38 results on '"Kalnapenkis, A."'
Search Results
2. Genetic determinants of plasma protein levels in the Estonian population
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Anette Kalnapenkis, Maarja Jõeloo, Kaido Lepik, Viktorija Kukuškina, Mart Kals, Kaur Alasoo, Estonian Biobank Research Team, Reedik Mägi, Tõnu Esko, and Urmo Võsa
- Subjects
Medicine ,Science - Abstract
Abstract The proteome holds great potential as an intermediate layer between the genome and phenome. Previous protein quantitative trait locus studies have focused mainly on describing the effects of common genetic variations on the proteome. Here, we assessed the impact of the common and rare genetic variations as well as the copy number variants (CNVs) on 326 plasma proteins measured in up to 500 individuals. We identified 184 cis and 94 trans signals for 157 protein traits, which were further fine-mapped to credible sets for 101 cis and 87 trans signals for 151 proteins. Rare genetic variation contributed to the levels of 7 proteins, with 5 cis and 14 trans associations. CNVs were associated with the levels of 11 proteins (7 cis and 5 trans), examples including a 3q12.1 deletion acting as a hub for multiple trans associations; and a CNV overlapping NAIP, a sensor component of the NAIP-NLRC4 inflammasome which is affecting pro-inflammatory cytokine interleukin 18 levels. In summary, this work presents a comprehensive resource of genetic variation affecting the plasma protein levels and provides the interpretation of identified effects.
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- 2024
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3. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
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Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Åsa K., Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E., Gieger, Christian, Needham, Elise J., Surendran, Praveen, Paul, Dirk S., Polasek, Ozren, Thorand, Barbara, Grallert, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Åsa, Gyllensten, Ulf, Powell, Nick, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K., Danesh, John, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F., Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam S., and Peters, James E.
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- 2023
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4. Author Correction: Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
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Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Åsa K., Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E., Gieger, Christian, Needham, Elise J., Surendran, Praveen, Paul, Dirk S., Polasek, Ozren, Thorand, Barbara, Grallert, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Åsa, Gyllensten, Ulf, Powell, Nick, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K., Danesh, John, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F., Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam S., and Peters, James E.
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- 2023
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5. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals
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Folkersen, Lasse, Gustafsson, Stefan, Wang, Qin, Hansen, Daniel Hvidberg, Hedman, Åsa K., Schork, Andrew, Page, Karen, Zhernakova, Daria V., Wu, Yang, Peters, James, Eriksson, Niclas, Bergen, Sarah E., Boutin, Thibaud S., Bretherick, Andrew D., Enroth, Stefan, Kalnapenkis, Anette, Gådin, Jesper R., Suur, Bianca E., Chen, Yan, Matic, Ljubica, Gale, Jeremy D., Lee, Julie, Zhang, Weidong, Quazi, Amira, Ala-Korpela, Mika, Choi, Seung Hoan, Claringbould, Annique, Danesh, John, Davey Smith, George, de Masi, Federico, Elmståhl, Sölve, Engström, Gunnar, Fauman, Eric, Fernandez, Celine, Franke, Lude, Franks, Paul W., Giedraitis, Vilmantas, Haley, Chris, Hamsten, Anders, Ingason, Andres, Johansson, Åsa, Joshi, Peter K., Lind, Lars, Lindgren, Cecilia M., Lubitz, Steven, Palmer, Tom, Macdonald-Dunlop, Erin, Magnusson, Martin, Melander, Olle, Michaelsson, Karl, Morris, Andrew P., Mägi, Reedik, Nagle, Michael W., Nilsson, Peter M., Nilsson, Jan, Orho-Melander, Marju, Polasek, Ozren, Prins, Bram, Pålsson, Erik, Qi, Ting, Sjögren, Marketa, Sundström, Johan, Surendran, Praveen, Võsa, Urmo, Werge, Thomas, Wernersson, Rasmus, Westra, Harm-Jan, Yang, Jian, Zhernakova, Alexandra, Ärnlöv, Johan, Fu, Jingyuan, Smith, J. Gustav, Esko, Tõnu, Hayward, Caroline, Gyllensten, Ulf, Landen, Mikael, Siegbahn, Agneta, Wilson, James F., Wallentin, Lars, Butterworth, Adam S., Holmes, Michael V., Ingelsson, Erik, and Mälarstig, Anders
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- 2020
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6. OTTERS:a powerful TWAS framework leveraging summary-level reference data
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Dai, Qile, Zhou, Geyu, Zhao, Hongyu, Võsa, Urmo, Franke, Lude, Battle, Alexis, Teumer, Alexander, Lehtimäki, Terho, Raitakari, Olli T., Esko, Tõnu, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Favé, Marie-Julie, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda, Perola, Markus, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Epstein, Michael P., Yang, Jingjing, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Biological Psychology, Amsterdam Reproduction & Development, APH - Methodology, APH - Personalized Medicine, Internal Medicine, Tampere University, Department of Clinical Chemistry, and Clinical Medicine
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Multidisciplinary ,1182 Biochemistry, cell and molecular biology ,General Physics and Astronomy ,3111 Biomedicine ,General Chemistry ,Medical Genetics ,General Biochemistry, Genetics and Molecular Biology ,Medicinsk genetik - Abstract
Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies. Godkänd;2023;Nivå 0;2023-04-06 (hanlid);Funder: for more funders see the article https://doi.org/10.1038/s41467-023-36862-w
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- 2023
7. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated 22 disease risk and therapeutic targets
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Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Asa K, Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E, Geiger, Christian, Needham, Elise J, Surendran, Praveen, Paul, Dirk S, Polasek, Ozren, Thorand, Barbara, Grallert, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Asa, Gyllensten, Ulf, Powell, Nicholas, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K, Danesh, John, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F, Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam S, Peters, James E, and Apollo - University of Cambridge Repository
- Abstract
Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identify 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease GWAS provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomisation (MR) to assess causality in aetiology, we identify both shared and distinct effects of specific proteins across immune mediated diseases, including directionally discordant functions for CD40 in rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the aetiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets for existing drugs and provide a powerful resource to facilitate future drug target prioritisation.
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- 2023
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8. Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and novel therapeutic targets
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Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Asa K, Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E, Geiger, Christian, J Needham, Elise, Surendran, Praveen, Pau, Dirk S, Polasek, Ozren, Thorand, Barbara, Graller, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Asa, Gyllensten, Ulf, Powell, Nicholas, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K, Danesh, Josh, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F, Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam, Peters, James E, and Apollo - University of Cambridge Repository
- Abstract
Circulating proteins play key roles in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs, of which 50 were novel. Integration of pQTL data with eQTL and disease GWAS provided insights into pathogenesis, implicating lymphotoxin-alpha (LTA) in multiple sclerosis. Using Mendelian randomisation (MR), we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant causal roles for CD40 in rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Our results highlight novel potential therapeutic avenues, including CXCL5 in ulcerative colitis (UC), a finding supported by elevated gut CXCL5 expression in UC patients. Our data provide a powerful resource to facilitate future drug target prioritization.
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- 2023
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9. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour
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Mills, Melinda C., Tropf, Felix C., Brazel, David M., van Zuydam, Natalie, Vaez, Ahmad, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda W. J. H., Perola, Markus, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Isaacs, Aaron, Pool, René, Jan Hottenga, Jouke, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Sasha, Tigchelaar, Ettje F., Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Akimova, Evelina T., Bergmann, Sven, Boardman, Jason D., Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey-Smith, George, Davies, Gail, Deary, Ian J., Franco, Oscar, Gaskins, Audrey J., de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Grabe, Hans Jörgen, Gunderson, Erica P., Harris, Kathleen Mullan, Hartwig, Fernando P., He, Chunyan, Hill, W. David, Homuth, Georg, Horta, Bernando Lessa, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M. Arfan, Johannesson, Magnus, Kamali, Zoha, Kavousi, Maryam, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, McQueen, Matthew B., Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Missmer, Stacey A., Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nolte, Ilja M., Noordam, Raymond, Peters, Annette, Power, Chris, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Waldenberger, Melanie, Wareham, Nicholas J., Willemsen, Gonneke, Zhao, Jing Hau, Pers, Tune H., Snieder, Harold, Perry, John R. B., Ong, Ken K., den Hoed, Marcel, Barban, Nicola, Day, Felix R., Mills, M. C., Tropf, F. C., Brazel, D. M., van Zuydam, N., Vaez, A., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A. K., Arindrarto, W., Awadalla, P., Battle, A., Beutner, F., Jan Bonder, M., Boomsma, D. I., Christiansen, M. W., Claringbould, A., Deelen, P., Esko, T., Fave, M. -J., Franke, L., Frayling, T., Gharib, S. A., Gibson, G., Heijmans, B. T., Hemani, G., Jansen, R., Kahonen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimaki, T., Loeffler, M., Marigorta, U. M., Mei, H., Milani, L., Montgomery, G. W., Muller-Nurasyid, M., Nauck, M., Nivard, M. G., Penninx, B. W. J. H., Perola, M., Pervjakova, N., Pierce, B. L., Powell, J., Prokisch, H., Psaty, B. M., Raitakari, O. T., Ripatti, S., Rotzschke, O., Rueger, S., Saha, A., Scholz, M., Schramm, K., Seppala, I., Slagboom, E. P., Stehouwer, C. D. A., Stumvoll, M., Sullivan, P., 