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34 results on '"Vadlamudi, Swarooparani"'

1. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Author

Williamson, Alice, Norris, Dougall M, Yin, Xianyong, Broadaway, K Alaine, Moxley, Anne H, Vadlamudi, Swarooparani, Wilson, Emma P, Jackson, Anne U, Ahuja, Vasudha, Andersen, Mette K, Arzumanyan, Zorayr, Bonnycastle, Lori L, Bornstein, Stefan R, Bretschneider, Maxi P, Buchanan, Thomas A, Chang, Yi-Cheng, Chuang, Lee-Ming, Chung, Ren-Hua, Clausen, Tine D, Damm, Peter, Delgado, Graciela E, de Mello, Vanessa D, Dupuis, Josée, Dwivedi, Om P, Erdos, Michael R, Silva, Lilian Fernandes, Frayling, Timothy M, Gieger, Christian, Goodarzi, Mark O, Guo, Xiuqing, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Hatem, Gad, Herrmann, Sandra, Højlund, Kurt, Horn, Katrin, Hsueh, Willa A, Hung, Yi-Jen, Hwu, Chii-Min, Jonsson, Anna, Kårhus, Line L, Kleber, Marcus E, Kovacs, Peter, Lakka, Timo A, Lauzon, Marie, Lee, I-Te, Lindgren, Cecilia M, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Luan, Jian’an, Aly, Dina Mansour, Mathiesen, Elisabeth, Moissl, Angela P, Morris, Andrew P, Narisu, Narisu, Perakakis, Nikolaos, Peters, Annette, Prasad, Rashmi B, Rodionov, Roman N, Roll, Kathryn, Rundsten, Carsten F, Sarnowski, Chloé, Savonen, Kai, Scholz, Markus, Sharma, Sapna, Stinson, Sara E, Suleman, Sufyan, Tan, Jingyi, Taylor, Kent D, Uusitupa, Matti, Vistisen, Dorte, Witte, Daniel R, Walther, Romy, Wu, Peitao, Xiang, Anny H, Zethelius, Björn, Ahlqvist, Emma, Bergman, Richard N, Chen, Yii-Der Ida, Collins, Francis S, Fall, Tove, Florez, Jose C, Fritsche, Andreas, Grallert, Harald, Groop, Leif, Hansen, Torben, Koistinen, Heikki A, Komulainen, Pirjo, Laakso, Markku, Lind, Lars, Loeffler, Markus, März, Winfried, Meigs, James B, Raffel, Leslie J, Rauramaa, Rainer, Rotter, Jerome I, Schwarz, Peter EH, and Stumvoll, Michael

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Diabetes, Clinical Research, Human Genome, Prevention, Nutrition, 2.1 Biological and endogenous factors, Aetiology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Metabolic and endocrine, Humans, Insulin, Genome-Wide Association Study, Insulin Resistance, Diabetes Mellitus, Type 2, Glucose, Blood Glucose, Meta-Analysis of Glucose and Insulin-related Traits Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P

Published
2023

5. Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans

Author

Schick, Ursula M, Jain, Deepti, Hodonsky, Chani J, Morrison, Jean V, Davis, James P, Brown, Lisa, Sofer, Tamar, Conomos, Matthew P, Schurmann, Claudia, McHugh, Caitlin P, Nelson, Sarah C, Vadlamudi, Swarooparani, Stilp, Adrienne, Plantinga, Anna, Baier, Leslie, Bien, Stephanie A, Gogarten, Stephanie M, Laurie, Cecelia A, Taylor, Kent D, Liu, Yongmei, Auer, Paul L, Franceschini, Nora, Szpiro, Adam, Rice, Ken, Kerr, Kathleen F, Rotter, Jerome I, Hanson, Robert L, Papanicolaou, George, Rich, Stephen S, Loos, Ruth JF, Browning, Brian L, Browning, Sharon R, Weir, Bruce S, Laurie, Cathy C, Mohlke, Karen L, North, Kari E, Thornton, Timothy A, and Reiner, Alex P

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Hematology, Underpinning research, 1.1 Normal biological development and functioning, Blood, Actinin, Adolescent, Adult, Aged, Alleles, Gene Frequency, Genetic Association Studies, Genetic Loci, Genotype, Genotyping Techniques, Hispanic or Latino, Humans, MEF2 Transcription Factors, Membrane Proteins, Middle Aged, Phenotype, Platelet Count, Polymorphism, Single Nucleotide, Receptors, GABA-B, Young Adult, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10(-28)) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits.

