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53. Genetically predicted cortisol levels and risk of venous thromboembolism

Author

Allarai, Elias, Lee, Wei-Hsuan, Burgess, Stephen, Larsson, Susanna C., Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, Van Hylckama Vlieg, Astrid, De Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben Michael, Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., Macdonald, James, Brækkan, Sigrid Kufaas, Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., Mccauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken Elvestad, Deleuze, Jean-Francois, O'Donnell, Chris J., Kim, Jihye, Mcknight, Barbara, Kraft, Peter, Hansen, John Bjarne, Rosendaal, Frits Richard, Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, Alexandretrégouët, David, Smith, Nicholas L., Allara, Elias [0000-0002-1634-8330], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Medicine and health sciences, Multidisciplinary, Kardiologi, Hydrocortisone, Biology and life sciences, FOS: Social sciences, Venous Thromboembolism, Mendelian Randomization Analysis, Endocrinology and Diabetes, Social sciences, Risk Factors, Endokrinologi och diabetes, Humans, Cardiac and Cardiovascular Systems, Pulmonary Embolism, Medical Genetics, Medicinsk genetik, Research Article
Abstract

Introduction In observational studies, venous thromboembolism (VTE) has been associated with Cushing’s syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. Methods Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. Results Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62–0.87, p Conclusions This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.

Published
2022

54. Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Author

Moksnes, Marta R, Graham, Sarah E, Wu, Kuan-Han, Hansen, Ailin Falkmo, Gagliano Taliun, Sarah A, Zhou, Wei, Thorstensen, Ketil, Fritsche, Lars G, Gill, Dipender, Mason, Amy, Cucca, Francesco, Schlessinger, David, Abecasis, Gonçalo R, Burgess, Stephen, Åsvold, Bjørn Olav, Nielsen, Jonas B, Hveem, Kristian, Willer, Cristen J, Brumpton, Ben M, Burgess, Stephen [0000-0001-5365-8760], Apollo - University of Cambridge Repository, Moksnes, Marta R [0000-0002-2690-5153], Graham, Sarah E [0000-0003-1271-2489], Wu, Kuan-Han [0000-0003-4286-4299], Gagliano Taliun, Sarah A [0000-0003-1306-1868], Zhou, Wei [0000-0001-7719-0859], Fritsche, Lars G [0000-0002-2110-1690], Gill, Dipender [0000-0001-7312-7078], Mason, Amy [0000-0002-8019-0777], Abecasis, Gonçalo R [0000-0003-1509-1825], Åsvold, Bjørn Olav [0000-0003-3837-2101], Willer, Cristen J [0000-0001-5645-4966], and Brumpton, Ben M [0000-0002-3058-1059]

Subjects
Iron, Transferrin, 631/208/205/2138, 45/43, article, Medicine (miscellaneous), Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 692/53, Ferritins, Humans, General Agricultural and Biological Sciences, Biomarkers, Genome-Wide Association Study
Abstract

Funder: EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant 116074 The Royal Society (204623/Z/16/Z) United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron-related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron-binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI), and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257,953 individuals. We identify 123 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate recently published results using genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.

Published
2022

56. Germline Mutations in CIDEB and Protection against Liver Disease

Author

Verweij, Niek, primary, Haas, Mary E., additional, Nielsen, Jonas B., additional, Sosina, Olukayode A., additional, Kim, Minhee, additional, Akbari, Parsa, additional, De, Tanima, additional, Hindy, George, additional, Bovijn, Jonas, additional, Persaud, Trikaldarshi, additional, Miloscio, Lawrence, additional, Germino, Mary, additional, Panagis, Lampros, additional, Watanabe, Kyoko, additional, Mbatchou, Joelle, additional, Jones, Marcus, additional, LeBlanc, Michelle, additional, Balasubramanian, Suganthi, additional, Lammert, Craig, additional, Enhörning, Sofia, additional, Melander, Olle, additional, Carey, David J., additional, Still, Christopher D., additional, Mirshahi, Tooraj, additional, Rader, Daniel J., additional, Parasoglou, Prodromos, additional, Walls, Johnathon R., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Economides, Aris, additional, Cantor, Michael N., additional, Zambrowicz, Brian, additional, Murphy, Andrew J., additional, Abecasis, Goncalo R., additional, Ferreira, Manuel A.R., additional, Smagris, Eriks, additional, Gusarova, Viktoria, additional, Sleeman, Mark, additional, Yancopoulos, George D., additional, Marchini, Jonathan, additional, Kang, Hyun M., additional, Karalis, Katia, additional, Shuldiner, Alan R., additional, Della Gatta, Giusy, additional, Locke, Adam E., additional, Baras, Aris, additional, and Lotta, Luca A., additional

Published
2022
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57. Associations between primary care electrocardiography and non-Alzheimer dementia

Author

Isaksen, Jonas L, Ghouse, Jonas, Skov, Morten W, Olesen, Morten S, Holst, Anders G, Pietersen, Adrian, Nielsen, Jonas B, Maier, Anja M., Graff, Claus, Frikke-Schmidt, Ruth, Kanters, Jørgen K, Isaksen, Jonas L, Ghouse, Jonas, Skov, Morten W, Olesen, Morten S, Holst, Anders G, Pietersen, Adrian, Nielsen, Jonas B, Maier, Anja M., Graff, Claus, Frikke-Schmidt, Ruth, and Kanters, Jørgen K

Abstract

OBJECTIVES: To determine whether electrocardiogram (ECG) markers are associated with incident non-Alzheimer's dementia (non-AD) and whether these markers also improve risk prediction for non-AD.MATERIALS AND METHODS: We retrospectively included 170,605 primary care patients aged 60 years or older referred for an ECG by their general practitioner and followed them for a median of 7.6 years. Using Cox regression, we reported hazard ratios (HRs) for electrocardiogram markers. Subsequently, we evaluated if addition of these electrocardiogram markers to a clinical model improved risk prediction for non-AD using change in area under the receiver-operator characteristics curve (AUC).RESULTS: The 5-year cumulative incidence of non-AD was 3.4 %. Increased heart rate (HR=1.06 pr. 10 bpm [95% confidence interval: 1.04-1.08], p<0.001), shorter QRS duration (HR=1.07 pr. 10 ms [1.05-1.09], p<0.001), elevated J-amplitude (HR=1.16 pr. mm [1.08-1.24], p<0.001), decreased T-peak amplitude (HR=1.02 pr. mm [1.01-1.04], p=0.002), and increased QTc (HR=1.08 pr. 20 ms [1.05-1.10], p<0.001) were associated with an increased rate of non-AD. Atrial fibrillation on the ECG (HR=1.18 [1.08-1.28], p<0.001) Sokolow-Lyon index > 35 mm (HR=1.31 [1.18-1.46], p<0.001) and borderline (HR=1.18 [1.11-1.26], p<0.001) or abnormal (HR=1.40 [1.27-1.55], p<0.001) QRS-T angle were also associated with an increased rate of non-AD. Upon addition of ECG markers to the Cox model, 5-year and 10-year C-statistic (AUC) improved significantly (delta-AUC, 0.36 [0.18-0.50] and 0.20 [0.03-0.35] %-points, respectively).CONCLUSIONS: ECG markers typical of an elevated cardiovascular risk profile were associated with non-AD and improved both 5-year and 10-year risk predictions for non-AD.