't Hoen, P. A. C., Teumer, A., Thiery, J., Tong, L., Tonjes, A., van Dongen, J., van Iterson, M., van Meurs, J., Veldink, J. H., Verlouw, J., Visscher, P. M., Volker, U., Vosa, U., Westra, H. -J., Wijmenga, C., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., van Greevenbroek, M. M. J., Schalkwijk, C. G., Deelen, J., van Heemst, D., van Duijn, C. M., Hofman, B. A., Isaacs, A., Uitterlinden, A. G., Verbiest, M., Suchiman, H. E. D., Verkerk, M., van der Breggen, R., van Rooij, J., Lakenberg, N., Bot, J., Zhernakova, D. V., Luijk, R., Bonder, M. J., Swertz, M. A., van Zwet, E. W., Akimova, E. T., Bergmann, S., Boardman, J. D., Buring, J. E., Cesarini, D., Chasman, D. I., Chavarro, J. E., Cocca, M., Concas, M. P., Davey-Smith, G., Davies, G., Deary, I. J., Gaskins, A. J., de Geus, E. J. C., Gieger, C., Girotto, G., Grabe, H. J., Gunderson, E. P., Harris, K. M., Hartwig, F. P., He, C., Homuth, G., Horta, B. L., Jan Hottenga, J., Huang, H., Hyppӧnen, E., Ikram, M. A., Johannesson, M., Kamali, Z., Kavousi, M., Kraft, P., Kuhnel, B., Langenberg, C., Study, L. C., Lind, P. A., Luan, J., Magi, R., Magnusson, P. K. E., Mahajan, A., Martin, N. G., Mbarek, H., Mccarthy, M. I., Mcmahon, G., Mcqueen, M. B., Medland, S. E., Meitinger, T., Metspalu, A., Mihailov, E., Missmer, S. A., Mollegaard, S., Mook-Kanamori, D. O., Morgan, A., van der Most, P. J., de Mutsert, R., Noordam, R., Power, C., Redmond, P., Rich-Edwards, J. W., Ridker, P. M., Rietveld, C. A., Ring, S. M., Rose, L. M., Rueedi, R., Stefansson, K., Stockl, D., Strauch, K., Thurik, A. R., Timpson, N. J., Turman, C., Wareham, N. J., Willemsen, G., Zhao, J. H., Pers, T. H., Snieder, H., Perry, J. R. B., Ong, K. K., den Hoed, M., Barban, N., Day, F. R., Mills, Melinda C, Tropf, Felix C, Brazel, David M, van Zuydam, Natalie, Vaez, Ahmad, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, den Hoed, Marcel, Barban, Nicola, Day, Felix R, Hyppӧnen, Elina, eQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Consortium, eQTLGen, Consortium, BIOS, Consortium, Human Reproductive Behaviour, Mahajan, A, McCarthy, MI, Mills, Melinda C., Tropf, Felix C., Brazel, David M., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexi, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johanne, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Marku, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthia, Nivard, Michel G., Penninx, Brenda W. J. H., Perola, Marku, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashi, Scholz, Marku, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Isaacs, Aaron, Pool, René, Jan Hottenga, Jouke, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Sasha, Tigchelaar, Ettje F., Beekman, Marian, Deelen, Jori, van Heemst, Diana, van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Nooren, Irene, Moed, Matthij, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Akimova, Evelina T., Bergmann, Sven, Boardman, Jason D., Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey-Smith, George, Davies, Gail, Deary, Ian J., Franco, Oscar, Gaskins, Audrey J., de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Grabe, Hans Jörgen, Gunderson, Erica P., Harris, Kathleen Mullan, Hartwig, Fernando P., He, Chunyan, Hill, W. David, Homuth, Georg, Horta, Bernando Lessa, Huang, Hongyang, Ikram, M. Arfan, Johannesson, Magnu, Kamali, Zoha, Kavousi, Maryam, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, McQueen, Matthew B., Medland, Sarah E., Meitinger, Thoma, Metspalu, Andre, Mihailov, Evelin, Missmer, Stacey A., Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nolte, Ilja M., Noordam, Raymond, Peters, Annette, Power, Chri, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Stefánsson, Kári, Stöckl, Dori, Strauch, Konstantin, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Waldenberger, Melanie, Wareham, Nicholas J., Willemsen, Gonneke, Zhao, Jing Hau, Pers, Tune H., Perry, John R. B., Ong, Ken K., Day, Felix R., Sociology [until 2010], Biological Psychology, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Management and Organisation, Urology, Medical Informatics, Department of Marketing Management, Epidemiology, Internal Medicine, Radiology & Nuclear Medicine, Neurology, Applied Economics, and Life Course Epidemiology (LCE)
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Male ,demography ,genetic variants ,reproductive biology ,externalising behavior ,environmental effects ,Disease ,Genome-wide association studies ,Behavioral Neuroscience ,0302 clinical medicine ,genetics ,media_common ,fertility ,0303 health sciences ,Reproduction ,Incidence (epidemiology) ,Coitus ,Age Factors ,Longevity ,sexual intercourse ,health ,Spermatid differentiation ,Single Nucleotide ,Reproduction/genetics ,3. Good health ,Behavioural genetics ,Parturition/genetics ,Female ,infertility ,Infertility ,genetic variant ,Adolescent ,Social Psychology ,media_common.quotation_subject ,Experimental and Cognitive Psychology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Reproductive biology ,medicine ,Humans ,Polymorphism ,behavioural genetics ,first sexual intercourse ,Genetic Association Studies ,Demography ,030304 developmental biology ,Parturition ,Coitus/physiology ,medicine.disease ,externalising behaviour ,Sexual intercourse ,Fertility ,age ,030217 neurology & neurosurgery ,first birth - Abstract
Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
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- 2021
10. Genetic landscape of the ACE2 coronavirus receptor
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Yang, Z, MacDonald-Dunlop, E, Chen, J, Zhai, R, Li, T, Richmond, A, Klaric, L, Pirastu, N, Ning, Z, Zheng, C, Wang, Y, Huang, T, He, Y, Guo, H, Ying, K, Gustafsson, S, Prins, B, Ramisch, A, Dermitzakis, ET, Png, G, Eriksson, N, Haessler, J, Hu, X, Zanetti, D, Boutin, T, Hwang, S-J, Wheeler, E, Pietzner, M, Raffield, LM, Kalnapenkis, A, Peters, JE, Viñuela, A, Gilly, A, Elmståhl, S, Dedoussis, G, Petrie, JR, Polašek, O, Folkersen, L, Chen, Y, Yao, C, Võsa, U, Pairo-Castineira, E, Clohisey, S, Bretherick, AD, Rawlik, K, Esko, T, Enroth, S, Johansson, Å, Gyllensten, U, Langenberg, C, Levy, D, Hayward, C, Assimes, TL, Kooperberg, C, Manichaikul, AW, Siegbahn, A, Wallentin, L, Lind, L, Zeggini, E, Schwenk, JM, Butterworth, AS, Michaëlsson, K, Pawitan, Y, Joshi, PK, Baillie, JK, Mälarstig, A, Reiner, AP, Wilson, JF, Shen, X, and GenOMICC Consortium and the IMI-DIRECT Consortium
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ANGIOTENSIN-CONVERTING ENZYME ,Cardiac & Cardiovascular Systems ,GenOMICC Consortium† ,DATABASE ,COVID ,genetic ,analysis ,ALPHA-1-ANTITRYPSIN DEFICIENCY ,1117 Public Health and Health Services ,angiotensin-converting enzyme 2 ,Physiology (medical) ,Humans ,Cardiac and Cardiovascular Systems ,1102 Cardiorespiratory Medicine and Haematology ,Medicinsk genetik ,RISK ,Kardiologi ,Science & Technology ,SARS-CoV-2 ,COVID-19 ,IMI-DIRECT Consortium† ,1103 Clinical Sciences ,COVID-19/genetics ,cardiovascular diseases ,Angiotensin-Converting Enzyme 2/genetics ,Cross-Sectional Studies ,Peripheral Vascular Disease ,Cardiovascular System & Hematology ,Cardiovascular System & Cardiology ,TRIAL ,Cardiology and Cardiovascular Medicine ,Medical Genetics ,Life Sciences & Biomedicine ,hormones, hormone substitutes, and hormone antagonists ,Genome-Wide Association Study ,Receptors, Coronavirus - Abstract
Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics–based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis–protein quantitative trait loci–based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42]; P =0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21]; P =0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37]; P =0.02). Tissue- and cell type–specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
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- 2022
11. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
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Mahmoud Elansary, Knut Krohn, Eleonora Porcu, Julia Dmitrieva, Michel Georges, Harm-Jan Westra, Isabel Alves, Matthias Nauck, Jan H. Veldink, Joost Verlouw, Anette Kalnapenkis, Silva Kasela, Alex W. Hewitt, Roy Oelen, Willem H. Ouwehand, Frank Beutner, Ilkka Seppälä, Yukihide Momozawa, Samuli Ripatti, Brenda W.J.H. Penninx, Patrick Deelen, Michael Stumvoll, Jenny van Dongen, Jonathan K. Pritchard, Roman Kreuzhuber, Marie-Julie Favé, Bernett Lee, Hailang Mei, Biao Zeng, Philip Awadalla, Shuang Li, Kate Downes, Gibran Hemani, Urko M. Marigorta, Anke Tönjes, Morris Swertz, Robert Warmerdam, Joseph E. Powell, Mika Kähönen, Urmo Võsa, Brandon L. Pierce, Benjamin P. Fairfax, Anand Kumar Andiappan, Bastiaan T. Heijmans, Martina Müller-Nurasyid, Sven Bergmann, Katharina Schramm, Hanieh Yaghootkar, Sina Rüeger, Monique G. P. van der Wijst, Lude Franke, Ting Qi, Rick Jansen, Greg Gibson, Cisca Wijmenga, Marc Jan Bonder, Yungil Kim, Viktorija Kukushkina, Johannes Kettunen, Joachim Thiery, Peter A C 't Hoen, Zoltán Kutalik, Jian Yang, Dylan H. de Vries, Olaf Rötzschke, Maarten van Iterson, Peter Kovacs, Peter M. Visscher, Wibowo Arindrarto, Oliver Stegle, Natalia Pervjakova, Julian C. Knight, Tõnu Esko, Annique Claringbould, Lili Milani, Patrick F. Sullivan, Habibul Ahsan, Timothy M. Frayling, Lin Tong, Uwe Völker, Reyhan Sönmez Flitman, Eline Slagboom, Dorret I. Boomsma, Holger Prokisch, Michel G. Nivard, Mawusse Agbessi, Joyce B. J. van Meurs, Alexis Battle, Futao Zhang, Emmanouil T. Dermitzakis, Morris A. Swertz, Grant W. Montgomery, Terho Lehtimäki, Coen D.A. Stehouwer, Jaanika Kronberg, Holger Kirsten, Olli T. Raitakari, Sina A. Gharib, Bruce M. Psaty, Seyhan Yazar, Markus Loeffler, Harm Brugge, Jose Alquicira Hernandez, Mark W. Christiansen, Andrew A. Brown, Markus Perola, Markus Scholz, Ashis Saha, Alexander Teumer, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), BIOS Consortium, i2QTL Consortium, 't Hoen, PAC, van Meurs, J., van Dongen, J., van Iterson, M., Swertz, M.A., Jan Bonder, M., Biological Psychology, APH - Personalized Medicine, APH - Methodology, Internal Medicine, Interne Geneeskunde, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), and RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome
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DISORDER ,Multifactorial Inheritance ,Quantitative Trait Loci ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Gene Expression Regulation/genetics ,DISEASE ,LINKS ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,RELEVANCE ,Blood Proteins/genetics ,Gene expression ,Genetics ,Humans ,GENOME-WIDE ASSOCIATION ,Polymorphism ,Gene ,Multifactorial Inheritance/genetics ,030304 developmental biology ,Regulation of gene expression ,RISK ,0303 health sciences ,ARCHITECTURE ,Blood Proteins ,Transcriptome/genetics ,Polymorphism, Single Nucleotide/genetics ,Phenotype ,SERINE BIOSYNTHESIS ,HUMAN TRANSCRIPTOME ,DEFICIENCY ,Gene Expression Regulation ,Expression quantitative trait loci ,genome-wide association studies ,gene expression ,gene regulation ,Quantitative Trait Loci/genetics ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Single Nucleotide/genetics ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.
