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51. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Author

Tin, Adrienne, Marten, Jonathan, Kuhns, Victoria L. Halperin, Li, Yong, Wuttke, Matthias, Kirsten, Holger, Sieber, Karsten B., Qiu, Chengxiang, Gorski, Mathias, Yu, Zhi, Giri, Ayush, Sveinbjornsson, Gardar, Li, Man, Chu, Audrey Y., Hoppmann, Anselm, O'Connor, Luke J., Prins, Bram, Nutile, Teresa, Noce, Damia, Akiyama, Masato, Cocca, Massimiliano, Ghasemi, Sahar, van Der Most, Peter J., Horn, Katrin, Xu, Yizhe, Fuchsberger, Christian, Sedaghat, Sanaz, Afaq, Saima, Amin, Najaf, Arnlov, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boerwinkle, Eric, Bottinger, Erwin P., Boutin, Thibaud S., Brumat, Marco, Burkhardt, Ralph, Campana, Eric, Campbell, Archie, Campbell, Harry, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Ciullo, Marina, Concas, Maria Pina, Coresh, Josef, Corre, Tanguy, Cusi, Daniele, Felicita, Sala Cinzia, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Rene, de Vries, Aiko P. J., Delgado, Graciela, Demirkan, Ayse, Devuyst, Olivier, Dittrich, Katalin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Evans, Michele K., Gansevoort, Ron T., Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Ggele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hayward, Caroline, Hicks, Andrew A., Hofer, Edith, Holm, Hilma, Huang, Wei, Hutri-Kahonen, Nina, Hwang, Shih-Jen, Ikram, M. Arfan, Lewis, Raychel M., Ingelsson, Erik, Jakobsdottir, Johanna, Jonsdottir, Ingileif, Jonsson, Helgi, Joshi, Peter K., Josyula, Navya Shilpa, Jung, Bettina, Kahonen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Kerr, Shona M., Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Korner, Antje, Kovacs, Peter, Kramer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kuhnel, Brigitte, La Bianca, Martina, Lange, Leslie A., Lehne, Benjamin, Lehtimaki, Terho, Liu, Jun, Loeffler, Markus, Loos, Ruth J. F., Lyytikainen, Leo-Pekka, Magi, Reedik, Mahajan, Anubha, Martin, Nicholas G., Marz, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Meisinger, Christa, Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, ODonnell, Christopher J., Wilson, Otis D., Gaziano, J. Michael, Mishra, Pashupati P., Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mueller-Nurasyid, Martina, Nadkarni, Girish N., Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., Noordam, Raymond, O'Connell, Jeffrey R., Olafsson, Isleifur, Padmanabhan, Sandosh, Penninx, Brenda W. J. H., Perls, Thomas, Peters, Annette, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Preuss, Michael H., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rizzi, Federica, Robino, Antonietta, Rudan, Igor, Krajcoviechova, Alena, Cifkova, Renata, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Shaffer, Christian M., Smith, Albert, V, Smith, Blair H., Spracklen, Cassandra N., Strauch, Konstantin, Stumvoll, Michael, Sulem, Patrick, Tajuddin, Salman M., Teren, Andrej, Thiery, Joachim, Thio, Chris H. L., Thorsteinsdottir, Unnur, Toniolo, Daniela, Tonjes, Anke, Tremblay, Johanne, Uitterlinden, Andre G., Vaccargiu, Simona, van der Harst, Pim, van Duijn, Cornelia M., Verweij, Niek, Voelker, Uwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Whitfield, John B., Wild, Sarah H., Wilson, James F., Yang, Qiong, Zhang, Weihua, Zonderman, Alan B., Bochud, Murielle, Wilson, James G., Pendergrass, Sarah A., Ho, Kevin, Parsa, Afshin, Pramstaller, Peter P., Psaty, Bruce M., Boeger, Carsten A., Snieder, Harold, Butterworth, Adam S., Okada, Yukinori, Edwards, Todd L., Stefansson, Kari, Susztak, Katalin, Scholz, Markus, Heid, Iris M., Hung, Adriana M., Teumer, Alexander, Pattaro, Cristian, Woodward, Owen M., Vitart, Veronique, Koettgen, Anna, Tin, Adrienne, Marten, Jonathan, Kuhns, Victoria L. Halperin, Li, Yong, Wuttke, Matthias, Kirsten, Holger, Sieber, Karsten B., Qiu, Chengxiang, Gorski, Mathias, Yu, Zhi, Giri, Ayush, Sveinbjornsson, Gardar, Li, Man, Chu, Audrey Y., Hoppmann, Anselm, O'Connor, Luke J., Prins, Bram, Nutile, Teresa, Noce, Damia, Akiyama, Masato, Cocca, Massimiliano, Ghasemi, Sahar, van Der Most, Peter J., Horn, Katrin, Xu, Yizhe, Fuchsberger, Christian, Sedaghat, Sanaz, Afaq, Saima, Amin, Najaf, Arnlov, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boerwinkle, Eric, Bottinger, Erwin P., Boutin, Thibaud S., Brumat, Marco, Burkhardt, Ralph, Campana, Eric, Campbell, Archie, Campbell, Harry, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Ciullo, Marina, Concas, Maria Pina, Coresh, Josef, Corre, Tanguy, Cusi, Daniele, Felicita, Sala Cinzia, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Rene, de Vries, Aiko P. J., Delgado, Graciela, Demirkan, Ayse, Devuyst, Olivier, Dittrich, Katalin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Evans, Michele K., Gansevoort, Ron T., Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Ggele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hayward, Caroline, Hicks, Andrew A., Hofer, Edith, Holm, Hilma, Huang, Wei, Hutri-Kahonen, Nina, Hwang, Shih-Jen, Ikram, M. Arfan, Lewis, Raychel M., Ingelsson, Erik, Jakobsdottir, Johanna, Jonsdottir, Ingileif, Jonsson, Helgi, Joshi, Peter K., Josyula, Navya Shilpa, Jung, Bettina, Kahonen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Kerr, Shona M., Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Korner, Antje, Kovacs, Peter, Kramer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kuhnel, Brigitte, La Bianca, Martina, Lange, Leslie A., Lehne, Benjamin, Lehtimaki, Terho, Liu, Jun, Loeffler, Markus, Loos, Ruth J. F., Lyytikainen, Leo-Pekka, Magi, Reedik, Mahajan, Anubha, Martin, Nicholas G., Marz, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Meisinger, Christa, Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, ODonnell, Christopher J., Wilson, Otis D., Gaziano, J. Michael, Mishra, Pashupati P., Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mueller-Nurasyid, Martina, Nadkarni, Girish N., Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., Noordam, Raymond, O'Connell, Jeffrey R., Olafsson, Isleifur, Padmanabhan, Sandosh, Penninx, Brenda W. J. H., Perls, Thomas, Peters, Annette, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Preuss, Michael H., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rizzi, Federica, Robino, Antonietta, Rudan, Igor, Krajcoviechova, Alena, Cifkova, Renata, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Shaffer, Christian M., Smith, Albert, V, Smith, Blair H., Spracklen, Cassandra N., Strauch, Konstantin, Stumvoll, Michael, Sulem, Patrick, Tajuddin, Salman M., Teren, Andrej, Thiery, Joachim, Thio, Chris H. L., Thorsteinsdottir, Unnur, Toniolo, Daniela, Tonjes, Anke, Tremblay, Johanne, Uitterlinden, Andre G., Vaccargiu, Simona, van der Harst, Pim, van Duijn, Cornelia M., Verweij, Niek, Voelker, Uwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Whitfield, John B., Wild, Sarah H., Wilson, James F., Yang, Qiong, Zhang, Weihua, Zonderman, Alan B., Bochud, Murielle, Wilson, James G., Pendergrass, Sarah A., Ho, Kevin, Parsa, Afshin, Pramstaller, Peter P., Psaty, Bruce M., Boeger, Carsten A., Snieder, Harold, Butterworth, Adam S., Okada, Yukinori, Edwards, Todd L., Stefansson, Kari, Susztak, Katalin, Scholz, Markus, Heid, Iris M., Hung, Adriana M., Teumer, Alexander, Pattaro, Cristian, Woodward, Owen M., Vitart, Veronique, and Koettgen, Anna

Abstract

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Published
2019
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52. Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

