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1,329 results on '"Harris, Sarah E."'

152. Alternative splicing regulation of membrane trafficking genes during myogenesis

Author

Hinkle, Emma R., primary, Wiedner, Hannah J., additional, Torres, Eduardo V., additional, Jackson, Micaela, additional, Black, Adam J., additional, Blue, R. Eric, additional, Harris, Sarah E., additional, Guzman, Bryan B., additional, Gentile, Gabrielle M., additional, Lee, Eunice Y., additional, Tsai, Yi-Hsuan, additional, Parker, Joel, additional, Dominguez, Daniel, additional, and Giudice, Jimena, additional

Published
2022
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154. Epigenetic scores for the circulating proteome as tools for disease prediction

Author

Gadd, Danni A, primary, Hillary, Robert F, primary, McCartney, Daniel L, primary, Zaghlool, Shaza B, primary, Stevenson, Anna J, additional, Cheng, Yipeng, additional, Fawns-Ritchie, Chloe, additional, Nangle, Cliff, additional, Campbell, Archie, additional, Flaig, Robin, additional, Harris, Sarah E, additional, Walker, Rosie M, additional, Shi, Liu, additional, Tucker-Drob, Elliot M, additional, Gieger, Christian, additional, Peters, Annette, additional, Waldenberger, Melanie, additional, Graumann, Johannes, additional, McRae, Allan F, additional, Deary, Ian J, additional, Porteous, David J, additional, Hayward, Caroline, additional, Visscher, Peter M, additional, Cox, Simon R, additional, Evans, Kathryn L, additional, McIntosh, Andrew M, additional, Suhre, Karsten, additional, and Marioni, Riccardo E, additional