Published
2022

58. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jurgenson, Tuuli, Namba, Shinichi, Posner, Daniel C, Kamanu, Frederick K, Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K, Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C, Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R, Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V, Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Carcel-Marquez, Jara, Nygaard, Marianne, Leonard, Hampton L, Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J, Lewis, Adam J, Judy, Renae L, Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D, Bakker, Mark K, Bartz, Traci M, Bennett, David A, Bis, Joshua C, Bordes, Constance, Borte, Sigrid, Cain, Anael, Ridker, Paul M, Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W, de Jager, Phil L, de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E, Geerlings, Mirjam I, Gasca, Natalie C, Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K, Ho, Yuk-Lam, Havulinna, Aki S, Hopewell, Jemma C, Hyacinth, Hyacinth I, Inouye, Michael, Jacob, Mina A, Jeon, Christina E, Jern, Christina, Kamouchi, Masahiro, Keene, Keith L, Kitazono, Takanari, Kittner, Steven J, Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J, Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S, Marston, Nicholas A, Meitinger, Thomas, Mitchell, Braxton D, Montellano, Felipe A, Morisaki, Takayuki, Mosley, Thomas H, Nalls, Mike A, Nordestgaard, Borge G, O'Donnell, Martin J, Okada, Yukinori, Onland-Moret, N Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M, Rich, Stephen S, Rosand, Jonathan, Sabatine, Marc S, Sacco, Ralph L, Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L, Schmidt, Carsten O, Shimizu, Atsushi, Smith, Nicholas L, Sloane, Kelly L, Sutoh, Yoichi, Sun, Yan V, Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P, Tiwari, Hemant K, Tregouet, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjaerg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S, Wiggins, Kerri L, Wennberg, Patrik, Woo, Daniel, Wilson, Peter WF, Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Lee, Jin-Moo, Cheng, Yu-Ching, Meschia, James F, Chen, Wei Min, Sale, Michele M, Zonderman, Alan B, Evans, Michele K, Wilson, James G, Correa, Adolfo, Traylor, Matthew, Lewis, Cathryn M, Carty, Cara L, Reiner, Alexander, Haessler, Jeffrey, Langefeld, Carl D, Gottesman, Rebecca F, Yaffe, Kristine, Liu, Yong Mei, Kooperberg, Charles, Lange, Leslie A, Furie, Karen L, Arnett, Donna K, Benavente, Oscar R, Grewal, Raji P, Peddareddygari, Leema Reddy, Hveem, Kristian, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Brumpton, Ben M, Suchon, Pierre, Chen, Ming-Huei, Frazer, Kelly A, Turman, Constance, Germain, Marine, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rebecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, McCauley, Bryan M, Taylor, Kent D, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean-Francois, O'Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R, Heit, John A, Tang, Weihong, Morange, Pierre-Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, van Dijk, Ewoud J, Koudstaal, Peter J, Luijckx, Gert-Jan, Nederkoorn, Paul J, van Oostenbrugge, Robert J, Visser, Marieke C, Wermer, Marieke JH, Kappelle, L Jaap, Esko, Tonu, Metspalu, Andres, Magi, Reedik, Nelis, Mari, Irvin, Marguerite R, de Leeuw, Frank-Erik, Levi, Christopher R, Maguire, Jane, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie LM, Rannikmae, Kristiina, Schmidt, Reinhold, Slowik, Agnieszka, Pera, Joanna, Thijs, Vincent NS, Lindgren, Arne G, Ilinca, Andreea, Melander, Olle, Engstrom, Gunnar, Rexrode, Kathryn M, Rothwell, Peter M, Stanne, Tara M, Johnson, Julie A, Danesh, John, Butterworth, Adam S, Heitsch, Laura, Boncoraglio, Giorgio B, Kubo, Michiaki, Pezzini, Alessandro, Rolfs, Arndt, Giese, Anne-Katrin, Weir, David, Ross, Owen A, Lemmons, Robin, Soderholm, Martin, Cushman, Mary, Jood, Katarina, McDonough, Caitrin W, Bell, Steven, Linkohr, Birgit, Lee, Tsong-Hai, Putaala, Jukka, Anderson, Christopher D, Lopez, Oscar L, Jian, Xueqiu, Schminke, Ulf, Cullell, Natalia, Delgado, Pilar, Ibanez, Laura, Krupinski, Jerzy, Lioutas, Vasileios, Matsuda, Koichi, Montaner, Joan, Muino, Elena, Roquer, Jaume, Sarnowski, Chloe, Sattar, Naveed, Sibolt, Gerli, Teumer, Alexander, Rutten-Jacobs, Loes, Kanai, Masahiro, Gretarsdottir, Solveig, Rost, Natalia S, Yusuf, Salim, Almgren, Peter, Ay, Hakan, Bevan, Steve, Brown, Robert D, Carrera, Caty, Buring, Julie E, Chen, Wei-Min, Cotlarciuc, Ioana, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gustafsson, Stefan, Hassan, Ahamad, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Ingelsson, Erik, Harris, Tamara B, Kissela, Brett M, Kleindorfer, Dawn O, Langenberg, Claudia, Lemmens, Robin, Leys, Didier, Lin, Wei-Yu, Lorentzen, Erik, Magnusson, Patrik K, McArdle, Patrick F, Pulit, Sara L, Rice, Kenneth, Sakaue, Saori, Sapkota, Bishwa R, Tanislav, Christian, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Amin, Najaf, Aparicio, Hugo J, Attia, John, Beiser, Alexa S, Berr, Claudine, Bustamante, Mariana, Caso, Valeria, Choi, Seung Hoan, Chowhan, Ayesha, Dartigues, Jean-Francois, Delavaran, Hossein, Dorr, Marcus, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Hozawa, Atsushi, Ingelsson, Martin, Iwasaki, Motoki, Kaffashian, Sara, Kalra, Lalit, Kjartansson, Olafur, Kloss, Manja, Labovitz, Daniel L, Laurie, Cathy C, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Makoto, Hirata, Minegishi, Naoko, Morris, Andrew P, Muller-Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Pedersen, Nancy L, Perola, Markus, Jousilahti, Pekka, Pileggi, Silvana, Rabionet, Raquel, Riba-Llena, Iolanda, Ribases, Marta, Romero, Jose R, Rudd, Anthony G, Sarin, Antti-Pekka, Sarju, Ralhan, Satoh, Mamoru, Sawada, Norie, Sigurdsson, Asgeir, Smith, Albert, Stine, O Colin, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Wakai, Kenji, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Yamaji, Taiki, Sanghera, Dharambir K, Stefansson, Kari, Martinez-Majander, Nicolas, Sobue, Kenji, Soriano-Tarraga, Carolina, Volzke, Henry, Akpa, Onoja, Sarfo, Fred S, Akpalu, Albert, Obiako, Reginald, Wahab, Kolawole, Osaigbovo, Godwin, Owolabi, Lukman, Komolafe, Morenikeji, Jenkins, Carolyn, Arulogun, Oyedunni, Ogbole, Godwin, Adeoye, Abiodun M, Akinyemi, Joshua, Agunloye, Atinuke, Fakunle, Adekunle G, Uvere, Ezinne, Olalere, Abimbola, Adebajo, Olayinka J, Chen, Junshi, Clarke, Robert, Collins, Rory, Guo, Yu, Wang, Chen, Lv, Jun, Peto, Richard, Chen, Yiping, Fairhurst-Hunter, Zammy, Hill, Michael, Pozarickij, Alfred, Schmidt, Dan, Stevens, Becky, Turnbull, Iain, Yu, Canqing, Nagai, Akiko, Murakami, Yoishinori, Shiroma, Eric J, Sigurdsson, Sigurdur, Ghanbari, Mohsen, Boerwinkle, Eric, Fongang, Bernard, Wang, Ruiqi, Ikram, Mohammad K, Volker, Uwe, de Laat, Karlijn F, van Norden, Anouk GW, de Kort, Paul L, Vermeer, Sarah E, Brouwers, Paul JAM, Gons, Rob AR, den Heijer, Tom, van Dijk, Gert W, van Rooij, Frank GW, Aamodt, Anne H, Skogholt, Anne H, Willer, Cristen J, Heuch, Ingrid, Hagen, Knut, Fritsche, Lars G, Pedersen, Linda M, Ellekjaer, Hanne, Zhou, Wei, Martinsen, Amy E, Kristoffersen, Espen S, Thomas, Laurent F, Kleinschnitz, Christoph, Frantz, Stefan, Ungethum, Kathrin, Gallego-Fabrega, Cristina, Lledos, Miquel, Llucia-Carol, Laia, Sobrino, Tomas, Campos, Francisco, Castillo, Jose, Freijo, Marimar, Arenillas, Juan Francisco, Obach, Victor, Alvarez-Sabin, Jose, Molina, Carlos A, Ribo, Marc, Munoz-Narbona, Lucia, Lopez-Cancio, Elena, Millan, Monica, Diaz-Navarro, Rosa, Vives-Bauza, Cristofol, Serrano-Heras, Gemma, Segura, Tomas, Dhar, Rajat, Delgado-Mederos, Raquel, Prats-Sanchez, Luis, Camps-Renom, Pol, Blay, Natalia, Sumoy, Lauro, Marti-Fabregas, Joan, Schnohr, Peter, Jensen, Gorm B, Benn, Marianne, Afzal, Shoaib, Kamstrup, Pia R, van Setten, Jessica, van der Laan, Sander W, Vonk, Jet MJ, Kim, Bong-Jo, Curtze, Sami, Tiainen, Marjaana, Kinnunen, Janne, Menon, Vilas, Sung, Yun Ju, Yang, Chengran, Saillour-Glenisson, Florence, Gravel, Simon, Millwood, Iona Y, Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J, Jukema, J Wouter, Rissanen, Ina L, Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna MM, Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A, Rundek, Tatjana, Worrall, Bradford B, Lathrop, G Mark, Riaz, Moeen, Simonsick, Eleanor M, Korv, Janika, Franca, Paulo HC, Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M, Heuschmann, Peter Ulrich, Longstreth, WT, Jung, Keum Ji, Bastarache, Lisa, Pare, Guillaume, Damrauer, Scott M, Chasman, Daniel I, Rotter, Jerome I, Zwart, John-Anker, Niiranen, Teemu J, Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernandez-Cadenas, Israel, Walters, Robin G, Ruff, Christian T, Owolabi, Mayowa O, Huffman, Jennifer E, Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, Debette, Stephanie, Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jurgenson, Tuuli, Namba, Shinichi, Posner, Daniel C, Kamanu, Frederick K, Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K, Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C, Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R, Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V, Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Carcel-Marquez, Jara, Nygaard, Marianne, Leonard, Hampton L, Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J, Lewis, Adam J, Judy, Renae L, Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D, Bakker, Mark K, Bartz, Traci M, Bennett, David A, Bis, Joshua C, Bordes, Constance, Borte, Sigrid, Cain, Anael, Ridker, Paul M, Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W, de Jager, Phil L, de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E, Geerlings, Mirjam I, Gasca, Natalie C, Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K, Ho, Yuk-Lam, Havulinna, Aki S, Hopewell, Jemma C, Hyacinth, Hyacinth I, Inouye, Michael, Jacob, Mina A, Jeon, Christina E, Jern, Christina, Kamouchi, Masahiro, Keene, Keith L, Kitazono, Takanari, Kittner, Steven J, Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J, Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S, Marston, Nicholas A, Meitinger, Thomas, Mitchell, Braxton D, Montellano, Felipe A, Morisaki, Takayuki, Mosley, Thomas H, Nalls, Mike A, Nordestgaard, Borge G, O'Donnell, Martin J, Okada, Yukinori, Onland-Moret, N Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M, Rich, Stephen S, Rosand, Jonathan, Sabatine, Marc S, Sacco, Ralph L, Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L, Schmidt, Carsten O, Shimizu, Atsushi, Smith, Nicholas L, Sloane, Kelly L, Sutoh, Yoichi, Sun, Yan V, Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P, Tiwari, Hemant K, Tregouet, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjaerg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S, Wiggins, Kerri L, Wennberg, Patrik, Woo, Daniel, Wilson, Peter WF, Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Lee, Jin-Moo, Cheng, Yu-Ching, Meschia, James F, Chen, Wei Min, Sale, Michele M, Zonderman, Alan B, Evans, Michele K, Wilson, James G, Correa, Adolfo, Traylor, Matthew, Lewis, Cathryn M, Carty, Cara L, Reiner, Alexander, Haessler, Jeffrey, Langefeld, Carl D, Gottesman, Rebecca F, Yaffe, Kristine, Liu, Yong Mei, Kooperberg, Charles, Lange, Leslie A, Furie, Karen L, Arnett, Donna K, Benavente, Oscar R, Grewal, Raji P, Peddareddygari, Leema Reddy, Hveem, Kristian, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Brumpton, Ben M, Suchon, Pierre, Chen, Ming-Huei, Frazer, Kelly A, Turman, Constance, Germain, Marine, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rebecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, McCauley, Bryan M, Taylor, Kent D, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean-Francois, O'Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R, Heit, John A, Tang, Weihong, Morange, Pierre-Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, van Dijk, Ewoud J, Koudstaal, Peter J, Luijckx, Gert-Jan, Nederkoorn, Paul J, van Oostenbrugge, Robert J, Visser, Marieke C, Wermer, Marieke JH, Kappelle, L Jaap, Esko, Tonu, Metspalu, Andres, Magi, Reedik, Nelis, Mari, Irvin, Marguerite R, de Leeuw, Frank-Erik, Levi, Christopher R, Maguire, Jane, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie LM, Rannikmae, Kristiina, Schmidt, Reinhold, Slowik, Agnieszka, Pera, Joanna, Thijs, Vincent NS, Lindgren, Arne G, Ilinca, Andreea, Melander, Olle, Engstrom, Gunnar, Rexrode, Kathryn M, Rothwell, Peter M, Stanne, Tara M, Johnson, Julie A, Danesh, John, Butterworth, Adam S, Heitsch, Laura, Boncoraglio, Giorgio B, Kubo, Michiaki, Pezzini, Alessandro, Rolfs, Arndt, Giese, Anne-Katrin, Weir, David, Ross, Owen A, Lemmons, Robin, Soderholm, Martin, Cushman, Mary, Jood, Katarina, McDonough, Caitrin W, Bell, Steven, Linkohr, Birgit, Lee, Tsong-Hai, Putaala, Jukka, Anderson, Christopher D, Lopez, Oscar L, Jian, Xueqiu, Schminke, Ulf, Cullell, Natalia, Delgado, Pilar, Ibanez, Laura, Krupinski, Jerzy, Lioutas, Vasileios, Matsuda, Koichi, Montaner, Joan, Muino, Elena, Roquer, Jaume, Sarnowski, Chloe, Sattar, Naveed, Sibolt, Gerli, Teumer, Alexander, Rutten-Jacobs, Loes, Kanai, Masahiro, Gretarsdottir, Solveig, Rost, Natalia S, Yusuf, Salim, Almgren, Peter, Ay, Hakan, Bevan, Steve, Brown, Robert D, Carrera, Caty, Buring, Julie E, Chen, Wei-Min, Cotlarciuc, Ioana, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gustafsson, Stefan, Hassan, Ahamad, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Ingelsson, Erik, Harris, Tamara B, Kissela, Brett M, Kleindorfer, Dawn O, Langenberg, Claudia, Lemmens, Robin, Leys, Didier, Lin, Wei-Yu, Lorentzen, Erik, Magnusson, Patrik K, McArdle, Patrick F, Pulit, Sara L, Rice, Kenneth, Sakaue, Saori, Sapkota, Bishwa R, Tanislav, Christian, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Amin, Najaf, Aparicio, Hugo J, Attia, John, Beiser, Alexa S, Berr, Claudine, Bustamante, Mariana, Caso, Valeria, Choi, Seung Hoan, Chowhan, Ayesha, Dartigues, Jean-Francois, Delavaran, Hossein, Dorr, Marcus, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Hozawa, Atsushi, Ingelsson, Martin, Iwasaki, Motoki, Kaffashian, Sara, Kalra, Lalit, Kjartansson, Olafur, Kloss, Manja, Labovitz, Daniel L, Laurie, Cathy C, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Makoto, Hirata, Minegishi, Naoko, Morris, Andrew P, Muller-Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Pedersen, Nancy L, Perola, Markus, Jousilahti, Pekka, Pileggi, Silvana, Rabionet, Raquel, Riba-Llena, Iolanda, Ribases, Marta, Romero, Jose R, Rudd, Anthony G, Sarin, Antti-Pekka, Sarju, Ralhan, Satoh, Mamoru, Sawada, Norie, Sigurdsson, Asgeir, Smith, Albert, Stine, O Colin, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Wakai, Kenji, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Yamaji, Taiki, Sanghera, Dharambir K, Stefansson, Kari, Martinez-Majander, Nicolas, Sobue, Kenji, Soriano-Tarraga, Carolina, Volzke, Henry, Akpa, Onoja, Sarfo, Fred S, Akpalu, Albert, Obiako, Reginald, Wahab, Kolawole, Osaigbovo, Godwin, Owolabi, Lukman, Komolafe, Morenikeji, Jenkins, Carolyn, Arulogun, Oyedunni, Ogbole, Godwin, Adeoye, Abiodun M, Akinyemi, Joshua, Agunloye, Atinuke, Fakunle, Adekunle G, Uvere, Ezinne, Olalere, Abimbola, Adebajo, Olayinka J, Chen, Junshi, Clarke, Robert, Collins, Rory, Guo, Yu, Wang, Chen, Lv, Jun, Peto, Richard, Chen, Yiping, Fairhurst-Hunter, Zammy, Hill, Michael, Pozarickij, Alfred, Schmidt, Dan, Stevens, Becky, Turnbull, Iain, Yu, Canqing, Nagai, Akiko, Murakami, Yoishinori, Shiroma, Eric J, Sigurdsson, Sigurdur, Ghanbari, Mohsen, Boerwinkle, Eric, Fongang, Bernard, Wang, Ruiqi, Ikram, Mohammad K, Volker, Uwe, de Laat, Karlijn F, van Norden, Anouk GW, de Kort, Paul L, Vermeer, Sarah E, Brouwers, Paul JAM, Gons, Rob AR, den Heijer, Tom, van Dijk, Gert W, van Rooij, Frank GW, Aamodt, Anne H, Skogholt, Anne H, Willer, Cristen J, Heuch, Ingrid, Hagen, Knut, Fritsche, Lars G, Pedersen, Linda M, Ellekjaer, Hanne, Zhou, Wei, Martinsen, Amy E, Kristoffersen, Espen S, Thomas, Laurent F, Kleinschnitz, Christoph, Frantz, Stefan, Ungethum, Kathrin, Gallego-Fabrega, Cristina, Lledos, Miquel, Llucia-Carol, Laia, Sobrino, Tomas, Campos, Francisco, Castillo, Jose, Freijo, Marimar, Arenillas, Juan Francisco, Obach, Victor, Alvarez-Sabin, Jose, Molina, Carlos A, Ribo, Marc, Munoz-Narbona, Lucia, Lopez-Cancio, Elena, Millan, Monica, Diaz-Navarro, Rosa, Vives-Bauza, Cristofol, Serrano-Heras, Gemma, Segura, Tomas, Dhar, Rajat, Delgado-Mederos, Raquel, Prats-Sanchez, Luis, Camps-Renom, Pol, Blay, Natalia, Sumoy, Lauro, Marti-Fabregas, Joan, Schnohr, Peter, Jensen, Gorm B, Benn, Marianne, Afzal, Shoaib, Kamstrup, Pia R, van Setten, Jessica, van der Laan, Sander W, Vonk, Jet MJ, Kim, Bong-Jo, Curtze, Sami, Tiainen, Marjaana, Kinnunen, Janne, Menon, Vilas, Sung, Yun Ju, Yang, Chengran, Saillour-Glenisson, Florence, Gravel, Simon, Millwood, Iona Y, Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J, Jukema, J Wouter, Rissanen, Ina L, Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna MM, Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A, Rundek, Tatjana, Worrall, Bradford B, Lathrop, G Mark, Riaz, Moeen, Simonsick, Eleanor M, Korv, Janika, Franca, Paulo HC, Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M, Heuschmann, Peter Ulrich, Longstreth, WT, Jung, Keum Ji, Bastarache, Lisa, Pare, Guillaume, Damrauer, Scott M, Chasman, Daniel I, Rotter, Jerome I, Zwart, John-Anker, Niiranen, Teemu J, Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernandez-Cadenas, Israel, Walters, Robin G, Ruff, Christian T, Owolabi, Mayowa O, Huffman, Jennifer E, Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Abstract