Published
2016

6. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol.

Author

Roman, Tamara, Marvelle, Amanda, Fogarty, Marie, Vadlamudi, Swarooparani, Gonzalez, Arlene, Buchkovich, Martin, Huyghe, Jeroen, Fuchsberger, Christian, Jackson, Anne, Wu, Ying, Civelek, Mete, Lusis, Aldons, Gaulton, Kyle, Sethupathy, Praveen, Kangas, Antti, Soininen, Pasi, Ala-Korpela, Mika, Kuusisto, Johanna, Collins, Francis, Laakso, Markku, Boehnke, Michael, and Mohlke, Karen

Subjects
Adipose Tissue, Alleles, CCAAT-Enhancer-Binding Protein-beta, Cholesterol, HDL, Chromatin, Chromatin Immunoprecipitation, Chromosome Mapping, Electrophoretic Mobility Shift Assay, Gene Frequency, Genes, Reporter, Genome, Human, Genome-Wide Association Study, Haplotypes, Hep G2 Cells, Humans, Luciferases, N-Acetylgalactosaminyltransferases, Primary Cell Culture, Protein Binding, Quantitative Trait Loci, Polypeptide N-acetylgalactosaminyltransferase
Abstract

Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus.

Published
2015

7. Adipose tissue eQTL meta-analysis reveals the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits

Author

Brotman, Sarah M., primary, El-Sayed Moustafa, Julia S., additional, Guan, Li, additional, Broadaway, K. Alaine, additional, Wang, Dongmeng, additional, Jackson, Anne U., additional, Welch, Ryan, additional, Currin, Kevin W., additional, Tomlinson, Max, additional, Vadlamudi, Swarooparani, additional, Stringham, Heather M., additional, Roberts, Amy L., additional, Lakka, Timo A., additional, Oravilahti, Anniina, additional, Fernandes Silva, Lilian, additional, Narisu, Narisu, additional, Erdos, Michael R., additional, Yan, Tingfen, additional, Bonnycastle, Lori L., additional, Raulerson, Chelsea K., additional, Raza, Yasrab, additional, Yan, Xinyu, additional, Parker, Stephen C.J., additional, Kuusisto, Johanna, additional, Pajukanta, Paivi, additional, Tuomilehto, Jaakko, additional, Collins, Francis S., additional, Boehnke, Michael, additional, Love, Michael I., additional, Koistinen, Heikki A., additional, Laakso, Markku, additional, Mohlke, Karen L., additional, Small, Kerrin S., additional, and Scott, Laura J., additional

Published
2023
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8. Cell-type composition affects adipose gene expression associations with cardiometabolic traits

Author

M. Brotman, Sarah, primary, Oravilahti, Anniina, primary, D. Rosen, Jonathan, primary, Alvarez, Marcus, primary, Heinonen, Sini, primary, van der Kolk, Birgitta, primary, Fernandes Silva, Lilian, primary, J. Perrin, Hannah, primary, Vadlamudi, Swarooparani, primary, Pylant, Cortney, primary, Deochand, Sonia, primary, V. Basta, Patricia, primary, M. Valon, Jordan, primary, N. Narain, Morgan, primary, M. Stringham, Heather, primary, Boehnke, Michael, primary, Kuusisto, Johanna, primary, I. Love, Michael, primary, H. Pietiläinen, Kirsi, primary, Pajukanta, Päivi, primary, Laakso, Markku, primary, and L. Mohlke, Karen, primary

Published
2023
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9. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

Author

NISC Comparative Sequencing Program, Varshney, Arushi, Scott, Laura J., Welch, Ryan P., Erdos, Michael R., Chines, Peter S., Narisu, Narisu, Albanus, Ricardo D’O., Orchard, Peter, Wolford, Brooke N., Kursawe, Romy, Vadlamudi, Swarooparani, Cannon, Maren E., Didion, John P., Hensley, John, Kirilusha, Anthony, Bonnycastle, Lori L., Taylor, D. Leland, Watanabe, Richard, Mohlke, Karen L., Boehnke, Michael, Collins, Francis S., Parker, Stephen C. J., and Stitzel, Michael L.