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- 2021
12. Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
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Erin Macdonald-Dunlop, Lucija Klarić, Lasse Folkersen, Paul R.H.J. Timmers, Stefan Gustafsson, Jing Hua Zhao, Niclas Eriksson, Anne Richmond, Stefan Enroth, Niklas Mattsson-Carlgren, Daria V. Zhernakova, Anette Kalnapenkis, Martin Magnusson, Eleanor Wheeler, Shih-Jen Hwang, Yan Chen, Andrew P Morris, Bram Prins, Urmo Võsa, Nicholas J. Wareham, John Danesh, Johan Sundstrom, Bruna Gigante, Damiano Baldassarre, Rona J. Strawbridge, Harry Campbell, Ulf Gyllensten, Chen Yao, Daniela Zanetti, Themistocles L. Assimes, Per Eriksson, Daniel Levy, Claudia Langenberg, J. Gustav Smith, Tõnu Esko, Jingyuan Fu, Oskar Hansson, Åsa Johansson, Caroline Hayward, Lars Wallentin, Agneta Siegbahn, Lars Lind, Adam S. Butterworth, Karl Michaëlsson, James E. Peters, Anders Mälarstig, Peter K. Joshi, and James F. Wilson
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Genetics ,medicine.medical_specialty ,Genetic epidemiology ,Expression quantitative trait loci ,DNA methylation ,medicine ,Medical genetics ,Disease ,Quantitative trait locus ,Biology ,medicine.disease ,Inflammatory bowel disease ,Genetic architecture - Abstract
We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
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- 2021
13. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences
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Karlsson Linnér, Richard, Biroli, Pietro, Kong, Edward, Meddens, S. Fleur W., Wedow, Robbee, Fontana, Mark Alan, Lebreton, Maël, Tino, Stephen P., Abdellaoui, Abdel, Hammerschlag, Anke R., Nivard, Michel G., Okbay, Aysu, Rietveld, Cornelius A., Timshel, Pascal N., Trzaskowski, Maciej, Vlaming, Ronald de, Zünd, Christian L., Bao, Yanchun, Buzdugan, Laura, Caplin, Ann H., Chen, Chia-Yen, Eibich, Peter, Fontanillas, Pierre, Gonzalez, Juan R., Joshi, Peter K., Karhunen, Ville, Kleinman, Aaron, Levin, Remy Z., Lill, Christina M., Meddens, Gerardus A., Muntané, Gerard, Sanchez-Roige, Sandra, Rooij, Frank J. van, Taskesen, Erdogan, Yang, Wu, Zhang, Futao, Agee, Michelle, Alipanahi, Babak, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Furlotte, Nicholas A., Huber, Karen E., Litterman, Nadia K., Mccreight, Jennifer C., Mcintyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark, Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Gregory, Heijmans, Bastiaan, Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg-Guzman, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Metspalu, Andres, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthias, Penninx, Brenda, Perola, Markus, Pervjakova, Natalia, Pierce, Brandon, Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli, Ring, Susan, Ripatti, Samuli, Rotzchke, Olaf, Rüeger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Stumvoll, Michael, Sullivan, Patrick, Hoen, Peter-Bram t, Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, Dongen, Jenny van, Meurs, Joyce van, Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Beauchamp, Jonathan P., Lee, James J., Pers, Tune H., Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, de Vlaming, Ronald, Ahluwalia, Tarunveer S., Bacelis, Jonas, Baumbach, Clemens, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, Maria Pina, Derringer, Jaime, Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Lee, Sven J. van der, de Leeuw, Christiaan, Lind, Penelope A., Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Most, Peter J. van der, Oldmeadow, Christopher, Payton, Antony, Peyrot, Wouter J., Qian, Yong, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., Pourcain, Beate St, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klaus, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Panos, Demuth, Ilja, Ding, Jun, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Heath, Andrew C., Hocking, Lynne J., Holliday, Elizabeth G., Homuth, Georg, Horan, Michael A., Hottenga, Jouke-Jan, de Jager, Philip L., Jugessur, Astanand, Kaakinen, Marika A., Kanoni, Stavroula, Keltigangas-Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki-Opas, Tomi, Marioni, Riccardo E., Marques-Vidal, Pedro, Mcmahon, George, Meisinger, Christa, Meitinger, Thomas, Milaneschi, Yusplitri, Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Räikkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti-Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen-Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Venturini, Cristina, Vinkhuyzen, Anna A. E., Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johannes, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klaus, Bertram, Lars, Bisgaard, Hans, Borecki, Ingrid B, Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Duijn, Cornelia M. van, Eriksson, Johan G., Franke, Barbara, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Harst, Pim van der, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Pendleton, Neil, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Johannesson, Magnus, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., Auton, Adam, Boardman, Jason D., Clark, David W., Conlin, Andrew, Dolan, Conor C., Fischbacher, Urs, Harris, Kathleen Mullan, Hasler, Gregor, Ikram, Mohammad A., Jain, Sonia, Kessler, Ronald C., Kooyman, Maarten, Mackillop, James, Männikkö, Minna, Morcillo-Suarez, Carlos, Mcqueen, Matthew B., Schmidt, Klaus M., Smart, Melissa C., Sutter, Matthias, White, Jon, Wit, Harriet de, Fehr, Ernst, Kumari, Meena, Laibson, David, Navarro, Arcadi, Palmer, Abraham A., Schunk, Daniel, Stein, Murray B., Svento, Rauli, Timmers, Paul R. H. J., Ursano, Robert J., Wagner, Gert G., Adult Psychiatry, APH - Mental Health, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, 23and Me Research Team, eQTLgen Consortium, International Cannabis Consortium, Economics, Biological Psychology, Complex Trait Genetics, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Tinbergen Institute, 23andme Research Team, Psychiatric Genomics Consortium, Social Science Genetic Association Consortium, Linner Richard Karlsson, Biroli P, Kong Edward, Meddens Fleur W., Wedow Robbee, Fontana Mark Alan, Lebreton Mael, Tino Stephen P., Abdellaoui Abdel, Hammerschlag Anke R., Nivard Michel G., Okbay Aysu, Rietveld Cornelius A., Timshel Pascal N., Trzaskowski Maciej, de Vlaming Ronald, Zund Christian L., Bao Yanchun, Buzdugan Laura, Caplin Ann H., Chen Chia-Yen, Eibich Peter, Fontanillas Pierre, Gonzalez Juan R., Joshi Peter K., Karhunen Ville, Kleinman Aaron, Levin Remy Z., Lill Christina M., Meddens Gerardus A., Muntane Gerard, Sanchez-Roige Sandra, van Rooij Frank J., Taskesen Erdogan, Wu Yang, Zhang Futao, Agee Michelle, Alipanahi Babak, Bell Robert K., Bryc Katarzyna, Elson Sarah L., Furlotte Nicholas A., Huber Karen E., Litterman Nadia K., McCreight Jennifer C., McIntyre Matthew H., Mountain Joanna L., Northover Carrie A. M., Pitts Steven J., Sathirapongsasuti J. Fah, Sazonova Olga V., Shelton Janie F., Shringarpure Suyash, Tian Chao, Tung Joyce Y., Vacic Vladimir, Wilson Catherine H., Agbessi Mawusse, Ahsan Habibul, Alves Isabel, Andiappan Anand, Awadalla Philip, Battle Alexi, Beutner Frank, Bonder Marc Jan, Boomsma Dorret I., Christiansen Mark, Claringbould Annique, Deelen Patrick, Esko Tonu, Fave Marie-Julie, Franke Lude, Frayling Timothy, Gharib Sina A., Gibson Gregory, Heijmans Bastiaan, Hemani Gibran, Jansen Rick, Kahonen Mika, Kalnapenkis Anette, Kasela Silva, Kettunen Johanne, Kim Yungil, Kirsten Holger, Kovacs Peter, Krohn Knut, Kronberg-Guzman Jaanika, Kukushkina Viktorija, Kutalik Zoltan, Lee Bernett, Lehtimaki Terho, Loeffler Marku, Marigorta Urko M., Metspalu Andre, Milani Lili, Montgomery Grant W., Mueller-Nurasyid Martina, Nauck Matthia, Penninx Brenda, Perola Marku, Pervjakova Natalia, Pierce Brandon, Powell Joseph, Prokisch Holger, Psaty Bruce M., Raitakari Olli, Ring Susan, Ripatti Samuli, Rotzchke Olaf, Rueger Sina, Saha Ashi, Scholz Marku, Schramm Katharina, Seppala Ilkka, Stumvoll Michael, Sullivan Patrick, Hoen Peter-Bramt, Teumer Alexander, Thiery Joachim, Tong Lin, Tonjes Anke, van Dongen Jenny, van Meurs Joyce, Verlouw Joost, Visscher Peter M., Voelker Uwe, Vosa Urmo, Westra Harm-Jan, Yaghootkar Hanieh, Yang Jian, Zeng Biao, Lee James J., Pers Tune H., Turley Patrick, Chen Guo-Bo, Emilsson Valur, Oskarsson Sven, Pickrell Joseph K., Thom Kevin, Timshel Pascal, Ahluwalia Tarunveer S., Bacelis Jona, Baumbach Clemen, Bjornsdottir Gyda, Brandsma Johannes H., Concas Maria Pina, Derringer Jaime, Galesloot Tessel E., Girotto Giorgia, Gupta Richa, Hall Leanne M., Harris Sarah E., Hofer Edith, Horikoshi Momoko, Huffman Jennifer E., Kaasik Kadri, Kalafati Ioanna P., Kong Augustine, Lahti Jari, van der Lee Sven J., de Leeuw Christiaan, Lind Penelope A., Lindgren Karl-Oskar, Liu Tian, Mangino Massimo, Marten Jonathan, Mihailov Evelin, Miller Michael B., van der Most Peter J., Oldmeadow Christopher, Payton Antony, Peyrot Wouter J., Qian Yong, Rueedi Rico, Salvi Erika, Schmidt Boerge, Schraut Katharina E., Shi Jianxin, Smith Albert V., Poot Raymond A., St Pourcain Beate, Thorleifsson Gudmar, Verweij Niek, Vuckovic Dragana, Wellmann Juergen, Yang Jingyun, Zhao Wei, Zhu Zhihong, Alizadeh Behrooz Z., Amin Najaf, Bakshi Andrew, Baumeister Sebastian E., Biino Ginevra, Bonnelykke Klau, Boyle Patricia A., Campbell Harry, Cappuccio Francesco P., Davies Gail, De Neve Jan-Emmanuel, Deloukas Pano, Demuth Ilja, Ding Jun, Eisele Lewin, Eklund Niina, Evans David M., Faul Jessica D., Feitosa Mary F., Forstner Andreas J., Gandin Ilaria, Gunnarsson Bjarni, Halldorsson Bjarni V., Harris Tamara B., Heath Andrew C., Hocking Lynne J., Holliday Elizabeth G., Homuth Georg, Horan Michael A., Hottenga Jouke-Jan, de Jager Philip L., Jugessur Astanand, Kaakinen Marika A., Kanoni Stavroula, Keltigangas-Jarvinen Liisa, Kiemeney Lambertus A. L. M., Kolcic Ivana, Koskinen Seppo, Kraja Aldi T., Kroh Martin, Latvala Antti, Launer Lenore J., Lebreton Mael P., Levinson Douglas F., Lichtenstein Paul, Lichtner Peter, Liewald David C. M., Loukola Anu, Madden Pamela A., Magi Reedik, Maki-Opas Tomi, Marioni Riccardo E., Marques-Vidal Pedro, McMahon George, Meisinger Christa, Meitinger Thoma, Milaneschi Yusplitri, Myhre Ronny, Nelson Christopher P., Nyholt Dale R., Ollier William E. R., Palotie Aarno, Paternoster Lavinia, Pedersen Nancy L., Petrovic Katja E., Porteous David J., Raikkonen Katri, Ring Susan M., Robino Antonietta, Rostapshova Olga, Rudan Igor, Rustichini Aldo, Salomaa Veikko, Sanders Alan R., Sarin Antti-Pekka, Schmidt Helena, Scott Rodney J., Smith Blair H., Smith Jennifer A., Staessen Jan A., Steinhagen-Thiessen Elisabeth, Strauch Konstantin, Terracciano Antonio, Tobin Martin D., Ulivi Sheila, Vaccargiu Simona, Quaye Lydia, Venturini Cristina, Vinkhuyzen Anna A. E., Voelzke Henry, Vonk Judith M., Vozzi Diego, Waage Johanne, Ware Erin B., Willemsen Gonneke, Attia John R., Bennett David A., Berger Klau, Bertram Lar, Bisgaard Han, Borecki Ingrid B., Bultmann Ute, Chabris Christopher F., Cucca Francesco, Cusi Daniele, Deary J., Dedoussis George V., van Duijn Cornelia M., Eriksson Johan G., Franke Barbara, Gasparini Paolo, Gejman Pablo V., Gieger Christian, Grabe Hans-Joergen, Gratten Jacob, Gudnason Vilmundur, van der Harst Pim, Hayward Caroline, Hinds David A., Hoffmann Wolfgang, Hypponen Elina, Iacono William G., Jacobsson Bo, Jarvelin Marjo-Riitta, Jockel Karl-Heinz, Kaprio Jaakko, Kardia Sharon L. R., Lehrer Steven F., Magnusson Patrik K. E., Martin Nicholas G., McGue Matt, Pendleton Neil, Pirastu Nicola, Pirastu Mario, Polasek Ozren, Posthuma Danielle, Power Christine, Province Michael A., Samani Nilesh J., Schlessinger David, Schmidt Reinhold, Sorensen Thorkild I. A., Spector Tim D., Stefansson Kari, Thorsteinsdottir Unnur, Thurik A. Roy, Timpson Nicholas J., Tiemeier Henning, Uitterlinden Andre G., Vitart Veronique, Vollenweider Peter, Weir David R., Wilson James F., Wright Alan F., Conley Dalton C., Krueger Robert F., Smith George Davey, Laibson David I., Medland Sarah E., Johannesson Magnu, Koellinger Philipp D., Cesarini David, Benjamin Daniel J., Auton Adam, Boardman Jason D., Clark David W., Conlin Andrew, Dolan Conor C., Fischbacher Ur, Groenen Patrick J. F., Harris Kathleen Mullan, Hasler Gregor, Hofman Albert, Ikram Mohammad A., Jain Sonia, Karlsson Robert, Kessler Ronald C., Kooyman Maarten, MacKillop Jame, Mannikko Minna, Morcillo-Suarez Carlo, McQueen Matthew B., Schmidt Klaus M., Smart Melissa C., Sutter Matthia, White Jon, de Wit Harriet, Fehr Ernst, Kumari Meena, Laibson David, Meyer Michelle N., Navarro Arcadi, Palmer Abraham A., Schunk Daniel, Stein Murray B., Svento Rauli, Timmers Paul R. H. J., Ursano Robert J., Wagner Gert G., Beauchamp Jonathan P., Karlsson Linnér, Richard, Biroli, Pietro, Kong, Edward, Meddens, S. Fleur W., Wedow, Robbee, Fontana, Mark Alan, Lebreton, Maël, Tino, Stephen P., Abdellaoui, Abdel, Hammerschlag, Anke R., Nivard, Michel G., Okbay, Aysu, Rietveld, Cornelius A., Timshel, Pascal N., Trzaskowski, Maciej, Vlaming, Ronald de, Zünd, Christian L., Bao, Yanchun, Buzdugan, Laura, Caplin, Ann H., Chen, Chia-Yen, Eibich, Peter, Fontanillas, Pierre, Gonzalez, Juan R., Joshi, Peter K., Karhunen, Ville, Kleinman, Aaron, Levin, Remy Z., Lill, Christina M., Meddens, Gerardus A., Muntané, Gerard, Sanchez-Roige, Sandra, Rooij, Frank J. van, Taskesen, Erdogan, Wu, Yang, Zhang, Futao, Agee, Michelle, Alipanahi, Babak, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Furlotte, Nicholas A., Huber, Karen E., Litterman, Nadia K., Mccreight, Jennifer C., Mcintyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand, Awadalla, Philip, Battle, Alexi, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark, Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Gregory, Heijmans, Bastiaan, Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johanne, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg-Guzman, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Marku, Marigorta, Urko M., Metspalu, Andre, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthia, Penninx, Brenda, Perola, Marku, Pervjakova, Natalia, Pierce, Brandon, Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli, Ring, Susan, Ripatti, Samuli, Rotzchke, Olaf, Rüeger, Sina, Saha, Ashi, Scholz, Marku, Schramm, Katharina, Seppälä, Ilkka, Stumvoll, Michael, Sullivan, Patrick, Hoen, Peter-Bram t, Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, Dongen, Jenny van, Meurs, Joyce van, Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Beauchamp, Jonathan P., Lee, James J., Pers, Tune H., Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, de Vlaming, Ronald, Ahluwalia, Tarunveer S., Bacelis, Jona, Baumbach, Clemen, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, Maria Pina, Derringer, Jaime, Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Lee, Sven