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

59. Clinical, genetic, and experimental increase in soluble urokinase plasminogen activator receptor levels promotes atherosclerosis

Author

Hindy, George, Tyrrell, Daniel J, Vasbinder, Alexi, Wei, Changli, Presswalla, Feriel, Wang, Hui, Blakely, Pennelope K, Ozel, Ayse Bilge, Graham, Sarah E, Holton, Grace H, Dowsett, Joseph, Fahed, Akl C, Amadi, Kingsley-Michael, Erne, Grace K, Tekumulla, Annika, Ismail, Anis, Launius, Christopher, Sotoodehnia, Nona, Pankow, James S, Thørner, Lise Wegner, Erikstrup, Christian, Pedersen, Ole Birger, Banasik, Karina, Brunak, Søren, Ullum, Henrik, Eugen-Olsen, Jesper, Ostrowski, Sisse Rye, Haas, Mary E, Nielsen, Jonas B, Lotta, Luca A, Engström, Gunnar, Melander, Olle, Orho-Melander, Marju, Zhao, Lili, Murthy, Venkatesh L, Pinsky, David J, Willer, Cristen J, Heckbert, Susan R, Reiser, Jochen, Goldstein, Daniel R, Desch, Karl C, Hayek, Salim S, Hindy, George, Tyrrell, Daniel J, Vasbinder, Alexi, Wei, Changli, Presswalla, Feriel, Wang, Hui, Blakely, Pennelope K, Ozel, Ayse Bilge, Graham, Sarah E, Holton, Grace H, Dowsett, Joseph, Fahed, Akl C, Amadi, Kingsley-Michael, Erne, Grace K, Tekumulla, Annika, Ismail, Anis, Launius, Christopher, Sotoodehnia, Nona, Pankow, James S, Thørner, Lise Wegner, Erikstrup, Christian, Pedersen, Ole Birger, Banasik, Karina, Brunak, Søren, Ullum, Henrik, Eugen-Olsen, Jesper, Ostrowski, Sisse Rye, Haas, Mary E, Nielsen, Jonas B, Lotta, Luca A, Engström, Gunnar, Melander, Olle, Orho-Melander, Marju, Zhao, Lili, Murthy, Venkatesh L, Pinsky, David J, Willer, Cristen J, Heckbert, Susan R, Reiser, Jochen, Goldstein, Daniel R, Desch, Karl C, and Hayek, Salim S

