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182 results on '"Jakobsdottir, Johanna"'

2. Elevated symptoms of depression and anxiety among family members and friends of critically ill COVID-19 patients – an observational study of five cohorts across four countries

Author

Lovik, Anikó, González-Hijón, Juan, Hoffart, Asle, Fawns-Ritchie, Chloe, Magnúsdóttir, Ingibjörg, Lu, Li, Unnarsdóttir, Anna Bára, Kähler, Anna K., Campbell, Archie, Hauksdóttir, Arna, Chourpiliadis, Charilaos, McCartney, Daniel L., Thordardóttir, Edda Björk, Joyce, Emily E., Frans, Emma M., Jakobsdóttir, Jóhanna, Trogstad, Lill, Andreassen, Ole A., Magnus, Per, Johnson, Sverre Urnes, Sullivan, Patrick F., Aspelund, Thor, Porteous, David J., Ask, Helga, Ebrahimi, Omid V., Valdimarsdóttir, Unnur Anna, and Fang, Fang

Published
2023
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3. 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, and Loeffler, Markus

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

Published
2019

4. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Alzheimer Disease Genetics Consortium, European Alzheimer’s Disease Initiative, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

5. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Neurosciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Aged, Alzheimer Disease, Amyloid beta-Peptides, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Haplotypes, Humans, Immunity, Lipid Metabolism, Lipids, Male, tau Proteins, Alzheimer Disease Genetics Consortium (ADGC), European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019

7. Acute COVID-19 severity and mental health morbidity trajectories in patient populations of six nations: an observational study

Author

Magnúsdóttir, Ingibjörg, Lovik, Anikó, Unnarsdóttir, Anna Bára, McCartney, Daniel, Ask, Helga, Kõiv, Kadri, Nordahl Christoffersen, Lea Arregui, Johnson, Sverre Urnes, McIntosh, Andrew, Kähler, Anna K., Campbell, Archie, Hauksdóttir, Arna, Fawns-Ritchie, Chloe, Erikstrup, Christian, Helenius, Dorte, Altschul, Drew, Thordardottir, Edda Bjork, Eyþórsson, Elías, Frans, Emma M., Tómasson, Gunnar, Jónsdóttir, Harpa Lind, Rúnarsdóttir, Harpa, Hjalgrim, Henrik, Harõardóttir, Hrönn, González-Hijón, Juan, Banasik, Karina, Dinh, Khoa Manh, Lu, Li, Milani, Lili, Trogstad, Lill, Didriksen, Maria, Ebrahimi, Omid V., Sullivan, Patrick F., Magnus, Per Minor, Shen, Qing, Nesvåg, Ragnar, Mägi, Reedik, Pálsson, Runólfur, Ostrowski, Sisse Rye, Werge, Thomas, Hoffart, Asle, Porteous, David J, Fang, Fang, Jakobsdóttir, Jóhanna, Lehto, Kelli, Andreassen, Ole A., Pedersen, Ole B.V., Aspelund, Thor, Valdimarsdóttir, Unnur Anna, Christoffersen, Lea Arregui Nordahl, Ebrahimi, Omid V, Andreassen, Ole A, and Pedersen, Ole B V

Published
2022
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8. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author

Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert V., Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I., Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I., Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K., Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel I., Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O’Connell, Jeffrey, Rotter, Jerome I., Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikäinen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O’Donoghue, Michelle L., Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimäki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tõnu, Haller, Toomas, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J., Stefansson, Kari, Böger, Carsten A., Hung, Adriana M., Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, and Heid, Iris M.

Published
2022
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9. Co-regulatory networks of human serum proteins link genetics to disease.

Author

Emilsson, Valur, Ilkov, Marjan, Lamb, John, Finkel, Nancy, Gudmundsson, Elias, Pitts, Rebecca, Hoover, Heather, Gudmundsdottir, Valborg, Horman, Shane, Aspelund, Thor, Shu, Le, Trifonov, Vladimir, Sigurdsson, Sigurdur, Manolescu, Andrei, Zhu, Jun, Olafsson, Örn, Jakobsdottir, Johanna, Lesley, Scott, To, Jeremy, Zhang, Jia, Harris, Tamara, Launer, Lenore, Zhang, Bin, Eiriksdottir, Gudny, Yang, Xia, Orth, Anthony, Jennings, Lori, and Gudnason, Vilmundur

Subjects
Aptamers, Nucleotide, Blood Proteins, Cardiovascular Diseases, Genetic Predisposition to Disease, Genetic Variation, Humans, Iceland, Metabolic Diseases, Metabolic Networks and Pathways, Proteome, Proteomics
Abstract

Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.

Published
2018

10. Mental illness and COVID-19 vaccination: a multinational investigation of observational & register-based data

Author

Barker, Mary M, primary, Koiv, Kadri, additional, Magnusdottir, Ingibjorg, additional, Milbourn, Hannah, additional, Wang, Bin, additional, Du, Xinkai, additional, Murphy, Gillian, additional, Herweijer, Eva, additional, Gisladottir, Elisabet U, additional, Li, Huiqi, additional, Lovik, Aniko, additional, Kahler, Anna K, additional, Campbell, Archie, additional, Feychting, Maria, additional, Hauksdottir, Arna, additional, Joyce, Emily E, additional, Thordardottir, Edda Bjork, additional, Frans, Emma, additional, Hoffart, Asle, additional, Magi, Reedik, additional, Tomasson, Gunnar, additional, Asbjornsdottir, Kristjana, additional, Jakobsdottir, Johanna, additional, Andreassen, Ole, additional, Sullivan, Patrick, additional, Johnson, Sverre Urnes, additional, Aspelund, Thor, additional, Brandlistuen, Ragnhild Eek, additional, Ask, Helga, additional, McCartney, Daniel L., additional, Ebrahimi, Omid V, additional, Lehto, Kelli, additional, Valdimarsdottir, Unnur, additional, Nyberg, Fredrik, additional, and Fang, Fang, additional

Published
2024
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11. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, and Boccardi, Virginia

Subjects
ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI, Microglia, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Immunologic, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Amino Acid Sequence, Sequence Homology, Amino Acid, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Phospholipase C gamma, Immunity, Innate, Protein Interaction Maps, Exome, Neurodegenerative, Brain Disorders, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017

12. Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2

Author

Nielson, Carrie M, Liu, Ching‐Ti, Smith, Albert V, Ackert‐Bicknell, Cheryl L, Reppe, Sjur, Jakobsdottir, Johanna, Wassel, Christina, Register, Thomas C, Oei, Ling, Alonso, Nerea, Oei, Edwin H, Parimi, Neeta, Samelson, Elizabeth J, Nalls, Mike A, Zmuda, Joseph, Lang, Thomas, Bouxsein, Mary, Latourelle, Jeanne, Claussnitzer, Melina, Siggeirsdottir, Kristin, Srikanth, Priya, Lorentzen, Erik, Vandenput, Liesbeth, Langefeld, Carl, Raffield, Laura, Terry, Greg, Cox, Amanda J, Allison, Matthew A, Criqui, Michael H, Bowden, Don, Ikram, M Arfan, Mellström, Dan, Karlsson, Magnus K, Carr, John, Budoff, Matthew, Phillips, Caroline, Cupples, L Adrienne, Chou, Wen‐Chi, Myers, Richard H, Ralston, Stuart H, Gautvik, Kaare M, Cawthon, Peggy M, Cummings, Steven, Karasik, David, Rivadeneira, Fernando, Gudnason, Vilmundur, Orwoll, Eric S, Harris, Tamara B, Ohlsson, Claes, Kiel, Douglas P, and Hsu, Yi‐Hsiang

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Human Genome, Aging, Osteoporosis, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Animals, Biopsy, Bone Density, Cancellous Bone, Excitatory Amino Acid Transporter 1, Gene Expression Regulation, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Lumbar Vertebrae, Mice, Molecular Sequence Annotation, Organ Size, Osteoblasts, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptor, EphB2, Risk Factors, Spinal Fractures, Spine, BONE QCT, CT, ANALYSIS, QUANTITATION OF BONE, OSTEOPOROSIS, DISEASES AND DISORDERS OF, RELATED TO BONE, GENERAL POPULATION STUDIES, EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES, GENETIC RESEARCH, FRACTURE RISK ASSESSMENT, ANALYSIS/QUANTITATION OF BONE, BONE QCT/μCT, DISEASES AND DISORDERS OF/RELATED TO BONE, EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