J. van der, de Leeuw, Christiaan, Lind, Penelope A., Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Most, Peter J. van der, Oldmeadow, Christopher, Payton, Antony, Peyrot, Wouter J., Qian, Yong, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., Pourcain, Beate St, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klau, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Pano, Demuth, Ilja, Ding, Jun, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Heath, Andrew C., Hocking, Lynne J., Holliday, Elizabeth G., Homuth, Georg, Horan, Michael A., Hottenga, Jouke-Jan, de Jager, Philip L., Jugessur, Astanand, Kaakinen, Marika A., Kanoni, Stavroula, Keltigangas-Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki-Opas, Tomi, Marioni, Riccardo E., Marques-Vidal, Pedro, Mcmahon, George, Meisinger, Christa, Meitinger, Thoma, Milaneschi, Yusplitri, Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Räikkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti-Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen-Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Venturini, Cristina, Vinkhuyzen, Anna A. E., Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Borecki, Ingrid B, Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Duijn, Cornelia M. van, Eriksson, Johan G., Franke, Barbara, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Harst, Pim van der, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Pendleton, Neil, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Johannesson, Magnu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., Auton, Adam, Boardman, Jason D., Clark, David W., Conlin, Andrew, Dolan, Conor C., Fischbacher, Ur, Harris, Kathleen Mullan, Hasler, Gregor, Ikram, Mohammad A., Jain, Sonia, Kessler, Ronald C., Kooyman, Maarten, Mackillop, Jame, Männikkö, Minna, Morcillo-Suarez, Carlo, Mcqueen, Matthew B., Schmidt, Klaus M., Smart, Melissa C., Sutter, Matthia, White, Jon, Wit, Harriet de, Fehr, Ernst, Kumari, Meena, Laibson, David, Navarro, Arcadi, Palmer, Abraham A., Schunk, Daniel, Stein, Murray B., Svento, Rauli, Timmers, Paul R. H. J., Ursano, Robert J., Wagner, Gert G., Applied Economics, Hematology, Epidemiology, Urology, Department of Marketing Management, Internal Medicine, Medical Informatics, Cell biology, Erasmus MC other, Molecular Genetics, Econometrics, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, RS: Carim - V02 Hypertension and target organ damage, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Linnér, Richard Karlsson, Biroli , Pietro, Meddens, S Fleur W, and Beauchamp, Jonathan P
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Netherlands Twin Register (NTR) ,Male ,LD ,Medizin ,Poison control ,Genome-wide association study ,DETERMINANTS ,Cathie Marsh Institute ,PREFERENCES ,Q1 ,Genome-wide association studies ,HV ,0302 clinical medicine ,Genetics, Behavioral/methods ,GWAS ,Genetics & Heredity ,Genetics ,0303 health sciences ,PERSONALITY ,Genetic Predisposition to Disease/genetics ,Behavior/physiology ,Polymorphism, Single Nucleotide/genetics ,3. Good health ,Manchester Institute for Collaborative Research on Ageing ,Meta-analysis ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Genetic Loci/genetics ,Behavioural genetics ,Genome-Wide Association Study/methods ,Medical genetics ,Female ,Life Sciences & Biomedicine ,Single Nucleotide/genetics ,medicine.medical_specialty ,ResearchInstitutes_Networks_Beacons/MICRA ,Genotype ,Single-nucleotide polymorphism ,Genetics, Behavioral ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:330 ,medicine ,GENDER-DIFFERENCES ,SNP ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,behavioural genetics ,Behavioral/methods ,030304 developmental biology ,Genetic association ,Behavior ,Science & Technology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Data Science ,Case-control study ,risk tolerance, GWAS, genetic architechture ,Genetic Loci ,Case-Control Studies ,genome-wide association studies ,ResearchInstitutes_Networks_Beacons/cathie_marsh_institute ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance. This research was carried out under the auspices of the Social Science Genetic Association Consortium. The research was also conducted using the UK Biobank Resource under application number 11425. The study was supported by funding from the Ragnar Söderberg Foundation (E9/11 and E42/15); the Swedish Research Council (421-2013-1061); the Jan Wallander and Tom Hedelius Foundation; an ERC Consolidator Grant to Philipp Koellinger (647648 EdGe); the Pershing Square Fund of the Foundations of Human Behavior; the Open Philanthropy Project; the National Institute on Aging, National Institutes of Health through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to the National Bureau of Economic Research and R01-AG042568-02 to the University of Southern California; the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-152); and the Social Sciences and Humanities Research Council of Canada. We thank the International Cannabis Consortium, the eQTLgen Consortium, and the Psychiatric Genomics Consortium for sharing summary statistics from the GWAS of lifetime cannabis use, eQTL summary statistics, and summary statistics from the GWAS of ADHD, respectively. A full list of acknowledgments is provided in the Supplementary Note.
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- 2019
14. Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19
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Barbara Thorand, Lars Lind, Anne Richmond, Artemis Papadaki, Erola Pairo-Castineira, Oskar Hansson, Andreas Göteson, Dirk S. Paul, Nicola Pirastu, Eleanor Wheeler, Stefan Enroth, Chen Yao, Karsten Suhre, John Danesh, Daniel Levy, Lucija Klaric, Tõnu Esko, Jingyuan Fu, Shih-Jen Hwang, Daniela Zanetti, Themistocles L. Assimes, James F. Wilson, Niclas Eriksson, Nicholas J. Wareham, Karl Michaëlsson, Caroline Hayward, Stefan Gustafsson, Daria V. Zhernakova, Anders Mälarstig, Peter K. Joshi, Martin Magnusson, Christian Gieger, John R. Petrie, Claudia Langenberg, Rona J Strawbridge, Christian Herder, James E. Peters, Åsa K. Hedman, Erin Macdonald-Dunlop, Arianna Landini, Bram Prins, Mikael Landén, J Kenneth Baillie, Niklas Mattsson-Carlgren, Harry Campbell, Johan Sundström, Charles Kooperberg, Jack Gisby, Yan Chen, Leonid Padyukov, Lars Wallentin, Paul R. H. J. Timmers, Alexander P. Reiner, Adam S. Butterworth, Agneta Siegbahn, Lasse Folkersen, Alex Tokolyi, Bruna Gigante, J. Gustav Smith, Mark Walker, Urmo Võsa, Ulf Gyllensten, Marisa D Muckian, Åsa Johansson, Anette Kalnapenkis, Andrew P. Morris, Elodie Persyn, and Jing Hua Zhao
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Exon ,Mediator ,Apoptosis ,Alternative splicing ,Immunology ,Locus (genetics) ,macromolecular substances ,Biology ,Quantitative trait locus ,Receptor ,Cytokine receptor ,Article - Abstract
Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at theFASlocus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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- 2021
15. Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
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Macdonald-Dunlop, Erin, primary, Klarić, Lucija, additional, Folkersen, Lasse, additional, Timmers, Paul R.H.J., additional, Gustafsson, Stefan, additional, Zhao, Jing Hua, additional, Eriksson, Niclas, additional, Richmond, Anne, additional, Enroth, Stefan, additional, Mattsson-Carlgren, Niklas, additional, Zhernakova, Daria V., additional, Kalnapenkis, Anette, additional, Magnusson, Martin, additional, Wheeler, Eleanor, additional, Hwang, Shih-Jen, additional, Chen, Yan, additional, Morris, Andrew P, additional, Prins, Bram, additional, Võsa, Urmo, additional, Wareham, Nicholas J., additional, Danesh, John, additional, Sundstrom, Johan, additional, Gigante, Bruna, additional, Baldassarre, Damiano, additional, Strawbridge, Rona J., additional, Campbell, Harry, additional, Gyllensten, Ulf, additional, Yao, Chen, additional, Zanetti, Daniela, additional, Assimes, Themistocles L., additional, Eriksson, Per, additional, Levy, Daniel, additional, Langenberg, Claudia, additional, Smith, J. Gustav, additional, Esko, Tõnu, additional, Fu, Jingyuan, additional, Hansson, Oskar, additional, Johansson, Åsa, additional, Hayward, Caroline, additional, Wallentin, Lars, additional, Siegbahn, Agneta, additional, Lind, Lars, additional, Butterworth, Adam S., additional, Michaëlsson, Karl, additional, Peters, James E., additional, Mälarstig, Anders, additional, Joshi, Peter K., additional, and Wilson, James F., additional
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- 2021
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16. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
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Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)
- Abstract
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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- 2021
17. Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19
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Klaric, Lucija, primary, Gisby, Jack S., additional, Papadaki, Artemis, additional, Muckian, Marisa D., additional, Macdonald-Dunlop, Erin, additional, Zhao, Jing Hua, additional, Tokolyi, Alex, additional, Persyn, Elodie, additional, Pairo-Castineira, Erola, additional, Morris, Andrew P, additional, Kalnapenkis, Anette, additional, Richmond, Anne, additional, Landini, Arianna, additional, Hedman, Åsa K., additional, Prins, Bram, additional, Zanetti, Daniela, additional, Wheeler, Eleanor, additional, Kooperberg, Charles, additional, Yao, Chen, additional, Petrie, John R., additional, Fu, Jingyuan, additional, Folkersen, Lasse, additional, Walker, Mark, additional, Magnusson, Martin, additional, Eriksson, Niclas, additional, Mattsson-Carlgren, Niklas, additional, Timmers, Paul R.H.J., additional, Hwang, Shih-Jen, additional, Enroth, Stefan, additional, Gustafsson, Stefan, additional, Vosa, Urmo, additional, Chen, Yan, additional, Siegbahn, Agneta, additional, Reiner, Alexander, additional, Johansson, Åsa, additional, Thorand, Barbara, additional, Gigante, Bruna, additional, Hayward, Caroline, additional, Herder, Christian, additional, Gieger, Christian, additional, Langenberg, Claudia, additional, Levy, Daniel, additional, Zhernakova, Daria V., additional, Smith, J. Gustav, additional, Campbell, Harry, additional, Sundstrom, Johan, additional, Danesh, John, additional, Michaëlsson, Karl, additional, Suhre, Karsten, additional, Lind, Lars, additional, Wallentin, Lars, additional, Padyukov, Leonid, additional, Landén, Mikael, additional, Wareham, Nicholas J., additional, Göteson, Andreas, additional, Hansson, Oskar, additional, Eriksson, Per, additional, Strawbridge, Rona J., additional, Assimes, Themistocles L., additional, Esko, Tonu, additional, Gyllensten, Ulf, additional, Baillie, J. Kenneth, additional, Paul, Dirk S., additional, Joshi, Peter K., additional, Butterworth, Adam S., additional, Mälarstig, Anders, additional, Pirastu, Nicola, additional, Wilson, James F., additional, and Peters, James E., additional
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- 2021
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18. Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies
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Anke R. Hammerschlag, Enda M. Byrne, Meike Bartels, Naomi R. Wray, Christel M. Middeldorp, Mawussé Agbessi, Habibul Ahsan, Isabel Alves, Anand Andiappan, Wibowo Arindrarto, Philip Awadalla, Alexis Battle, Frank Beutner, Marc Jan Bonder, Dorret I. Boomsma, Mark Christiansen, Annique Claringbould, Patrick Deelen, Tõnu Esko, Marie-Julie Favé, Lude Franke, Timothy Frayling, Sina A. Gharib, Gregory Gibson, Bastiaan T. Heijmans, Gibran Hemani, Rick Jansen, Mika Kähönen, Anette Kalnapenkis, Silva Kasela, Johannes Kettunen, Yungil Kim, Holger Kirsten, Peter Kovacs, Knut Krohn, Jaanika Kronberg-Guzman, Viktorija Kukushkina, Zoltan Kutalik, Bernett Lee, Terho Lehtimäki, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Lili Milani, Grant W. Montgomery, Martina Müller-Nurasyid, Matthias Nauck, Michel Nivard, Brenda Penninx, Markus Perola, Natalia Pervjakova, Brandon L. Pierce, Joseph Powell, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Samuli Ripatti, Olaf Rotzschke, Sina Rüeger, Ashis Saha, Markus Scholz, Katharina Schramm, Ilkka Seppälä, Eline P. Slagboom, Coen D.A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Alexander Teumer, Joachim Thiery, Lin Tong, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Joyce van Meurs, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Urmo Võsa, Harm-Jan Westra, Cisca Wijmenga, Hanieh Yaghootkar, Jian Yang, Biao Zeng, Futao Zhang, Aaron Isaacs, René Pool, Jouke J. Hottenga, Marleen MJ. van Greevenbroek, Carla J.H. van der Kallen, Casper G. Schalkwijk, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H.Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Michiel van Galen, Jan Bot, Daria V. Zhernakova, Peter van ‘t Hof, Irene Nooren, Matthijs Moed, Martijn Vermaat, René Luijk, Freerk van Dijk, Szymon M. Kielbasa, Morris A. Swertz, Erik. W. van Zwet, Peter-Bram ‘t Hoen, MUMC+: Centrum voor Chronische Zieken (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: HVC Pieken Maastricht Studie (9), Interne Geneeskunde, MUMC+: MA Interne Geneeskunde (3), Urology, Medical Informatics, Department of Marketing Management, Epidemiology, Internal Medicine, Dermatology, Ophthalmology, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, VU University medical center, Clinical chemistry, Human genetics, APH - Digital Health, APH - Methodology, Biological Psychology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
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0301 basic medicine ,Candidate gene ,mQTL ,Autism Spectrum Disorder ,Gene Expression ,Genome-wide association study ,Biology ,Quantitative trait locus ,VARIANTS ,eQTL ,03 medical and health sciences ,0302 clinical medicine ,Mendelian randomization ,mental disorders ,Humans ,GWAS ,BRAIN ,Biological Psychiatry ,Genetic association ,Genetics ,Regulation of gene expression ,Pleiotropy ,HERITABILITY ,dNaM ,DNA Methylation ,SMR ,Fetal brain ,PREVALENCE ,030104 developmental biology ,Attention Deficit Disorder with Hyperactivity ,DNA methylation ,17Q21.31 ,Psychiatric disorders ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
BACKGROUND: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels.METHODS: We applied summary-data-based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data-based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels.RESULTS: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before.CONCLUSIONS: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies.
