized variants. Disclosure: A. Wesolowska-Andersen: None. M. Thurner: None. A. Mahajan: None. F. Abaitua: None. J. Torres: None. V. Nylander: None. A.L. Gloyn: Consultant; Spouse/Partner; Eli Lilly and Company, Merck & Co., Inc. Consultant; Self; Merck & Co., Inc. Consultant; Spouse/Partner; Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Diabetes UK, European Foundation for the Study of Diabetes. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck & Co., Inc. Consultant; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. [ABSTRACT FROM AUTHOR]

Published
2019
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26. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels, Cook, James P, Schmidt, Ellen M, Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H, Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F, Below, Jennifer E, Bowden, Donald W, Chambers, John Campbell, Kim, Young Jin, Ng, Maggie CY, Petty, Lauren E, Sim, Xueling, Zhang, Weihua, Bennett, Amanda J, Bork-Jensen, Jette, Brummett, Chad M, Canouil, Mickaël, Ec Kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon LR, Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E, Luan, Jian'an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P, Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C, Ford, Ian, Franco, Oscar H, Frayling, Timothy M, Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T, Herder, Christian, Ikram, M Arfan, Ingelsson, Martin, Jørgensen, Marit E, Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L, Morris, Andrew D, Nadkarni, Girish, Pankow, James S, Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R, Dupuis, Josée, Peyser, Patricia A, Zeggini, Eleftheria, Loos, Ruth JF, Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S, Jukema, J Wouter, Palmer, Colin NA, Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R, Meigs, James B, Rotter, Jerome I, Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J, Stefansson, Kari, Gloyn, Anna L, Morris, Andrew P, Boehnke, Michael, and McCarthy, Mark I

Subjects
Male, endocrine system diseases, Genome, Human, Chromosome Mapping, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, 3. Good health, Body Mass Index, Epigenesis, Genetic, High-Throughput Screening Assays, Islets of Langerhans, Sex Factors, Diabetes Mellitus, Type 2, Gene Frequency, Meta-Analysis as Topic, Genetic Loci, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

27. Inferring causal genes at type 2 diabetes GWAS loci through chromosome interactions in islet cells.

Author

Torres JM, Sun H, Nylander V, Downes DJ, van de Bunt M, McCarthy MI, Hughes JR, and Gloyn AL

Abstract

Background: Resolving causal genes for type 2 diabetes at loci implicated by genome-wide association studies (GWAS) requires integrating functional genomic data from relevant cell types. Chromatin features in endocrine cells of the pancreatic islet are particularly informative and recent studies leveraging chromosome conformation capture (3C) with Hi-C based methods have elucidated regulatory mechanisms in human islets. However, these genome-wide approaches are less sensitive and afford lower resolution than methods that target specific loci. Methods: To gauge the extent to which targeted 3C further resolves chromatin-mediated regulatory mechanisms at GWAS loci, we generated interaction profiles at 23 loci using next-generation (NG) capture-C in a human beta cell model (EndoC-βH1) and contrasted these maps with Hi-C maps in EndoC-βH1 cells and human islets and a promoter capture Hi-C map in human islets. Results: We found improvements in assay sensitivity of up to 33-fold and resolved ~3.6X more chromatin interactions. At a subset of 18 loci with 25 co-localised GWAS and eQTL signals, NG Capture-C interactions implicated effector transcripts at five additional genetic signals relative to promoter capture Hi-C through physical contact with gene promoters. Conclusions: High resolution chromatin interaction profiles at selectively targeted loci can complement genome- and promoter-wide maps., Competing Interests: Competing interests: As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. J.R.H. is a founder and shareholder of, and J.R.H. and D.J.D. are paid consultants for Nucleome Therapeutics. J.R.H holds patents for NG Capture-C (WO2017068379A1, EP3365464B1, US10934578B2). ALG’s spouse is an employee of Genentech and a holder of Roche stock., (Copyright: © 2023 Torres JM et al.)

Published
2023
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