Published
2016

13. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

Author

Jakobsdottir, Johanna, van der Lee, Sven J, Bis, Joshua C, Chouraki, Vincent, Li-Kroeger, David, Yamamoto, Shinya, Grove, Megan L, Naj, Adam, Vronskaya, Maria, Salazar, Jose L, DeStefano, Anita L, Brody, Jennifer A, Smith, Albert V, Amin, Najaf, Sims, Rebecca, Ibrahim-Verbaas, Carla A, Choi, Seung-Hoan, Satizabal, Claudia L, Lopez, Oscar L, Beiser, Alexa, Ikram, M Arfan, Garcia, Melissa E, Hayward, Caroline, Varga, Tibor V, Ripatti, Samuli, Franks, Paul W, Hallmans, Göran, Rolandsson, Olov, Jansson, Jan-Håkon, Porteous, David J, Salomaa, Veikko, Eiriksdottir, Gudny, Rice, Kenneth M, Bellen, Hugo J, Levy, Daniel, Uitterlinden, Andre G, Emilsson, Valur, Rotter, Jerome I, Aspelund, Thor, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium, O'Donnell, Christopher J, Fitzpatrick, Annette L, Launer, Lenore J, Hofman, Albert, Wang, Li-San, Williams, Julie, Schellenberg, Gerard D, Boerwinkle, Eric, Psaty, Bruce M, Seshadri, Sudha, Shulman, Joshua M, Gudnason, Vilmundur, and van Duijn, Cornelia M

Subjects
Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium, Animals, Humans, Drosophila melanogaster, Alzheimer Disease, Intracellular Signaling Peptides and Proteins, Amyloid beta-Protein Precursor, Apolipoproteins E, Tropomyosin, Drosophila Proteins, Membrane Proteins, Genomics, Age of Onset, Phenotype, Mutation, Alleles, Aged, European Continental Ancestry Group, Iceland, Female, Male, Receptors, Notch, Genome-Wide Association Study, Exome, Receptors, Notch, Genetics, Developmental Biology
Abstract

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus

Published
2016

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

Author

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

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

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

Published
2016

15. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Author

Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie-France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen-Torvik, Laura J, Grarup, Niels, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork-Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater-Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J, Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii-DerI, Cheng, Ching-Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abbas, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki-Eleni, Frånberg, Mattias, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, IT, Lee, Wen-Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, and Malerba, Giovanni

Subjects
EPIC-InterAct Consortium, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Insulin, Glucose-6-Phosphatase, Blood Glucose, Oligonucleotide Array Sequence Analysis, Fasting, Polymorphism, Single Nucleotide, African Continental Ancestry Group, European Continental Ancestry Group, Genetic Variation, Genetic Loci, Genetic Association Studies, Mutation Rate, Exome, Glucagon-Like Peptide-1 Receptor, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Diabetes, Genetics, Nutrition, Clinical Research, Prevention, Human Genome, 2.1 Biological and endogenous factors, Metabolic and Endocrine
Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Published
2015

16. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Author

Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G, Zheng, Hou-Feng, Smith, Albert V, Pye, Stephen R, Leo, Paul J, Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L, Hayward, Caroline, Olmos, José M, Lyytikäinen, Leo-Pekka, Lewis, Joshua R, Swart, Karin MA, Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G, Cheng, Sulin, van Schoor, Natasja M, Harvey, Nicholas C, Kruk, Marcin, del Greco M, Fabiola, Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J, Williams, Frances M, Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L, Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W, McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Åsa, Hicks, Andrew A, Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie AM, van der Velde, Nathalie, Kähönen, Mika, Viikari, Jorma S, Sievänen, Harri, Raitakari, Olli T, González-Macías, Jesús, Hernández, Jose L, Mellström, Dan, Ljunggren, Osten, Cho, Yoon Shin, Völker, Uwe, Nauck, Matthias, Homuth, Georg, Völzke, Henry, Haring, Robin, Brown, Matthew A, McCloskey, Eugene, Nicholson, Geoffrey C, Eastell, Richard, Eisman, John A, Jones, Graeme, Reid, Ian R, Dennison, Elaine M, Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick CW, Aspelund, Thor, Richards, J Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P, and Lorenc, Roman S

Subjects
Calcaneus, Humans, Osteoporosis, Genetic Predisposition to Disease, Ultrasonography, Cohort Studies, Bone Density, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Fractures, Bone, Genome-Wide Association Study, Young Adult, Human Genome, Genetics, Aging, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Published
2014

17. Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

Author

Peloso, Gina M, Auer, Paul L, Bis, Joshua C, Voorman, Arend, Morrison, Alanna C, Stitziel, Nathan O, Brody, Jennifer A, Khetarpal, Sumeet A, Crosby, Jacy R, Fornage, Myriam, Isaacs, Aaron, Jakobsdottir, Johanna, Feitosa, Mary F, Davies, Gail, Huffman, Jennifer E, Manichaikul, Ani, Davis, Brian, Lohman, Kurt, Joon, Aron Y, Smith, Albert V, Grove, Megan L, Zanoni, Paolo, Redon, Valeska, Demissie, Serkalem, Lawson, Kim, Peters, Ulrike, Carlson, Christopher, Jackson, Rebecca D, Ryckman, Kelli K, Mackey, Rachel H, Robinson, Jennifer G, Siscovick, David S, Schreiner, Pamela J, Mychaleckyj, Josyf C, Pankow, James S, Hofman, Albert, Uitterlinden, Andre G, Harris, Tamara B, Taylor, Kent D, Stafford, Jeanette M, Reynolds, Lindsay M, Marioni, Riccardo E, Dehghan, Abbas, Franco, Oscar H, Patel, Aniruddh P, Lu, Yingchang, Hindy, George, Gottesman, Omri, Bottinger, Erwin P, Melander, Olle, Orho-Melander, Marju, Loos, Ruth JF, Duga, Stefano, Merlini, Piera Angelica, Farrall, Martin, Goel, Anuj, Asselta, Rosanna, Girelli, Domenico, Martinelli, Nicola, Shah, Svati H, Kraus, William E, Li, Mingyao, Rader, Daniel J, Reilly, Muredach P, McPherson, Ruth, Watkins, Hugh, Ardissino, Diego, Project, NHLBI GO Exome Sequencing, Zhang, Qunyuan, Wang, Judy, Tsai, Michael Y, Taylor, Herman A, Correa, Adolfo, Griswold, Michael E, Lange, Leslie A, Starr, John M, Rudan, Igor, Eiriksdottir, Gudny, Launer, Lenore J, Ordovas, Jose M, Levy, Daniel, Chen, Y-D Ida, Reiner, Alexander P, Hayward, Caroline, Polasek, Ozren, Deary, Ian J, Borecki, Ingrid B, Liu, Yongmei, Gudnason, Vilmundur, Wilson, James G, van Duijn, Cornelia M, Kooperberg, Charles, Rich, Stephen S, Psaty, Bruce M, Rotter, Jerome I, O’Donnell, Christopher J, Rice, Kenneth, Boerwinkle, Eric, Kathiresan, Sekar, and Cupples, L Adrienne

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease - Coronary Heart Disease, Human Genome, Cardiovascular, Heart Disease, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, Aged, Alleles, Animals, Black People, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Coronary Disease, Female, Gene Frequency, Genetic Association Studies, Genetic Code, Genetic Variation, Humans, Linear Models, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins, Middle Aged, Phenotype, Sequence Analysis, DNA, Subtilisins, Triglycerides, White People, NHLBI GO Exome Sequencing Project, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Published
2014

18. Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol

Author

Lange, Leslie A, Hu, Youna, Zhang, He, Xue, Chenyi, Schmidt, Ellen M, Tang, Zheng-Zheng, Bizon, Chris, Lange, Ethan M, Smith, Joshua D, Turner, Emily H, Jun, Goo, Kang, Hyun Min, Peloso, Gina, Auer, Paul, Li, Kuo-ping, Flannick, Jason, Zhang, Ji, Fuchsberger, Christian, Gaulton, Kyle, Lindgren, Cecilia, Locke, Adam, Manning, Alisa, Sim, Xueling, Rivas, Manuel A, Holmen, Oddgeir L, Gottesman, Omri, Lu, Yingchang, Ruderfer, Douglas, Stahl, Eli A, Duan, Qing, Li, Yun, Durda, Peter, Jiao, Shuo, Isaacs, Aaron, Hofman, Albert, Bis, Joshua C, Correa, Adolfo, Griswold, Michael E, Jakobsdottir, Johanna, Smith, Albert V, Schreiner, Pamela J, Feitosa, Mary F, Zhang, Qunyuan, Huffman, Jennifer E, Crosby, Jacy, Wassel, Christina L, Do, Ron, Franceschini, Nora, Martin, Lisa W, Robinson, Jennifer G, Assimes, Themistocles L, Crosslin, David R, Rosenthal, Elisabeth A, Tsai, Michael, Rieder, Mark J, Farlow, Deborah N, Folsom, Aaron R, Lumley, Thomas, Fox, Ervin R, Carlson, Christopher S, Peters, Ulrike, Jackson, Rebecca D, van Duijn, Cornelia M, Uitterlinden, André G, Levy, Daniel, Rotter, Jerome I, Taylor, Herman A, Gudnason, Vilmundur, Siscovick, David S, Fornage, Myriam, Borecki, Ingrid B, Hayward, Caroline, Rudan, Igor, Chen, Y Eugene, Bottinger, Erwin P, Loos, Ruth JF, Sætrom, Pål, Hveem, Kristian, Boehnke, Michael, Groop, Leif, McCarthy, Mark, Meitinger, Thomas, Ballantyne, Christie M, Gabriel, Stacey B, O’Donnell, Christopher J, Post, Wendy S, North, Kari E, Reiner, Alexander P, Boerwinkle, Eric, Psaty, Bruce M, Altshuler, David, Kathiresan, Sekar, Lin, Dan-Yu, Jarvik, Gail P, Cupples, L Adrienne, Kooperberg, Charles, Wilson, James G, Nickerson, Deborah A, Abecasis, Goncalo R, and Rich, Stephen S