Abstract

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the PLAUR gene (rs4760) confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, Pcsk9 transfection in mice over-expressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared to wild-type mice, despite similar cholesterol levels. Pre-atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared to wild-type aortas. Aortic and circulating suPARTg monocytes exhibited a pro-inflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Published
2022

60. Genome-wide association study of liver fat, iron, and extracellular fluid fraction in the UK Biobank

Author

O’Dushlaine, Colm, primary, Germino, Mary, additional, Verweij, Niek, additional, Nielsen, Jonas B., additional, Yadav, Ashish, additional, Benner, Christian, additional, Backman, Joshua D., additional, Lin, Nan, additional, R. Abecasis, Gonçalo, additional, Baras, Aris, additional, Ferreira, Manuel A., additional, Lotta, Luca A., additional, Walls, Johnathon R., additional, Parasoglou, Prodromos, additional, and Marchini, Jonathan L., additional

Published
2021
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61. Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Author

Moksnes, Marta R, primary, Hansen, Ailin Falkmo, additional, Graham, Sarah E, additional, Gagliano Taliun, Sarah A, additional, Wu, Kuan-Han, additional, Zhou, Wei, additional, Thorstensen, Ketil, additional, Fritsche, Lars G, additional, Gill, Dipender, additional, Mason, Amy, additional, Cucca, Francesco, additional, Schlessinger, David, additional, Abecasis, Gonçalo R., additional, Burgess, Stephen, additional, Åsvold, Bjørn Olav, additional, Nielsen, Jonas B, additional, Hveem, Kristian, additional, Willer, Cristen J, additional, and Brumpton, Ben M, additional

Published
2021
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62. Model-based assessment of replicability for genome-wide association meta-analysis

Author

McGuire, Daniel, Jiang, Yu, Liu, Mengzhen, Weissenkampen, J. Dylan, Eckert, Scott, Yang, Lina, Chen, Fang, Liu, MengZhen, Wedow, Robbee, Li, Yue, Brazel, David M., Datta, Gargi, Davila-Velderrain, Jose, Tian, Chao, Zhan, Xiaowei, Choquet, H. éléne, Docherty, Anna R., Faul, Jessica D., Foerster, Johanna R., Fritsche, Lars, Gabrielsen, Maiken Elvestad, Gordon, Scott D., Haessler, Jeffrey, Hottenga, Jouke-Jan, Huang, Hongyan, Jang, Seon-Kyeong, Jansen, Philip R., Ling, Yueh, Ma ̈gi, Reedik, Matoba, Nana, McMahon, George, Mulas, Antonella, Orru, Valeria, Palviainen, Teemu, Pandit, Anita, Reginsson, Gunnar W., Skogholt, Anne Heidi, Smith, Jennifer A., Taylor, Amy E., Turman, Constance, Willemsen, Gonneke, Young, Hannah, Young, Kendra A., Zajac, Gregory J. M., Zhao, Wei, Zhou, Wei, Bjornsdottir, Gyda, Boardman, Jason D., Boehnke, Michael, Boomsma, Dorret I., Chen, Chu, Cucca, Francesco, Davies, Gareth E., Eaton, Charles B., Ehringer, Marissa A., Esko, Tõnu, Fiorillo, Edoardo, Gillespie, Nathan A., Gudbjartsson, Daniel F., Haller, Toomas, Harris, Kathleen Mullan, Heath, Andrew C., Hewitt, John K., Hickie, Ian B., Hokanson, John E., Hopfer, Christian J., Hunter, David J., Iacono, William G., Johnson, Eric O., Kamatani, Yoichiro, Kardia, Sharon L. R., Keller, Matthew C., Kellis, Manolis, Kooperberg, Charles, Kraft, Peter, Krauter, Kenneth S., Laakso, Markku, Lind, Penelope A., Loukola, Anu, Lutz, Sharon M., Madden, Pamela A. F., Martin, Nicholas G., McGue, Matt, McQueen, Matthew B., Medland, Sarah E., Metspalu, Andres, Mohlke, Karen L., Nielsen, Jonas B., Okada, Yukinori, Peters, Ulrike, Polderman, Tinca J. C., Posthuma, Danielle, Reiner, Alexander P., Rice, JP, Rimm, Eric, Rose, Richard J., Runarsdottir, Valgerdur, Stallings, Michael C., Stanˇca ́kova, Alena, Stefansson, Hreinn, Thai, Khanh K., Tindle, Hilary A., Tyrfingsson, Thorarinn, Wall, Tamara L., Weir, David R., Weisner, Constance M, Whitfield, John B., Winsvold, Bendik K S, Yin, Jie, Zuccolo, Luisa, Bierut, Laura J., Hveem, Kristian, Lee, James J., Munafo, Marcus R., Saccone, Nancy L., Willer, Cristen J, Cornelis, Marilyn C., David, Sean P., Hinds, David, Jorgenson, Eric, Kaprio, Jaakko, Stitzel, Jerry A., Stefansson, Kari, Thorgeirsson, Thorgeir E., Abecasis, Goncalo, Liu, Dajiang J., Vrieze, Scott, Berg, Arthur, Jiang, Bibo, Li, Qunhua, Technology Centre, Institute for Molecular Medicine Finland, Genetic Epidemiology, HUSLAB, Centre of Excellence in Complex Disease Genetics, Jaakko Kaprio / Principal Investigator, Department of Public Health, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Aging & Later Life, APH - Mental Health, Child and Adolescent Psychiatry / Psychology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, APH - Methodology, and Clinical Developmental Psychology

Subjects
0301 basic medicine, Genotype, Computer science, Science, General Physics and Astronomy, Genome-wide association study, Genomics, Computational biology, Genome-wide association studies, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Consistency (database systems), 0302 clinical medicine, Meta-Analysis as Topic, Replication (statistics), Genetic Association Studies, Multidisciplinary, biology, Models, Genetic, Statistics, Mamba, Computational Biology, Reproducibility of Results, General Chemistry, Replicate, biology.organism_classification, 030104 developmental biology, Phenotype, Sample size determination, Sample Size, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine, 030217 neurology & neurosurgery, Imputation (genetics), Software, Algorithms, Genome-Wide Association Study
Abstract

Genome-wide association meta-analysis (GWAMA) is an effective approach to enlarge sample sizes and empower the discovery of novel associations between genotype and phenotype. Independent replication has been used as a gold-standard for validating genetic associations. However, as current GWAMA often seeks to aggregate all available datasets, it becomes impossible to find a large enough independent dataset to replicate new discoveries. Here we introduce a method, MAMBA (Meta-Analysis Model-based Assessment of replicability), for assessing the “posterior-probability-of-replicability” for identified associations by leveraging the strength and consistency of association signals between contributing studies. We demonstrate using simulations that MAMBA is more powerful and robust than existing methods, and produces more accurate genetic effects estimates. We apply MAMBA to a large-scale meta-analysis of addiction phenotypes with 1.2 million individuals. In addition to accurately identifying replicable common variant associations, MAMBA also pinpoints novel replicable rare variant associations from imputation-based GWAMA and hence greatly expands the set of analyzable variants., In genome-wide association meta-analysis, it is often difficult to find an independent dataset of sufficient size to replicate associations. Here, the authors have developed MAMBA to calculate the probability of replicability based on consistency between datasets within the meta-analysis.

Published
2021
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65. Utility of family history in disease prediction in the era of polygenic scores

Author

Wolford, Brooke N., primary, Surakka, Ida, additional, Graham, Sarah E., additional, Nielsen, Jonas B., additional, Zhou, Wei, additional, Gabrielsen, Maiken Elvestad, additional, Skogholt, Anne Heidi, additional, Brumpton, Ben M., additional, Douville, Nicholas, additional, Hornsby, Whitney E., additional, Fritsche, Lars G., additional, Boehnke, Michael, additional, Lee, Seunggeun, additional, Kang, Hyun M., additional, Hveem, Kristian, additional, and Willer, Cristen J., additional

Published
2021
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66. MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk

Author

Surakka, Ida, Fritsche, Lars, Zhou, Wei, Backman, Joshua, Kosmicki, Jack A., Lu, Haocheng, Brumpton, Ben Michael, Nielsen, Jonas B., Gabrielsen, Maiken Elvestad, Skogholt, Anne Heidi, Wolford, Brooke N., Graham, Sarah E., Chen, Y. Eugene, Lee, Seunggeun, Kang, Hyun Min, Langhammer, Arnulf, Forsmo, Siri, Åsvold, Bjørn Olav, Styrkarsdottir, Unnur, Holm, Hilma, Gudbjartsson, Daniel F., Stefansson, Kari, Baras, Aris, Bai, Xiaodong, Balasubramanian, Suganthi, Barnard, Leland, Blumenfeld, Andrew, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Eom, Gisu, Habegger, Lukas, Hahn, Young, Hawes, Alicia, Jones, Marcus B., Khalid, Shareef, Lotta, Luca A., Maxwell, Evan K., Mitnaul, Lyndon J., Overton, John D., Reid, Jeffrey G., Ferreira, Manuel Allen Revez, Salerno, William, Sharma, Deepika, Shuldiner, Alan R., Staples, Jeffrey C., Yadav, Ashish, Abecasis, Goncalo R., Hveem, Kristian, and Willer, Cristen J.