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- 2020
19. Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
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Tõnu Esko, Lars Wallentin, Andrew D. Bretherick, Adam S. Butterworth, Jesper R. Gådin, Anders Hamsten, Anders Mälarstig, Gunnar Engström, Johan Ärnlöv, Andres Ingason, Céline Fernandez, Jian Yang, Peter M. Nilsson, George Davey-Smith, Weidong Zhang, Agneta Siegbahn, Lasse Folkersen, Thibaud Boutin, Michael V. Holmes, Lars Lind, Julie Lee, Erik Ingelsson, James F. Wilson, Olle Melander, Eric B. Fauman, Lude Franke, Amira Quazi, John Danesh, Ozren Polasek, Niclas Ericsson, Sarah E. Bergen, Mika Ala-Korpela, Andrew J. Schork, Marketa Sjögren, Seung Hoan Choi, Jan Nilsson, Åsa K Hedman, Cecilia M. Lindgren, Bram P. Prins, Daria V. Zhernakova, Yang Wu, Karl Michaëlsson, James E. Peters, Andrew P. Morris, Marju Orho-Melander, Stefan Enroth, Reedik Mägi, Stefan Gustafsson, Mikael Landén, Martin Magnusson, Qin Wang, Steven A. Lubitz, Johan Sundström, Federico De Masi, Jingyuan Fu, Rasmus Wernersson, Thomas Werge, Praveen Surendran, Tom Palmer, Paul W. Franks, Caroline Hayward, Daniel Hvidberg Hansen, Ulf Gyllensten, Vilmantas Giedraitis, Ljubica Perisic Matic, Urmo Võsa, Åsa Johansson, Alexandra Zhernakova, Bianca E. Suur, Karen Page, Gustav Smith, Erik Pålsson, Ting Qi, Harm-Jan Westra, Michael W. Nagle, Erin Macdonald-Dunlop, Annique Claringbould, Peter K. Joshi, Sölve Elmståhl, Anettne Kalnapenkis, Yan Chen, Chris Haley, and Jeremy D. Gale
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Drug ,0303 health sciences ,media_common.quotation_subject ,Drug target ,Disease ,Computational biology ,030204 cardiovascular system & hematology ,Biology ,Quantitative trait locus ,Precision medicine ,3. Good health ,03 medical and health sciences ,Human health ,0302 clinical medicine ,Mendelian randomization ,Gene ,030304 developmental biology ,media_common - Abstract
Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping usingtrans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.
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- 2020
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20. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals
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Tom Palmer, Lars Lind, George Davey Smith, Ting Qi, Michael W. Nagle, Paul W. Franks, Bram P. Prins, Julie Lee, Jingyuan Fu, Niclas Eriksson, Peter K. Joshi, Chris Haley, Ljubica Perisic Matic, Jeremy D. Gale, Mika Ala-Korpela, Michael V. Holmes, Urmo Võsa, Adam S. Butterworth, Eric B. Fauman, Anette Kalnapenkis, Reedik Mägi, Åsa Johansson, James F. Wilson, Mikael Landén, Gunnar Engström, Johan Ärnlöv, Anders Hamsten, Ozren Polasek, Andres Ingason, Andrew J. Schork, Agneta Siegbahn, Lasse Folkersen, Qin Wang, Andrew P. Morris, Johan Sundström, Daria V. Zhernakova, Olle Melander, Erik Ingelsson, Federico De Masi, Lude Franke, James E. Peters, Alexandra Zhernakova, Seung Hoan Choi, Rasmus Wernersson, Thibaud Boutin, Karl Michaëlsson, Stefan Gustafsson, Bianca E. Suur, Karen Page, Yang Wu, Caroline Hayward, Marketa Sjögren, Cecilia M. Lindgren, Stefan Enroth, Tõnu Esko, Amira Quazi, John Danesh, Anders Mälarstig, Daniel Hvidberg Hansen, Åsa K Hedman, Jan Nilsson, Ulf Gyllensten, Vilmantas Giedraitis, J. Gustav Smith, Martin Magnusson, Marju Orho-Melander, Steven A. Lubitz, Erin Macdonald-Dunlop, Thomas Werge, Praveen Surendran, Yan Chen, Céline Fernandez, Weidong Zhang, Lars Wallentin, Andrew D. Bretherick, Jian Yang, Peter M. Nilsson, Jesper R. Gådin, Annique Claringbould, Sölve Elmståhl, Sarah E Bergen, Harm-Jan Westra, Erik Pålsson, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), United Kingdom Research and Innovation, Folkersen, Lasse [0000-0003-0708-9530], Hansen, Daniel Hvidberg [0000-0003-3285-605X], Wu, Yang [0000-0002-0128-7280], Eriksson, Niclas [0000-0002-2152-4343], Bretherick, Andrew D [0000-0001-9258-3140], Enroth, Stefan [0000-0002-5056-9137], Lee, Julie [0000-0001-6090-6718], Ala-Korpela, Mika [0000-0001-5905-1206], Claringbould, Annique [0000-0002-9201-6557], Davey Smith, George [0000-0002-1407-8314], Fauman, Eric [0000-0002-9739-0249], Fernandez, Celine [0000-0003-1290-4982], Franke, Lude [0000-0002-5159-8802], Franks, Paul W [0000-0002-0520-7604], Giedraitis, Vilmantas [0000-0003-3423-2021], Haley, Chris [0000-0002-9811-0210], Johansson, Åsa [0000-0002-2915-4498], Lubitz, Steven [0000-0002-9599-4866], Palmer, Tom [0000-0003-4655-4511], Macdonald-Dunlop, Erin [0000-0001-6569-6086], Magnusson, Martin [0000-0003-1710-5936], Michaelsson, Karl [0000-0003-2815-1217], Nagle, Michael W [0000-0002-4677-7582], Nilsson, Peter M [0000-0002-5652-8459], Nilsson, Jan [0000-0002-9752-7479], Prins, Bram [0000-0001-5774-034X], Sundström, Johan [0000-0003-2247-8454], Werge, Thomas [0000-0003-1829-0766], Westra, Harm-Jan [0000-0001-7038-567X], Fu, Jingyuan [0000-0001-5578-1236], Esko, Tõnu [0000-0003-1982-6569], Hayward, Caroline [0000-0002-9405-9550], Landen, Mikael [0000-0002-4496-6451], Butterworth, Adam S [0000-0002-6915-9015], Holmes, Michael V [0000-0001-6617-0879], Ingelsson, Erik [0000-0003-2256-6972], Mälarstig, Anders [0000-0003-2608-1358], Apollo - University of Cambridge Repository, and 30387078 - Magnusson, P. Martin
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Proteomics ,Proteome ,Endocrinology, Diabetes and Metabolism ,Asthma ,ATP Binding Cassette Transporter 1 ,Cardiovascular System ,Chromosome Mapping ,Drug Delivery Systems ,Gene Knockdown Techniques ,Genome-Wide Association Study ,Genomics ,Humans ,Inflammatory Bowel Diseases ,Interleukin-1 Receptor-Like 1 Protein ,Intracellular Signaling Peptides and Proteins ,Linkage Disequilibrium ,Mendelian Randomization Analysis ,Protein-Serine-Threonine Kinases ,Quantitative Trait Loci ,Receptors, CCR2 ,Receptors, CCR5 ,Genome-wide association study ,030204 cardiovascular system & hematology ,Chemokine receptor ,0302 clinical medicine ,RECEPTOR ANTAGONIST ,GWAS ,Cardiac and Cardiovascular Systems ,0303 health sciences ,Molecular medicine ,3. Good health ,Medical genetics ,Medical Genetics ,Life Sciences & Biomedicine ,medicine.medical_specialty ,Computational biology ,Biology ,Protein Serine-Threonine Kinases ,Article ,03 medical and health sciences ,Endocrinology & Metabolism ,Physiology (medical) ,Mendelian randomization ,Internal Medicine ,medicine ,030304 developmental biology ,Science & Technology ,Cell Biology ,GENE ,ANTIBODY - Abstract
Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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- 2020
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21. Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies
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Hammerschlag, Anke R., primary, Byrne, Enda M., additional, Bartels, Meike, additional, Wray, Naomi R., additional, Middeldorp, Christel M., additional, Agbessi, Mawussé, additional, Ahsan, Habibul, additional, Alves, Isabel, additional, Andiappan, Anand, additional, Arindrarto, Wibowo, additional, Awadalla, Philip, additional, Battle, Alexis, additional, Beutner, Frank, additional, Bonder, Marc Jan, additional, Boomsma, Dorret I., additional, Christiansen, Mark, additional, Claringbould, Annique, additional, Deelen, Patrick, additional, Esko, Tõnu, additional, Favé, Marie-Julie, additional, Franke, Lude, additional, Frayling, Timothy, additional, Gharib, Sina A., additional, Gibson, Gregory, additional, Heijmans, Bastiaan T., additional, Hemani, Gibran, additional, Jansen, Rick, additional, Kähönen, Mika, additional, Kalnapenkis, Anette, additional, Kasela, Silva, additional, Kettunen, Johannes, additional, Kim, Yungil, additional, Kirsten, Holger, additional, Kovacs, Peter, additional, Krohn, Knut, additional, Kronberg-Guzman, Jaanika, additional, Kukushkina, Viktorija, additional, Kutalik, Zoltan, additional, Lee, Bernett, additional, Lehtimäki, Terho, additional, Loeffler, Markus, additional, Marigorta, Urko M., additional, Mei, Hailang, additional, Milani, Lili, additional, Montgomery, Grant W., additional, Müller-Nurasyid, Martina, additional, Nauck, Matthias, additional, Nivard, Michel, additional, Penninx, Brenda, additional, Perola, Markus, additional, Pervjakova, Natalia, additional, Pierce, Brandon L., additional, Powell, Joseph, additional, Prokisch, Holger, additional, Psaty, Bruce M., additional, Raitakari, Olli T., additional, Ripatti, Samuli, additional, Rotzschke, Olaf, additional, Rüeger, Sina, additional, Saha, Ashis, additional, Scholz, Markus, additional, Schramm, Katharina, additional, Seppälä, Ilkka, additional, Slagboom, Eline P., additional, Stehouwer, Coen D.A., additional, Stumvoll, Michael, additional, Sullivan, Patrick, additional, ‘t Hoen, Peter A.C., additional, Teumer, Alexander, additional, Thiery, Joachim, additional, Tong, Lin, additional, Tönjes, Anke, additional, van Dongen, Jenny, additional, van Iterson, Maarten, additional, van Meurs, Joyce, additional, Veldink, Jan H., additional, Verlouw, Joost, additional, Visscher, Peter M., additional, Völker, Uwe, additional, Võsa, Urmo, additional, Westra, Harm-Jan, additional, Wijmenga, Cisca, additional, Yaghootkar, Hanieh, additional, Yang, Jian, additional, Zeng, Biao, additional, Zhang, Futao, additional, Isaacs, Aaron, additional, Pool, René, additional, Hottenga, Jouke J., additional, van Greevenbroek, Marleen MJ., additional, van der Kallen, Carla J.H., additional, Schalkwijk, Casper G., additional, Zhernakova, Sasha, additional, Tigchelaar, Ettje F., additional, Slagboom, P. Eline, additional, Beekman, Marian, additional, Deelen, Joris, additional, van Heemst, Diana, additional, van den Berg, Leonard H., additional, van Duijn, Cornelia M., additional, Hofman, Bert A., additional, Uitterlinden, André G., additional, Jhamai, P. Mila, additional, Verbiest, Michael, additional, Suchiman, H.Eka D., additional, Verkerk, Marijn, additional, van der Breggen, Ruud, additional, van Rooij, Jeroen, additional, Lakenberg, Nico, additional, van Galen, Michiel, additional, Bot, Jan, additional, Zhernakova, Daria V., additional, Hof, Peter van ‘t, additional, Nooren, Irene, additional, Moed, Matthijs, additional, Vermaat, Martijn, additional, Luijk, René, additional, van Dijk, Freerk, additional, Kielbasa, Szymon M., additional, Swertz, Morris A., additional, van Zwet, Erik. W., additional, and Hoen, Peter-Bram ‘t, additional
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- 2020
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22. Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