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Prevention, Clinical Research, Heart Disease, Cardiovascular, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Apolipoproteins E, Cholesterol, LDL, Cohort Studies, Dyslipidemias, Exome, Female, Follow-Up Studies, Gene Frequency, Genetic Code, Genome-Wide Association Study, Genotype, Humans, Lipase, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Sequence Analysis, DNA, Serine Endopeptidases, NHLBI Grand Opportunity Exome Sequencing Project, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or

Published
2014

19. Childhood maltreatment and subsequent risk of hospitalization or death due to COVID-19: a cohort study in the UK Biobank

Author

Wang, Yue, primary, Ge, Fenfen, additional, Aspelund, Thor, additional, Ask, Helga, additional, Hauksdottir, Arna, additional, Hu, Kejia, additional, Jakobsdottir, Johanna, additional, Zoega, Helga, additional, Shen, Qing, additional, Whalley, Heather C, additional, Pedersen, Ole Birger Vesterager, additional, Lehto, Kelli, additional, Andreassen, Ole A, additional, Fang, Fang, additional, Song, Huan, additional, and Valdimarsdottir, Unnur A, additional

Published
2023
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20. COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark

Author

Shen, Qing, primary, Joyce, Emily E., additional, Ebrahimi, Omid V., additional, Didriksen, Maria, additional, Lovik, Aniko, additional, Savarsdottir, Karen Sol, additional, Magnusdottir, Ingibjorg, additional, Mikkelsen, Dorte Helenius, additional, Unnarsdottir, Anna Bara, additional, Hauksdottir, Arna, additional, Hoffart, Asle, additional, Kahler, Anna, additional, Thordardottir, Edda Bjork, additional, Eythorsson, Elias, additional, Frans, Emma M., additional, Tomasson, Gunnar, additional, Ask, Helga, additional, Hardardottir, Hronn, additional, Jakobsdottir, Johanna, additional, Lehto, Kelli, additional, Lu, Li, additional, Andreassen, Ole, additional, Sullivan, Patrick, additional, Palsson, Runolfur, additional, Erikstrup, Christian, additional, Ostrowski, Sisse Rye, additional, Werge, Thomas, additional, Aspelund, Thor, additional, Pedersen, Ole B. V., additional, Johnson, Sverre Urnes, additional, Fang, Fang, additional, and Valdimarsdottir, Unnur, additional

Published
2023
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21. Interpretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers.

Author

Jakobsdottir, Johanna, Gorin, Michael B, Conley, Yvette P, Ferrell, Robert E, and Weeks, Daniel E

Subjects
Humans, Prostatic Neoplasms, Inflammatory Bowel Diseases, Macular Degeneration, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genetic Markers, Logistic Models, Odds Ratio, Polymorphism, Single Nucleotide, Male, Genome-Wide Association Study, Genetic Testing, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

Recent successful discoveries of potentially causal single nucleotide polymorphisms (SNPs) for complex diseases hold great promise, and commercialization of genomics in personalized medicine has already begun. The hope is that genetic testing will benefit patients and their families, and encourage positive lifestyle changes and guide clinical decisions. However, for many complex diseases, it is arguable whether the era of genomics in personalized medicine is here yet. We focus on the clinical validity of genetic testing with an emphasis on two popular statistical methods for evaluating markers. The two methods, logistic regression and receiver operating characteristic (ROC) curve analysis, are applied to our age-related macular degeneration dataset. By using an additive model of the CFH, LOC387715, and C2 variants, the odds ratios are 2.9, 3.4, and 0.4, with p-values of 10(-13), 10(-13), and 10(-3), respectively. The area under the ROC curve (AUC) is 0.79, but assuming prevalences of 15%, 5.5%, and 1.5% (which are realistic for age groups 80 y, 65 y, and 40 y and older, respectively), only 30%, 12%, and 3% of the group classified as high risk are cases. Additionally, we present examples for four other diseases for which strongly associated variants have been discovered. In type 2 diabetes, our classification model of 12 SNPs has an AUC of only 0.64, and two SNPs achieve an AUC of only 0.56 for prostate cancer. Nine SNPs were not sufficient to improve the discrimination power over that of nongenetic predictors for risk of cardiovascular events. Finally, in Crohn's disease, a model of five SNPs, one with a quite low odds ratio of 0.26, has an AUC of only 0.66. Our analyses and examples show that strong association, although very valuable for establishing etiological hypotheses, does not guarantee effective discrimination between cases and controls. The scientific community should be cautious to avoid overstating the value of association findings in terms of personalized medicine before their time.

Published
2009

22. C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes.

Author

Jakobsdottir, Johanna, Conley, Yvette P, Weeks, Daniel E, Ferrell, Robert E, and Gorin, Michael B

Subjects
Humans, Macular Degeneration, Genetic Predisposition to Disease, Complement Factor B, Complement Factor H, Case-Control Studies, Aging, Polymorphism, Single Nucleotide, Complement C2, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

BackgroundAge-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement factor H (CFH) and the poorly characterized LOC387715 (ARMS2), are widely recognized as ARM risk factors. CFH is important in regulation of the alternative complement pathway suggesting this pathway is involved in ARM pathogenesis. Two other complement pathway genes, the closely linked complement component receptor (C2) and complement factor B (CFB), were recently shown to harbor variants associated with ARM.Methods/principal findingsWe investigated two SNPs in C2 and two in CFB in independent case-control and family cohorts of white subjects and found rs547154, an intronic SNP in C2, to be significantly associated with ARM in both our case-control (P-value 0.00007) and family data (P-value 0.00001). Logistic regression analysis suggested that accounting for the effect at this locus significantly (P-value 0.002) improves the fit of a genetic risk model of CFH and LOC387715 effects only. Modeling with the generalized multifactor dimensionality reduction method showed that adding C2 to the two-factor model of CFH and LOC387715 increases the sensitivity (from 63% to 73%). However, the balanced accuracy increases only from 71% to 72%, and the specificity decreases from 80% to 72%.Conclusions/significanceC2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant.

Published
2008

23. Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Author

Nagtegaal, Andries Paul, Broer, Linda, Zilhao, Nuno R., Jakobsdottir, Johanna, Bishop, Charles E., Brumat, Marco, Christiansen, Mark W., Cocca, Massimiliano, Gao, Yan, Heard-Costa, Nancy L., Evans, Daniel S., Pankratz, Nathan, Pratt, Sheila R., Price, T. Ryan, Spankovich, Christopher, Stimson, Mary R., Valle, Karen, Vuckovic, Dragana, Wells, Helena, Eiriksdottir, Gudny, Fransen, Erik, Ikram, Mohammad Arfan, Li, Chuang-Ming, Longstreth, Jr, W. T., Steves, Claire, Van Camp, Guy, Correa, Adolfo, Cruickshanks, Karen J., Gasparini, Paolo, Girotto, Giorgia, Kaplan, Robert C., Nalls, Michael, Schweinfurth, John M., Seshadri, Sudha, Sotoodehnia, Nona, Tranah, Gregory J., Uitterlinden, André G., Wilson, James G., Gudnason, Vilmundur, Hoffman, Howard J., Williams, Frances M. K., and Goedegebure, André

Published
2019
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24. CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses

Author

Conley, Yvette P, Jakobsdottir, Johanna, Mah, Tammy, Weeks, Daniel E, Klein, Ronald, Kuller, Lewis, Ferrell, Robert E, and Gorin, Michael B

Subjects
Biological Sciences, Genetics, Aging, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, Aetiology, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Complement Factor H, Eye Proteins, Female, Genetic Predisposition to Disease, Humans, Intracellular Signaling Peptides and Proteins, Macular Degeneration, Male, Membrane Proteins, Proteins, Medical and Health Sciences, Genetics & Heredity
Abstract

Age-related maculopathy (ARM) is an important cause of visual impairment in the elderly population. It is of crucial importance to identify genetic factors and their interactions with environmental exposures for this disorder. This study was aimed at investigating the CFH, ELOVL4, PLEKHA1 and LOC387715 genes in independent cohorts collected using different ascertainment schemes. The study used a case-control design with subjects originally recruited through the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). CFH was significantly associated with ARM in both cohorts (P

Published
2006

25. Susceptibility Genes for Age-Related Maculopathy on Chromosome 10q26

Author

Jakobsdottir, Johanna, Conley, Yvette P, Weeks, Daniel E, Mah, Tammy S, Ferrell, Robert E, and Gorin, Michael B