Published
2017

10. Cell-type composition affects adipose gene expression associations with cardiometabolic traits

Author

Brotman, Sarah M., primary, Oravilahti, Anniina, additional, Rosen, Jonathan D., additional, Alvarez, Marcus, additional, Heinonen, Sini, additional, van der Kolk, Birgitta, additional, Silva, Lilian Fernandes, additional, Perrin, Hannah J., additional, Vadlamudi, Swarooparani, additional, Pylant, Cortney, additional, Deochand, Sonia, additional, Basta, Patricia V., additional, Valone, Jordan M., additional, Narain, Morgan N., additional, Stringham, Heather M., additional, Boehnke, Michael, additional, Kuusisto, Johanna, additional, Love, Michael I., additional, Pietiläinen, Kirsi H., additional, Pajukanta, Päivi, additional, Laakso, Markku, additional, and Mohlke, Karen L., additional

Published
2023
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11. 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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12. Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Author

Broadaway, K Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A, Wilson, Emma P, Moxley, Anne H, Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U, Ahuja, Vasudha, Bornstein, Stefan R, Corbin, Laura J, Delgado, Graciela E, Dwivedi, Om P, Silva, Lilian Fernandes, Frayling, Timothy M, Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A, Kleber, Marcus E, Lindgren, Cecilia M, Liu, Ching-Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P, Morris, Andrew P, Perakakis, Nikolaos, Peters, Annette, Petrie, John R, Roden, Michael, Schwarz, Peter E H, Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J, Tuomi, Tiinamaija, Wood, Andrew R, Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G, Fall, Tove, Florez, Jose C, Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A, Lind, Lars, März, Winfried, Meigs, James B, Sundström, Johan, Timpson, Nicholas J, Wagner, Robert, Walker, Mark, Wareham, Nicholas J, Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, Mohlke, Karen L, Broadaway, K Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A, Wilson, Emma P, Moxley, Anne H, Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U, Ahuja, Vasudha, Bornstein, Stefan R, Corbin, Laura J, Delgado, Graciela E, Dwivedi, Om P, Silva, Lilian Fernandes, Frayling, Timothy M, Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A, Kleber, Marcus E, Lindgren, Cecilia M, Liu, Ching-Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P, Morris, Andrew P, Perakakis, Nikolaos, Peters, Annette, Petrie, John R, Roden, Michael, Schwarz, Peter E H, Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J, Tuomi, Tiinamaija, Wood, Andrew R, Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G, Fall, Tove, Florez, Jose C, Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A, Lind, Lars, März, Winfried, Meigs, James B, Sundström, Johan, Timpson, Nicholas J, Wagner, Robert, Walker, Mark, Wareham, Nicholas J, Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, and Mohlke, Karen L

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Published
2023
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13. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author

Broadaway, K. Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A., Wilson, Emma P., Moxley, Anne H., Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U., Ahuja, Vasudha, Bornstein, Stefan R., Corbin, Laura J., Delgado, Graciela E., Dwivedi, Om P., Silva, Lilian Fernandes, Frayling, Timothy M., Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A., Kleber, Marcus E., Lindgren, Cecilia M., Liu, Ching Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P., Morris, Andrew P., Perakakis, Nikolaos, Peters, Annette, Petrie, John R., Roden, Michael, Schwarz, Peter E.H., Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J., Tuomi, Tiinamaija, Wood, Andrew R., Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G., Fall, Tove, Florez, Jose C., Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A., Lind, Lars, März, Winfried, Meigs, James B., Sundström, Johan, Timpson, Nicholas J., Wagner, Robert, Walker, Mark, Wareham, Nicholas J., Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, Mohlke, Karen L., Broadaway, K. Alaine, Yin, Xianyong, Williamson, Alice, Parsons, Victoria A., Wilson, Emma P., Moxley, Anne H., Vadlamudi, Swarooparani, Varshney, Arushi, Jackson, Anne U., Ahuja, Vasudha, Bornstein, Stefan R., Corbin, Laura J., Delgado, Graciela E., Dwivedi, Om P., Silva, Lilian Fernandes, Frayling, Timothy M., Grallert, Harald, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Herder, Christian, Herrmann, Sandra, Højlund, Kurt, Hughes, David A., Kleber, Marcus E., Lindgren, Cecilia M., Liu, Ching Ti, Luan, Jian'an, Malmberg, Anni, Moissl, Angela P., Morris, Andrew P., Perakakis, Nikolaos, Peters, Annette, Petrie, John R., Roden, Michael, Schwarz, Peter E.H., Sharma, Sapna, Silveira, Angela, Strawbridge, Rona J., Tuomi, Tiinamaija, Wood, Andrew R., Wu, Peitao, Zethelius, Björn, Baldassarre, Damiano, Eriksson, Johan G., Fall, Tove, Florez, Jose C., Fritsche, Andreas, Gigante, Bruna, Hamsten, Anders, Kajantie, Eero, Laakso, Markku, Lahti, Jari, Lawlor, Deborah A., Lind, Lars, März, Winfried, Meigs, James B., Sundström, Johan, Timpson, Nicholas J., Wagner, Robert, Walker, Mark, Wareham, Nicholas J., Watkins, Hugh, Barroso, Inês, O'Rahilly, Stephen, Grarup, Niels, Parker, Stephen Cj, Boehnke, Michael, Langenberg, Claudia, Wheeler, Eleanor, and Mohlke, Karen L.