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Folkersen, Lasse, primary, Gustafsson, Stefan, additional, Wang, Qin, additional, Hansen, Daniel Hvidberg, additional, Hedman, Åsa K, additional, Schork, Andrew, additional, Page, Karen, additional, Zhernakova, Daria V, additional, Wu, Yang, additional, Peters, James, additional, Ericsson, Niclas, additional, Bergen, Sarah E, additional, Boutin, Thibaud, additional, Bretherick, Andrew D, additional, Enroth, Stefan, additional, Kalnapenkis, Anettne, additional, Gådin, Jesper R, additional, Suur, Bianca, additional, Chen, Yan, additional, Matic, Ljubica, additional, Gale, Jeremy D, additional, Lee, Julie, additional, Zhang, Weidong, additional, Quazi, Amira, additional, Ala-Korpela, Mika, additional, Choi, Seung Hoan, additional, Claringbould, Annique, additional, Danesh, John, additional, Davey-Smith, George, additional, de Masi, Federico, additional, Elmståhl, Sölve, additional, Engström, Gunnar, additional, Fauman, Eric, additional, Fernandez, Celine, additional, Franke, Lude, additional, Franks, Paul, additional, Giedraitis, Vilmantas, additional, Haley, Chris, additional, Hamsten, Anders, additional, Ingason, Andres, additional, Johansson, Åsa, additional, Joshi, Peter K, additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Lubitz, Steven, additional, Palmer, Tom, additional, Macdonald-Dunlop, Erin, additional, Magnusson, Martin, additional, Melander, Olle, additional, Michaelsson, Karl, additional, Morris, Andrew P., additional, Mägi, Reedik, additional, Nagle, Michael, additional, Nilsson, Peter M, additional, Nilsson, Jan, additional, Orho-Melander, Marju, additional, Polasek, Ozren, additional, Prins, Bram, additional, Pålsson, Erik, additional, Qi, Ting, additional, Sjögren, Marketa, additional, Sundström, Johan, additional, Surendran, Praveen, additional, Võsa, Urmo, additional, Werge, Thomas, additional, Wernersson, Rasmus, additional, Westra, Harm-Jan, additional, Yang, Jian, additional, Zhernakova, Alexandra, additional, Ärnlöv, Johan, additional, Fu, Jingyuan, additional, Smith, Gustav, additional, Esko, Tonu, additional, Hayward, Caroline, additional, Gyllensten, Ulf, additional, Landen, Mikael, additional, Siegbahn, Agneta, additional, Wilson, Jim F, additional, Wallentin, Lars, additional, Butterworth, Adam S, additional, Holmes, Michael V, additional, Ingelsson, Erik, additional, and Mälarstig, Anders, additional
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- 2020
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23. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances
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Timmers, P.R., Mounier, N., Lall, K., Fischer, K., Ning, Z., Feng, X., Bretherick, A.D., Clark, D.W., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., van Dongen, J., Esko, T., Favé, M., Franke, L., Frayling, T., Gharib, S.A., Gibson, G., Hemani, G., Jansen, R., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Kähönen, M., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U., Metspalu, A., van Meurs, J., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B.M., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., Verlouw, J., Visscher, P.M., Võsa, U., Völker, U., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., Shen, X., Wilson, J.F., Joshi, P.K., eQTLGen Consortium, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and APH - Digital Health
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Male ,Parents ,Multifactorial Inheritance ,QH301-705.5 ,Science ,Longevity ,Complex Trait ,Genetics ,Genomics ,Human ,Lifespan ,Age Factors ,Aged ,Bayes Theorem ,DNA Methylation/genetics ,Disease/genetics ,Female ,Genetic Loci ,Genome-Wide Association Study ,Humans ,Longevity/genetics ,Middle Aged ,Multifactorial Inheritance/genetics ,Polymorphism, Single Nucleotide/genetics ,Risk Factors ,Sex Characteristics ,Signal Transduction/genetics ,Survival Analysis ,complex trait ,genetics ,genomics ,human ,lifespan ,longevity ,Polymorphism, Single Nucleotide ,Research Communication ,Disease ,Biology (General) ,Genetics and Genomics ,DNA Methylation ,Medicine ,Signal Transduction - Abstract
We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer – but not other cancers – explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., eLife digest Ageing happens to us all, and as the cabaret singer Maurice Chevalier pointed out, "old age is not that bad when you consider the alternative". Yet, the growing ageing population of most developed countries presents challenges to healthcare systems and government finances. For many older people, long periods of ill health are part of the end of life, and so a better understanding of ageing could offer the opportunity to prolong healthy living into old age. Ageing is complex and takes a long time to study – a lifetime in fact. This makes it difficult to discern its causes, among the countless possibilities based on an individual’s genes, behaviour or environment. While thousands of regions in an individual’s genetic makeup are known to influence their risk of different diseases, those that affect how long they will live have proved harder to disentangle. Timmers et al. sought to pinpoint such regions, and then use this information to predict, based on their DNA, whether someone had a better or worse chance of living longer than average. The DNA of over 500,000 people was read to reveal the specific ‘genetic fingerprints’ of each participant. Then, after asking each of the participants how long both of their parents had lived, Timmers et al. pinpointed 12 DNA regions that affect lifespan. Five of these regions were new and had not been linked to lifespan before. Across the twelve as a whole several were known to be involved in Alzheimer’s disease, smoking-related cancer or heart disease. Looking at the entire genome, Timmers et al. could then predict a lifespan score for each individual, and when they sorted participants into ten groups based on these scores they found that top group lived five years longer than the bottom, on average. Many factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone. Nevertheless, Timmers et al. had hoped to narrow down their search and discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.
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- 2019
24. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
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Porcu, E. (Eleonora), Rueger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawusse), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A. (Anand), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M. J. (Marc Jan), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tonu), Fave, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T. (Timothy), Gharib, S. A. (Sina A.), Gibson, G. (Gregory), Heijmans, B. T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kahonen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimaki, T. (Terho), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G. W. (Grant W.), Mueler-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, B. L. (Brandon L.), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppala, I. (Ilkka), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), van Meurs, J. (Joyce), Veldink, J. H. (Jan H.), Verlouw, J. (Joost), Visscher, P. M. (Peter M.), Volker, U. (Uwe), Vosa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D. I. (Dorret I.), Bot, J. (Jan), Deelen, J. (Joris), Hofman, B. A. (Bert A.), Hottenga, J. J. (Jouke J.), Isaacs, A. (Aaron), Jhamai, P. M. (P. Mila), Kielbasa, S. M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (Rene), Mei, H. (Hailiang), Moed, M. (Matthijs), Nooren, I. (Irene), Pool, R. (Rene), Schalkwijk, C. G. (Casper G.), Slagboom, P. E. (P. Eline), Suchiman, H. E. (H. Eka D.), Swertz, M. A. (Morris A.), Tigchelaar, E. F. (Ettje F.), Uitterlinden, A. G. (Andre G.), van den Berg, L. H. (Leonard H.), van der Breggen, R. (Ruud), van der Kallen, C. J. (Carla J. H.), van Dijk, F. (Freerk), van Duijn, C. M. (Cornelia M.), van Galen, M. (Michiel), van Greevenbroek, M. M. (Marleen M. J.), van Heemst, D. (Diana), van Rooij, J. (Jeroen), Van't Hof, P. (Peter), van Zwet, E. W. (Erik. W.), Vermaat, M. (Martijn), Verbiest, M. (Michael), Verkerk, M. (Marijn), Zhernakova, D. V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F. A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltan)
- Abstract
Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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- 2019
25. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
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Qi, Ting, Wu, Yang, Zeng, Jian, Zhang, Futao, Xue, Angli, Jiang, Longda, Zhu, Zhihong, Kemper, Kathryn, Yengo, Loic, Zheng, Zhili, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret, Christiansen, Mark, Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina, Gibson, Gregory, Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg-Guzman, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Metspalu, Andres, Milani, Lili, Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel, Penninx, Brenda, Perola, Markus, Pervjakova, Natalia, Pierce, Brandon, Powell, Joseph, Prokisch, Holger, Psaty, Bruce, Raitakari, Olli, Ring, Susan, Ripatti, Samuli, Rotzschke, Olaf, Ruëger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Stumvoll, Michael, Sullivan, Patrick, Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, Van Dongen, Jenny, Van Meurs, Joyce, Verlouw, Joost, Völker, Uwe, Võsa, Urmo, Yaghootkar, Hanieh, Zeng, Biao, Marioni, Riccardo E., Montgomery, Grant W., Deary, Ian J., Wray, Naomi R., Visscher, Peter M., McRae, Allan F., Yang, Jian, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Integrative Neurophysiology, APH - Personalized Medicine, Psychiatry, APH - Digital Health, Internal Medicine, Institute for Molecular Medicine Finland, University Management, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Doctoral Programme in Population Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, and Complex Disease Genetics
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0301 basic medicine ,Netherlands Twin Register (NTR) ,General Physics and Astronomy ,Genome-wide association study ,data set ,Transcriptome ,0302 clinical medicine ,quantitative trait locus ,expression quantitative trait locus ,genetics ,Tissue Distribution ,lcsh:Science ,Promoter Regions, Genetic ,Regulation of gene expression ,Genetics ,0303 health sciences ,Multidisciplinary ,DNA methylation ,quantitative analysis ,Brain ,Phenotype ,sample size ,Enhancer Elements, Genetic ,CpG site ,genetic marker ,enhancer region ,Genetic Markers ,Science ,Quantitative Trait Loci ,Quantitative trait locus ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,promoter region ,blood ,genetics of the nervous system ,MD Multidisciplinary ,Humans ,human ,gene ,Gene ,030304 developmental biology ,dNaM ,General Chemistry ,DNA ,DNA Methylation ,major clinical study ,030104 developmental biology ,Gene Expression Regulation ,Genetic marker ,Expression quantitative trait loci ,genome-wide association studies ,gene expression ,RNA ,lcsh:Q ,methylation ,3111 Biomedicine ,gene regulation ,metabolism ,030217 neurology & neurosurgery ,meta analysis ,Genome-Wide Association Study - Abstract
Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (rb). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hat r_b = 0.70$$\end{document}r^b=0.70 for cis-eQTLs and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hat r_ b = 0.78$$\end{document}r^b=0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes., To comprehend the genetic regulatory mechanisms underlying brain-related traits in humans, Qi et al. estimate the correlation of expression and DNA methylation QTL effects in cis between blood and brain and show that using blood eQTL/mQTL data of large sample size can increase power in gene discovery for brain-related traits and diseases.