Subjects
0301 basic medicine, Oncology, Male, Osteoporosis, Iceland, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Cohort Studies, Fractures, Bone, 0302 clinical medicine, Gene Frequency, Bone Density, lcsh:Science, Bone mineral, Aged, 80 and over, Extracellular Matrix Proteins, Multidisciplinary, Middle Aged, Cohort, Female, musculoskeletal diseases, Adult, medicine.medical_specialty, Science, Predictive medicine, 030209 endocrinology & metabolism, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, Genetic Association Studies, Genetic association, Genetic association study, Aged, Glycoproteins, business.industry, Genome, Human, Computational Biology, General Chemistry, medicine.disease, Phosphoproteins, Computational biology and bioinformatics, Minor allele frequency, 030104 developmental biology, MEPE, lcsh:Q, business, Imputation (genetics)
Abstract

A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10−18), and increased osteoporosis (P-value = 4.2 × 10−5) and fracture risk (P-value = 1.6 × 10−5). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10−16, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores., Bone mineral density (BMD) is associated with fracture risk and many genetic loci with small effect sizes have been discovered by genome-wide association studies (GWAS). Here, the authors discover a large-effect rare loss-of-function genetic variant for BMD in the MEPE gene in the Norwegian HUNT study which replicates in the UK Biobank.

Published
2020

67. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study

Author

Georgakis, Marios K, Malik, Rainer, Gordon, William, Davey-Smith, George, Morrison, Alanna C, Hicks, Andrew, van Duijn, Cornelia M, Ward-Caviness, Cavin, Boerwinkle, Eric, Rotter, J., Rice, Ken, Lange, Leslie, Perola, Markus, van Hylckama Vlieg, Astrid, de Geus, Eco, Morris, Andrew P, Makela, Kari Matti, Stacey, David, Eriksson, Johan, Frayling, Tim M, Slagboom, Eline P, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming-Huei, Gill, Dipender, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Franceschini, Nora, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Damrauer, Scott M, Natarajan, Pradeep, Klarin, Derek, de Vries, Paul S, SabaterLleal, Maria, Huffman, Jennifer E, Bammler, Theo K, Sudlow, Cathie L M, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean-François, O'Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Dichgans, Martin, Kraft, Peter, Hansen, JohnBjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre Emmanuel, INVENT Consortium, CHARGE Inflammation Working Group, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David-Alexandre, Smith, Nicholas L, Benjamin, Emelia, Dehghan, Abbas, Ahluwalia, Tarunveer Singh, Meigs, James, Tracy, Russell, Lindstrom, Sara, Alizadeh, Behrooz Z, Ligthart, Symen, Bis, Josh, Eiriksdottir, Gudny, Gross, Myron, Rainer, Alex, Snieder, Harold, Wilson, James G, Wang, Lu, Dupuis, Josee, Prins, Bram, Vaso, Urmo, Stathopoulou, Maria, Franke, Lude, Lehtimaki, Terho, Koenig, Wolfgang, Jamshidi, Yalda, Siest, Sophie, Abbasi, Ali, Smith, Erin N, Uitterlinden, Andre G, Abdollahi, Mohammadreza, Schnabel, Renate, Schick, Ursula M, Nolte, Ilja M, Kraja, Aldi, Hsu, Yi-Hsiang, Tylee, Daniel S, Zwicker, Alyson, Uher, Rudolf, Environmental Geography (former), and Biological Psychology

Subjects
Male, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, Medicine, genetics, Myocardial infarction, Stroke, diagnostic imaging [Ischemic Stroke], 0303 health sciences, Atrial fibrillation, General Medicine, stroke, 3. Good health, Cardiology, Female, coronary artery disease, INVENT Consortium,CHARGE Inflammation Working Group, Signal Transduction, medicine.medical_specialty, genetics [Interleukin-6], Lower risk, genetics [Signal Transduction], 03 medical and health sciences, Internal medicine, Mendelian randomization, Research Letter, Humans, Genetic Predisposition to Disease, ddc:610, Ischemic Stroke, 030304 developmental biology, Interleukin-6, business.industry, Odds ratio, genetics [Ischemic Stroke], Mendelian Randomization Analysis, medicine.disease, cardiovascular diseases, inflammation, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BackgroundStudies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown.MethodsIn a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.ResultsWe identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque.ConclusionsWe provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.CLINICAL PERSPECTIVEWhat is newWe identified genetic proxies for downregulated IL-6 signaling that had effects on upstream and downstream regulators of the IL-6 signaling pathway consistent with those of pharmacological IL-6R blockadeGenetically downregulated IL-6 signaling was associated with a lower risk of ischemic stroke, and in particular large artery and small vessel strokeSimilar associations were obtained for a broad range of other cardiovascular outcomesWhat are the clinical implicationsInhibition of IL-6 signaling is a promising therapeutic target for lowering risk of stroke and other cardiovascular outcomes and should be further investigated in clinical trials

Published
2020
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68. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study):a randomised controlled trial

Author

Svendsen, Jesper H., Diederichsen, Søren Z., Højberg, Søren, Krieger, Derk W., Graff, Claus, Kronborg, Christian, Olesen, Morten S., Nielsen, Jonas B., Holst, Anders G., Brandes, Axel, Haugan, Ketil J., Køber, Lars, Svendsen, Jesper H., Diederichsen, Søren Z., Højberg, Søren, Krieger, Derk W., Graff, Claus, Kronborg, Christian, Olesen, Morten S., Nielsen, Jonas B., Holst, Anders G., Brandes, Axel, Haugan, Ketil J., and Køber, Lars

Abstract

Background: It is unknown whether screening for atrial fibrillation and subsequent treatment with anticoagulants if atrial fibrillation is detected can prevent stroke. Continuous electrocardiographic monitoring using an implantable loop recorder (ILR) can facilitate detection of asymptomatic atrial fibrillation episodes. We aimed to investigate whether atrial fibrillation screening and use of anticoagulants can prevent stroke in individuals at high risk. Methods: We did a randomised controlled trial in four centres in Denmark. We included individuals without atrial fibrillation, aged 70–90 years, with at least one additional stroke risk factor (ie, hypertension, diabetes, previous stroke, or heart failure). Participants were randomly assigned in a 1:3 ratio to ILR monitoring or usual care (control) via an online system in permuted blocks with block sizes of four or eight participants stratified according to centre. In the ILR group, anticoagulation was recommended if atrial fibrillation episodes lasted 6 min or longer. The primary outcome was time to first stroke or systemic arterial embolism. This study is registered with ClinicalTrials.gov, NCT02036450. Findings: From Jan 31, 2014, to May 17, 2016, 6205 individuals were screened for inclusion, of whom 6004 were included and randomly assigned: 1501 (25·0%) to ILR monitoring and 4503 (75·0%) to usual care. Mean age was 74·7 years (SD 4·1), 2837 (47·3%) were women, and 5444 (90·7%) had hypertension. No participants were lost to follow-up. During a median follow-up of 64·5 months (IQR 59·3–69·8), atrial fibrillation was diagnosed in 1027 participants: 477 (31·8%) of 1501 in the ILR group versus 550 (12·2%) of 4503 in the control group (hazard ratio [HR] 3·17 [95% CI 2·81–3·59]; p<0·0001). Oral anticoagulation was initiated in 1036 participants: 445 (29·7%) in the ILR group versus 591 (13·1%) in the control group (HR 2·72 [95% CI 2·41–3·08]; p<0·0001), and the primary outcome occurred in 318 participants (315

Published
2021

69. Early glycemic changes after initiation of oral anti-diabetic medication and risk of major adverse cardiovascular events:results from a large primary care population of patients with type 2 diabetes

Author

Ghouse, Jonas, Blanche, Paul, Skov, Morten W, Lind, Bent, Vaag, Allan, Kanters, Jørgen K, Svendsen, Jesper H, Køber, Lars, Olesen, Morten S, Gerds, Thomas A, Holst, Anders G, Nielsen, Jonas B, Ghouse, Jonas, Blanche, Paul, Skov, Morten W, Lind, Bent, Vaag, Allan, Kanters, Jørgen K, Svendsen, Jesper H, Køber, Lars, Olesen, Morten S, Gerds, Thomas A, Holst, Anders G, and Nielsen, Jonas B

Abstract

AIMS: To determine the risk of major cardiovascular events (MACE) and death, associated with an early large and rapid decline in HbA1C following first time initiation of an oral antidiabetic drug (OAD).METHODS AND RESULTS: We included 10,518 primary care patients with T2D, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5-4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep (≥ 9 mmol/mol [≥ 0.8%]) and flat decline (< 9 mmol/mol per 3 mo. [< 0.8%]). Pre-treatment HbA1C was categorized by the median, into levels of low (48-62 mmol/mol) and high (> 62 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C. Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7 years, 1,625 developed MACE and 2,323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high (HR 0.81; 95% CI 0.69-0.94; P = 0.005) and low pre-treatment HbA1C (HR 0.79; 95% CI 0.66-0.96; P = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C. We found no significant association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA1C and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00-2.29; P = 0.048) and hypoglycemia (HR 1.82; 95% C

Published
2021

70. Electrocardiographic T-wave morphology and risk of mortality

Author

Isaksen, Jonas L, Ghouse, Jonas, Graff, Claus, Olesen, Morten S, Holst, Anders G, Pietersen, Adrian, Nielsen, Jonas B, Skov, Morten W, Kanters, Jørgen K, Isaksen, Jonas L, Ghouse, Jonas, Graff, Claus, Olesen, Morten S, Holst, Anders G, Pietersen, Adrian, Nielsen, Jonas B, Skov, Morten W, and Kanters, Jørgen K

Abstract

BACKGROUND: Electrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QTc interval, but few measurements of T-wave morphology can be interpreted in clinical practice. Morphology combination score (MCS) is a combination of T-wave flatness/peakedness, asymmetry, and notching, enabling easy visual assessment of T-wave morphology. We aimed to test the association between T-wave morphology, quantified by MCS, and mortality.METHODS: We included electrocardiograms recorded in 2001-2011 from 342,294 primary care patients. Using Cox regression, we evaluated the association between MCS, cardiovascular death, and all-cause mortality, adjusting for heart rate, QTc, QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure.RESULTS: 270,039 individuals (44% men, median age 55 [inter-quartile range: 42-67 years]) were included and followed for a median of 9.3 years, during which time 13,489 (5.0%) died from cardiovascular causes and 50,481 (18.7%) from any cause. High values of MCS (i.e. asymmetric, flattened, and/or notched T waves) were associated with an adjusted mortality Hazard Ratio of 1.75 (95% CI 1.62-1.89) and 1.61 (1.43-1.92) for women and men, respectively. Low values of MCS (i.e. peaked and symmetric T waves) were associated with a Hazard Ratio of 1.18 (1.08-1.28) and 1.71 (1.48-1.98) for women and men, respectively.CONCLUSIONS: In a large primary care population, we found that T-wave asymmetry, flatness, and notching provided prognostic information on mortality independent of heart rate, QTc, and baseline comorbidities.