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Clinical Research, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 10, Cohort Studies, Gene Frequency, Genetic Linkage, Genetic Predisposition to Disease, Humans, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Macular Degeneration, Membrane Proteins, Odds Ratio, Pedigree, Polymorphism, Single Nucleotide, United States, White People, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

On the basis of genomewide linkage studies of families affected with age-related maculopathy (ARM), we previously identified a significant linkage peak on 10q26, which has been independently replicated by several groups. We performed a focused SNP genotyping study of our families and an additional control cohort. We identified a strong association signal overlying three genes, PLEKHA1, LOC387715, and PRSS11. All nonsynonymous SNPs in this critical region were genotyped, yielding a highly significant association (P < .00001) between PLEKHA1/LOC387715 and ARM. Although it is difficult to determine statistically which of these two genes is most important, SNPs in PLEKHA1 are more likely to account for the linkage signal in this region than are SNPs in LOC387715; thus, this gene and its alleles are implicated as an important risk factor for ARM. We also found weaker evidence supporting the possible involvement of the GRK5/RGS10 locus in ARM. These associations appear to be independent of the association of ARM with the Y402H allele of complement factor H, which has previously been reported as a major susceptibility factor for ARM. The combination of our analyses strongly implicates PLEKHA1/LOC387715 as primarily responsible for the evidence of linkage of ARM to the 10q26 locus and as a major contributor to ARM susceptibility. The association of either a single or a double copy of the high-risk allele within the PLEKHA1/LOC387715 locus accounts for an odds ratio of 5.0 (95% confidence interval 3.2-7.9) for ARM and a population attributable risk as high as 57%.

Published
2005

26. Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy.

Author

Conley, Yvette P, Thalamuthu, Anbupalam, Jakobsdottir, Johanna, Weeks, Daniel E, Mah, Tammy, Ferrell, Robert E, and Gorin, Michael B

Subjects
Humans, Macular Degeneration, Fatty Acids, DNA Primers, Case-Control Studies, Base Sequence, Aging, Gene Frequency, Phenotype, Polymorphism, Genetic, Alleles, Complement System Proteins, Human Genome, Neurodegenerative, Genetics, 2.1 Biological and endogenous factors, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract

Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case-control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case-control allele (P=0.001), case-control genotype (P=0.001) and case-control family (P

Published
2005

27. Genetic variants near TIMP3 and high-density lipoprotein—associated loci influence susceptibility to age-related macular degeneration

Author

Chen, Wei, Stambolian, Dwight, Edwards, Albert O., Branham, Kari E., Othman, Mohammad, Jakobsdottir, Johanna, Tosakulwong, Nirubol, Pericak-Vance, Margaret A., Campochiaro, Peter A., Klein, Michael L., Tan, Perciliz L., Conley, Yvette P., Kanda, Atsuhiro, Kopplin, Laura, Li, Yanming, Augustaitis, Katherine J., Karoukis, Athanasios J., Scott, William K., Agarwal, Anita, Kovach, Jaclyn L., Schwartz, Stephen G., Postel, Eric A., Brooks, Matthew, Baratz, Keith H., Brown, William L., Brucker, Alexander J., Orlin, Anton, Brown, Gary, Ho, Allen, Regillo, Carl, Donoso, Larry, Tian, Lifeng, Kaderli, Brian, Hadley, Dexter, Hagstrom, Stephanie A., Peachey, Neal S., Klein, Ronald, Klein, Barbara E. K., Gotoh, Norimoto, Yamashiro, Kenji, Ferris,, Frederick, Fagerness, Jesen A., Reynolds, Robyn, Farrer, Lindsay A., Kim, Ivana K., Miller, Joan W., Cortón, Marta, Carracedo, Angel, Sanchez-Salorio, Manuel, Pugh, Elizabeth W., Doheny, Kimberly F., Brion, Maria, DeAngelis, Margaret M., Weeks, Daniel E., Zack, Donald J., Chew, Emily Y., Heckenlively, John R., Yoshimura, Nagahisa, Iyengar, Sudha K., Francis, Peter J., Katsanis, Nicholas, Seddon, Johanna M., Haines, Jonathan L., Gorin, Michael B., Abecasis, Gonçalo R., Swaroop, Anand, and Keating, Mark T.

Published
2010

30. PLD3 variants in population studies

Author

van der Lee, Sven J., Holstege, Henne, Wong, Tsz Hang, Jakobsdottir, Johanna, Bis, Joshua C., Chouraki, Vincent, van Rooij, Jeroen G. J., Grove, Megan L., Smith, Albert V., Amin, Najaf, Choi, Seung-Hoan, Beiser, Alexa S., Garcia, Melissa E., van IJcken, Wilfred F. J., Pijnenburg, Yolande A. L., Louwersheimer, Eva, Brouwer, Rutger W. W., van den Hout, Mirjam C. G. N., Oole, Edwin, Eirkisdottir, Gudny, Levy, Daniel, Rotter, Jerome I., Emilsson, Valur, OʼDonnell, Christopher J., Aspelund, Thor, Uitterlinden, Andre G., Launer, Lenore J., Hofman, Albert, Boerwinkle, Eric, Psaty, Bruce M., DeStefano, Anita L., Scheltens, Philip, Seshadri, Sudha, van Swieten, John C., Gudnason, Vilmundur, van der Flier, Wiesje M., Ikram, Arfan M., and van Duijn, Cornelia M.

Published
2015
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31. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype

Author

Sofat, Reecha, Casas, Juan P, Webster, Andrew R, Bird, Alan C, Mann, Samantha S, Yates, John RW, Moore, Anthony T, Sepp, Tiina, Cipriani, Valentina, Bunce, Catey, Khan, Jane C, Shahid, Humma, Swaroop, Anand, Abecasis, Gonçalo, Branham, Kari E H, Zareparsi, Sepideh, Bergen, Arthur A, Klaver, Caroline CW, Baas, Dominique C, Zhang, Kang, Chen, Yuhong, Gibbs, Daniel, Weber, Bernhard H F, Keilhauer, Claudia N, Fritsche, Lars G, Lotery, Andrew, Cree, Angela J, Griffiths, Helen L, Bhattacharya, Shomi S, Chen, Li L, Jenkins, Sharon A, Peto, Tunde, Lathrop, Mark, Leveillard, Thierry, Gorin, Michael B, Weeks, Daniel E, Ortube, Maria Carolina, Ferrell, Robert E, Jakobsdottir, Johanna, Conley, Yvette P, Rahu, Mati, Seland, Johan H, Soubrane, Gisele, Topouzis, Fotis, Vioque, Jesus, Tomazzoli, Laura, Young, Ian, Whittaker, John, Chakravarthy, Usha, de Jong, Paulus T V M, Smeeth, Liam, Fletcher, Astrid, and Hingorani, Aroon D

Published
2012
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33. A catalog of genetic loci associated with kidney function from analyses of a million individuals