Author

Salem, Rany M., Todd, Jennifer N., Sandholm, Niina, Cole, Joanne B., Chen, Wei-Min, Andrews, Darrell, Pezzolesi, Marcus G., McKeigue, Paul M., Hiraki, Linda T., Qiu, Chengxiang, Nair, Viji, Di Liao, Chen, Cao, Jing Jing, Valo, Erkka, Onengut-Gumuscu, Suna, Smiles, Adam M., McGurnaghan, Stuart J., Haukka, Jani K., Harjutsalo, Valma, Brennan, Eoin P., van Zuydam, Natalie, Ahlqvist, Emma, Doyle, Ross, Ahluwalia, Tarunveer S., Lajer, Maria, Hughes, Maria F., Park, Jihwan, Skupien, Jan, Spiliopoulou, Athina, Liu, Andrew, Menon, Rajasree, Boustany-Kari, Carine M., Kang, Hyun M., Nelson, Robert G., Klein, Ronald, Klein, Barbara E., Lee, Kristine E., Gao, Xiaoyu, Mauer, Michael, Maestroni, Silvia, Caramori, Maria Luiza, de Boer, Ian H., Miller, Rachel G., Guo, Jingchuan, Boright, Andrew P., Tregouet, David, Gyorgy, Beata, Snell-Bergeon, Janet K., Maahs, David M., Bull, Shelley B., Canty, Angelo J., Palmer, Colin N. A., Stechemesser, Lars, Paulweber, Bernhard, Weitgasser, Raimund, Sokolovska, Jelizaveta, Rovite, Vita, Pirags, Valdis, Prakapiene, Edita, Radzeviciene, Lina, Verkauskiene, Rasa, Panduru, Nicolae Mircea, Groop, Leif C., McCarthy, Mark, I, Gu, Harvest F., Möllsten, Anna, Falhammar, Henrik, Brismar, Kerstin, Martin, Finian, Rossing, Peter, Costacou, Tina, Zerbini, Gianpaolo, Marre, Michel, Hadjadj, Samy, McKnight, Amy J., Forsblom, Carol, McKay, Gareth, Godson, Catherine, Maxwell, A. Peter, Kretzler, Matthias, Susztak, Katalin, Colhoun, Helen M., Krolewski, Andrzej, Paterson, Andrew D., Groop, Per-Henrik, Rich, Stephen S., Hirschhorn, Joel N., Florez, Jose C., Salem, Rany M., Todd, Jennifer N., Sandholm, Niina, Cole, Joanne B., Chen, Wei-Min, Andrews, Darrell, Pezzolesi, Marcus G., McKeigue, Paul M., Hiraki, Linda T., Qiu, Chengxiang, Nair, Viji, Di Liao, Chen, Cao, Jing Jing, Valo, Erkka, Onengut-Gumuscu, Suna, Smiles, Adam M., McGurnaghan, Stuart J., Haukka, Jani K., Harjutsalo, Valma, Brennan, Eoin P., van Zuydam, Natalie, Ahlqvist, Emma, Doyle, Ross, Ahluwalia, Tarunveer S., Lajer, Maria, Hughes, Maria F., Park, Jihwan, Skupien, Jan, Spiliopoulou, Athina, Liu, Andrew, Menon, Rajasree, Boustany-Kari, Carine M., Kang, Hyun M., Nelson, Robert G., Klein, Ronald, Klein, Barbara E., Lee, Kristine E., Gao, Xiaoyu, Mauer, Michael, Maestroni, Silvia, Caramori, Maria Luiza, de Boer, Ian H., Miller, Rachel G., Guo, Jingchuan, Boright, Andrew P., Tregouet, David, Gyorgy, Beata, Snell-Bergeon, Janet K., Maahs, David M., Bull, Shelley B., Canty, Angelo J., Palmer, Colin N. A., Stechemesser, Lars, Paulweber, Bernhard, Weitgasser, Raimund, Sokolovska, Jelizaveta, Rovite, Vita, Pirags, Valdis, Prakapiene, Edita, Radzeviciene, Lina, Verkauskiene, Rasa, Panduru, Nicolae Mircea, Groop, Leif C., McCarthy, Mark, I, Gu, Harvest F., Möllsten, Anna, Falhammar, Henrik, Brismar, Kerstin, Martin, Finian, Rossing, Peter, Costacou, Tina, Zerbini, Gianpaolo, Marre, Michel, Hadjadj, Samy, McKnight, Amy J., Forsblom, Carol, McKay, Gareth, Godson, Catherine, Maxwell, A. Peter, Kretzler, Matthias, Susztak, Katalin, Colhoun, Helen M., Krolewski, Andrzej, Paterson, Andrew D., Groop, Per-Henrik, Rich, Stephen S., Hirschhorn, Joel N., and Florez, Jose C.

Abstract

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). Conclusions: The 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Published
2019
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53. Loss of Mitochondrial Transcription Factor A (TFAM) in Tubule Cells Causes Renal Failure Via Activating the cGAS-STING Innate Immune Pathway

Author

Chung, Ki Wung, primary, Huang, Shizheng, additional, Sheng, Xin, additional, Dhillon, Poonam, additional, Shrestha, Rojesh, additional, Qiu, Chengxiang, additional, Kaufman, Brett A., additional, Park, Jihwan, additional, Pei, Liming, additional, Baur, Joseph, additional, Palmer, Matthew, additional, and Susztak, Katalin, additional

Published
2019
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56. Epigenome-wide association studies identify DNA methylation associated with kidney function

Author

Chu, Audrey Y., primary, Tin, Adrienne, additional, Schlosser, Pascal, additional, Ko, Yi-An, additional, Qiu, Chengxiang, additional, Yao, Chen, additional, Joehanes, Roby, additional, Grams, Morgan E., additional, Liang, Liming, additional, Gluck, Caroline A., additional, Liu, Chunyu, additional, Coresh, Josef, additional, Hwang, Shih-Jen, additional, Levy, Daniel, additional, Boerwinkle, Eric, additional, Pankow, James S., additional, Yang, Qiong, additional, Fornage, Myriam, additional, Fox, Caroline S., additional, Susztak, Katalin, additional, and Köttgen, Anna, additional

Published
2017
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60. Phenome-wide association analysis suggests the APOL1linked disease spectrum primarily drives kidney-specific pathways

Author

Bajaj, Archna, Ihegword, Andrea, Qiu, Chengxiang, Small, Aeron M., Wei, Wei-Qi, Bastarache, Lisa, Feng, QiPing, Kember, Rachel L., Risman, Marjorie, Bloom, Roy D., Birtwell, David L., Williams, Heather, Shaffer, Christian M., Chen, Jinbo, Center, Regeneron Genetics, Denny, Joshua C., Rader, Daniel J., Stein, C. Michael, Damrauer, Scott M., and Susztak, Katalin

Abstract

The relationship between commonly occurring genetic variants (G1 and G2) in the APOL1gene in African Americans and different disease traits, such as kidney disease, cardiovascular disease, and pre-eclampsia, remains the subject of controversy. Here we took a genotype-first approach, a phenome-wide association study, to define the spectrum of phenotypes associated with APOL1high-risk variants in 1,837 African American participants of Penn Medicine Biobank and 4,742 African American participants of Vanderbilt BioVU. In the Penn Medicine Biobank, outpatient creatinine measurement-based estimated glomerular filtration rate and multivariable regression models were used to evaluate the association between high-risk APOL1status and renal outcomes. In meta-analysis of both cohorts, the strongest phenome-wide association study associations were for the high-risk APOL1variants and diagnoses codes were highly significant for “kidney dialysis” (odds ratio 3.75) and “end stage kidney disease” (odds ratio 3.42). A number of phenotypes were associated with APOL1high-risk genotypes in an analysis adjusted only for demographic variables. However, no associations were detected with non-renal phenotypes after controlling for chronic/end stage kidney disease status. Using calculated estimated glomerular filtration rate -based phenotype analysis in the Penn Medicine Biobank, APOL1high-risk status was associated with prevalent chronic/end stage kidney disease /kidney transplant (odds ratio 2.27, 95% confidence interval 1.67-3.08). In high-risk participants, the estimated glomerular filtration rate was 15.4 mL/min/1.73m2; significantly lower than in low-risk participants. Thus, although APOL1high-risk variants are associated with a range of phenotypes, the risks for other associated phenotypes appear much lower and in our dataset are driven by a primary effect on renal disease.