Published
2022
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157. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, Peter K., Esko, Tonu, Mattsson, Hannele, Eklund, Niina, Gandin, Ilaria, Nutile, Teresa, Jackson, Anne U., Schurmann, Claudia, Smith, Albert V., Zhang, Weihua, Okada, Yukinori, Stančáková, Alena, Faul, Jessica D., Zhao, Wei, Bartz, Traci M., Concas, Maria Pina, Franceschini, Nora, Enroth, Stefan, Vitart, Veronique, Trompet, Stella, Guo, Xiuqing, Chasman, Daniel I., OʼConnel, Jeffrey R., Corre, Tanguy, Nongmaithem, Suraj S., Chen, Yuning, Mangino, Massimo, Ruggiero, Daniela, Traglia, Michela, Farmaki, Aliki-Eleni, Kacprowski, Tim, Bjonnes, Andrew, van der Spek, Ashley, Wu, Ying, Giri, Anil K., Yanek, Lisa R., Wang, Lihua, Hofer, Edith, Rietveld, Cornelius A., McLeod, Olga, Cornelis, Marilyn C., Pattaro, Cristian, Verweij, Niek, Baumbach, Clemens, Abdellaoui, Abdel, Warren, Helen R., Vuckovic, Dragana, Mei, Hao, Bouchard, Claude, Perry, John R. B., Cappellani, Stefania, Mirza, Saira S., Benton, Miles C., Broeckel, Ulrich, Medland, Sarah E., Lind, Penelope A., Malerba, Giovanni, Drong, Alexander, Yengo, Loic, Bielak, Lawrence F., Zhi, Degui, van der Most, Peter J., Shriner, Daniel, Mägi, Reedik, Hemani, Gibran, Karaderi, Tugce, Wang, Zhaoming, Liu, Tian, Demuth, Ilja, Zhao, Jing Hua, Meng, Weihua, Lataniotis, Lazaros, van der Laan, Sander W., Bradfield, Jonathan P., Wood, Andrew R., Bonnefond, Amelie, Ahluwalia, Tarunveer S., Hall, Leanne M., Salvi, Erika, Yazar, Seyhan, Carstensen, Lisbeth, de Haan, Hugoline G., Abney, Mark, Afzal, Uzma, Allison, Matthew A., Amin, Najaf, Asselbergs, Folkert W., Bakker, Stephan J. L., Barr, Graham R., Baumeister, Sebastian E., Benjamin, Daniel J., Bergmann, Sven, Boerwinkle, Eric, Bottinger, Erwin P., Campbell, Archie, Chakravarti, Aravinda, Chan, Yingleong, Chanock, Stephen J., Chen, Constance, Chen, Ida Y.-D., Collins, Francis S., Connell, John, Correa, Adolfo, Cupples, Adrienne L., Smith, George Davey, Davies, Gail, Dörr, Marcus, Ehret, Georg, Ellis, Stephen B., Feenstra, Bjarke, Feitosa, Mary F., Ford, Ian, Fox, Caroline S., Frayling, Timothy M., Friedrich, Nele, Geller, Frank, Scotland, Generation, Gillham-Nasenya, Irina, Gottesman, Omri, Graff, Misa, Grodstein, Francine, Gu, Charles, Haley, Chris, Hammond, Christopher J., Harris, Sarah E., Harris, Tamara B., Hastie, Nicholas D., Heard-Costa, Nancy L., Heikkilä, Kauko, Hocking, Lynne J., Homuth, Georg, Hottenga, Jouke-Jan, Huang, Jinyan, Huffman, Jennifer E., Hysi, Pirro G., Ikram, Arfan M., Ingelsson, Erik, Joensuu, Anni, Johansson, Åsa, Jousilahti, Pekka, Jukema, Wouter J., Kähönen, Mika, Kamatani, Yoichiro, Kanoni, Stavroula, Kerr, Shona M., Khan, Nazir M., Koellinger, Philipp, Koistinen, Heikki A., Kooner, Manraj K., Kubo, Michiaki, Kuusisto, Johanna, Lahti, Jari, Launer, Lenore J., Lea, Rodney A., Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C.M., Lind, Lars, Loh, Marie, Lokki, Marja-Liisa, London, Stephanie J., Loomis, Stephanie J., Loukola, Anu, Lu, Yingchang, Lumley, Thomas, Lundqvist, Annamari, Männistö, Satu, Marques-Vidal, Pedro, Masciullo, Corrado, Matchan, Angela, Mathias, Rasika A., Matsuda, Koichi, Meigs, James B., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Mentch, Frank D., Mihailov, Evelin, Milani, Lili, Montasser, May E., Montgomery, Grant W., Morrison, Alanna, Myers, Richard H., Nadukuru, Rajiv, Navarro, Pau, Nelis, Mari, Nieminen, Markku S., Nolte, Ilja M., OʼConnor, George T., Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Pankow, James S., Patarcic, Inga, Pavani, Francesca, Peyser, Patricia A., Pietilainen, Kirsi, Poulter, Neil, Prokopenko, Inga, Ralhan, Sarju, Redmond, Paul, Rich, Stephen S., Rissanen, Harri, Robino, Antonietta, Rose, Lynda M., Rose, Richard, Sala, Cinzia, Salako, Babatunde, Salomaa, Veikko, Sarin, Antti-Pekka, Saxena, Richa, Schmidt, Helena, Scott, Laura J., Scott, William R., Sennblad, Bengt, Seshadri, Sudha, Sever, Peter, Shrestha, Smeeta, Smith, Blair H., Smith, Jennifer A., Soranzo, Nicole, Sotoodehnia, Nona, Southam, Lorraine, Stanton, Alice V., Stathopoulou, Maria G., Strauch, Konstantin, Strawbridge, Rona J., Suderman, Matthew J., Tandon, Nikhil, Tang, Sian-Tsun, Taylor, Kent D., Tayo, Bamidele O., Töglhofer, Anna Maria, Tomaszewski, Maciej, Tšernikova, Natalia, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vaidya, Dhananjay, van Hylckama Vlieg, Astrid, van Setten, Jessica, Vasankari, Tuula, Vedantam, Sailaja, Vlachopoulou, Efthymia, Vozzi, Diego, Vuoksimaa, Eero, Waldenberger, Melanie, Ware, Erin B., Wentworth-Shields, William, Whitfield, John B., Wild, Sarah, Willemsen, Gonneke, Yajnik, Chittaranjan S., Yao, Jie, Zaza, Gianluigi, Zhu, Xiaofeng, Salem, Rany M., Melbye, Mads, Bisgaard, Hans, Samani, Nilesh J., Cusi, Daniele, Mackey, David A., Cooper, Richard S., Froguel, Philippe, Pasterkamp, Gerard, Grant, Struan F.A., Hakonarson, Hakon, Ferrucci, Luigi, Scott, Robert A., Morris, Andrew D., Palmer, Colin N. A., Dedoussis, George, Deloukas, Panos, Bertram, Lars, Lindenberger, Ulman, Berndt, Sonja I., Lindgren, Cecilia M., Timpson, Nicholas J., Tönjes, Anke, Munroe, Patricia B., Sørensen, Thorkild I. A., Rotimi, Charles N., Arnett, Donna K., Oldehinkel, Albertine J., Kardia, Sharon L. R., Balkau, Beverley, Gambaro, Giovanni, Morris, Andrew P., Eriksson, Johan G., Wright, Margie J., Martin, Nicholas G., Hunt, Steven C., Starr, John M., Deary, Ian J., Griffiths, Lyn R., Tiemeier, Henning, Pirastu, Nicola, Kaprio, Jaakko, Wareham, Nicholas J., Pérusse, Louis, Wilson, James G., Girotto, Giorgia, Caulfield, Mark J., Raitakari, Olli, Boomsma, Dorret I., Gieger, Christian, van der Harst, Pim, Hicks, Andrew A., Kraft, Peter, Sinisalo, Juha, Knekt, Paul, Johannesson, Magnus, Magnusson, Patrik K. E., Hamsten, Anders, Schmidt, Reinhold, Borecki, Ingrid B., Vartiainen, Erkki, Becker, Diane M., Bharadwaj, Dwaipayan, Mohlke, Karen L., Boehnke, Michael, van Duijn, Cornelia M., Sanghera, Dharambir K., Teumer, Alexander, Zeggini, Eleftheria, Metspalu, Andres, Gasparini, Paolo, Ulivi, Sheila, Ober, Carole, Toniolo, Daniela, Rudan, Igor, Porteous, David J., Ciullo, Marina, Spector, Tim D., Hayward, Caroline, Dupuis, Josée, Loos, Ruth J. F., Wright, Alan F., Chandak, Giriraj R., Vollenweider, Peter, Shuldiner, Alan R., Ridker, Paul M., Rotter, Jerome I., Sattar, Naveed, Gyllensten, Ulf, North, Kari E., Pirastu, Mario, Psaty, Bruce M., Weir, David R., Laakso, Markku, Gudnason, Vilmundur, Takahashi, Atsushi, Chambers, John C., Kooner, Jaspal S., Strachan, David P., Campbell, Harry, Hirschhorn, Joel N., Perola, Markus, Polašek, Ozren, and Wilson, James F.