Author

Wuttke, Matthias, Li, Yong, Li, Man, Sieber, Karsten B., Feitosa, Mary F., Gorski, Mathias, Tin, Adrienne, Wang, Lihua, Chu, Audrey Y., Hoppmann, Anselm, Kirsten, Holger, Giri, Ayush, Chai, Jin-Fang, Sveinbjornsson, Gardar, Tayo, Bamidele O., Nutile, Teresa, Fuchsberger, Christian, Marten, Jonathan, Cocca, Massimiliano, Ghasemi, Sahar, Xu, Yizhe, Horn, Katrin, Noce, Damia, van der Most, Peter J., Sedaghat, Sanaz, Yu, Zhi, Akiyama, Masato, Afaq, Saima, Ahluwalia, Tarunveer S., Almgren, Peter, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boehnke, Michael, Boerwinkle, Eric, Boissel, Mathilde, Bottinger, Erwin P., Boutin, Thibaud S., Brenner, Hermann, Brumat, Marco, Burkhardt, Ralph, Butterworth, Adam S., Campana, Eric, Campbell, Archie, Campbell, Harry, Canouil, Mickaël, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Chee, Miao-Ling, Chee, Miao-Li, Chen, Xu, Cheng, Ching-Yu, Cheng, Yurong, Christensen, Kaare, Cifkova, Renata, Ciullo, Marina, Pina Concas, Maria, Cook, James P., Coresh, Josef, Corre, Tanguy, Sala, Cinzia Felicita, Cusi, Daniele, Danesh, John, Daw, E. Warwick, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Degenhardt, Frauke, Delgado, Graciela, Demirkan, Ayse, Di Angelantonio, Emanuele, Dittrich, Katalin, Divers, Jasmin, Dorajoo, Rajkumar, Eckardt, Kai-Uwe, Ehret, Georg, Elliott, Paul, Endlich, Karlhans, Evans, Michele K., Felix, Janine F., Foo, Valencia Hui Xian, Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Friedlander, Yechiel, Froguel, Philippe, Gansevoort, Ron T., Gao, He, Gasparini, Paolo, Gaziano, J. Michael, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Giulianini, Franco, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hartman, Catharina A., Hayward, Caroline, Hellwege, Jacklyn N., Heng, Chew-Kiat, Hickst, Andrew A., Hofer, Edith, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, ikram, M. Arfan, indridason, Olafur S., Ingelsson, Erik, ising, Marcus, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Jonas, Jost B, Joshi, Peter K., Shilpa Josyula, Navya, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kammerer, Candace M., Kanai, Masahiro, Kastarinen, Mika, Kerr, Shona M., Khor, Chiea-Chuen, Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kraja, Aldi T., Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, Kuokkanen, Mikko, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lange, Leslie A., Langefeld, Carl D., Jen-Mai Lee, Jeannette, Lehne, Benjamin, Lehtimäki, Terho, Lieb, Wolfgang, Cohort Study, Lifelines, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jun, Liu, Jianjun, Loeffler, Markus, Loos, Ruth J. F., Lucae, Susanne, Ann Lukas, Mary, Lyytikäinen, Leo-Pekka, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Martins, Jade, März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Christa Meisinger, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mikaelsdottir, Evgenia K., Milaneschi, Yuri, Miliku, Kozeta, Mishra, Pashupati P., Veteran Program, V. A. Million, Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mychaleckyj, Josyf C., Nadkarni, Girish N, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, ilja M., Noordam, Raymond, O’Connell, Jeffrey, O’Donoghue, Michelle L., Olafsson, Isleifur, Oldehinkel, Albertine J., Orho-Melander, Marju, Ouwehand, Willem H., Padmanabhan, Sandosh, Palmer, Nicholette D., Palsson, Runolfur, Penninx, Brenda W. J. H., Perls, Thomas, Perola, Markus, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Podgornaia, Anna I., Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Pramstaller, Peter P., Preuss, Michael H., Prins, Bram P., Province, Michael A., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Reilly, Dermot F., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Ridker, Paul M., Rivadeneira, Fernando, Rizzi, Federica, Roberts, David J., Robino, Antonietta, Rossing, Peter, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Sabanayagam, Charumathi, Salomaa, Veikko, Salvi, Erika, Saum, Kai-Uwe, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Schupf, Nicole, Shaffer, Christian M., Shi, Yuan, Smith, Albert V., Smith, Blair H., Soranzo, Nicole, Spracklen, Cassandra N., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Svensson, Per O., Szymczak, Silke, Tai, E-Shyong, Tajuddin, Salman M., Tan, Nicholas Y. Q., Taylor, Kent D., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomsen, Hauke, Thorleifsson, Gudmar, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Tzoulaki, Ioanna, Uitterlinden, André G., Vaccargiu, Simona, van Dam, Rob M., van der Harst, Pim, van Duijn, Cornelia M., Velez Edward, Digna R., Verweij, Niek, Vogelezang, suzanne, Völker, üwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Wallentin, Lars, Wang, Ya Xing, Wang, Chaolong, Waterworth, Dawn M., Bin Wei, Wen, White, Harvey, Whitfield, John B., Wild, Sarah H., Wilson, James F., Wojczynski, Mary K., Wong, Charlene, Wong, Tien-Yin, Xu, Liang, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Weihua, Zonderman, Alan B., Rotter, Jerome I., Bochud, Murielle, Psaty, Bruce M., Vitart, Veronique, Wilson, James G., Dehghan, Abbas, Parsa, Afshin, Chasman, Daniel I., Ho, Kevin, Morris, Andrew P., Devuyst, Olivier, Akilesh, Shreeram, Pendergrass, Sarah A., Sim, Xueling, Böger, Carsten A., Okada, Yukinori, Edwards, Todd L., Snieder, Harold, Stefansson, Kari, Hung, Adriana M., Heid, Iris M., Markus Scholz, Teumer, Alexander, Köttgen, Anna, Pattaro, Cristian, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Internal Medicine, Epidemiology, Erasmus MC other, Pediatrics, Psychiatry, APH - Mental Health, APH - Digital Health, Wuttke, M, Li, Y, Li, M, Sieber, Kb, Feitosa, Mf, Gorski, M, Tin, A, Wang, L, Chu, Ay, Hoppmann, A, Kirsten, H, Giri, A, Chai, Jf, Sveinbjornsson, G, Tayo, Bo, Nutile, T, Fuchsberger, C, Marten, J, Cocca, M, Ghasemi, S, Xu, Y, Horn, K, Noce, D, van der Most, Pj, Sedaghat, S, Yu, Z, Akiyama, M, Afaq, S, Ahluwalia, T, Almgren, P, Amin, N, Ärnlöv, J, Bakker, Sjl, Bansal, N, Baptista, D, Bergmann, S, Biggs, Ml, Biino, G, Boehnke, M, Boerwinkle, E, Boissel, M, Bottinger, Ep, Boutin, T, Brenner, H, Brumat, M, Burkhardt, R, Butterworth, A, Campana, Eric, Campbell, A, Campbell, H, Canouil, M, Carroll, Rj, Catamo, E, Chambers, Jc, Chee, Ml, Chen, X, Cheng, Cy, Cheng, Y, Christensen, K, Cifkova, R, Ciullo, M, Concas, Mp, Cook, Jp, Coresh, J, Corre, T, Sala, Cf, Cusi, D, Danesh, J, Daw, Ew, de Borst, Mh, De Grandi, A, de Mutsert, R, de Vries, Apj, Degenhardt, F, Delgado, G, Demirkan, A, Di Angelantonio, E, Dittrich, K, Divers, J, Dorajoo, R, Eckardt, Ku, Ehret, G, Elliott, P, Endlich, K, Evans, Mk, Felix, Jf, Foo, Vhx, Franco, Oh, Franke, A, Freedman, Bi, Freitag-Wolf, S, Friedlander, Y, Froguel, P, Gansevoort, Rt, Gao, H, Gasparini, P, Gaziano, Jm, Giedraitis, V, Gieger, C, Girotto, G, Giulianini, F, Gögele, M, Gordon, Sd, Gudbjartsson, Df, Gudnason, V, Haller, T, Hamet, P, Harris, Tb, Hartman, Ca, Hayward, C, Hellwege, Jn, Heng, Ck, Hicks, Aa, Hofer, E, Huang, W, Hutri-Kähönen, N, Hwang, Sj, Ikram, Ma, Indridason, O, Ingelsson, E, Ising, M, Jaddoe, Vwv, Jakobsdottir, J, Jonas, Jb, Joshi, Pk, Josyula, N, Jung, B, Kähönen, M, Kamatani, Y, Kammerer, Cm, Kanai, M, Kastarinen, M, Kerr, Sm, Khor, Cc, Kiess, W, Kleber, Me, Koenig, W, Kooner, J, Körner, A, Kovacs, P, Kraja, At, Krajcoviechova, A, Kramer, H, Krämer, Bk, Kronenberg, F, Kubo, M, Kühnel, B, Kuokkanen, M, Kuusisto, J, La Bianca, M, Laakso, M, Lange, La, Langefeld, Cd, Lee, Jj, Lehne, B, Lehtimäki, T, Lieb, W, Lifelines Cohort, Study, Lim, Sc, Lind, L, Lindgren, Cm, Liu, J, Loeffler, M, Loos, Rjf, Lucae, S, Lukas, Ma, Lyytikäinen, Lp, Mägi, R, Magnusson, Pke, Mahajan, A, Martin, Ng, Martins, J, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Melander, O, Metspalu, A, Mikaelsdottir, Ek, Milaneschi, Y, Miliku, K, Mishra, Pp, V. A., Million Veteran Program, Mohlke, Kl, Mononen, N, Montgomery, Gw, Mook-Kanamori, Do, Mychaleckyj, Jc, Nadkarni, Gn, Nalls, Ma, Nauck, M, Nikus, K, Ning, B, Nolte, Im, Noordam, R, O'Connell, J, O'Donoghue, Ml, Olafsson, I, Oldehinkel, Aj, Orho-Melander, M, Ouwehand, Wh, Padmanabhan, S, Palmer, Nd, Palsson, R, Penninx, Bwjh, Perls, T, Perola, M, Pirastu, M, Pirastu, N, Pistis, G, Podgornaia, Ai, Polasek, O, Ponte, B, Porteous, Dj, Poulain, T, Pramstaller, Pp, Preuss, Mh, Prins, Bp, Province, Ma, Rabelink, Tj, Raffield, Lm, Raitakari, Ot, Reilly, Df, Rettig, R, Rheinberger, M, Rice, Km, Ridker, Pm, Rivadeneira, F, Rizzi, F, Roberts, Dj, Robino, A, Rossing, P, Rudan, I, Rueedi, R, Ruggiero, D, Ryan, Ka, Saba, Y, Sabanayagam, C, Salomaa, V, Salvi, E, Saum, Ku, Schmidt, H, Schmidt, R, Schöttker, B, Schulz, Ca, Schupf, N, Shaffer, Cm, Shi, Y, Smith, Av, Smith, Bh, Soranzo, N, Spracklen, Cn, Strauch, K, Stringham, Hm, Stumvoll, M, Svensson, Po, Szymczak, S, Tai, E, Tajuddin, Sm, Tan, Nyq, Taylor, Kd, Teren, A, Tham, Yc, Thiery, J, Thio, Chl, Thomsen, H, Thorleifsson, G, Toniolo, D, Tönjes, A, Tremblay, J, Tzoulaki, I, Uitterlinden, Ag, Vaccargiu, S, van Dam, Rm, van der Harst, P, van Duijn, Cm, Velez Edward, Dr, Verweij, N, Vogelezang, S, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Wallentin, L, Wang, Yx, Wang, C, Waterworth, Dm, Bin Wei, W, White, H, Whitfield, Jb, Wild, Sh, Wilson, Jf, Wojczynski, Mk, Wong, C, Wong, Ty, Xu, L, Yang, Q, Yasuda, M, Yerges-Armstrong, Lm, Zhang, W, Zonderman, Ab, Rotter, Ji, Bochud, M, Psaty, Bm, Vitart, V, Wilson, Jg, Dehghan, A, Parsa, A, Chasman, Di, Ho, K, Morris, Ap, Devuyst, O, Akilesh, S, Pendergrass, Sa, Sim, X, Böger, Ca, Okada, Y, Edwards, Tl, Snieder, H, Stefansson, K, Hung, Am, Heid, Im, Scholz, M, Teumer, A, Köttgen, A, and Pattaro, C.