Published
2021

71. Genome-wide association study of cardiac troponin I in the general population

Author

Moksnes, Marta R, primary, Røsjø, Helge, additional, Richmond, Anne, additional, Lyngbakken, Magnus N, additional, Graham, Sarah E, additional, Hansen, Ailin Falkmo, additional, Wolford, Brooke N, additional, Gagliano Taliun, Sarah A, additional, LeFaive, Jonathon, additional, Rasheed, Humaira, additional, Thomas, Laurent F, additional, Zhou, Wei, additional, Aung, Nay, additional, Surakka, Ida, additional, Douville, Nicholas J, additional, Campbell, Archie, additional, Porteous, David J, additional, Petersen, Steffen E, additional, Munroe, Patricia B, additional, Welsh, Paul, additional, Sattar, Naveed, additional, Smith, George Davey, additional, Fritsche, Lars G, additional, Nielsen, Jonas B, additional, Åsvold, Bjørn Olav, additional, Hveem, Kristian, additional, Hayward, Caroline, additional, Willer, Cristen J, additional, Brumpton, Ben M, additional, and Omland, Torbjørn, additional

Published
2021
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74. Association Between ECG Abnormalities and Fatal Cardiovascular Disease Among Patients With and Without Severe Mental Illness

Author

Polcwiartek, Christoffer, primary, Atwater, Brett D., additional, Kragholm, Kristian, additional, Friedman, Daniel J., additional, Barcella, Carlo A., additional, Attar, Rubina, additional, Graff, Claus, additional, Nielsen, Jonas B., additional, Pietersen, Adrian, additional, Søgaard, Peter, additional, Torp‐Pedersen, Christian, additional, and Jensen, Svend E., additional

Published
2021
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78. Using human genetics to understand the causes and consequences of circulating cardiac troponin I in the general population

Author

Moksnes, Marta R, primary, Røsjø, Helge, additional, Richmond, Anne, additional, Lyngbakken, Magnus N, additional, Graham, Sarah E, additional, Hansen, Ailin Falkmo, additional, Wolford, Brooke N, additional, Taliun, Sarah A Gagliano, additional, LeFaive, Jonathon, additional, Rasheed, Humaira, additional, Thomas, Laurent F, additional, Zhou, Wei, additional, Surakka, Ida, additional, Douville, Nicholas J, additional, Campbell, Archie, additional, Porteous, David J, additional, Welsh, Paul, additional, Sattar, Naveed, additional, Smith, George Davey, additional, Fritsche, Lars G, additional, Nielsen, Jonas B, additional, Åsvold, Bjørn Olav, additional, Hveem, Kristian, additional, Hayward, Caroline, additional, Willer, Cristen J, additional, Brumpton, Ben M, additional, and Omland, Torbjørn, additional

Published
2020
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79. Early glycaemic changes after initiation of oral antidiabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes

Author

Ghouse, Jonas, primary, Blanche, Paul, additional, Skov, Morten W, additional, Lind, Bent, additional, Vaag, Allan, additional, Kanters, Jørgen K, additional, Svendsen, Jesper H, additional, Køber, Lars, additional, Olesen, Morten S, additional, Gerds, Thomas A, additional, Holst, Anders G, additional, and Nielsen, Jonas B, additional

Published
2020
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81. Exploring and visualizing large-scale genetic associations by using PheWeb

Author

Gagliano Taliun, Sarah A., primary, VandeHaar, Peter, additional, Boughton, Andrew P., additional, Welch, Ryan P., additional, Taliun, Daniel, additional, Schmidt, Ellen M., additional, Zhou, Wei, additional, Nielsen, Jonas B., additional, Willer, Cristen J., additional, Lee, Seunggeun, additional, Fritsche, Lars G., additional, Boehnke, Michael, additional, and Abecasis, Gonçalo R., additional

Published
2020
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82. Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts

Author

Zhou, Wei, primary, Zhao, Zhangchen, additional, Nielsen, Jonas B., additional, Fritsche, Lars G., additional, LeFaive, Jonathon, additional, Gagliano Taliun, Sarah A., additional, Bi, Wenjian, additional, Gabrielsen, Maiken E., additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Hveem, Kristian, additional, Abecasis, Goncalo R., additional, Willer, Cristen J., additional, and Lee, Seunggeun, additional

Published
2020
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83. Is disrupted sleep a risk factor for Alzheimer’s disease? Evidence from a two-sample Mendelian randomization analysis

Author

Anderson, Emma L, primary, Richmond, Rebecca C, additional, Jones, Samuel E, additional, Hemani, Gibran, additional, Wade, Kaitlin H, additional, Dashti, Hassan S, additional, Lane, Jacqueline M, additional, Wang, Heming, additional, Saxena, Richa, additional, Brumpton, Ben, additional, Korologou-Linden, Roxanna, additional, Nielsen, Jonas B, additional, Åsvold, Bjørn Olav, additional, Abecasis, Gonçalo, additional, Coulthard, Elizabeth, additional, Kyle, Simon D, additional, Beaumont, Robin N, additional, Tyrrell, Jessica, additional, Frayling, Timothy M, additional, Munafò, Marcus R, additional, Wood, Andrew R, additional, Ben-Shlomo, Yoav, additional, Howe, Laura D, additional, Lawlor, Deborah A, additional, Weedon, Michael N, additional, and Davey Smith, George, additional

Published
2020
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84. Chloroquine, but not hydroxychlorquine, prolongs the QT interval in a primary care population

Author

Isaksen, Jonas L., Holst, Anders G., Pietersen, Adrian, Nielsen, Jonas B., Graff, Claus, and Kanters, Jørgen K.

Subjects
cardiovascular diseases
Abstract

Background: Chloroquine (CQ) and Hydroxychloroquine (HCQ) have recently been suggested as treatment for the current Corona Virus Disease 2019 (COVID-19) pandemic. However, despite their long-term use and only few case reports on adverse effects, CQ and HCQ are listed as a known risk of the lethal ventricular arrhythmia Torsade de Pointes and their cardiac safety profile is being questioned. Thus, we aimed to investigate the electrocardiographic and mortality effects of CQ and HCQ in a primary care population. Methods: We used Danish health care registers and electrocardiograms (ECGs) from primary care to define three studies. 1) A paired study of subjects with ECGs before and during use of CQ/HCQ, 2) a matched ECG study of subjects taking CQ/HCQ compared to controls, and 3) a mortality study on people taking HCQ matched to control. In both matched studies, we adjusted for connective tissue diseases, use of QT-prolonging drugs, and cardiac disease. We used the QTc interval as the marker for electrocardiographic safety. In the mortality study, cases were followed from first claimed prescription until 300 days after estimated completion of the last prescription. 95% confidence intervals follow estimates in parenthesis. Results: Use of CQ was associated with a 5.5 (0.7;10) ms increase in QTc in the paired study (n=10). In the matched study (n=28, controls=280), QTc was insignificantly increased in subjects taking CQ by 4.7 (-3.4;13) ms. With a ΔQTc of 1.0 (-5.6;7.5), use of HCQ was not associated with an increased QTc in the paired study (n=32). In the matched study (n=172, controls=1,720), QTc also was not different between groups (p=0.5). In the mortality study (n=3,368), use of HCQ was associated with a hazard ratio of 0.67 (0.43;1.05). Conclusions: In subjects free of COVID-19, we found a small increase in QTc associated with use of chloroquine, but not hydroxychloroquine. We found no increased mortality associated with use of hydroxychloroquine.

Published
2020
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85. CEP906835 Supplemental table 1 - Supplemental material for Mitochondrial genome-wide association study of migraine – the HUNT Study

Author

Børte, Sigrid, John-Anker Zwart, Skogholt, Anne Heidi, Gabrielsen, Maiken Elvestad, Thomas, Laurent F, Fritsche, Lars G, Surakka, Ida, Nielsen, Jonas B, Zhou, Wei, Wolford, Brooke N, Vigeland, Magnus D, Hagen, Knut, Kristoffersen, Espen Saxhaug, Nyholt, Dale R, Chasman, Daniel I, Brumpton, Ben M, Cristen J Willer, and Winsvold, Bendik S

Subjects
FOS: Psychology, FOS: Clinical medicine, 170199 Psychology not elsewhere classified, 110319 Psychiatry (incl. Psychotherapy), 110306 Endocrinology, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, CEP906835 Supplemental table 1 for Mitochondrial genome-wide association study of migraine – the HUNT Study by Sigrid Børte, John-Anker Zwart, Anne Heidi Skogholt, Maiken Elvestad Gabrielsen, Laurent F Thomas, Lars G Fritsche, Ida Surakka, Jonas B Nielsen, Wei Zhou, Brooke N Wolford, Magnus D Vigeland, Knut Hagen, Espen Saxhaug Kristoffersen, Dale R Nyholt, Daniel I Chasman, Ben M Brumpton, Cristen J Willer and Bendik S Winsvold in Cephalalgia

Published
2020
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86. Mitochondrial genome-wide association study of migraine - the HUNT Study