Published
2020
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61. Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

Author

Beckerman, Pazit, primary, Bi-Karchin, Jing, additional, Park, Ae Seo Deok, additional, Qiu, Chengxiang, additional, Dummer, Patrick D, additional, Soomro, Irfana, additional, Boustany-Kari, Carine M, additional, Pullen, Steven S, additional, Miner, Jeffrey H, additional, Hu, Chien-An A, additional, Rohacs, Tibor, additional, Inoue, Kazunori, additional, Ishibe, Shuta, additional, Saleem, Moin A, additional, Palmer, Matthew B, additional, Cuervo, Ana Maria, additional, Kopp, Jeffrey B, additional, and Susztak, Katalin, additional

Published
2017
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64. Genetic Effects on Fine-Grained Human Cortical Regionalization

Author

Cui, Yue, primary, Liu, Bing, additional, Zhou, Yuan, additional, Fan, Lingzhong, additional, Li, Jin, additional, Zhang, Yun, additional, Wu, Huawang, additional, Hou, Bing, additional, Wang, Chao, additional, Zheng, Fanfan, additional, Qiu, Chengxiang, additional, Rao, Li-Lin, additional, Ning, Yuping, additional, Li, Shu, additional, and Jiang, Tianzi, additional

Published
2015
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68. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Author

Giri, Ayush, Hellwege, Jacklyn N., Keaton, Jacob M., Park, Jihwan, Qiu, Chengxiang, Warren, Helen R., Torstenson, Eric S., Kovesdy, Csaba P., Sun, Yan V., Wilson, Otis D., Robinson-Cohen, Cassianne, Roumie, Christianne L., Chung, Cecilia P., Birdwell, Kelly A., Damrauer, Scott M., DuVall, Scott L., Klarin, Derek, Cho, Kelly, Wang, Yu, Evangelou, Evangelos, Cabrera, Claudia P., Wain, Louise V., Shrestha, Rojesh, Mautz, Brian S., Akwo, Elvis A., Sargurupremraj, Muralidharan, Debette, Stéphanie, Boehnke, Michael, Scott, Laura J., Luan, Jian’an, Zhao, Jing-Hua, Willems, Sara M., Thériault, Sébastien, Shah, Nabi, Oldmeadow, Christopher, Almgren, Peter, Li-Gao, Ruifang, Verweij, Niek, Boutin, Thibaud S., Mangino, Massimo, Ntalla, Ioanna, Feofanova, Elena, Surendran, Praveen, Cook, James P., Karthikeyan, Savita, Lahrouchi, Najim, Liu, Chunyu, Sepúlveda, Nuno, Richardson, Tom G., Kraja, Aldi, Amouyel, Philippe, Farrall, Martin, Poulter, Neil R., Laakso, Markku, Zeggini, Eleftheria, Sever, Peter, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Conen, David, Palmer, Colin Neil Alexander, Attia, John, Chasman, Daniel I., Ridker, Paul M., Melander, Olle, Mook-Kanamori, Dennis Owen, Harst, Pim van der, Cucca, Francesco, Schlessinger, David, Hayward, Caroline, Spector, Tim D., Jarvelin, Marjo-Riitta, Hennig, Branwen J., Timpson, Nicholas J., Wei, Wei-Qi, Smith, Joshua C., Xu, Yaomin, Matheny, Michael E., Siew, Edward E., Lindgren, Cecilia, Herzig, Karl-Heinz, Dedoussis, George, Denny, Joshua C., Psaty, Bruce M., Howson, Joanna M. M., Munroe, Patricia B., Newton-Cheh, Christopher, Caulfield, Mark J., Elliott, Paul, Gaziano, J. Michael, Concato, John, Wilson, Peter W. F., Tsao, Philip S., Velez Edwards, Digna R., Susztak, Katalin, O’Donnell, Christopher J., Hung, Adriana M., and Edwards, Todd L.

Abstract

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Published
2019
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82. Rice TAL Effector–Dependent Resistance Protein XA10 Triggers Cell Death and Calcium Depletion in the Endoplasmic Reticulum.

Author

Tian, Dongsheng, Wang, Junxia, Zeng, Xuan, Gu, Keyu, Qiu, Chengxiang, Yang, Xiaobei, Zhou, Zhiyun, Goh, Meiling, Luo, Yanchang, Murata-Hori, Maki, White, Frank F., and Yin, Zhongchao

Subjects
CELL death, ENDOPLASMIC reticulum, APOPTOSIS, PLANT genes, HELA cells, CALCIUM channels
Abstract

The recognition between disease resistance (R) genes in plants and their cognate avirulence (Avr) genes in pathogens can produce a hypersensitive response of localized programmed cell death. However, our knowledge of the early signaling events of the R gene–mediated hypersensitive response in plants remains limited. Here, we report the cloning and characterization of Xa10 , a transcription activator–like (TAL) effector-dependent R gene for resistance to bacterial blight in rice (Oryza sativa). Xa10 contains a binding element for the TAL effector AvrXa10 (EBE  AvrXa10) in its promoter, and AvrXa10 specifically induces Xa10 expression. Expression of Xa10 induces programmed cell death in rice, Nicotiana benthamiana , and mammalian HeLa cells. The Xa10 gene product XA10 localizes as hexamers in the endoplasmic reticulum (ER) and is associated with ER Ca2+ depletion in plant and HeLa cells. XA10 variants that abolish programmed cell death and ER Ca2+ depletion in N. benthamiana and HeLa cells also abolish disease resistance in rice. We propose that XA10 is an inducible, intrinsic terminator protein that triggers programmed cell death by a conserved mechanism involving disruption of the ER and cellular Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]

Published
2014
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83. Isolation and characterization of a class III homeodomain-leucine zipper-like gene from Gossypium barbadense

Author

Qiu, Chengxiang, Zuo, Kaijing, Qin, Jie, Zhao, Jingya, Ling, Hua, and Tang, Kexuan

Abstract

Class III homeodomain-leucine zipper (HD-Zip III) genes are important plant-specific transcription factors which have key roles in different stages of vascular and interfascicular fiber differentiation. A novel HD-Zip III gene, designated GbHB1, was isolated by suppression subtraction hybridization and RACE (rapid amplification of cDNA ends) from Gossypium barbadense (sea-island cotton). The GbHB1 cDNA has a total length of 3061 bp with an open reading frame of 2508 bp, encoding a predicated polypeptide of 836 amino acids with a molecular weight of 91.6 kDa and a calculated pI of 5.93. The putative polypeptide of GbHB1 is structurally characterized by a homeodomain positioned adjacent to a leucine zipper domain, which shares high identity with other reported HD-Zip III domains. DNA gel blotting analysis shows that GbHB1 is a low-copy gene. Organ expression pattern analysis reveals that GbHB1 expressed highly in ovule and stem, followed by in root, and low in leaf and cotyledon. The result suggests that GbHB1 may play a regulatory role in cotton interfascicular fiber development.

Published
2006
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84. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P., Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B., Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y., Bansal, Nisha, Feitosa, Mary F., Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O., Van Der Most, Peter J., Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan J. L., Baptista, Daniela, Biggs, Mary L., Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J., Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P., Coresh, Josef, Corre, Tanguy, Danesh, John, De Borst, Martin H., De Grandi, Alessandro, De Mutsert, Renée, De Vries, Aiko P. J., Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F., Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Gansevoort, Ron T., Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B., Hicks, Andrew A., Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M. Arfan, Ingelsson, Erik, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Lange, Leslie A., Langefeld, Carl D., Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Maranville, Joseph C., Mascalzoni, Deborah, McMullen, Barbara, Meisinger, Christa, Meitinger, Thomas, Miliku, Kozeta, Mook-Kanamori, Dennis O., Müller-Nurasyid, Martina, Mychaleckyj, Josyf C., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Noordam, Raymond, Connell, Jeffrey O’, Olafsson, Isleifur, Palmer, Nicholette D., Peters, Annette, Podgornaia, Anna I., Ponte, Belen, Poulain, Tanja, Pramstaller, Peter P., Rabelink, Ton J., Raffield, Laura M., Reilly, Dermot F., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rivadeneira, Fernando, Runz, Heiko, Ryan, Kathleen A., Sabanayagam, Charumathi, Saum, Kai-Uwe, Schöttker, Ben, Shaffer, Christian M., Shi, Yuan, Smith, Albert V., Strauch, Konstantin, Stumvoll, Michael, Sun, Benjamin B., Szymczak, Silke, Tai, E-Shyong, Tan, Nicholas Y. Q., Taylor, Kent D., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomsen, Hauke, Thorsteinsdottir, Unnur, Tönjes, Anke, Tremblay, Johanne, Uitterlinden, André G., Van Der Harst, Pim, Verweij, Niek, Vogelezang, Suzanne, Völker, Uwe, Waldenberger, Melanie, Wang, Chaolong, Wilson, Otis D., Wong, Charlene, Wong, Tien-Yin, Yang, Qiong, Yasuda, Masayuki, Akilesh, Shreeram, Bochud, Murielle, Böger, Carsten A., Devuyst, Olivier, Edwards, Todd L., Ho, Kevin, Morris, Andrew P., Parsa, Afshin, Pendergrass, Sarah A., Psaty, Bruce M., Rotter, Jerome I., Stefansson, Kari, Wilson, James G., Susztak, Katalin, Snieder, Harold, Heid, Iris M., Scholz, Markus, Butterworth, Adam S., Hung, Adriana M., Pattaro, Cristian, and Köttgen, Anna

Subjects
692/4022/1585, 631/208/205/2138, 45/43, article, 3. Good health
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

85. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Author

Tin, Adrienne, Marten, Jonathan, Halperin Kuhns, Victoria L, Li, Yong, Wuttke, Matthias, Kirsten, Holger, Sieber, Karsten B, Qiu, Chengxiang, Gorski, Mathias, Yu, Zhi, Giri, Ayush, Sveinbjornsson, Gardar, Li, Man, Chu, Audrey Y, Hoppmann, Anselm, O'Connor, Luke J, Prins, Bram, Nutile, Teresa, Noce, Damia, Akiyama, Masato, Cocca, Massimiliano, Ghasemi, Sahar, Van Der Most, Peter J, Horn, Katrin, Xu, Yizhe, Fuchsberger, Christian, Sedaghat, Sanaz, Afaq, Saima, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan JL, Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L, Biino, Ginevra, Boerwinkle, Eric, Bottinger, Erwin P, Boutin, Thibaud S, Brumat, Marco, Burkhardt, Ralph, Campana, Eric, Campbell, Archie, Campbell, Harry, Carroll, Robert J, Catamo, Eulalia, Chambers, John C, Ciullo, Marina, Concas, Maria Pina, Coresh, Josef, Corre, Tanguy, Cusi, Daniele, Felicita, Sala Cinzia, De Borst, Martin H, De Grandi, Alessandro, De Mutsert, Renée, De Vries, Aiko PJ, Delgado, Graciela, Demirkan, Ayşe, Devuyst, Olivier, Dittrich, Katalin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Evans, Michele K, Gansevoort, Ron T, Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Gögele, Martin, Gordon, Scott D, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Study, German Chronic Kidney Disease, Haller, Toomas, Hamet, Pavel, Harris, Tamara B, Hayward, Caroline, Hicks, Andrew A, Hofer, Edith, Holm, Hilma, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M Arfan, Lewis, Raychel M, Ingelsson, Erik, Jakobsdottir, Johanna, Jonsdottir, Ingileif, Jonsson, Helgi, Joshi, Peter K, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Kerr, Shona M, Kiess, Wieland, Kleber, Marcus E, Koenig, Wolfgang, Kooner, Jaspal S, Körner, Antje, Kovacs, Peter, Krämer, Bernhard K, Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, La Bianca, Martina, Lange, Leslie A, Lehne, Benjamin, Lehtimäki, Terho, Lifelines Cohort Study, Liu, Jun, Loeffler, Markus, Loos, Ruth JF, Lyytikäinen, Leo-Pekka, Magi, Reedik, Mahajan, Anubha, Martin, Nicholas G, März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Meisinger, Christa, Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, V. A. Million Veteran Program, O'Donnell, Christopher J, Wilson, Otis D, Gaziano, J Michael, Mishra, Pashupati P, Mohlke, Karen L, Mononen, Nina, Montgomery, Grant W, Mook-Kanamori, Dennis O, Müller-Nurasyid, Martina, Nadkarni, Girish N, Nalls, Mike A, Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M, Noordam, Raymond, O'Connell, Jeffrey R, Olafsson, Isleifur, Padmanabhan, Sandosh, Penninx, Brenda WJH, Perls, Thomas, Peters, Annette, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Polasek, Ozren, Ponte, Belen, Porteous, David J, Poulain, Tanja, Preuss, Michael H, Rabelink, Ton J, Raffield, Laura M, Raitakari, Olli T, Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M, Rizzi, Federica, Robino, Antonietta, Rudan, Igor, Krajcoviechova, Alena, Cifkova, Renata, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A, Saba, Yasaman, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Shaffer, Christian M, Smith, Albert V, Smith, Blair H, Spracklen, Cassandra N, Strauch, Konstantin, Stumvoll, Michael, Sulem, Patrick, Tajuddin, Salman M, Teren, Andrej, Thiery, Joachim, Thio, Chris HL, Thorsteinsdottir, Unnur, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Uitterlinden, André G, Vaccargiu, Simona, Van Der Harst, Pim, Van Duijn, Cornelia M, Verweij, Niek, Völker, Uwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Whitfield, John B, Wild, Sarah H, Wilson, James F, Yang, Qiong, Zhang, Weihua, Zonderman, Alan B, Bochud, Murielle, Wilson, James G, Pendergrass, Sarah A, Ho, Kevin, Parsa, Afshin, Pramstaller, Peter P, Psaty, Bruce M, Böger, Carsten A, Snieder, Harold, Butterworth, Adam S, Okada, Yukinori, Edwards, Todd L, Stefansson, Kari, Susztak, Katalin, Scholz, Markus, Heid, Iris M, Hung, Adriana M, Teumer, Alexander, Pattaro, Cristian, Woodward, Owen M, Vitart, Veronique, and Köttgen, Anna

Subjects
Genetic Markers, Gout, Kidney, Polymorphism, Single Nucleotide, 3. Good health, Neoplasm Proteins, Uric Acid, Cohort Studies, Hepatocyte Nuclear Factor 4, Liver, Metabolic Diseases, Cardiovascular Diseases, Genetic Loci, Organ Specificity, ATP Binding Cassette Transporter, Subfamily G, Member 2, Humans, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-alpha, Genome-Wide Association Study, Signal Transduction
Abstract

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

86. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, Van Der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan J L, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, De Borst, Martin H, De Grandi, Alessandro, De Mutsert, Renée, De Vries, Aiko P J, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent W V, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Maranville, Joseph C, Mascalzoni, Deborah, McMullen, Barbara, Meisinger, Christa, Meitinger, Thomas, Miliku, Kozeta, Mook-Kanamori, Dennis O, Müller-Nurasyid, Martina, Mychaleckyj, Josyf C, Nauck, Matthias, Nikus, Kjell, Ning, Boting, Noordam, Raymond, Connell, Jeffrey O', Olafsson, Isleifur, Palmer, Nicholette D, Peters, Annette, Podgornaia, Anna I, Ponte, Belen, Poulain, Tanja, Pramstaller, Peter P, Rabelink, Ton J, Raffield, Laura M, Reilly, Dermot F, Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M, Rivadeneira, Fernando, Runz, Heiko, Ryan, Kathleen A, Sabanayagam, Charumathi, Saum, Kai-Uwe, Schöttker, Ben, Shaffer, Christian M, Shi, Yuan, Smith, Albert V, Strauch, Konstantin, Stumvoll, Michael, Sun, Benjamin B, Szymczak, Silke, Tai, E-Shyong, Tan, Nicholas Y Q, Taylor, Kent D, Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H L, Thomsen, Hauke, Thorsteinsdottir, Unnur, Tönjes, Anke, Tremblay, Johanne, Uitterlinden, André G, Van Der Harst, Pim, Verweij, Niek, Vogelezang, Suzanne, Völker, Uwe, Waldenberger, Melanie, Wang, Chaolong, Wilson, Otis D, Wong, Charlene, Wong, Tien-Yin, Yang, Qiong, Yasuda, Masayuki, Akilesh, Shreeram, Bochud, Murielle, Böger, Carsten A, Devuyst, Olivier, Edwards, Todd L, Ho, Kevin, Morris, Andrew P, Parsa, Afshin, Pendergrass, Sarah A, Psaty, Bruce M, Rotter, Jerome I, Stefansson, Kari, Wilson, James G, Susztak, Katalin, Snieder, Harold, Heid, Iris M, Scholz, Markus, Butterworth, Adam S, Hung, Adriana M, Pattaro, Cristian, and Köttgen, Anna

Subjects
610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

87. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, Van Der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan JL, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, De Borst, Martin H, De Grandi, Alessandro, De Mutsert, Renée, De Vries, Aiko PJ, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent WV, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Maranville, Joseph C, Mascalzoni, Deborah, McMullen, Barbara, Meisinger, Christa, Meitinger, Thomas, Miliku, Kozeta, Mook-Kanamori, Dennis O, Müller-Nurasyid, Martina, Mychaleckyj, Josyf C, Nauck, Matthias, Nikus, Kjell, Ning, Boting, Noordam, Raymond, Connell, Jeffrey O', Olafsson, Isleifur, Palmer, Nicholette D, Peters, Annette, Podgornaia, Anna I, Ponte, Belen, Poulain, Tanja, Pramstaller, Peter P, Rabelink, Ton J, Raffield, Laura M, Reilly, Dermot F, Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M, Rivadeneira, Fernando, Runz, Heiko, Ryan, Kathleen A, Sabanayagam, Charumathi, Saum, Kai-Uwe, Schöttker, Ben, Shaffer, Christian M, Shi, Yuan, Smith, Albert V, Strauch, Konstantin, Stumvoll, Michael, Sun, Benjamin B, Szymczak, Silke, Tai, E-Shyong, Tan, Nicholas YQ, Taylor, Kent D, Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris HL, Thomsen, Hauke, Thorsteinsdottir, Unnur, Tönjes, Anke, Tremblay, Johanne, Uitterlinden, André G, Van Der Harst, Pim, Verweij, Niek, Vogelezang, Suzanne, Völker, Uwe, Waldenberger, Melanie, Wang, Chaolong, Wilson, Otis D, Wong, Charlene, Wong, Tien-Yin, Yang, Qiong, Yasuda, Masayuki, Akilesh, Shreeram, Bochud, Murielle, Böger, Carsten A, Devuyst, Olivier, Edwards, Todd L, Ho, Kevin, Morris, Andrew P, Parsa, Afshin, Pendergrass, Sarah A, Psaty, Bruce M, Rotter, Jerome I, Stefansson, Kari, Wilson, James G, Susztak, Katalin, Snieder, Harold, Heid, Iris M, Scholz, Markus, Butterworth, Adam S, Hung, Adriana M, Pattaro, Cristian, and Köttgen, Anna