Subjects
catalog, Inheritance Patterns, Hasso-Plattner-Institut für Digital Engineering GmbH, Genome-wide association study, Disease, Kidney Function Tests, Bioinformatics, DISEASE, 0302 clinical medicine, Uromodulin/urine, kidney function, 11 Medical and Health Sciences, Genetics & Heredity, ddc:616, 0303 health sciences, Kidney, Genome-wide association, HERITABILITY, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, RENAL-FUNCTION, TRANS-EQTLS, METAANALYSIS, TRANSPORTER, CLASSIFICATION, INTEGRATION, Chromosome Mapping, 3. Good health, Phenotype, medicine.anatomical_structure, Medical genetics, Common variants, Renal function, Trans-EQTLS, Metaanalysis, Heritability, Transporter, Life Sciences & Biomedicine, Glomerular Filtration Rate, Metaanalysi, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Common variant, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, White People, V. A. Million Veteran Program, 03 medical and health sciences, Quantitative Trait, Heritable, Lifelines Cohort Study, Uromodulin, Genetics, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Genetic Association Studies, 030304 developmental biology, Genetic association, Science & Technology, urogenital system, association, genetic loci, 06 Biological Sciences, medicine.disease, Renal Insufficiency, Chronic/genetics/physiopathology/urine, Genetic Association Studies/methods, ddc:000, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Kidney disease
Abstract

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Published
2019

34. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Author

Ng, Natasha, primary, Willems, Sara M., additional, Fernandez, Juan, additional, Fine, Rebecca S., additional, Wheeler, Eleanor, additional, Wessel, Jennifer, additional, Kitajima, Hidetoshi, additional, Marenne, Gaëlle, additional, Rundle, Jana K., additional, Sim, Xueling, additional, Yeghootkar, Hanieh, additional, Beer, Nicola L., additional, Raimondo, Anne, additional, Tarasov, Andrei I., additional, Thomsen, Soren K., additional, van de Bunt, Martijn, additional, Wang, Shuai, additional, Chen, Sai, additional, Chen, Yuning, additional, Chen, Yii-Der Ida, additional, de Haan, Hugoline G., additional, Grarup, Niels, additional, Li-Gao, Ruifang, additional, Varga, Tibor V., additional, Asimit, Jennifer L, additional, Feng, Shuang, additional, Strawbridge, Rona J., additional, Kleinbrink, Erica L., additional, Ahluwalia, Tarunveer S., additional, An, Ping, additional, Appel, Emil V., additional, Arking, Dan E, additional, Auvinen, Juha, additional, Bielak, Lawrence F., additional, Bihlmeyer, Nathan A., additional, Bork-Jensen, Jette, additional, Brody, Jennifer A., additional, Campbell, Archie, additional, Chu, Audrey Y, additional, Davies, Gail, additional, Demirkan, Ayse, additional, Floyd, James S., additional, Giulianini, Franco, additional, Guo, Xiuqing, additional, Gustafsson, Stefan, additional, Hastoy, Benoit, additional, Jackson, Anne U., additional, Jakobsdottir, Johanna, additional, Järvelin, Marjo-Riitta, additional, Jensen, Richard A., additional, Kanoni, Stavroula, additional, Keinanen-Kiukaanniemi, Sirkka, additional, Li, Jin, additional, Li, Man, additional, Lohman, Kurt, additional, Lu, Yingchang, additional, Luan, Jian’an, additional, Manning, Alisa K., additional, Marten, Jonathan, additional, Marzi, Carola, additional, Meidtner, Karina, additional, Mook-Kanamori, Dennis O., additional, Muka, Taulant, additional, Pistis, Giorgio, additional, Prins, Bram, additional, Rice, Kenneth M., additional, Robertson, Neil, additional, Sanna, Serena, additional, Shi, Yuan, additional, Smith, Albert Vernon, additional, Smith, Jennifer A., additional, Southam, Lorraine, additional, Stringham, Heather M., additional, Tajuddin, Salman M., additional, Tragante, Vinicius, additional, van der Laan, Sander W., additional, Warren, Helen R., additional, Yao, Jie, additional, Yiorkas, Andrianos M., additional, Zhang, Weihua, additional, Zhao, Wei, additional, Ahlqvist, Emma, additional, Graff, Mariaelisa, additional, Highland, Heather M., additional, Justice, Anne E., additional, Lo, Ken Sin, additional, Marouli, Eirini, additional, Medina-Gomez, Carolina, additional, Afaq, Saima, additional, Alhejily, Wesam A., additional, Amin, Najaf, additional, Asselbergs, Folkert W., additional, Bonnycastle, Lori L., additional, Bots, Michiel L., additional, Brandslund, Ivan, additional, Chen, Ji, additional, Christensen, Cramer, additional, Danesh, John, additional, de Mutsert, Renée, additional, Dehghan, Abbas, additional, Ebeling, Tapani, additional, Elliott, Paul, additional, Consortium, EPIC-InterAct, additional, Farmaki, Aliki-Eleni, additional, Faul, Jessica D., additional, Franks, Paul W., additional, Franks, Steve, additional, Fritsche, Andreas, additional, Gjesing, Anette P., additional, Goodarzi, Mark O., additional, Gudnason, Vilmundur, additional, Hallmans, Göran, additional, Harris, Tamara B., additional, Herzig, Karl-Heinz, additional, Hivert, Marie-France, additional, Jansson, Jan-Håkan, additional, Jhun, Min A., additional, Beck Jørgensen, Torben, additional, Jørgensen, Marit E., additional, Jousilahti, Pekka, additional, Kajantie, Eero, additional, Karaleftheri, Maria, additional, Kardia, Sharon L.R., additional, Kinnunen, Leena, additional, Koistinena, Heikki A., additional, Komulainen, Pirjo, additional, Kovacs, Peter, additional, Kuusisto, Johanna, additional, Laakso, Markku, additional, Lange, Leslie A., additional, Launer, Lenore J., additional, Lee, Jung-Jin, additional, Leong, Aaron, additional, Lindström, Jaana, additional, Fox, Jocelyn E. Manning, additional, Männistö, Satu, additional, Maruthur, Nisa M., additional, Moilanen, Leena, additional, Mulas, Antonella, additional, Nalls, Mike A., additional, Neville, Matthew, additional, Pankow, James S., additional, Pattie, Alison, additional, Petersen, Eva R. B., additional, Puolijoki, Hannu, additional, Rasheed, Asif, additional, Redmond, Paul, additional, Renström, Frida, additional, Roden, Michael, additional, Saleheen, Danish, additional, Saltevo, Juha, additional, Savonen, Kai, additional, Sébert, Sylvain P., additional, Skaaby, Tea, additional, Small, Kerrin S., additional, Stančáková, Alena, additional, Stokholm, Jakob, additional, Strauch, Konstantin, additional, Tai, E-Shyong, additional, Taylor, Kent D., additional, Thuesen, Betina H., additional, Tönjes, Anke, additional, Tsafantakis, Emmanouil, additional, Tuomi, Tiinamaija, additional, Tuomilehto, Jaakko, additional, Group, Understanding Society Scientific, additional, Uusitupa, Matti I., additional, Vääräsmäki, Marja, additional, Vaartjes, Ilonca, additional, Zoledziewska, Magdalena, additional, Abecasis, Goncalo, additional, Balkau, Beverley, additional, Bisgaard, Hans, additional, Blakemore, Alexandra I., additional, Blüher, Matthias, additional, Boeing, Heiner, additional, Boerwinkle, Eric, additional, Bønnelykke, Klaus, additional, Bottinger, Erwin P., additional, Caulfield, Mark J., additional, Chambers, John C., additional, Chasman, Daniel I., additional, Cheng, Ching-Yu, additional, Clark, Anne, additional, Collins, Francis S., additional, Coresh, Josef, additional, Cucca, Francesco, additional, de Borst, Gert J., additional, Deary, Ian J., additional, Dedoussis, George, additional, Deloukas, Panos, additional, den Ruijter, Hester M., additional, Dupuis, Josée, additional, Evans, Michele K., additional, Ferrannini, Ele, additional, Franco, Oscar H., additional, Grallert, Harald, additional, Groop, Leif, additional, Hansen, Torben, additional, Hattersley, Andrew T., additional, Hayward, Caroline, additional, Hirschhorn, Joel N., additional, Ikram, M. Arfan, additional, Ingelsson, Erik, additional, Karpe, Fredrik, additional, Kaw, Kay-Tee, additional, Kiess, Wieland, additional, Kooner, Jaspal S., additional, Körner, Antje, additional, Lakka, Timo, additional, Langenberg, Claudia, additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Linneberg, Allan, additional, Lipovich, Leonard, additional, Liu, Ching-Ti, additional, Liu, Jun, additional, Liu, Yongmei, additional, Loos, Ruth J. F., additional, MacDonald, Patrick E., additional, Mohlke, Karen L., additional, Morris, Andrew D., additional, Munroe, Patricia B., additional, Murray, Alison, additional, Padmanabhan, Sandosh, additional, Palmer, Colin N. A., additional, Pasterkamp, Gerard, additional, Pedersen, Oluf, additional, Peyser, Patricia A., additional, Polasek, Ozren, additional, Porteous, David, additional, Province, Michael A., additional, Psaty, Bruce M., additional, Rauramaa, Rainer, additional, Ridker, Paul M., additional, Rolandsson, Olov, additional, Rorsman, Patrik, additional, Rosendaal, Frits, additional, Rudan, Igor, additional, Salomaa, Veikko, additional, Schulze, Matthias B., additional, Sladek, Robert, additional, Smith, Blair H., additional, Spector, Timothy D., additional, Starr, John M., additional, Stumvoll, Michael, additional, van Duijn, Cornelia M., additional, Walker, Mark, additional, Wareham, Nick J., additional, Weir, David R., additional, Wilson, James G., additional, Wong, Tien Yin, additional, Zeggini, Eleftheria, additional, Zonderman, Alan B., additional, Rotter, Jerome I., additional, Morris, Andrew P., additional, Boehnke, Michael, additional, Florez, Jose, additional, McCarthy, Mark I., additional, Meigs, James B., additional, Mahajan, Anubha, additional, Scott, Robert A., additional, Gloyn, Anna L., additional, and Barroso, Ines, additional