Author

Børte, Sigrid, Zwart, John-Anker, Skogholt, Anne Heidi, Gabrielsen, Maiken Elvestad, Thomas, Laurent F, Fritsche, Lars G, Surakka, Ida, Nielsen, Jonas B, Zhou, Wei, Wolford, Brooke N, Vigeland, Magnus D, Hagen, Knut, Kristoffersen, Espen Saxhaug, Nyholt, Dale R, Chasman, Daniel I, Brumpton, Ben M, Willer, Cristen J, Winsvold, Bendik S, Børte, Sigrid, Zwart, John-Anker, Skogholt, Anne Heidi, Gabrielsen, Maiken Elvestad, Thomas, Laurent F, Fritsche, Lars G, Surakka, Ida, Nielsen, Jonas B, Zhou, Wei, Wolford, Brooke N, Vigeland, Magnus D, Hagen, Knut, Kristoffersen, Espen Saxhaug, Nyholt, Dale R, Chasman, Daniel I, Brumpton, Ben M, Willer, Cristen J, and Winsvold, Bendik S

Abstract

BACKGROUND: Variation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. We aimed to perform the first mitochondrial genome-wide association study of migraine, examining both single variants and mitochondrial haplogroups.METHODS: In total, 71,860 participants from the population-based Nord-Trøndelag Health Study were genotyped. We excluded samples not passing quality control for nuclear genotypes, in addition to samples with low call rate and closely maternally related. We analysed 775 mitochondrial DNA variants in 4021 migraine cases and 14,288 headache-free controls, using logistic regression. In addition, we analysed 3831 cases and 13,584 controls who could be reliably assigned to a mitochondrial haplogroup. Lastly, we attempted to replicate previously reported mitochondrial DNA candidate variants.RESULTS: Neither of the mitochondrial variants or haplogroups were associated with migraine. In addition, none of the previously reported mtDNA candidate variants replicated in our data.CONCLUSIONS: Our findings do not support a major role of mitochondrial genetic variation in migraine pathophysiology, but a larger sample is needed to detect rare variants and future studies should also examine heteroplasmic variation, epigenetic changes and copy-number variation.

Published
2020

87. Age-of-onset information helps identify 76 genetic variants associated with allergic disease

Author

Ferreira, Manuel A R, Vonk, Judith M, Baurecht, Hansjörg, Marenholz, Ingo, Tian, Chao, Hoffman, Joshua D, Helmer, Quinta, Tillander, Annika, Ullemar, Vilhelmina, Lu, Yi, Grosche, Sarah, Rüschendorf, Franz, Granell, Raquel, Brumpton, Ben M, Fritsche, Lars G, Bhatta, Laxmi, Gabrielsen, Maiken E, Nielsen, Jonas B, Zhou, Wei, Hveem, Kristian, Langhammer, Arnulf, Holmen, Oddgeir L, Løset, Mari, Abecasis, Gonçalo R, Willer, Cristen J, Emami, Nima C, Cavazos, Taylor B, Witte, John S, Szwajda, Agnieszka, Hinds, David A, Hübner, Norbert, Weidinger, Stephan, Magnusson, Patrik Ke, Jorgenson, Eric, Karlsson, Robert, Paternoster, Lavinia, Boomsma, Dorret I, Almqvist, Catarina, Lee, Young-Ae, Koppelman, Gerard H, Ferreira, Manuel A R, Vonk, Judith M, Baurecht, Hansjörg, Marenholz, Ingo, Tian, Chao, Hoffman, Joshua D, Helmer, Quinta, Tillander, Annika, Ullemar, Vilhelmina, Lu, Yi, Grosche, Sarah, Rüschendorf, Franz, Granell, Raquel, Brumpton, Ben M, Fritsche, Lars G, Bhatta, Laxmi, Gabrielsen, Maiken E, Nielsen, Jonas B, Zhou, Wei, Hveem, Kristian, Langhammer, Arnulf, Holmen, Oddgeir L, Løset, Mari, Abecasis, Gonçalo R, Willer, Cristen J, Emami, Nima C, Cavazos, Taylor B, Witte, John S, Szwajda, Agnieszka, Hinds, David A, Hübner, Norbert, Weidinger, Stephan, Magnusson, Patrik Ke, Jorgenson, Eric, Karlsson, Robert, Paternoster, Lavinia, Boomsma, Dorret I, Almqvist, Catarina, Lee, Young-Ae, and Koppelman, Gerard H

Abstract

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Published
2020
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88. Electrocardiogram Characteristics and Their Association With Psychotropic Drugs Among Patients With Schizophrenia

Author

Polcwiartek, Christoffer, Kragholm, Kristian, Hansen, Steen M, Atwater, Brett D, Friedman, Daniel J, Barcella, Carlo A, Graff, Claus, Nielsen, Jonas B, Pietersen, Adrian, Nielsen, Jimmi, Søgaard, Peter, Torp-Pedersen, Christian, Jensen, Svend E, Polcwiartek, Christoffer, Kragholm, Kristian, Hansen, Steen M, Atwater, Brett D, Friedman, Daniel J, Barcella, Carlo A, Graff, Claus, Nielsen, Jonas B, Pietersen, Adrian, Nielsen, Jimmi, Søgaard, Peter, Torp-Pedersen, Christian, and Jensen, Svend E

Abstract

BACKGROUND: There are limited data on electrocardiogram (ECG) characteristics and their association with psychotropic drugs in schizophrenia.METHODS: Using a cross-sectional design, we included Danish primary care patients with first-time digital ECGs from 2001 to 2015. Patients diagnosed with schizophrenia before ECG recording were matched 1:5 on age, sex, and ECG recording year to controls without psychiatric disease. Multivariable logistic regression was used to compute odds ratios (ORs) with 95% confidence intervals (CIs).RESULTS: We included 4486 patients with schizophrenia matched with 22 430 controls (median age, 47 years; male, 55%). Between groups, the prevalence of abnormal ECGs was similar (54%, P = .536), but patients with schizophrenia demonstrated higher median heart rate (79 vs 69 beats per minute, P < .001) and Fridericia-corrected QT (QTc) interval (416 vs 412 ms, P < .001) than controls. QTc prolongation was also more prevalent among patients with schizophrenia (3.4% vs 1.1%, P < .001), and so were pathological Q waves (5.3% vs 3.9%, P < .001). Patients with schizophrenia less frequently demonstrated left ventricular hypertrophy (6.1% vs 9.6%, P < .001) and atrial fibrillation or flutter (0.7% vs 1.4%, P < .001). Among patients with schizophrenia only, particularly antipsychotics were associated with abnormal ECGs (OR, 1.20; 95% CI, 1.04-1.39).CONCLUSIONS: Patients with schizophrenia demonstrate a different cardiovascular risk profile than matched controls without psychiatric disease, with higher prevalence of elevated heart rate, QTc prolongation, and pathological Q waves, and lower prevalence of left ventricular hypertrophy and atrial fibrillation or flutter. Particularly antipsychotics were associated with abnormal ECGs. This underscores an integrated care approach when ECG abnormalities are detected in this group.

Published
2020

89. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Author

Nielsen, Jonas B., Rom, Oren, Surakka, Ida, Graham, Sarah E., Zhou, Wei, Roychowdhury, Tanmoy, Fritsche, Lars G., Taliun, Sarah A. Gagliano, Sidore, Carlo, Liu, Yuhao, Gabrielsen, Maiken E., Skogholt, Anne Heidi, Wolford, Brooke, Overton, William, Zhao, Ying, Chen, Jin, Zhang, He, Hornsby, Whitney E., Acheampong, Akua, Grooms, Austen, Schaefer, Amanda, Zajac, Gregory J. M., Villacorta, Luis, Zhang, Jifeng, Brumpton, Ben, Loset, Mari, Rai, Vivek, Lundegaard, Pia R., Olesen, Morten S., Taylor, Kent D., Palmer, Nicholette D., Chen, Yii-Der, Choi, Seung H., Lubitz, Steven A., Ellinor, Patrick T., Barnes, Kathleen C., Daya, Michelle, Rafaels, Nicholas, Weiss, Scott T., Lasky-Su, Jessica, Tracy, Russell P., Vasan, Ramachandran S., Cupples, L. Adrienne, Mathias, Rasika A., Yanek, Lisa R., Becker, Lewis C., Peyser, Patricia A., Bielak, Lawrence F., Smith, Jennifer A., Aslibekyan, Stella, Nielsen, Jonas B., Rom, Oren, Surakka, Ida, Graham, Sarah E., Zhou, Wei, Roychowdhury, Tanmoy, Fritsche, Lars G., Taliun, Sarah A. Gagliano, Sidore, Carlo, Liu, Yuhao, Gabrielsen, Maiken E., Skogholt, Anne Heidi, Wolford, Brooke, Overton, William, Zhao, Ying, Chen, Jin, Zhang, He, Hornsby, Whitney E., Acheampong, Akua, Grooms, Austen, Schaefer, Amanda, Zajac, Gregory J. M., Villacorta, Luis, Zhang, Jifeng, Brumpton, Ben, Loset, Mari, Rai, Vivek, Lundegaard, Pia R., Olesen, Morten S., Taylor, Kent D., Palmer, Nicholette D., Chen, Yii-Der, Choi, Seung H., Lubitz, Steven A., Ellinor, Patrick T., Barnes, Kathleen C., Daya, Michelle, Rafaels, Nicholas, Weiss, Scott T., Lasky-Su, Jessica, Tracy, Russell P., Vasan, Ramachandran S., Cupples, L. Adrienne, Mathias, Rasika A., Yanek, Lisa R., Becker, Lewis C., Peyser, Patricia A., Bielak, Lawrence F., Smith, Jennifer A., and Aslibekyan, Stella

Abstract

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n=69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P=1.3x10(-8)) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD. Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Published
2020

90. Effect of diabetes duration on the relationship between glycaemic control and risk of death in older adults with type 2 diabetes

Author

Ghouse, Jonas, Isaksen, Jonas L, Skov, Morten W, Lind, Bent, Svendsen, Jesper H, Kanters, Jørgen K, Olesen, Morten S, Holst, Anders G., Nielsen, Jonas B., Ghouse, Jonas, Isaksen, Jonas L, Skov, Morten W, Lind, Bent, Svendsen, Jesper H, Kanters, Jørgen K, Olesen, Morten S, Holst, Anders G., and Nielsen, Jonas B.