Subjects
Chromosome Mapping, 3. Good health, Drosophila melanogaster, Gene Expression Regulation, Meta-Analysis as Topic, Genetic Loci, Risk Factors, Creatinine, Diabetes Mellitus, Albuminuria, Animals, Humans, Genetic Predisposition to Disease, Phenomics, Genome-Wide Association Study
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

88. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Author

Giri, Ayush, Hellwege, Jacklyn N, Keaton, Jacob M, Park, Jihwan, Qiu, Chengxiang, Warren, Helen R, Torstenson, Eric S, Kovesdy, Csaba P, Sun, Yan V, Wilson, Otis D, Robinson-Cohen, Cassianne, Roumie, Christianne L, Chung, Cecilia P, Birdwell, Kelly A, Damrauer, Scott M, DuVall, Scott L, Klarin, Derek, Cho, Kelly, Wang, Yu, Evangelou, Evangelos, Cabrera, Claudia P, Wain, Louise V, Shrestha, Rojesh, Mautz, Brian S, Akwo, Elvis A, Sargurupremraj, Muralidharan, Debette, Stéphanie, Boehnke, Michael, Scott, Laura J, Luan, Jian'an, Zhao, Jing-Hua, Willems, Sara M, Thériault, Sébastien, Shah, Nabi, Oldmeadow, Christopher, Almgren, Peter, Li-Gao, Ruifang, Verweij, Niek, Boutin, Thibaud S, Mangino, Massimo, Ntalla, Ioanna, Feofanova, Elena, Surendran, Praveen, Cook, James P, Karthikeyan, Savita, Lahrouchi, Najim, Liu, Chunyu, Sepúlveda, Nuno, Richardson, Tom G, Kraja, Aldi, Amouyel, Philippe, Farrall, Martin, Poulter, Neil R, Understanding Society Scientific Group, International Consortium For Blood Pressure, Blood Pressure-International Consortium Of Exome Chip Studies, Laakso, Markku, Zeggini, Eleftheria, Sever, Peter, Scott, Robert A, Langenberg, Claudia, Wareham, Nicholas J, Conen, David, Palmer, Colin Neil Alexander, Attia, John, Chasman, Daniel I, Ridker, Paul M, Melander, Olle, Mook-Kanamori, Dennis Owen, Harst, Pim Van Der, Cucca, Francesco, Schlessinger, David, Hayward, Caroline, Spector, Tim D, Jarvelin, Marjo-Riitta, Hennig, Branwen J, Timpson, Nicholas J, Wei, Wei-Qi, Smith, Joshua C, Xu, Yaomin, Matheny, Michael E, Siew, Edward E, Lindgren, Cecilia, Herzig, Karl-Heinz, Dedoussis, George, Denny, Joshua C, Psaty, Bruce M, Howson, Joanna MM, Munroe, Patricia B, Newton-Cheh, Christopher, Caulfield, Mark J, Elliott, Paul, Gaziano, J Michael, Concato, John, Wilson, Peter WF, Tsao, Philip S, Velez Edwards, Digna R, Susztak, Katalin, Million Veteran Program, O'Donnell, Christopher J, Hung, Adriana M, and Edwards, Todd L

Subjects
Male, Adolescent, Gene Expression, Blood Pressure, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, Up-Regulation, Mice, Kidney Tubules, Ethnicity, Animals, Humans, Female, Transcriptome, Genome-Wide Association Study
Abstract

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

89. Embryo model completes gastrulation to neurulation and organogenesis

Author

Gianluca Amadei, Charlotte E. Handford, Chengxiang Qiu, Joachim De Jonghe, Hannah Greenfeld, Martin Tran, Beth K. Martin, Dong-Yuan Chen, Alejandro Aguilera-Castrejon, Jacob H. Hanna, Michael B. Elowitz, Florian Hollfelder, Jay Shendure, David M. Glover, Magdalena Zernicka-Goetz, Handford, Charlotte E [0000-0002-5245-8027], Qiu, Chengxiang [0000-0002-6346-8669], De Jonghe, Joachim [0000-0003-0584-8265], Martin, Beth K [0000-0002-9661-014X], Chen, Dong-Yuan [0000-0003-2179-2847], Aguilera-Castrejon, Alejandro [0000-0002-1339-7778], Hanna, Jacob H [0000-0003-2042-9974], Elowitz, Michael B [0000-0002-1221-0967], Hollfelder, Florian [0000-0002-1367-6312], Shendure, Jay [0000-0002-1516-1865], Zernicka-Goetz, Magdalena [0000-0002-7004-2471], and Apollo - University of Cambridge Repository

Subjects
Neural Tube, Multidisciplinary, PAX6 Transcription Factor, Organogenesis, Endoderm, Gastrulation, Heart, Embryo, Mammalian, Models, Biological, Mice, Prosencephalon, Somites, Mesencephalon, Animals, Cell Lineage, Neurulation, Embryonic Stem Cells
Abstract

Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro1–5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells6–11. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.