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- 2018
26. Author response: Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances
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Uwe Völker, Ninon Mounier, J. M. van Dongen, Martina Müller-Nurasyid, Peter K. Joshi, David W. Clark, Jaanika Kronberg-Guzman, Holger Kirsten, Viktorija Kukushkina, Xia Shen, Patrick Deelen, Mawusse Agbessi, Alexis Battle, Susan M. Ring, Marie-Julie Favé, Anke Tönjes, Tõnu Esko, Z. Kutalik, Alexander Teumer, Biao Zeng, Michael Stumvoll, Katharina Schramm, Natalia Pervjakova, Greg Gibson, Hanieh Yaghootkar, Yungil Kim, Annique Claringbould, Patrick F. Sullivan, Habibul Ahsan, Lin Tong, Markus Scholz, Philip Awadalla, Mark W. Christiansen, Brenda W.J.H. Penninx, Ashis Saha, Urmo Võsa, Urko M. Marigorta, D.I. Boomsma, Peter Kovacs, Isabel Alves, Gibran Hemani, Knut Krohn, Jarno Kettunen, Krista Fischer, Anand Kumar Andiappan, James F. Wilson, Holger Prokisch, Timothy M. Frayling, Joost Verlouw, Anette Kalnapenkis, Markus Perola, Andrew D. Bretherick, Jian Yang, Peter M. Visscher, Markus Loeffler, Joseph E. Powell, Lude Franke, Marc Jan Bonder, Zoltán Kutalik, Silva Kasela, Kristi Läll, Sina A. Gharib, Paul R. H. J. Timmers, Lili Milani, Olli T. Raitakari, T Esko, Zheng Ning, Ilkka Seppälä, Andres Metspalu, Bernett Lee, Michel G. Nivard, Matthias Nauck, Brandon L. Pierce, Joachim Thiery, J.B. van Meurs, Sina Rüeger, Olaf Rötzschke, Samuli Ripatti, Mika Kähönen, Bruce M. Psaty, Rick Jansen, Futao Zhang, Terho Lehtimäki, and Xiao Feng
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Evolutionary biology ,Genomics ,Biology - Published
- 2018
27. Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis
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Dmitreva J, van Iterson M, Brenda W.J.H. Penninx, Reyhan Sonmez, Michel Georges, Tõnu Esko, Matthias Nauck, Eline Slagboom, Bruce M. Psaty, Urko M. Marigorta, Michel G. Nivard, C Wijmenga, Markus Perola, Joost Verlouw, Jaanika Kronberg-Guzman, Bastiaan T. Heijmans, van Dongen J, Martina Müller-Nurasyid, Yukihide Momozawa, Silva Kasela, Joseph E. Powell, Sina Rüeger, Brandon L. Pierce, Sven Bergmann, van Meurs J, Lude Franke, Uwe Völker, Futao Zhang, Marc Jan Bonder, Z. Kutalik, Frank Beutner, Ilkka Seppälä, Jarno Kettunen, Morris A. Swertz, Harm-Jan Westra, Jan H. Veldink, Hailiang Mei, Joachim Thiery, Jian Yang, Anand Kumar Andiappan, Grant W. Montgomery, Wibowo Arindrarto, Julian C. Knight, Markus Scholz, Mark W. Christiansen, Alexander Teumer, Bernett Lee, Patrick Deelen, Willem H. Ouwehand, Roman Kreuzhuber, Ashis Saha, Andrew A. Brown, Marie-Julie Favé, Eleonora Porcu, Mawusse Agbessi, Samuli Ripatti, Terho Lehtimäki, Jonathan K. Pritchard, Lili Milani, Alexis Battle, Holger Kirsten, Sina A. Gharib, Natalia Pervjakova, Annique Claringbould, Patrick F. Sullivan, Habibul Ahsan, Katharina Schramm, Hanieh Yaghootkar, Oliver Stegle, D.I. Boomsma, Anette Kalnapenkis, Mika Kähönen, Harm Brugge, Lin Tong, Biao Zeng, Holger Prokisch, Kate Downes, Rick Jansen, Peter M. Visscher, Benjamin P. Fairfax, Shuang Li, Urmo Võsa, Emmanouil T. Dermitzakis, Michael Stumvoll, Markus Loeffler, Alvaes I, Rotzchke O, Philip Awadalla, Coen D.A. Stehouwer, Olli T. Raitakari, Gibran Hemani, Peter Kovacs, Peter A C 't Hoen, Timothy M. Frayling, Anke Tönjes, Greg Gibson, Yungil Kim, Kukushkina, Mahmoud Elansary, and Knut Krohn
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Genetics ,0303 health sciences ,Genome-wide association study ,Genomics ,Quantitative trait locus ,Biology ,Genetic architecture ,03 medical and health sciences ,0302 clinical medicine ,Expression quantitative trait loci ,Trait ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association - Abstract
SummaryWhile many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.To identify these effects, we performedcis-andtrans-expressionquantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.We observed thatcis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to usecis-eQTLs to pinpoint causal genes within susceptibility loci.In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.
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- 2018
28. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
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Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K.E., Zheng, Z., Yengo, L., Lloyd-Jones, L.R., Sidorenko, J., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.-J., Franke, L., Frayling, T., Gharib, S., Gibson, G., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Völker, U., Võsa, U., Yaghootkar, H., Zeng, B., McRae, A.F., Visscher, P.M., Zeng, J., Yang, J., Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Clinicum, Complex Disease Genetics, Psychiatry, APH - Digital Health, and Internal Medicine
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0301 basic medicine ,Epigenomics ,Netherlands Twin Register (NTR) ,endocrine system diseases ,General Physics and Astronomy ,Genome-wide association study ,Epigenesis, Genetic ,Genotype ,lcsh:Science ,Heat-Shock Proteins ,Genetics ,Multidisciplinary ,Mitochondrial Proton-Translocating ATPases ,3. Good health ,DNA methylation ,Risk ,endocrine system ,Science ,education ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,White People ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Genetic variation ,Humans ,Genetic Predisposition to Disease ,Epigenetics ,Gene ,Genetic association ,Genetic Variation ,nutritional and metabolic diseases ,General Chemistry ,DNA Methylation ,030104 developmental biology ,Calcium-Calmodulin-Dependent Protein Kinase Type 1 ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,3121 General medicine, internal medicine and other clinical medicine ,lcsh:Q ,3111 Biomedicine ,Carrier Proteins ,human activities ,Genome-Wide Association Study - Abstract
Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants., GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
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- 2018
29. Analytical strategies to include the X-chromosome in variance heterogeneity analyses: evidence for trait-specific polygenic variance structure
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Shihong Mao, Tõnu Esko, Lei Sun, Wei Deng, Guillaume Paré, Reedik Mägi, and Anette Kalnapenkis
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Male ,Multifactorial Inheritance ,Waist ,Genotype ,Epidemiology ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Quantitative trait locus ,Biology ,Genetic Heterogeneity ,03 medical and health sciences ,Humans ,SNP ,Computer Simulation ,Human height ,Gene–environment interaction ,Genetics (clinical) ,030304 developmental biology ,2. Zero hunger ,Genetics ,Chromosomes, Human, X ,Sex Characteristics ,0303 health sciences ,030305 genetics & heredity ,Variance (accounting) ,Sexual dimorphism ,Phenotype ,Evolutionary biology ,Expression quantitative trait loci ,Trait ,Female ,Gene-Environment Interaction ,Waist Circumference ,Genome-Wide Association Study - Abstract
Genotype-stratified variance of a quantitative trait could differ in the presence of gene-gene or gene-environment interactions. Genetic markers associated with phenotypic variance are thus considered promising candidates for follow-up interaction or joint location-scale analyses. However, as in studies of main effects, the X-chromosome is routinely excluded from ‘whole-genome’ scans due to analytical challenges. Specifically, as males carry only one copy of the X-chromosome, the inherent sex-genotype dependency could bias the trait-genotype association, through sexual dimorphism in quantitative traits with sex-specific means or variances. Here we investigate phenotypic variance heterogeneity associated with X-chromosome SNPs and propose valid and powerful strategies. Among those, a generalized Levene’s test has adequate power and remains robust to sexual dimorphism. An alternative approach is sex-stratified analysis but at the cost of slightly reduced power and modeling flexibility. We applied both methods to an Estonian study of gene expression quantitative trait loci (eQTL; n=841), and two complex trait studies of height, hip and waist circumferences, and body mass index from multi-ethnic study of atherosclerosis (MESA; n=2,073) and UK Biobank (UKB; n=327,393). Consistent with previous eQTL findings on mean, we found some but no conclusive evidence for cis regulators being enriched for variance association. SNP rs2681646 is associated with variance of waist circumference (p=9.5E-07) at X-chromosome-wide significance in UKB, with a suggestive female-specific effect in MESA (p=0.048). Collectively, an enrichment analysis using permutated UKB (pp
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- 2018
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30. Analytical strategies to include the X‐chromosome in variance heterogeneity analyses: Evidence for trait‐specific polygenic variance structure
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Deng, Wei Q., primary, Mao, Shihong, additional, Kalnapenkis, Anette, additional, Esko, Tõnu, additional, Mägi, Reedik, additional, Paré, Guillaume, additional, and Sun, Lei, additional
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- 2019
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31. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
- Author
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Võsa, Urmo, Claringbould, Annique, Westra, Harm-Jan, Bonder, Marc Jan, Deelen, Patrick, Zeng, Biao, Kirsten, Holger, Saha, Ashis, Kreuzhuber, Roman, Yazar, Seyhan, Brugge, Harm, Oelen, Roy, de Vries, Dylan H., van der Wijst, Monique G. P., Kasela, Silva, Pervjakova, Natalia, Alves, Isabel, Favé, Marie-Julie, Agbessi, Mawussé, Christiansen, Mark W., Jansen, Rick, Seppälä, Ilkka, Tong, Lin, Teumer, Alexander, Schramm, Katharina, Hemani, Gibran, Verlouw, Joost, Yaghootkar, Hanieh, Sönmez Flitman, Reyhan, Brown, Andrew, Kukushkina, Viktorija, Kalnapenkis, Anette, Rüeger, Sina, Porcu, Eleonora, Kronberg, Jaanika, Kettunen, Johannes, Lee, Bernett, Zhang, Futao, Qi, Ting, Hernandez, Jose Alquicira, Arindrarto, Wibowo, Beutner, Frank, Dmitrieva, Julia, Elansary, Mahmoud, Fairfax, Benjamin P., Georges, Michel, Heijmans, Bastiaan T., Hewitt, Alex W., Kähönen, Mika, Kim, Yungil, Knight, Julian C., Kovacs, Peter, Krohn, Knut, Li, Shuang, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Momozawa, Yukihide, Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda W. J. H., Pritchard, Jonathan K., Raitakari, Olli T., Rotzschke, Olaf, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ’t Hoen, Peter A. C., Thiery, Joachim, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, Veldink, Jan H., Völker, Uwe, Warmerdam, Robert, Wijmenga, Cisca, Swertz, Morris, Andiappan, Anand, Montgomery, Grant W., Ripatti, Samuli, Perola, Markus, Kutalik, Zoltan, Dermitzakis, Emmanouil, Bergmann, Sven, Frayling, Timothy, van Meurs, Joyce, Prokisch, Holger, Ahsan, Habibul, Pierce, Brandon L., Lehtimäki, Terho, Boomsma, Dorret I., Psaty, Bruce M., Gharib, Sina A., Awadalla, Philip, Milani, Lili, Ouwehand, Willem H., Downes, Kate, Stegle, Oliver, Battle, Alexis, Visscher, Peter M., Yang, Jian, Scholz, Markus, Powell, Joseph, Gibson, Greg, Esko, Tõnu, and Franke, Lude