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Published
2023

14. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author

Broadaway, K. Alaine, primary, Yin, Xianyong, additional, Williamson, Alice, additional, Parsons, Victoria A., additional, Wilson, Emma P., additional, Moxley, Anne H., additional, Vadlamudi, Swarooparani, additional, Varshney, Arushi, additional, Jackson, Anne U., additional, Ahuja, Vasudha, additional, Bornstein, Stefan R., additional, Corbin, Laura J., additional, Delgado, Graciela E., additional, Dwivedi, Om P., additional, Fernandes Silva, Lilian, additional, Frayling, Timothy M., additional, Grallert, Harald, additional, Gustafsson, Stefan, additional, Hakaste, Liisa, additional, Hammar, Ulf, additional, Herder, Christian, additional, Herrmann, Sandra, additional, Højlund, Kurt, additional, Hughes, David A., additional, Kleber, Marcus E., additional, Lindgren, Cecilia M., additional, Liu, Ching-Ti, additional, Luan, Jian’an, additional, Malmberg, Anni, additional, Moissl, Angela P., additional, Morris, Andrew P., additional, Perakakis, Nikolaos, additional, Peters, Annette, additional, Petrie, John R., additional, Roden, Michael, additional, Schwarz, Peter E.H., additional, Sharma, Sapna, additional, Silveira, Angela, additional, Strawbridge, Rona J., additional, Tuomi, Tiinamaija, additional, Wood, Andrew R., additional, Wu, Peitao, additional, Zethelius, Björn, additional, Baldassarre, Damiano, additional, Eriksson, Johan G., additional, Fall, Tove, additional, Florez, Jose C., additional, Fritsche, Andreas, additional, Gigante, Bruna, additional, Hamsten, Anders, additional, Kajantie, Eero, additional, Laakso, Markku, additional, Lahti, Jari, additional, Lawlor, Deborah A., additional, Lind, Lars, additional, März, Winfried, additional, Meigs, James B., additional, Sundström, Johan, additional, Timpson, Nicholas J., additional, Wagner, Robert, additional, Walker, Mark, additional, Wareham, Nicholas J., additional, Watkins, Hugh, additional, Barroso, Inês, additional, O’Rahilly, Stephen, additional, Grarup, Niels, additional, Parker, Stephen CJ., additional, Boehnke, Michael, additional, Langenberg, Claudia, additional, Wheeler, Eleanor, additional, and Mohlke, Karen L., additional

Published
2023
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15. Subcutaneous adipose tissue splice quantitative trait loci reveal differences in isoform usage associated with cardiometabolic traits

Author

Brotman, Sarah M., primary, Raulerson, Chelsea K., additional, Vadlamudi, Swarooparani, additional, Currin, Kevin W., additional, Shen, Qiujin, additional, Parsons, Victoria A., additional, Iyengar, Apoorva K., additional, Roman, Tamara S., additional, Furey, Terrence S., additional, Kuusisto, Johanna, additional, Collins, Francis S., additional, Boehnke, Michael, additional, Laakso, Markku, additional, Pajukanta, Päivi, additional, and Mohlke, Karen L., additional

Published
2022
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16. Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits

Author

Orchard, Peter, primary, Manickam, Nandini, additional, Ventresca, Christa, additional, Vadlamudi, Swarooparani, additional, Varshney, Arushi, additional, Rai, Vivek, additional, Kaplan, Jeremy, additional, Lalancette, Claudia, additional, Mohlke, Karen L., additional, Gallagher, Katherine, additional, Burant, Charles F., additional, and Parker, Stephen C.J., additional

Published
2021
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18. Genetic effects on liver chromatin accessibility identify disease regulatory variants

Author

Currin, Kevin W., primary, Erdos, Michael R., additional, Narisu, Narisu, additional, Rai, Vivek, additional, Vadlamudi, Swarooparani, additional, Perrin, Hannah J., additional, Idol, Jacqueline R., additional, Yan, Tingfen, additional, Albanus, Ricardo D’Oliveira, additional, Broadaway, K. Alaine, additional, Etheridge, Amy S., additional, Bonnycastle, Lori L., additional, Orchard, Peter, additional, Didion, John P., additional, Chaudhry, Amarjit S., additional, Innocenti, Federico, additional, Schuetz, Erin G., additional, Scott, Laura J., additional, Parker, Stephen C.J., additional, Collins, Francis S., additional, Mohlke, Karen L., additional, Barnabas, Beatrice B., additional, Black, Sean, additional, Bouffard, Gerard G., additional, Brooks, Shelise Y., additional, Coleman, Holly, additional, Dekhtyar, Lyudmila, additional, Han, Joel, additional, Ho, Shi-ling, additional, Kim, Juyun, additional, Legaspi, Richelle, additional, Maduro, Quino L., additional, Masiello, Catherine A., additional, McDowell, Jennifer C., additional, Montemayor, Casandra, additional, Mullikin, James C., additional, Park, Morgan, additional, Riebow, Nancy L., additional, Schandler, Karen, additional, Schmidt, Brian, additional, Sison, Christina, additional, Stantripop, Sirintorn, additional, Thomas, James W., additional, Thomas, Pamela J., additional, Vemulapalli, Meghana, additional, and Young, Alice C., additional

Published
2021
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21. Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences

Author

Spracklen, Cassandra N., primary, Iyengar, Apoorva K., additional, Vadlamudi, Swarooparani, additional, Raulerson, Chelsea K., additional, Jackson, Anne U., additional, Brotman, Sarah M., additional, Wu, Ying, additional, Cannon, Maren E., additional, Davis, James P., additional, Crain, Aaron T., additional, Currin, Kevin W., additional, Perrin, Hannah J., additional, Narisu, Narisu, additional, Stringham, Heather M., additional, Fuchsberger, Christian, additional, Locke, Adam E., additional, Welch, Ryan P., additional, Kuusisto, Johanna K., additional, Pajukanta, Päivi, additional, Scott, Laura J., additional, Li, Yun, additional, Collins, Francis S., additional, Boehnke, Michael, additional, Laakso, Markku, additional, and Mohlke, Karen L., additional

Published
2020
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22. Open Chromatin Profiling in Adipose Tissue Marks Genomic Regions with Functional Roles in Cardiometabolic Traits

Author

Cannon, Maren E, primary, Currin, Kevin W, additional, Young, Kristin L, additional, Perrin, Hannah J, additional, Vadlamudi, Swarooparani, additional, Safi, Alexias, additional, Song, Lingyun, additional, Wu, Ying, additional, Wabitsch, Martin, additional, Laakso, Markku, additional, Crawford, Gregory E, additional, and Mohlke, Karen L, additional

Published
2019
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23. 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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25. Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey

Author

Spracklen, Cassandra N., primary, Shi, Jinxiu, additional, Vadlamudi, Swarooparani, additional, Wu, Ying, additional, Zou, Meng, additional, Raulerson, Chelsea K., additional, Davis, James P., additional, Zeynalzadeh, Monica, additional, Jackson, Kayla, additional, Yuan, Wentao, additional, Wang, Haifeng, additional, Shou, Weihua, additional, Wang, Ying, additional, Luo, Jingchun, additional, Lange, Leslie A., additional, Lange, Ethan M., additional, Popkin, Barry M., additional, Gordon-Larsen, Penny, additional, Du, Shufa, additional, Huang, Wei, additional, and Mohlke, Karen L., additional

Published
2018
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26. A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression

Author

Kycia, Ina, primary, Wolford, Brooke N., additional, Huyghe, Jeroen R., additional, Fuchsberger, Christian, additional, Vadlamudi, Swarooparani, additional, Kursawe, Romy, additional, Welch, Ryan P., additional, Albanus, Ricardo d’Oliveira, additional, Uyar, Asli, additional, Khetan, Shubham, additional, Lawlor, Nathan, additional, Bolisetty, Mohan, additional, Mathur, Anubhuti, additional, Kuusisto, Johanna, additional, Laakso, Markku, additional, Ucar, Duygu, additional, Mohlke, Karen L., additional, Boehnke, Michael, additional, Collins, Francis S., additional, Parker, Stephen C.J., additional, and Stitzel, Michael L., additional

Published
2018
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27. Abstract MP63: Fine-mapping and Characterization of Adiponectin Gwas Loci Harboring Extensive Allelic Heterogeneity

Author

Spracklen, Cassandra N, primary, Jackson, Anne U, additional, Iyengar, Apoorva, additional, Vadlamudi, Swarooparani, additional, Stringham, Heather, additional, Raulerson, Chelsea K, additional, Cannon, Maren E, additional, Currin, Kevin W, additional, Wu, Ying, additional, Fuchsberger, Christian, additional, Welch, Ryan, additional, Chines, Peter, additional, Narisu, Narisu, additional, Kuusisto, Johanna, additional, Pajukanta, Paivi, additional, Collins, Francis, additional, Boehnke, Michael, additional, Laakso, Markku, additional, and Mohlke, Karen, additional

Published
2018
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29. The genetic regulatory signature of type 2 diabetes in human skeletal muscle

Author

Scott, Laura J., primary, Erdos, Michael R., additional, Huyghe, Jeroen R., additional, Welch, Ryan P., additional, Beck, Andrew T., additional, Wolford, Brooke N., additional, Chines, Peter S., additional, Didion, John P., additional, Narisu, Narisu, additional, Stringham, Heather M., additional, Taylor, D. Leland, additional, Jackson, Anne U., additional, Vadlamudi, Swarooparani, additional, Bonnycastle, Lori L., additional, Kinnunen, Leena, additional, Saramies, Jouko, additional, Sundvall, Jouko, additional, Albanus, Ricardo D'Oliveira, additional, Kiseleva, Anna, additional, Hensley, John, additional, Crawford, Gregory E., additional, Jiang, Hui, additional, Wen, Xiaoquan, additional, Watanabe, Richard M., additional, Lakka, Timo A., additional, Mohlke, Karen L., additional, Laakso, Markku, additional, Tuomilehto, Jaakko, additional, Koistinen, Heikki A., additional, Boehnke, Michael, additional, Collins, Francis S., additional, and Parker, Stephen C. J., additional

Published
2016
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30. A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the Locus.

Author

Roman, Tamara S., Cannon, Maren E., Vadlamudi, Swarooparani, Buchkovich, Martin L., Wolford, Brooke N., Welch, Ryan P., Morken, Mario A., Kwon, Grace J., Varshney, Arushi, Kursawe, Romy, Ying Wu, Jackson, Anne U., Erdos, Michael R., Kuusisto, Johanna, Laakso, Markku, Scott, Laura J., Boehnke, Michael, Collins, Francis S., Parker, Stephen C. J., and Stitzel, Michael L.

Subjects
TYPE 2 diabetes, GLUCOSE analysis, ISLANDS of Langerhans, NUCLEAR proteins, CARRIER proteins, GENES, GENETICS, INSULIN, RESEARCH funding, SEQUENCE analysis
Abstract

Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent β-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion. [ABSTRACT FROM AUTHOR]

Published
2017
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31. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes.

Author

Varshney, Arushi, Scott, Laura J., Welch, Ryan P., Erdos, Michael R., Chines, Peter S., Narisu, Narisu, Albanus, Ricardo D’O., Orchard, Peter, Wolford, Brooke N., Kursawe, Romy, Vadlamudi, Swarooparani, Cannon, Maren E., Didion, John P., Hensley, John, Kirilusha, Anthony, Bonnycastle, Lori L., Taylor, D. Leland, Watanabe, Richard, Mohlke, Karen L., and Boehnke, Michael

Subjects
GENETICS of type 2 diabetes, GENETIC regulation, GENE expression, TRANSCRIPTION factors, SINGLE nucleotide polymorphisms
Abstract

Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition. [ABSTRACT FROM AUTHOR]

Published
2017
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32. Adipose tissue eQTL meta-analysis reveals the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

Author

Brotman SM, El-Sayed Moustafa JS, Guan L, Broadaway KA, Wang D, Jackson AU, Welch R, Currin KW, Tomlinson M, Vadlamudi S, Stringham HM, Roberts AL, Lakka TA, Oravilahti A, Silva LF, Narisu N, Erdos MR, Yan T, Bonnycastle LL, Raulerson CK, Raza Y, Yan X, Parker SCJ, Kuusisto J, Pajukanta P, Tuomilehto J, Collins FS, Boehnke M, Love MI, Koistinen HA, Laakso M, Mohlke KL, Small KS, and Scott LJ

Abstract

Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. Here, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34K conditionally distinct expression quantitative trait locus (eQTL) signals in 18K genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared to primary signals, non-primary signals had lower effect sizes, lower minor allele frequencies, and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTL with conditionally distinct genome-wide association study signals for 28 cardiometabolic traits identified 3,605 eQTL signals for 1,861 genes. Inclusion of non-primary eQTL signals increased colocalized signals by 46%. Among 30 genes with ≥2 pairs of colocalized signals, 21 showed a mediating gene dosage effect on the trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation., Competing Interests: Competing interests The authors declare no competing interests.

Published
2023
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33. Open Chromatin Profiling in Adipose Tissue Marks Genomic Regions with Functional Roles in Cardiometabolic Traits.

Author

Cannon ME, Currin KW, Young KL, Perrin HJ, Vadlamudi S, Safi A, Song L, Wu Y, Wabitsch M, Laakso M, Crawford GE, and Mohlke KL

Subjects
Adipocytes metabolism, Aged, Alleles, Allelic Imbalance, Animals, Binding Sites, Chromatin Immunoprecipitation Sequencing, Chromosome Mapping, Disease Susceptibility, Genome-Wide Association Study, Humans, Male, Mice, Middle Aged, Protein Binding, Adipose Tissue metabolism, Chromatin genetics, Gene Expression Profiling, Genome, Human, Genomics methods, Quantitative Trait Loci, Quantitative Trait, Heritable
Abstract

Identifying the regulatory mechanisms of genome-wide association study (GWAS) loci affecting adipose tissue has been restricted due to limited characterization of adipose transcriptional regulatory elements. We profiled chromatin accessibility in three frozen human subcutaneous adipose tissue needle biopsies and preadipocytes and adipocytes from the Simpson Golabi-Behmel Syndrome (SGBS) cell strain using an assay for transposase-accessible chromatin (ATAC-seq). We identified 68,571 representative accessible chromatin regions (peaks) across adipose tissue samples (FDR < 5%). GWAS loci for eight cardiometabolic traits were enriched in these peaks ( P < 0.005), with the strongest enrichment for waist-hip ratio. Of 110 recently described cardiometabolic GWAS loci colocalized with adipose tissue eQTLs, 59 loci had one or more variants overlapping an adipose tissue peak. Annotated variants at the SNX10 waist-hip ratio locus and the ATP2A1-SH2B1 body mass index locus showed allelic differences in regulatory assays. These adipose tissue accessible chromatin regions elucidate genetic variants that may alter adipose tissue function to impact cardiometabolic traits., (Copyright © 2019 Cannon et al.)

Published
2019
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34. A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus.

Author

Roman TS, Cannon ME, Vadlamudi S, Buchkovich ML, Wolford BN, Welch RP, Morken MA, Kwon GJ, Varshney A, Kursawe R, Wu Y, Jackson AU, Erdos MR, Kuusisto J, Laakso M, Scott LJ, Boehnke M, Collins FS, Parker SCJ, Stitzel ML, and Mohlke KL

Subjects
Adenylyl Cyclases genetics, Diabetes Mellitus, Type 2 genetics, Humans, Insulin metabolism, Insulin Secretion, Adenylyl Cyclases metabolism, Diabetes Mellitus, Type 2 metabolism, Gene Expression Regulation physiology, Genetic Variation, Genome-Wide Association Study, Islets of Langerhans metabolism
Abstract

Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5 , a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent β-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5 , but not adjacent gene Sec22a , and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion., (© 2017 by the American Diabetes Association.)

Published
2017
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