Published
2022

90. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Tobias Hermle, Holger Kirsten, Karsten B. Sieber, Aiko P. J. de Vries, Su Chi Lim, Peter Kovacs, Charumathi Sabanayagam, Carl D. Langefeld, Bernhard K. Krämer, Kent D. Taylor, Janine F. Felix, Belen Ponte, Markus Loeffler, Mary F. Feitosa, Kai-Uwe Eckardt, Jianjun Liu, Katalin Dittrich, Charlene A. Wong, Uwe Völker, Adriana M. Hung, Thomas Meitinger, Anubha Mahajan, Anselm Hoppmann, Erik Ingelsson, Martin H. de Borst, Oscar H. Franco, Niek Verweij, Kai-Uwe Saum, Vilmundur Gudnason, Bram P. Prins, Carsten A. Böger, Terho Lehtimäki, Andrew A. Hicks, Todd L. Edwards, Olivier Devuyst, Peter P. Pramstaller, Katrin Horn, Leslie A. Lange, Johanne Tremblay, Jin-Fang Chai, Sahar Ghasemi, Kjell Nikus, Tanja Poulain, Massimiliano Cocca, Anna Köttgen, Eric Boerwinkle, Barry I. Freedman, Miao-Ling Chee, Man Li, Stephan J. L. Bakker, Tamara B. Harris, Albert V. Smith, Ton J. Rabelink, Dennis O. Mook-Kanamori, Iris M. Heid, Jasmin Divers, Chaolong Wang, Kathleen A. Ryan, Pavel Hamet, Silke Szymczak, Shih-Jen Hwang, Hauke Thomsen, Rainer Rettig, Ayush Giri, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Cristian Pattaro, Andrej Teren, Valencia Hui Xian Foo, Myriam Rheinberger, Audrey Y. Chu, Barbara McMullen, Franziska Grundner-Culemann, Masayuki Yasuda, Murielle Bochud, Martin Gögele, Anke Tönjes, Jeannette Lee, Adrienne Tin, Kevin Ho, Konstantin Strauch, Josef Coresh, Renée de Mutsert, Sandra Freitag-Wolf, Gardar Sveinbjornsson, Yizhe Xu, Katalin Susztak, Tien Yin Wong, Mary L. Biggs, Isleifur Olafsson, Qiong Yang, Antje Körner, Chengxiang Qiu, E-Shyong Tai, Martina Müller-Nurasyid, Ben Schöttker, Jeffrey O' Connell, Mengmeng Chen, Daniel F. Gudbjartsson, Dermot F. Reilly, Vincent W. V. Jaddoe, Damia Noce, Pim van der Harst, Sanaz Sedaghat, Chiea Chuen Khor, Adam S. Butterworth, Mathias Gorski, Robert J. Carroll, James G. Wilson, Johan Ärnlöv, Christa Meisinger, Kenneth Rice, Bettina Jung, Christian M. Shaffer, Unnur Thorsteinsdottir, Matthias Nauck, Shreeram Akilesh, Mika Kähönen, Johanna Jakobsdottir, Melanie Waldenberger, Ralph Burkhardt, Daniela Baptista, John Danesh, Benjamin B. Sun, Karlhans Endlich, Holly Kramer, Frauke Degenhardt, Wolfgang Lieb, Kari Stefansson, Joachim Thiery, Lars Lind, Nicholette D. Palmer, Sarah A. Pendergrass, Suzanne Vogelezang, Peter J. van der Most, Afshin Parsa, Markus Scholz, Florian Kronenberg, Joseph C. Maranville, Laura M. Raffield, Hermann Brenner, Wieland Kiess, Anna I. Podgornaia, Yuan Shi, Tanguy Corre, Miao-Li Chee, Deborah Mascalzoni, Bamidele O. Tayo, Navya Shilpa Josyula, Ching-Yu Cheng, Lea Gerstner, Nisha Bansal, Jerome I. Rotter, Alexander Teumer, Vilmantas Giedraitis, Raymond Noordam, Ron T. Gansevoort, Lihua Wang, Andrew P. Morris, Bruce M. Psaty, Boting Ning, Zhi Yu, Christian Fuchsberger, Matthias Wuttke, Heiko Runz, Annette Peters, Yih Chung Tham, James P. Cook, Yong Li, Chris H. L. Thio, Hilma Holm, Alessandro De Grandi, Jonathan Marten, André G. Uitterlinden, Andre Franke, Nicholas Y. Q. Tan, Otis D. Wilson, Georg Ehret, Cecilia M. Lindgren, Josyf C. Mychaleckyj, Wolfgang Koenig, Harold Snieder, Michael Stumvoll, Kozeta Miliku, M. Arfan Ikram, Teresa Nutile, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands, University of Iceland, Teumer, Alexander [0000-0002-8309-094X], Li, Yong [0000-0003-2651-8791], Wuttke, Matthias [0000-0003-3420-5082], Giri, Ayush [0000-0002-7786-4670], Qiu, Chengxiang [0000-0002-6346-8669], Kirsten, Holger [0000-0002-3126-7950], Tin, Adrienne [0000-0002-4207-5866], Feitosa, Mary F. [0000-0002-0933-2410], Chai, Jin-Fang [0000-0003-3770-1137], Cocca, Massimiliano [0000-0002-1127-7596], Gorski, Mathias [0000-0002-9103-5860], Horn, Katrin [0000-0002-5307-6936], Li, Man [0000-0002-3839-0281], Marten, Jonathan [0000-0001-6916-2014], van der Most, Peter J. [0000-0001-8450-3518], Burkhardt, Ralph [0000-0003-1924-1202], Coresh, Josef [0000-0002-4598-0669], de Borst, Martin H. [0000-0002-4127-8733], Ehret, Georg [0000-0002-5730-0675], Endlich, Karlhans [0000-0001-6052-6061], Felix, Janine F. [0000-0002-9801-5774], Franke, Andre [0000-0003-1530-5811], Freedman, Barry I. [0000-0003-0275-5530], Freitag-Wolf, Sandra [0000-0002-1069-7740], Giedraitis, Vilmantas [0000-0003-3423-2021], Grundner-Culemann, Franziska [0000-0001-9649-281X], Gudnason, Vilmundur [0000-0001-5696-0084], Hicks, Andrew A. [0000-0001-6320-0411], Ikram, M. Arfan [0000-0003-0372-8585], Ingelsson, Erik [0000-0003-2256-6972], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Josyula, Navya Shilpa [0000-0003-2782-8812], Khor, Chiea-Chuen [0000-0002-1128-4729], Koenig, Wolfgang [0000-0002-2064-9603], Kovacs, Peter [0000-0002-0290-5423], Kronenberg, Florian [0000-0003-2229-1120], Lindgren, Cecilia M. [0000-0002-4903-9374], Liu, Jianjun [0000-0002-3255-3019], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Mahajan, Anubha [0000-0001-5585-3420], Mascalzoni, Deborah [0000-0003-4156-1464], Miliku, Kozeta [0000-0002-9614-7191], Müller-Nurasyid, Martina [0000-0003-3793-5910], Mychaleckyj, Josyf C. [0000-0003-2595-0005], Palmer, Nicholette D. [0000-0001-8883-2511], Poulain, Tanja [0000-0003-3825-5829], Raffield, Laura M. [0000-0002-7892-193X], Rice, Kenneth M. [0000-0002-3071-7278], Rivadeneira, Fernando [0000-0001-9435-9441], Sabanayagam, Charumathi [0000-0002-4042-4719], Smith, Albert V. [0000-0003-1942-5845], Sun, Benjamin B. [0000-0001-6347-2281], Szymczak, Silke [0000-0002-8897-9035], Taylor, Kent D. [0000-0002-2756-4370], Thio, Chris H. L. [0000-0003-2623-7172], Uitterlinden, André G. [0000-0002-7276-3387], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Völker, Uwe [0000-0002-5689-3448], Wang, Chaolong [0000-0003-3945-1012], Yang, Qiong [0000-0002-3658-1375], Devuyst, Olivier [0000-0003-3744-4767], Edwards, Todd L. [0000-0003-4318-6119], Ho, Kevin [0000-0002-3054-8697], Morris, Andrew P. [0000-0002-6805-6014], Pendergrass, Sarah A. [0000-0002-0565-6522], Rotter, Jerome I. [0000-0001-7191-1723], Stefansson, Kari [0000-0003-1676-864X], Susztak, Katalin [0000-0002-1005-3726], Scholz, Markus [0000-0002-4059-1779], Butterworth, Adam S. [0000-0002-6915-9015], Hung, Adriana M. [0000-0002-3203-1608], Pattaro, Cristian [0000-0002-4119-0109], Köttgen, Anna [0000-0002-4671-3714], Apollo - University of Cambridge Repository, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Feitosa, Mary F [0000-0002-0933-2410], van der Most, Peter J [0000-0001-8450-3518], de Borst, Martin H [0000-0002-4127-8733], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jaddoe, Vincent WV [0000-0003-2939-0041], Lindgren, Cecilia M [0000-0002-4903-9374], Mychaleckyj, Josyf C [0000-0003-2595-0005], Palmer, Nicholette D [0000-0001-8883-2511], Raffield, Laura M [0000-0002-7892-193X], Rice, Kenneth M [0000-0002-3071-7278], Smith, Albert V [0000-0003-1942-5845], Sun, Benjamin B [0000-0001-6347-2281], Taylor, Kent D [0000-0002-2756-4370], Thio, Chris HL [0000-0003-2623-7172], Uitterlinden, André G [0000-0002-7276-3387], Edwards, Todd L [0000-0003-4318-6119], Morris, Andrew P [0000-0002-6805-6014], Pendergrass, Sarah A [0000-0002-0565-6522], Rotter, Jerome I [0000-0001-7191-1723], Butterworth, Adam S [0000-0002-6915-9015], and Hung, Adriana M [0000-0002-3203-1608]

Subjects
0301 basic medicine, Drosophila melanogaster/genetics, Diabetes Mellitus/genetics, LD SCORE REGRESSION, 030232 urology & nephrology, 45/43, General Physics and Astronomy, Genome-wide association study, BLOOD-PRESSURE, Bioinformatics, GLOMERULAR-FILTRATION-RATE, Genome-wide association studies, Diabetes mellitus genetics, 0302 clinical medicine, Creatinine/urine, Risk Factors, Genome-wide, Phenomics, lcsh:Science, ddc:616, Regulation of gene expression, RISK, Gene knockdown, Kidney diseases, Multidisciplinary, HERITABILITY, Albuminuria/genetics, article, Chromosome Mapping, Kidney disease, ddc, 3. Good health, Drosophila melanogaster, Creatinine, Nýrnasjúkdómar, 692/4022/1585, Slit diaphragm, Medical genetics, medicine.symptom, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, Science, 631/208/205/2138, 610 Medicine & health, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Meta-Analysis as Topic, 360 Social problems & social services, Diabetes Mellitus, medicine, Animals, Humans, Albuminuria, Genetic Predisposition to Disease, ddc:610, EXCRETION RATE, CARDIOVASCULAR EVENTS, Genetic association, Medicinsk genetik, TRANS-EQTLS, KIDNEY-DISEASE, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, COLLABORATIVE METAANALYSIS, lcsh:Q, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Published
2019
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91. Multi-condition and multi-modal temporal profile inference during mouse embryonic development.

Author

Zhang R, Qiu C, Filippova G, Li G, Shendure J, Vert JP, Deng X, Disteche C, and Noble WS

Abstract

The emergence of single-cell time-series datasets enables modeling of changes in various types of cellular profiles over time. However, due to the disruptive nature of single-cell measurements, it is impossible to capture the full temporal trajectory of a particular cell. Furthermore, single-cell profiles can be collected at mismatched time points across different conditions (e.g., sex, batch, disease) and data modalities (e.g., scRNA-seq, scATAC-seq), which makes modeling challenging. Here we propose a joint modeling framework, Sunbear, for integrating multi-condition and multi-modal single-cell profiles across time. Sunbear can be used to impute single-cell temporal profile changes, align multi-dataset and multi-modal profiles across time, and extrapolate single-cell profiles in a missing modality. We applied Sunbear to reveal sex-biased transcription during mouse embryonic development and predict dynamic relationships between epigenetic priming and transcription for cells in which multi-modal profiles are unavailable. Sunbear thus enables the projection of single-cell time-series snapshots to multi-modal and multi-condition views of cellular trajectories., Competing Interests: Ethics declarations The authors declare that they have no conflict of interest.