- Abstract
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
- Published
- 2021
- Full Text
- View/download PDF
32. Analytical strategies to include the X-chromosome in variance heterogeneity analyses: evidence for trait-specific polygenic variance structure
- Author
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Deng, Wei Q., primary, Mao, Shihong, additional, Kalnapenkis, Anette, additional, Esko, Tõnu, additional, Mägi, Reedik, additional, Paré, Guillaume, additional, and Sun, Lei, additional
- Published
- 2018
- Full Text
- View/download PDF
33. Naiste viljakusega seotud tunnuste geneetilised korrelatsioonid
- Author
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Kalnapenkis, Anette, Tartu Ülikool. Loodus- ja tehnoloogiateaduskond, and Tartu Ülikool. Molekulaar- ja rakubioloogia instituut
- Subjects
GWAS ,geneetilised korrelatsioonid ,magistritööd ,naiste viljakus - Abstract
Naiste reproduktiivne eluiga vältab enamasti aastakümneid, seda ilmestavad mitmed muutused, mille tulemusena naiste viljakuse hetkeseis muutub. Käesolevas töös leiti erinevate naiste viljakust peegeldavate tunnustega seotud geneetilised variandid geenides, millele on omane kõrge ekspressioon testistes ja naiste reproduktiivtraktis. Ühtlasi on mitmetel leitud geenidel kõrge ekspressioon kesknärvisüsteemis, millest tulenevalt on alust arvata, et need mõjutavad reproduktiivkäitumist. Antud magistritöö raames ei leitud erinevate naiste viljakusega seotud tunnuste vahel jagatud geneetilist tausta, kuid neid võivad siduda töös käsitlemata tunnused. Naiste viljakust peegeldavad tunnused omavad seost mitmete tunnustega epidemioloogilisel tasandil, kõige sagedamini on kirjeldatud seost kehamassiindeksiga. Magistritöös leiti, et kehamassiindeks on geneetilises korrelatsioonis nii vanusega menarhe ajal kui ka vanusega esimese raseduse ajal, mille võimalikud ühised bioloogilised komponendid on leptiini ja insuliiniga seotud geenirajad
- Published
- 2016
34. Tsirkadiaansete geenide funktsiooni uurimine, kasutades nende ekspressiooni mõjutavate kvantitatiivsete tunnuste lookuste seost metaboliitidega
- Author
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Kalnapenkis, Anette, Teder-Laving, Maris, juhendaja, Reinmaa, Eva, juhendaja, Mägi, Reedik, juhendaja, Tartu Ülikool. Loodus- ja tehnoloogiateaduskond, and Tartu Ülikool. Molekulaar- ja rakubioloogia instituut
- Subjects
bakalaureusetööd ,tsirkadiaanne geenid ,SNP ,eQTL ,metaboliidid - Published
- 2015
35. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals
- Author
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Folkersen, Lasse, Gustafsson, Stefan, Wang, Qin, Hansen, Daniel Hvidberg, Hedman, Åsa K, Schork, Andrew, Page, Karen, Zhernakova, Daria V, Wu, Yang, Peters, James, Eriksson, Niclas, Bergen, Sarah E, Boutin, Thibaud S, Bretherick, Andrew D, Enroth, Stefan, Kalnapenkis, Anette, Gådin, Jesper R, Suur, Bianca E, Chen, Yan, Matic, Ljubica, Gale, Jeremy D, Lee, Julie, Zhang, Weidong, Quazi, Amira, Ala-Korpela, Mika, Choi, Seung Hoan, Claringbould, Annique, Danesh, John, Davey Smith, George, De Masi, Federico, Elmståhl, Sölve, Engström, Gunnar, Fauman, Eric, Fernandez, Celine, Franke, Lude, Franks, Paul W, Giedraitis, Vilmantas, Haley, Chris, Hamsten, Anders, Ingason, Andres, Johansson, Åsa, Joshi, Peter K, Lind, Lars, Lindgren, Cecilia M, Lubitz, Steven, Palmer, Tom, Macdonald-Dunlop, Erin, Magnusson, Martin, Melander, Olle, Michaelsson, Karl, Morris, Andrew P, Mägi, Reedik, Nagle, Michael W, Nilsson, Peter M, Nilsson, Jan, Orho-Melander, Marju, Polasek, Ozren, Prins, Bram, Pålsson, Erik, Qi, Ting, Sjögren, Marketa, Sundström, Johan, Surendran, Praveen, Võsa, Urmo, Werge, Thomas, Wernersson, Rasmus, Westra, Harm-Jan, Yang, Jian, Zhernakova, Alexandra, Ärnlöv, Johan, Fu, Jingyuan, Smith, J Gustav, Esko, Tõnu, Hayward, Caroline, Gyllensten, Ulf, Landen, Mikael, Siegbahn, Agneta, Wilson, James F, Wallentin, Lars, Butterworth, Adam S, Holmes, Michael V, Ingelsson, Erik, and Mälarstig, Anders
- Subjects
Proteome ,Receptors, CCR5 ,Receptors, CCR2 ,Quantitative Trait Loci ,Intracellular Signaling Peptides and Proteins ,Chromosome Mapping ,Genomics ,Mendelian Randomization Analysis ,Protein Serine-Threonine Kinases ,Inflammatory Bowel Diseases ,Cardiovascular System ,Interleukin-1 Receptor-Like 1 Protein ,Asthma ,Linkage Disequilibrium ,3. Good health ,Drug Delivery Systems ,Gene Knockdown Techniques ,Humans ,ATP Binding Cassette Transporter 1 ,Genome-Wide Association Study - Abstract
Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
36. C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis
- Author
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Zoltán Kutalik, Joyce Van Meurs, Urmo Võsa, Martina Müller-Nurasyid, Marc Jan Bonder, Michael Stumvoll, Joseph Powell, Kaido Lepik, Michel Nivard, Peter Kovacs, Holger Prokisch, Pärt Peterson, Jenny Van Dongen, Silva Kasela, Kai Kisand, Annique Claringbould, Tarmo Annilo, Joost Verlouw, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Personalized Medicine, eQTLGen Consortium, Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.J., Franke, L., Frayling, T., Gharib, S., Gibson, G., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Visscher, P., Völker, U., Võsa, U., Yaghootkar, H., Yang, J., Zeng, B., and Zhang, F.
- Subjects
0301 basic medicine ,Netherlands Twin Register (NTR) ,Physiology ,Economics ,Economic Models ,Complement System ,Gene Expression ,Social Sciences ,Adult ,Antigens, CD59/blood ,Antigens, CD59/metabolism ,C-Reactive Protein/metabolism ,Cohort Studies ,Estonia ,Humans ,Inflammation/metabolism ,Up-Regulation/physiology ,Bioinformatics ,Biochemistry ,Sequencing techniques ,Immune Physiology ,Gene expression ,Medicine and Health Sciences ,Biology (General) ,Whole blood ,Regulation of gene expression ,Immune System Proteins ,Ecology ,RNA sequencing ,Mendelian Randomization Analysis ,C-Reactive Proteins ,Body Fluids ,Up-Regulation ,3. Good health ,Blood ,C-Reactive Protein ,Computational Theory and Mathematics ,Modeling and Simulation ,Biological Cultures ,Anatomy ,medicine.symptom ,Research Article ,QH301-705.5 ,Inflammatory Diseases ,Immunology ,CD59 Antigens ,Inflammation ,CD59 ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Genetics ,medicine ,Journal Article ,Molecular Biology ,Gene ,Ecology, Evolution, Behavior and Systematics ,C-reactive protein ,Biology and Life Sciences ,Proteins ,Cell Cultures ,ta3121 ,Research and analysis methods ,Molecular biology techniques ,030104 developmental biology ,Immune System ,biology.protein - Abstract
Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits., Author summary Chronic inflammation is associated with chronic diseases, morbidity and mortality while lower base inflammation levels are thought to be predictive of healthy aging. Thus, to pursue a long and healthy lifespan, it is essential to understand the inflammatory regulatory mechanisms. To that end, we studied the functional role of C-reactive protein (CRP)–an inflammatory biomarker that is used to measure cardiovascular risk in clinical practice. There is evidence for a strong genetic component of elevated CRP levels but it is still unclear if it has a direct impact on the processes that lead to inflammatory diseases. In order to elucidate the function of CRP in the blood, we used statistical methods for causal inference to infer causal relationships between changes in CRP and gene expression levels. Our statistical analysis and cell culture experiments suggest that CRP drives the expression of complement regulatory protein CD59. Thus, CRP can have a functional role in protecting human blood cells from the adverse effects of the immune defence system.
- Published
- 2017
37. Genetic Landscape of the ACE2 Coronavirus Receptor.
- Author
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Yang Z, Macdonald-Dunlop E, Chen J, Zhai R, Li T, Richmond A, Klarić L, Pirastu N, Ning Z, Zheng C, Wang Y, Huang T, He Y, Guo H, Ying K, Gustafsson S, Prins B, Ramisch A, Dermitzakis ET, Png G, Eriksson N, Haessler J, Hu X, Zanetti D, Boutin T, Hwang SJ, Wheeler E, Pietzner M, Raffield LM, Kalnapenkis A, Peters JE, Viñuela A, Gilly A, Elmståhl S, Dedoussis G, Petrie JR, Polašek O, Folkersen L, Chen Y, Yao C, Võsa U, Pairo-Castineira E, Clohisey S, Bretherick AD, Rawlik K, Esko T, Enroth S, Johansson Å, Gyllensten U, Langenberg C, Levy D, Hayward C, Assimes TL, Kooperberg C, Manichaikul AW, Siegbahn A, Wallentin L, Lind L, Zeggini E, Schwenk JM, Butterworth AS, Michaëlsson K, Pawitan Y, Joshi PK, Baillie JK, Mälarstig A, Reiner AP, Wilson JF, and Shen X
- Subjects
- Cross-Sectional Studies, Genome-Wide Association Study, Humans, Receptors, Coronavirus, SARS-CoV-2, Angiotensin-Converting Enzyme 2 genetics, COVID-19 genetics
- Abstract
Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood., Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data., Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P =0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P =0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P =0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells., Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
- Published
- 2022
- Full Text
- View/download PDF
38. Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- Author
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Klaric L, Gisby JS, Papadaki A, Muckian MD, Macdonald-Dunlop E, Zhao JH, Tokolyi A, Persyn E, Pairo-Castineira E, Morris AP, Kalnapenkis A, Richmond A, Landini A, Hedman ÅK, Prins B, Zanetti D, Wheeler E, Kooperberg C, Yao C, Petrie JR, Fu J, Folkersen L, Walker M, Magnusson M, Eriksson N, Mattsson-Carlgren N, Timmers PRHJ, Hwang SJ, Enroth S, Gustafsson S, Vosa U, Chen Y, Siegbahn A, Reiner A, Johansson Å, Thorand B, Gigante B, Hayward C, Herder C, Gieger C, Langenberg C, Levy D, Zhernakova DV, Smith JG, Campbell H, Sundstrom J, Danesh J, Michaëlsson K, Suhre K, Lind L, Wallentin L, Padyukov L, Landén M, Wareham NJ, Göteson A, Hansson O, Eriksson P, Strawbridge RJ, Assimes TL, Esko T, Gyllensten U, Baillie JK, Paul DS, Joshi PK, Butterworth AS, Mälarstig A, Pirastu N, Wilson JF, and Peters JE
- Abstract
Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
- Published
- 2021
- Full Text
- View/download PDF
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