Published
2015
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159. Apolipoprotein E e4 allele status and later-life depression in the Lothian Birth Cohort 1936.

Author

Iveson, Matthew H., Taylor, Adele, Harris, Sarah E., Deary, Ian J., and McIntosh, Andrew M.

Subjects
MENTAL depression risk factors, PATIENT aftercare, ALLELES, FUNCTIONAL assessment, APOLIPOPROTEINS, MENTAL depression, AGING, RESEARCH funding, CARRIER state (Communicable diseases), PHYSIOLOGY
Abstract

Background: Previous results have been mixed regarding the role of the apolipoprotein E e4 (APOE e4) allele in later-life depression: some studies note that carriers experience greater symptoms and increased risk while others find no such association. However, there are few prospective, population-based studies of the APOE e4-depression association and fewer that examine depressive symptom trajectory and depression risk longitudinally. We examined the association between APOE e4 allele status and longitudinal change in depressive symptoms and depression risk in later-life, over a 12-year follow-up period. Methods: We used data from 690 participants of the Lothian Birth Cohort 1936 who took part in the Scottish Mental Survey 1947 (aged 11) and were followed-up in later-life over five waves from 2004 to 2019 (aged 70–82). We used APOE e4 allele status to predict longitudinal change in depressive symptom scores and risk of depression (defined by a symptom score threshold or use of depression-related medication). Models were adjusted for sex, childhood cognitive ability, childhood social class, education, adult social class, smoking status and functional limitations at baseline. Results: Depressive symptom scores increased with age. Once adjusted for covariates, APOE e4 allele status did not significantly predict symptom score trajectories or depression risk. Greater functional limitations at baseline significantly predicted poorer symptom score trajectories and increased depression risk (defined by medications). APOE e4 allele status did not significantly moderate the contribution of sex, education or functional limitations. Conclusions: There was no evidence that APOE e4 carriers experience an increased risk for later-life depression. [ABSTRACT FROM AUTHOR]

Published
2022
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160. Author response: Epigenetic scores for the circulating proteome as tools for disease prediction

Author

Gadd, Danni A, primary, Hillary, Robert F, primary, McCartney, Daniel L, primary, Zaghlool, Shaza B, primary, Stevenson, Anna J, additional, Cheng, Yipeng, additional, Fawns-Ritchie, Chloe, additional, Nangle, Cliff, additional, Campbell, Archie, additional, Flaig, Robin, additional, Harris, Sarah E, additional, Walker, Rosie M, additional, Shi, Liu, additional, Tucker-Drob, Elliot M, additional, Gieger, Christian, additional, Peters, Annette, additional, Waldenberger, Melanie, additional, Graumann, Johannes, additional, McRae, Allan F, additional, Deary, Ian J, additional, Porteous, David J, additional, Hayward, Caroline, additional, Visscher, Peter M, additional, Cox, Simon R, additional, Evans, Kathryn L, additional, McIntosh, Andrew M, additional, Suhre, Karsten, additional, and Marioni, Riccardo E, additional

Published
2021
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162. Genetic contributions to stability and change in intelligence from childhood to old age

Author

Deary, Ian J., Yang, Jian, Davies, Gail, Harris, Sarah E., Tenesa, Albert, Liewald, David, Luciano, Michelle, Lopez, Lorna M., Gow, Alan J., Corley, Janie, Redmond, Paul, Fox, Helen C., Rowe, Suzanne J., Haggarty, Paul, McNeill, Geraldine, Goddard, Michael E., Porteous, David J., Whalley, Lawrence J., Starr, John M., and Visscher, Peter M.