Published
2024
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92. Induction and in silico staging of human gastruloids with neural tube, segmented somites & advanced cell types.

Author

Hamazaki N, Yang W, Kubo C, Qiu C, Martin BK, Garge RK, Regalado SG, Nichols E, Lee C, Daza RM, Srivatsan S, and Shendure J

Abstract

Embryonic organoids are emerging as powerful models for studying early mammalian development. For example, stem cell-derived 'gastruloids' form elongating structures containing all three germ layers 1-4 . However, although elongated, human gastruloids do not morphologically resemble post-implantation embryos. Here we show that a specific, discontinuous regimen of retinoic acid (RA) robustly induces human gastruloids with embryo-like morphological structures, including a neural tube and segmented somites. Single cell RNA-seq (sc-RNA-seq) further reveals that these human 'RA-gastruloids' contain more advanced cell types than conventional gastruloids, including neural crest cells, renal progenitor cells, skeletal muscle cells, and, rarely, neural progenitor cells. We apply a new approach to computationally stage human RA-gastruloids relative to somite-resolved mouse embryos, early human embryos and other gastruloid models, and find that the developmental stage of human RA-gastruloids is comparable to that of E9.5 mouse embryos, although some cell types show greater or lesser progression. We chemically perturb WNT and BMP signaling in human RA-gastruloids and find that these signaling pathways regulate somite patterning and neural tube length, respectively, while genetic perturbation of the transcription factors PAX3 and TBX6 markedly compromises the formation of neural crest and somites/renal cells, respectively. Human RA-gastruloids complement other embryonic organoids in serving as a simple, robust and screenable model for decoding early human embryogenesis., Competing Interests: Competing Financial Interests The authors declare that they have no competing financial interests.

Published
2024
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93. A single-cell transcriptional timelapse of mouse embryonic development, from gastrula to pup.

Author

Qiu C, Martin BK, Welsh IC, Daza RM, Le TM, Huang X, Nichols EK, Taylor ML, Fulton O, O'Day DR, Gomes AR, Ilcisin S, Srivatsan S, Deng X, Disteche CM, Noble WS, Hamazaki N, Moens CB, Kimelman D, Cao J, Schier AF, Spielmann M, Murray SA, Trapnell C, and Shendure J

Abstract

The house mouse, Mus musculus , is an exceptional model system, combining genetic tractability with close homology to human biology. Gestation in mouse development lasts just under three weeks, a period during which its genome orchestrates the astonishing transformation of a single cell zygote into a free-living pup composed of >500 million cells. Towards a global framework for exploring mammalian development, we applied single cell combinatorial indexing (sci-*) to profile the transcriptional states of 12.4 million nuclei from 83 precisely staged embryos spanning late gastrulation (embryonic day 8 or E8) to birth (postnatal day 0 or P0), with 2-hr temporal resolution during somitogenesis, 6-hr resolution through to birth, and 20-min resolution during the immediate postpartum period. From these data (E8 to P0), we annotate dozens of trajectories and hundreds of cell types and perform deeper analyses of the unfolding of the posterior embryo during somitogenesis as well as the ontogenesis of the kidney, mesenchyme, retina, and early neurons. Finally, we leverage the depth and temporal resolution of these whole embryo snapshots, together with other published data, to construct and curate a rooted tree of cell type relationships that spans mouse development from zygote to pup. Throughout this tree, we systematically nominate sets of transcription factors (TFs) and other genes as candidate drivers of the in vivo differentiation of hundreds of mammalian cell types. Remarkably, the most dramatic shifts in transcriptional state are observed in a restricted set of cell types in the hours immediately following birth, and presumably underlie the massive changes in physiology that must accompany the successful transition of a placental mammal to extrauterine life., Competing Interests: Competing Financial Interests Statement J.S. is a scientific advisory board member, consultant and/or co-founder of Scale Biosciences, Prime Medicine, Cajal Neuroscience, Guardant Health, Maze Therapeutics, Camp4 Therapeutics, Phase Genomics, Adaptive Biotechnologies, Sixth Street Capital and Pacific Biosciences. C.T. is a co-founder of Scale Biosciences. All other authors declare no competing interests.

Published
2023
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94. Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

Author

Salem RM, Todd JN, Sandholm N, Cole JB, Chen WM, Andrews D, Pezzolesi MG, McKeigue PM, Hiraki LT, Qiu C, Nair V, Di Liao C, Cao JJ, Valo E, Onengut-Gumuscu S, Smiles AM, McGurnaghan SJ, Haukka JK, Harjutsalo V, Brennan EP, van Zuydam N, Ahlqvist E, Doyle R, Ahluwalia TS, Lajer M, Hughes MF, Park J, Skupien J, Spiliopoulou A, Liu A, Menon R, Boustany-Kari CM, Kang HM, Nelson RG, Klein R, Klein BE, Lee KE, Gao X, Mauer M, Maestroni S, Caramori ML, de Boer IH, Miller RG, Guo J, Boright AP, Tregouet D, Gyorgy B, Snell-Bergeon JK, Maahs DM, Bull SB, Canty AJ, Palmer CNA, Stechemesser L, Paulweber B, Weitgasser R, Sokolovska J, Rovīte V, Pīrāgs V, Prakapiene E, Radzeviciene L, Verkauskiene R, Panduru NM, Groop LC, McCarthy MI, Gu HF, Möllsten A, Falhammar H, Brismar K, Martin F, Rossing P, Costacou T, Zerbini G, Marre M, Hadjadj S, McKnight AJ, Forsblom C, McKay G, Godson C, Maxwell AP, Kretzler M, Susztak K, Colhoun HM, Krolewski A, Paterson AD, Groop PH, Rich SS, Hirschhorn JN, and Florez JC

Subjects
Cohort Studies, Female, Humans, Male, Autoantigens genetics, Collagen Type IV genetics, Diabetes Mellitus, Type 1 genetics, Diabetic Nephropathies genetics, Genome-Wide Association Study, Glomerular Basement Membrane, Mutation
Abstract

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown., Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function., Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( BMP7) or renal biology ( COLEC11 and DDR1 )., Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment., (Copyright © 2019 by the American Society of Nephrology.)

Published
2019
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95. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Author

Tin A, Marten J, Halperin Kuhns VL, Li Y, Wuttke M, Kirsten H, Sieber KB, Qiu C, Gorski M, Yu Z, Giri A, Sveinbjornsson G, Li M, Chu AY, Hoppmann A, O'Connor LJ, Prins B, Nutile T, Noce D, Akiyama M, Cocca M, Ghasemi S, van der Most PJ, Horn K, Xu Y, Fuchsberger C, Sedaghat S, Afaq S, Amin N, Ärnlöv J, Bakker SJL, Bansal N, Baptista D, Bergmann S, Biggs ML, Biino G, Boerwinkle E, Bottinger EP, Boutin TS, Brumat M, Burkhardt R, Campana E, Campbell A, Campbell H, Carroll RJ, Catamo E, Chambers JC, Ciullo M, Concas MP, Coresh J, Corre T, Cusi D, Felicita SC, de Borst MH, De Grandi A, de Mutsert R, de Vries APJ, Delgado G, Demirkan A, Devuyst O, Dittrich K, Eckardt KU, Ehret G, Endlich K, Evans MK, Gansevoort RT, Gasparini P, Giedraitis V, Gieger C, Girotto G, Gögele M, Gordon SD, Gudbjartsson DF, Gudnason V, Haller T, Hamet P, Harris TB, Hayward C, Hicks AA, Hofer E, Holm H, Huang W, Hutri-Kähönen N, Hwang SJ, Ikram MA, Lewis RM, Ingelsson E, Jakobsdottir J, Jonsdottir I, Jonsson H, Joshi PK, Josyula NS, Jung B, Kähönen M, Kamatani Y, Kanai M, Kerr SM, Kiess W, Kleber ME, Koenig W, Kooner JS, Körner A, Kovacs P, Krämer BK, Kronenberg F, Kubo M, Kühnel B, La Bianca M, Lange LA, Lehne B, Lehtimäki T, Liu J, Loeffler M, Loos RJF, Lyytikäinen LP, Magi R, Mahajan A, Martin NG, März W, Mascalzoni D, Matsuda K, Meisinger C, Meitinger T, Metspalu A, Milaneschi Y, O'Donnell CJ, Wilson OD, Gaziano JM, Mishra PP, Mohlke KL, Mononen N, Montgomery GW, Mook-Kanamori DO, Müller-Nurasyid M, Nadkarni GN, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Noordam R, O'Connell JR, Olafsson I, Padmanabhan S, Penninx BWJH, Perls T, Peters A, Pirastu M, Pirastu N, Pistis G, Polasek O, Ponte B, Porteous DJ, Poulain T, Preuss MH, Rabelink TJ, Raffield LM, Raitakari OT, Rettig R, Rheinberger M, Rice KM, Rizzi F, Robino A, Rudan I, Krajcoviechova A, Cifkova R, Rueedi R, Ruggiero D, Ryan KA, Saba Y, Salvi E, Schmidt H, Schmidt R, Shaffer CM, Smith AV, Smith BH, Spracklen CN, Strauch K, Stumvoll M, Sulem P, Tajuddin SM, Teren A, Thiery J, Thio CHL, Thorsteinsdottir U, Toniolo D, Tönjes A, Tremblay J, Uitterlinden AG, Vaccargiu S, van der Harst P, van Duijn CM, Verweij N, Völker U, Vollenweider P, Waeber G, Waldenberger M, Whitfield JB, Wild SH, Wilson JF, Yang Q, Zhang W, Zonderman AB, Bochud M, Wilson JG, Pendergrass SA, Ho K, Parsa A, Pramstaller PP, Psaty BM, Böger CA, Snieder H, Butterworth AS, Okada Y, Edwards TL, Stefansson K, Susztak K, Scholz M, Heid IM, Hung AM, Teumer A, Pattaro C, Woodward OM, Vitart V, and Köttgen A