Abstract

AIM: To investigate the effect of diabetes duration on glycaemic control, measured according to mean glycated haemoglobin (HbA1c) level, and mortality risk within different age, sex and clinically relevant, comorbidity-defined subgroups in an elderly population with type 2 diabetes (T2D).METHODS: We studied older (≥ 65 years) primary care patients with T2D, who had three successive annual measurements of HbA1c taken between 2005 and 2013. The primary exposure was the mean of all three HbA1c measurements. Follow-up began on the date of the third measurement. Individual mean HbA1c levels were categorized into clinically relevant groups (<48 mmol/mol [<6.5%]; 48-52 mmol/mol [6.5%-6.9 %]; 53-63 mmol/mol [7%-7.9%]; 64-74 mmol/mol [8%-8.9%]; and ≥ 75 mmol/mol [≥ 9%]). We used multiple Cox regression to study the effect of glycaemic control on the hazard of all-cause mortality, adjusted for age, sex, use of concomitant medication, and age- and disease-related comorbidities.RESULTS: A total of 9734 individuals were included. During a median (interquartile range) follow-up of 7.3 (4.6-8.7) years, 3320 individuals died. We found that the effect of mean HbA1c on all-cause mortality depended on the duration of diabetes (P for interaction <0.001). For individuals with short diabetes duration (<5 years), the risk of death increased with poorer glycaemic control (increasing HbA1c), whereas for individuals with longstanding diabetes (≥ 5 years), we found a J-shaped association, where a mean HbA1c level between 48 and 63 mmol/mol (6.5% and 7.9%) was associated with the lowest risk of death. For individuals with longstanding diabetes, both low (< 48 mmol/mol [<6.5 %]; hazard ratio [HR] 1.21, 95 % confidence interval [CI] 1.07-1.37, P = 0.002), and high mean HbA1c levels ( ≥ 75 mmol/mol [≥9.0 %]; HR 1.60, 95 % CI 1.28-1.99, P < 0.001) were associated with an increased risk of death. We also calculated 5-year absolute risks of all-cause mortality

Published
2020

92. Mitochondrial genome-wide association study of migraine – the HUNT Study

Author

Børte, Sigrid, primary, Zwart, John-Anker, additional, Skogholt, Anne Heidi, additional, Gabrielsen, Maiken Elvestad, additional, Thomas, Laurent F, additional, Fritsche, Lars G, additional, Surakka, Ida, additional, Nielsen, Jonas B, additional, Zhou, Wei, additional, Wolford, Brooke N, additional, Vigeland, Magnus D, additional, Hagen, Knut, additional, Kristoffersen, Espen Saxhaug, additional, Nyholt, Dale R, additional, Chasman, Daniel I, additional, Brumpton, Ben M, additional, Willer, Cristen J, additional, and Winsvold, Bendik S, additional

Published
2020
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93. Mutations in the potassium channel subunit KCNE1 are associated with early-onset familial atrial fibrillation

Author

Olesen Morten S, Bentzen Bo H, Nielsen Jonas B, Steffensen Annette B, David Jens-Peter, Jabbari Javad, Jensen Henrik K, Haunsø Stig, Svendsen Jesper H, and Schmitt Nicole

Subjects
Lone AF, Genetics, KV7.1, KCNE1, IKs current, Internal medicine, RC31-1245, QH426-470
Abstract

Abstract Background Atrial fibrillation (AF) is the most common arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutations in KV7.1, the pore-forming α-subunit of the IKs channel, have been associated with AF. We hypothesized that early-onset lone AF is associated with mutations in the IKs channel regulatory subunit KCNE1. Methods In 209 unrelated early-onset lone AF patients (< 40 years) the entire coding sequence of KCNE1 was bidirectionally sequenced. We analyzed the identified KCNE1 mutants electrophysiologically in heterologous expression systems. Results Two non-synonymous mutations G25V and G60D were found in KCNE1 that were not present in the control group (n = 432 alleles) and that have not previously been reported in any publicly available databases or in the exom variant server holding exom data from more than 10.000 alleles. Proband 1 (female, age 45, G25V) had onset of paroxysmal AF at the age of 39 years. Proband 2 (G60D) was diagnosed with lone AF at the age of 33 years. The patient has inherited the mutation from his mother, who also has AF. Both probands had no mutations in genes previously associated with AF. In heterologous expression systems, both mutants showed significant gain-of-function for IKs both with respect to steady-state current levels, kinetic parameters, and heart rate-dependent modulation. Conclusions Mutations in KV7.1 leading to gain-of-function of IKs current have previously been described in lone AF, yet this is the first time a mutation in the beta-subunit KCNE1 is associated with the disease. This finding further supports the hypothesis that increased potassium current enhances AF susceptibility.

Published
2012
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96. Electrocardiogram Characteristics and Their Association With Psychotropic Drugs Among Patients With Schizophrenia

Author

Polcwiartek, Christoffer, primary, Kragholm, Kristian, additional, Hansen, Steen M, additional, Atwater, Brett D, additional, Friedman, Daniel J, additional, Barcella, Carlo A, additional, Graff, Claus, additional, Nielsen, Jonas B, additional, Pietersen, Adrian, additional, Nielsen, Jimmi, additional, Søgaard, Peter, additional, Torp-Pedersen, Christian, additional, and Jensen, Svend E, additional

Published
2019
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97. Genetic variants on chromosomes 7p31 and 12p12 are associated with abnormal atrial electrical activation in patients with early‐onset lone atrial fibrillation

Author

Seifert, Mariam B., primary, Olesen, Morten S., additional, Christophersen, Ingrid E., additional, Nielsen, Jonas B., additional, Carlson, Jonas, additional, Holmqvist, Fredrik, additional, Tveit, Arnljot, additional, Haunsø, Stig, additional, Svendsen, Jesper H., additional, and Platonov, Pyotr G., additional

Published
2019
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98. Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease

Author

Nielsen, Jonas B., primary, Rom, Oren, additional, Surakka, Ida, additional, Graham, Sarah E., additional, Zhou, Wei, additional, Fritsche, Lars G., additional, Gagliano Taliun, Sarah A., additional, Sidore, Carlo, additional, Liu, Yuhao, additional, Gabrielsen, Maiken E., additional, Skogholt, Anne Heidi, additional, Wolford, Brooke, additional, Overton, William, additional, Hornsby, Whitney E., additional, Acheampong, Akua, additional, Grooms, Austen, additional, Roychowdhury, Tanmoy, additional, Schaefer, Amanda, additional, Zajac, Gregory JM, additional, Villacorta, Luis, additional, Zhang, Jifeng, additional, Brumpton, Ben, additional, Løset, Mari, additional, Rai, Vivek, additional, Taylor, Kent D., additional, Palmer, Nicholette D., additional, Chen, Yii-Der, additional, Choi, Seung Hoan, additional, Lubitz, Steven A., additional, Ellinor, Patrick T., additional, Barnes, Kathleen C., additional, Daya, Michelle, additional, Rafaels, Nicholas, additional, Weiss, Scott T., additional, Lasky-Su, Jessica, additional, Tracy, Russell P., additional, Vasan, Ramachandran S., additional, Cupples, L. Adrienne, additional, Mathias, Rasika A., additional, Yanek, Lisa R., additional, Becker, Lewis C., additional, Peyser, Patricia A., additional, Bielak, Lawrence F., additional, Smith, Jennifer A., additional, Aslibekyan, Stella, additional, Hildalgo, Bertha A., additional, Arnett, Donna K., additional, Irvin, Marguerite R., additional, Wilson, James G., additional, Musani, Solomon K., additional, Correa, Adolfo, additional, Rich, Stephen S., additional, Guo, Xiuqing, additional, Rotter, Jerome I., additional, Konkle, Barbara A., additional, Johnsen, Jill M., additional, Ashley-Koch, Allison E., additional, Telen, Marilyn J., additional, Sheehan, Vivien A., additional, Blangero, John, additional, Curran, Joanne E., additional, Peralta, Juan M., additional, Montgomery, Courtney, additional, Sheu, Wayne H-H, additional, Chung, Ren-Hua, additional, Schwander, Karen, additional, Nouraie, Seyed M., additional, Gordeuk, Victor R., additional, Zhang, Yingze, additional, Kooperberg, Charles, additional, Reiner, Alexander P., additional, Jackson, Rebecca D., additional, Bleecker, Eugene R., additional, Meyers, Deborah A., additional, Li, Xingnan, additional, Das, Sayantan, additional, Yu, Ketian, additional, LeFaive, Jonathon, additional, Smith, Albert, additional, Blackwell, Tom, additional, Taliun, Daniel, additional, Zollner, Sebastian, additional, Forer, Lukas, additional, Schoenherr, Sebastian, additional, Fuchsberger, Christian, additional, Pandit, Anita, additional, Zawistowski, Matthew, additional, Kheterpal, Sachin, additional, Brummett, Chad M., additional, Natarajan, Pradeep, additional, Schlessinger, David, additional, Lee, Seunggeun, additional, Kang, Hyun Min, additional, Cucca, Francesco, additional, Holmen, Oddgeir L., additional, Åsvold, Bjørn O., additional, Boehnke, Michael, additional, Kathiresan, Sekar, additional, Abecasis, Goncalo, additional, Chen, Y. Eugene, additional, Willer, Cristen J., additional, and Hveem, Kristian, additional

Published
2019
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99. Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts

Author

Zhou, Wei, primary, Zhao, Zhangchen, additional, Nielsen, Jonas B., additional, Fritsche, Lars G., additional, LeFaive, Jonathon, additional, Gagliano Taliun, Sarah A., additional, Bi, Wenjian, additional, Gabrielsen, Maiken E., additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Hveem, Kristian, additional, Abecasis, Goncalo R., additional, Willer, Cristen J., additional, and Lee, Seunggeun, additional

Published
2019
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