Subjects
Genetic aspects, Research, Intelligence (Psychology) -- Genetic aspects -- Research, Aging (Biology) -- Research -- Genetic aspects, Single nucleotide polymorphisms -- Research -- Genetic aspects, Intellect -- Genetic aspects -- Research, Intelligence levels -- Genetic aspects -- Research, Aging -- Research -- Genetic aspects
Abstract

General cognitive ability (also known as general intelligence, or g (18)) is an important human trait. It shows consistent and strong associations with important life outcomes such as educational and [...], Understanding the determinants of healthy mental ageing is a priority for society today (1,2). So far, we know that intelligence differences show high stability from childhood to old age (3,4) and there are estimates of the genetic contribution to intelligence at different ages (5,6). However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative (7-10). Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years) (11,12). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals (13-17). We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change.

Published
2012
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164. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Author

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

Subjects
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.

Published
2019
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166. Genes From a Translational Analysis Support a Multifactorial Nature of White Matter Hyperintensities

Author

Lopez, Lorna M., Hill, W. David, Harris, Sarah E., Valdes Hernandez, Maria, Munoz Maniega, Susana, Bastin, Mark E., Bailey, Emma, Smith, Colin, McBride, Martin, McClure, John, Graham, Delyth, Dominiczak, Anna, Yang, Qiong, Fornage, Myriam, Ikram, M. Arfan, Debette, Stephanie, Launer, Lenore, Bis, Joshua C., Schmidt, Reinhold, Seshadri, Sudha, Porteous, David J., Starr, John, Deary, Ian J., and Wardlaw, Joanna M.

Published
2015
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170. Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time

Author

Houlihan, Lorna M., Davies, Gail, Tenesa, Albert, Harris, Sarah E., Luciano, Michelle, Gow, Alan J., McGhee, Kevin A., Liewald, David C., Porteous, David J., Starr, John M., Lowe, Gordon D., Visscher, Peter M., and Deary, Ian J.

Subjects
Scots -- Genetic aspects, Scots -- Health aspects, Single nucleotide polymorphisms -- Research, Thromboplastin -- Research, Thromboplastin -- Health aspects, Blood clot -- Genetic aspects, Thrombosis -- Genetic aspects, Biological sciences
Abstract

A genome-wide association study (GWAS) study was conducted for activated partial thromboplastin time (aPTT) to gain insight into the association of aPTT with risk of thrombosis and coagulation disorders. The study identified significant associations with SNPs in three coagulation cascade genes, namely F12, KnG1, and HRG which explain phenotypic variance in aPTT in the Lothian Birth cohorts.

Published
2010

171. No Association Between Cholinergic Muscarinic Receptor 2 (CHRM2) Genetic Variation and Cognitive Abilities in Three Independent Samples

Author

Lind, Penelope A., Luciano, Michelle, Horan, Michael A., Marioni, Riccardo E., Wright, Margaret J., Bates, Timothy C., Rabbitt, Patrick, Harris, Sarah E., Davidson, Yvonne, Deary, Ian J., Gibbons, Linda, Pickles, Andrew, Ollier, William, Pendleton, Neil, Price, Jackie F., Payton, Antony, and Martin, Nicholas G.

Published
2009
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172. A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

Author

Bochdanovits, Zoltán, Gosso, Florencia M., van den Berg, Linda, Rizzu, Patrizia, Polderman, Tinca J. C., Pardo, Luba M., Houlihan, Lorna M., Luciano, Michelle, Starr, John M., Harris, Sarah E., Deary, Ian J., de Geus, Eco J. C., Boomsma, Dorret I., Heutink, Peter, and Posthuma, Danielle

Published
2009
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174. Predictors of longitudinal cognitive ageing from age 70 to 82 including APOEe4 status, early-life and lifestyle factors: the Lothian Birth Cohort 1936

Author

Corley, Janie, Conte, Federica, Harris, Sarah E., Taylor, Adele M., Redmond, Paul, Russ, Tom C., Deary, Ian J., and Cox, Simon R.