Subjects
ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, Cardiovascular Diseases epidemiology, Cardiovascular Diseases genetics, Cohort Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Gout epidemiology, Gout genetics, Hepatocyte Nuclear Factor 1-alpha genetics, Hepatocyte Nuclear Factor 4 genetics, Humans, Kidney metabolism, Kidney pathology, Liver metabolism, Liver pathology, Metabolic Diseases epidemiology, Metabolic Diseases genetics, Neoplasm Proteins genetics, Organ Specificity, Cardiovascular Diseases blood, Genetic Markers, Gout blood, Metabolic Diseases blood, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid blood
Abstract

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Published
2019
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96. Genetic Effects on Fine-Grained Human Cortical Regionalization.

Author

Cui Y, Liu B, Zhou Y, Fan L, Li J, Zhang Y, Wu H, Hou B, Wang C, Zheng F, Qiu C, Rao LL, Ning Y, Li S, and Jiang T

Subjects
Connectome methods, Female, Humans, Male, Neural Pathways anatomy & histology, Neural Pathways physiology, Young Adult, Cerebral Cortex anatomy & histology, Cerebral Cortex physiology, Nerve Net anatomy & histology, Nerve Net physiology, Twins genetics
Abstract

Various brain structural and functional features such as cytoarchitecture, topographic mapping, gyral/sulcal anatomy, and anatomical and functional connectivity have been used in human brain parcellation. However, the fine-grained intrinsic genetic architecture of the cortex remains unknown. In the present study, we parcellated specific regions of the cortex into subregions based on genetic correlations (i.e., shared genetic influences) between the surface area of each pair of cortical locations within the seed region. The genetic correlations were estimated by comparing the correlations of the surface area between monozygotic and dizygotic twins using bivariate twin models. Our genetic subdivisions of diverse brain regions were reproducible across 2 independent datasets and corresponded closely to fine-grained functional specializations. Furthermore, subregional genetic correlation profiles were generally consistent with functional connectivity patterns. Our findings indicate that the magnitude of the genetic covariance in brain anatomy could be used to delineate the boundaries of functional subregions of the brain and may be of value in the next generation human brain atlas., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Published
2016
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97. [Isolation and characterization of a 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase gene from Taxus media].

Author

Jin H, Gong Y, Guo B, Qiu C, Liu D, Miao Z, Sun X, and Tang K

Subjects
Amino Acid Sequence, Base Sequence, Computational Biology, Evolution, Molecular, Genes, Plant, Molecular Sequence Data, Phosphorus-Oxygen Lyases classification, Phylogeny, Taxus genetics, Cloning, Molecular, Gene Expression, Phosphorus-Oxygen Lyases chemistry, Phosphorus-Oxygen Lyases genetics, Taxus enzymology
Abstract

2C-methyl-D-erythritol 2,4-cyclodiphosphate (MEC) synthase (MECS, EC: 4.6.1.12) is the fifth enzyme of the nonmevalonate terpenoid pathway for isopentenyl diphosphate biosynthesis and further Taxol biosynthesis. The full-length MECS cDNA sequence (GenBank accession number DQ286391) was cloned and characterized for the first time from Taxus media, using Rapid Amplification of cDNA Ends (RACE) technique. The full-length cDNA of Tmmecs was 1081 bp containing a 741 bp open reading frame (ORF) encoding a peptide of 247 amino acids with a calculated molecular mass of 26.1 kDa and an isoelectric point of 8.97. Comparative and bioinformatic analyses revealed that TmMECS had extensive homology with MECSs from other plant species. Phylogenetic analysis indicated that TmMECS was more ancient than other plant MECSs. Southern blot analysis revealed that Tmmecs belonged to a small gene family. Tissue expression pattern analysis indicated that Tmmecs expressed constitutively in all tissues including roots, stems and leaves. The cloning and characterization of Tmmecs will be helpful to understand more about the role of MECS involved in the Taxol biosynthesis at the molecular level.

Published
2006

98. Isolation and characterization of a class III homeodomain-leucine zipper-like gene from Gossypium barbadense.

Author

Qiu C, Zuo K, Qin J, Zhao J, Ling H, and Tang K

Subjects
Amino Acid Sequence, Base Sequence, Homeodomain Proteins chemistry, Leucine Zippers physiology, Molecular Sequence Data, Plant Proteins chemistry, Transcription Factors chemistry, Gossypium genetics, Homeodomain Proteins genetics, Homeodomain Proteins isolation & purification, Leucine Zippers genetics, Plant Proteins genetics, Plant Proteins isolation & purification, Transcription Factors genetics, Transcription Factors isolation & purification
Abstract

Class III homeodomain-leucine zipper (HD-Zip III) genes are important plant-specific transcription factors which have key roles in different stages of vascular and interfascicular fiber differentiation. A novel HD-Zip III gene, designated GbHB1, was isolated by suppression subtraction hybridization and RACE (rapid amplification of cDNA ends) from Gossypium barbadense (sea-island cotton). The GbHB1 cDNA has a total length of 3061 bp with an open reading frame of 2508 bp, encoding a predicated polypeptide of 836 amino acids with a molecular weight of 91.6 kDa and a calculated pI of 5.93. The putative polypeptide of GbHB1 is structurally characterized by a homeodomain positioned adjacent to a leucine zipper domain, which shares high identity with other reported HD-Zip III domains. DNA gel blotting analysis shows that GbHB1 is a low-copy gene. Organ expression pattern analysis reveals that GbHB1 expressed highly in ovule and stem, followed by in root, and low in leaf and cotyledon. The result suggests that GbHB1 may play a regulatory role in cotton interfascicular fiber development.

Published
2006
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99. Isolation and expression analysis of a GDSL-like lipase gene from Brassica napus L.

Author

Ling H, Zhao J, Zuo K, Qiu C, Yao H, Qin J, Sun X, and Tang K

Subjects
Amino Acid Sequence, Arabidopsis Proteins, Base Sequence, Brassica napus enzymology, Carboxylic Ester Hydrolases, Gene Expression Profiling, Genes, Plant, Lipase chemistry, Molecular Sequence Data, Phylogeny, Sequence Analysis, DNA, Brassica napus genetics, Lipase genetics
Abstract

As lipolytic enzymes, GDSL lipases play an important role in plant growth and development. In order to identify their functions and roles, the full-length cDNA of a GDSL lipase gene, designated BnLIP2, was isolated from Brassica napus L. BnLIP2 was 1,300 bp long, with 1,122 bp open reading frame (ORF) encoding 373 amino acid residues. Sequence analysis indicated that BnLIP2 belonged to GDSL family. Southern blot analysis indicated that BnLIP2 belonged to a small gene family in rapeseed genome. RT-PCR analysis revealed that BnLIP2 was a tissue-specific expressing gene during reproductive growth and strongly expressed during seed germination. BnLIP2 expression could not be detected until three days after germination, and it subsequently became stronger. The transcript of this gene was deficient in root of seedlings growing at different stages. When juvenile seedlings were treated by methyl jasmonate (MeJ), salicylic acid (SA) and naphthalene acetic acid (NAA), BnLIP2 expression could not be induced in root. Our study implicates that BnLIP2 probably plays an important role in rapeseed germination, morphogenesis, flowering, but independent of root growth and development.

Published
2006
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