Published
2019
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35. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Grarup, Niels, Fox, Keolu, An, Ping, Li, Li, Hivert, Marie-France, Rasmussen-Torvik, Laura J, Lipovich, Leonard, Raghavan, Sridharan, Baldridge, Abigail S, Dauriz, Marco, Huffman, Jennifer E, Besse, Céline, Guo, Xiuqing, Bork-Jensen, Jette, Chu, Audrey Y, Hidalgo, Bertha, Hara, Kazuo, Fornage, Myriam, Yaghootkar, Hanieh, Willems, Sara M, Stančáková, Alena, Wessel, Jennifer, Abrol, Ravinder, Freitag, Daniel F, Wang, Shuai, Jakobsdottir, Johanna, Garcia, Melissa E, Lu, Yingchang, Brody, Jennifer A, Isaacs, Aaron, Boland, Anne, and Ehm, Margaret G

Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.

Published
2015
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36. 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 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, Renée, de Vries, Aiko P. J., 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, 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, Liu, Jun, Loeffler, Markus, Loos, Ruth J. F., Lyytikäinen, Leo-Pekka, Magi, Reedik, Mahajan, Anubha, Martin, Nicholas G., März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Meisinger, Christa, Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, 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 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, 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

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, HNF1Aand 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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37. The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE).

Author

Wolters, Frank J., Yang, Qiong, Biggs, Mary L., Jakobsdottir, Johanna, Li, Shuo, Evans, Daniel S., Bis, Joshua C., Harris, Tamara B., Vasan, Ramachandran S., Zilhao, Nuno R., Ghanbari, Mohsen, Ikram, M. Arfan, Launer, Lenore, Psaty, Bruce M., Tranah, Gregory J., Kulminski, Alexander M., Gudnason, Vilmundur, Seshadri, Sudha, and null, null

Subjects
FRAIL elderly, GENOTYPES, APOLIPOPROTEIN E, LONGEVITY, ALZHEIMER'S disease
Abstract

Background: Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive. Methods: We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-ε2, with survival in the population. Results: During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-ε3 carriers, APOE-ε2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90–0.99; P = 1.1*10−2), whereas APOE-ε4 carriers were at increased risk of death (HR 1.17,1.12–1.21; P = 2.8*10−16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-ε2 (HR 0.89,0.74–1.08), and highest for homozygous APOE-ε4 (HR 1.52,1.37–1.70). After censoring for dementia, effect estimates remained similar for APOE-ε2 (HR 0.95,0.90–1.01), but attenuated for APOE-ε4 (HR 1.07,1.01–1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ε2 versus ε33: -17.1(-18.1–16.0), and ε4 versus ε33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities. Conclusion: Compared with APOE-ε3, APOE-ε2 is associated with prolonged survival, whereas mortality risk is increased for APOE-ε4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-ε2 in health and disease. [ABSTRACT FROM AUTHOR]

Published
2019
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39. P3-071: A GENOME-WIDE META-ANALYSIS OF PLASMA CLUSTERIN LEVELS IN THE CHARGE CONSORTIUM

Author

Chouraki, Vincent Antoine, primary, Jakobsdottir, Johanna, additional, Mather, Karen, additional, Adams, Hieab, additional, Mollon, Jennifer, additional, Oldmeadow, Christopher, additional, Thalamuthu, Anbupalam, additional, Tanaka, Toshiko, additional, Scott, Rodney, additional, Levy, Daniel, additional, Holliday, Liz, additional, Song, Fei, additional, Thambisetty, Madhav, additional, Poljak, Anne, additional, Eiriksdottir, Gudny, additional, Sachdev, Perminder S., additional, Gupta, Veer Bala, additional, Martins, Ralph, additional, Launer, Lenore, additional, Dobson, Richard, additional, Brodaty, Henry, additional, Attia, John, additional, Lovestone, Simon, additional, Gudnason, Vilmundur, additional, Ikram, Mohammad, additional, and Seshadri, Sudha, additional

Published
2014
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40. Exome-wide association study of plasma lipids in >300,000 individuals

Author

Liu, Dajiang J, Peloso, Gina M, Yu, Haojie, Butterworth, Adam S, Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L, Auer, Paul L, Baber, Usman, Ballantyne, Christie M, Bang, Lia E, Benn, Marianne, Bis, Joshua C, Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P, Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Y Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Connell, John M, Cucca, Francesco, Cupples, L Adrienne, Damrauer, Scott M, Davies, Gail, Deary, Ian J, Dedoussis, George, Denny, Joshua C, Dominiczak, Anna, Dubé, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Farmaki, Aliki-Eleni, Feitosa, Mary F, Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W, Frayling, Timothy M, Frikke-Schmidt, Ruth, Fritsche, Lars G, Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K, Gao, Wei, Garcia, Melissa E, Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O, Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B, Hayward, Caroline, Hirschhorn, Joel N, Holmen, Oddgeir L, Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U, Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B, Jørgensen, Marit E, Jukema, J Wouter, Justesen, Johanne M, Kamstrup, Pia R, Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V, Klarin, Derek, Koistinen, Heikki A, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J, Lauritzen, Torsten, Liewald, David C M, Lin, Li An, Linneberg, Allan, Loos, Ruth J F, Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K, Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas G D, Maschio, Andrea, Meigs, James B, Melander, Olle, Metspalu, Andres, Morris, Andrew P, Morrison, Alanna C, Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B, Neville, Matt J, Nielsen, Jonas B, Nielsen, Sune F, Nordestgaard, Børge G, Ordovas, Jose M, Mehran, Roxana, O'Donnell, Christoper J, Orho-Melander, Marju, Molony, Cliona M, Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N A, Pasko, Dorota, Patel, Aniruddh P, Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M, Rader, Daniel J, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Renström, Frida, Rich, Stephen S, Ridker, Paul M, Rioux, John D, Robertson, Neil R, Roden, Dan M, Rotter, Jerome I, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M, Scott, Robert A, Sever, Peter, Sevilla, Raquel S, Shaffer, Christian M, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, Smith, Albert V, Smith, Blair H, Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stirrups, Kathleen E, Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M, Surendran, Praveen, Tada, Hayato, Tall, Alan R, Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D, Trompet, Stella, Tsao, Philip S, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R, Varbo, Anette, Varga, Tibor V, Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J, Warren, Helen R, Weeke, Peter E, Weinstock, Joshua, Wessel, Jennifer, Wilson, James G, Wilson, Peter W F, Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S, Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M M, Danesh, John, McCarthy, Mark I, Cowan, Chad A, Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J, and Kathiresan, Sekar

Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Published
2017
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41. O3-01-05: The role of functional genetic variation in Alzheimer's disease: The CHARGE consortium

Author

Jakobsdottir, Johanna, primary, Bis, Joshua, additional, Ibrahim-Verbaas, Carla, additional, Chouraki, Vincent, additional, Destefano, Anita, additional, van der Lee, Sven, additional, Grove-Gaona, Megan, additional, Smith, Albert, additional, Launer, Lenore, additional, Hofman, Albert, additional, Uitterlinden, André, additional, Ikram, Mohammad, additional, O'Donnell, Christopher, additional, Boerwinkle, Eric, additional, Fitzpatrick, Annette, additional, Seshadri, Sudha, additional, Gudnason, Vilmundur, additional, and van Duijn, Cornelia, additional

Published
2013
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43. Dissection of Chromosome 16p12 Linkage Peak Suggests a Possible Role forCACNG3Variants in Age-Related Macular Degeneration Susceptibility

Author

Spencer, Kylee L., primary, Olson, Lana M., additional, Schnetz-Boutaud, Nathalie, additional, Gallins, Paul, additional, Wang, Gaofeng, additional, Scott, William K., additional, Agarwal, Anita, additional, Jakobsdottir, Johanna, additional, Conley, Yvette, additional, Weeks, Daniel E., additional, Gorin, Michael B., additional, Pericak-Vance, Margaret A., additional, and Haines, Jonathan L., additional

Published
2011
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45. Exome-wide association study of plasma lipids in >300,000 individuals

Author

Liu, Dajiang J., Peloso, Gina M., Yu, Haojie, Butterworth, Adam S., Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L., Auer, Paul L., Baber, Usman, Ballantyne, Christie M., Bang, Lia E., Benn, Marianne, Bis, Joshua C., Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P., Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I., Chen, Y. Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Connell, John M, Cucca, Francesco, Cupples, L. Adrienne, Damrauer, Scott M., Davies, Gail, Deary, Ian J, Dedoussis, George, Denny, Joshua C., Dominiczak, Anna, Dubé, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Farmaki, Aliki-Eleni, Feitosa, Mary F, Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Frayling, Timothy M., Frikke-Schmidt, Ruth, Fritsche, Lars, Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K., Gao, Wei, Garcia, Melissa E., Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O., Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L., Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hirschhorn, Joel N., Holmen, Oddgeir L., Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U, Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B, Jørgensen, Marit E., Jukema, J. Wouter, Justesen, Johanne M., Kamstrup, Pia R., Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V., Klarin, Derek, Koistinen, Heikki A., Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J., Lauritzen, Torsten, Liewald, David CM, Lin, Li An, Linneberg, Allan, Loos, Ruth J.F., Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K., Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas GD, Maschio, Andrea, Meigs, James B., Melander, Olle, Metspalu, Andres, Morris, Andrew P, Morrison, Alanna C., Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B., Neville, Matt J, Nielsen, Jonas B., Nielsen, Sune F, Nordestgaard, Børge G, Ordovas, Jose M., Mehran, Roxana, O’Donnell, Christoper J., Orho-Melander, Marju, Molony, Cliona M., Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin NA, Pasko, Dorota, Patel, Aniruddh P., Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M., Rader, Daniel J., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot, Reiner, Alex P., Renström, Frida, Rich, Stephen S, Ridker, Paul M, Rioux, John D., Robertson, Neil R, Roden, Dan M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M., Scott, Robert A., Sever, Peter, Sevilla, Raquel S., Shaffer, Christian M., Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, Smith, Albert V., Smith, Blair H, Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K., Starr, John M, Stirrups, Kathleen E, Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M, Surendran, Praveen, Tada, Hayato, Tall, Alan R., Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D, Trompet, Stella, Tsao, Philip S., Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R, Varbo, Anette, Varga, Tibor V, Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J., Warren, Helen R, Weeke, Peter E., Weinstock, Joshua, Wessel, Jennifer, Wilson, James G., Wilson, Peter W. F., Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S., Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna MM, Danesh, John, McCarthy, Mark I, Cowan, Chad, Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J., and Kathiresan, Sekar

Abstract

We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.

Published
2017
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49. Genetic variants near TIMP3 and high-density lipoprotein—associated loci influence susceptibility to age-related macUlar degeneration.

Author

Wei Chen, Stambolian, Dwight, Edwards, Albert O., Branham, Kari E., Othman, Mohammad, Jakobsdottir, Johanna, Tosakulwong, Nirubol, Pericak-Vance, Margaret A., Campochiaro, Peter A., Klein, Michael L., Tan, Perciliz L., Conley, Yvette P., Kanda, Atsuhiro, KoppIin, Laura, Yanming Li, Augustaitis, Katherine J., Karoukis, Athanasios J., Scott, William K., Agarwal, Anita, and Kovach, Jaclyn L.

Subjects
GENOMES, HIGH density lipoproteins, RETINAL degeneration, METALLOPROTEINASES, LOCUS (Genetics), EXTRACELLULAR matrix
Abstract

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2.157 cases and 1.150 controls. Our results validate AMD susceptibility loci near CFH (P < 10-75). ARMS2 (P < 10-59), C2/CFB (P < 10-20), C3 (P < 10-9), and CFI (P < 10-6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4.625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10-11). a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC. P= 1.3 x 10-7 CETP, P = 7.4 x 10-7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL (P - 3.0 x 10-3) and ABCA1 (P = 5.6 x 10-4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. [ABSTRACT FROM AUTHOR]

Published
2010

50. A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

Author

Jun, Gyungah, Ibrahim-Verbaas, Carla A., Vronskaya, Maria, Lambert, Jean-Charles, Chung, Jaeyoon, Naj, Adam C., Kunkle, Brian W., Wang, Li-San, Bis, Joshua C., Bellenguez, Céline, Harold, Denise, Lunetta, Kathryn L., Destefano, Anita L., Grenier-Boley, Benjamin, Sims, Rebecca, Beecham, Gary W., Smith, Albert V., Chouraki, Vincent, Hamilton-Nelson, Kara L., Ikram, M. Arfan, Fievet, Nathalie, Denning, Nicola, Martin, Eden R., Schmidt, Helena, Kamatani, Yochiro, Dunstan, Melanie L, Valladares, Otto, Laza, Agustin Ruiz, Zelenika, Diana, Ramirez, Alfredo, Foroud, Tatiana M., Choi, Seung-Hoan, Boland, Anne, Becker, Tim, Kukull, Walter A., van der Lee, Sven J., Pasquier, Florence, Cruchaga, Carlos, Beekly, Duane, Fitzpatrick, Annette L., Hanon, Oliver, Gill, Michael, Barber, Robert, Gudnason, Vilmundur, Campion, Dominique, Love, Seth, Bennett, David A., Amin, Najaf, Berr, Claudine, Tsolaki, Magda, Buxbaum, Joseph D., Lopez, Oscar L., Deramecourt, Vincent, Fox, Nick C, Cantwell, Laura B., Tárraga, Lluis, Dufouil, Carole, Hardy, John, Crane, Paul K., Eiriksdottir, Gudny, Hannequin, Didier, Clarke, Robert, Evans, Denis, Mosley, Thomas H., Letenneur, Luc, Brayne, Carol, Maier, Wolfgang, De Jager, Philip, Emilsson, Valur, Dartigues, Jean-François, Hampel, Harald, Kamboh, M. Ilyas, de Bruijn, Renee F.A.G., Tzourio, Christophe, Pastor, Pau, Larson, Eric B., Rotter, Jerome I., O’Donovan, Michael C, Montine, Thomas J., Nalls, Michael A., Mead, Simon, Reiman, Eric M., Jonsson, Palmi V., Holmes, Clive, St George-Hyslop, Peter H., Boada, Mercè, Passmore, Peter, Wendland, Jens R., Schmidt, Reinhold, Morgan, Kevin, Winslow, Ashley R., Powell, John F, Carasquillo, Minerva, Younkin, Steven G., Jakobsdóttir, Jóhanna, Kauwe, John SK, Wilhelmsen, Kirk C., Rujescu, Dan, Nöthen, Markus M, Hofman, Albert, Jones, Lesley, Haines, Jonathan L., Psaty, Bruce M., Van Broeckhoven, Christine, Holmans, Peter, Launer, Lenore J., Mayeux, Richard, Lathrop, Mark, Goate, Alison M., Escott-Price, Valentina, Seshadri, Sudha, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, van Duijn, Cornelia M., Schellenberg, Gerard D., and Farrer, Lindsay A.

Abstract

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Published
2015
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