Abstract

Discovering why some people’s cognitive abilities decline more than others is a key challenge for cognitive ageing research. The most effective strategy may be to address multiple risk factors from across the life-course simultaneously in relation to robust longitudinal cognitive data. We conducted a 12-year follow-up of 1091 (at age 70) men and women from the longitudinal Lothian Birth Cohort 1936 study. Comprehensive repeated cognitive measures of visuospatial ability, processing speed, memory, verbal ability, and a general cognitive factor were collected over five assessments (age 70, 73, 76, 79, and 82 years) and analysed using multivariate latent growth curve modelling. Fifteen life-course variables were used to predict variation in cognitive ability levels at age 70 and cognitive slopes from age 70 to 82. Only APOEe4 carrier status was found to be reliably informative of general- and domain-specific cognitive decline, despite there being many life-course correlates of cognitive level at age 70. APOEe4 carriers had significantly steeper slopes across all three fluid cognitive domains compared with non-carriers, especially for memory (β= −0.234, p< 0.001) and general cognitive function (β= −0.246, p< 0.001), denoting a widening gap in cognitive functioning with increasing age. Our findings suggest that when many other candidate predictors of cognitive ageing slope are entered en masse, their unique contributions account for relatively small proportions of variance, beyond variation in APOEe4 status. We conclude that APOEe4 status is important for identifying those at greater risk for accelerated cognitive ageing, even among ostensibly healthy individuals.

Published
2023
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175. Additional file 6 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 6. Review history.

Published
2021
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176. Additional file 1 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 1. Individual cohort descriptions and acknowledgements.

Published
2021
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177. Additional file 5 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 5. Colocalization plots.

Published
2021
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178. Additional file 4 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 4. Assessment of genomic inflation and heterogeneity.

Published
2021
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179. Additional file 3 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 3. Supplementary Figures - Figures S1-S31.

Published
2021
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180. Local CpG density affects the trajectory of age-associated epigenetic changes

Author

Higham, Jonathan, primary, Zhang, Qian, additional, Walker, Rosie M., additional, Harris, Sarah E., additional, Howard, David M., additional, Hawkins, Emma L., additional, Sandu, Anca-Larisa, additional, Steele, J. Douglas, additional, Waiter, Gordon D., additional, Murray, Alison D., additional, Evans, Kathryn L., additional, McIntosh, Andrew M., additional, Visscher, Peter M., additional, Deary, Ian J., additional, Cox, Simon R., additional, and Sproul, Duncan, additional

Published
2021
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182. DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses.

Author

Shen, Xueyi, Caramaschi, Doretta, Adams, Mark J., Walker, Rosie M., Min, Josine L., Kwong, Alex, Hemani, Gibran, Barbu, Miruna C., Whalley, Heather C., Harris, Sarah E., Deary, Ian J., Morris, Stewart W., Cox, Simon R., Relton, Caroline L., Marioni, Riccardo E., Evans, Kathryn L., and McIntosh, Andrew M.

Subjects
ANTIGEN processing, HLA histocompatibility antigens, IMMUNE response, DISEASE risk factors, MONOGENIC & polygenic inheritance (Genetics)
Abstract

Background: Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods: We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm. Results: Widespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10−8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10−30; depression to DNAm: pFDR ranged from 0.028 to 0.003). Conclusions: PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression. [ABSTRACT FROM AUTHOR]

Published
2022
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184. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author

Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L., Brazel, David M., Chambers, John C., Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P., de Boer, Rudolf A., de Leeuw, Christiaan A., Dennis, Joe G., Dominiczak, Anna F., Dunning, Alison M., Easton, Douglas F., Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D., Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J., Haessler, Jeff, Haiman, Christopher, Hallmans, G. ran, Hammerschlag, Anke R., Harris, Sarah E., Hattersley, Andrew, Heath, Andrew, Posthuma, Danielle, van der Harst, Pim, Abecasis, Goncalo R., Danesh, John, Tobin, Martin D., Vrieze, Scott, Liu, Dajiang J., Howson, Joanna M. M., Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Abstract

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 −8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10 −8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10 −3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Published
2020
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185. Estimating the effect-size of gene dosage on cognitive ability across the coding genome

Author

Huguet, Guillaume, Schramm, Catherine, Douard, Elise, Petra, Tamer, Main, Antoine, Monin, Pauline, England, Jade, Jizi, Khadije, Renne, Thomas, Poirier, Myriam, Nowak, Sabrina, Martin, Charles-Olivier, Younis, Nadine, Knoth, Inga Sophia, Jean-Louis, Martineau, Saci, Zohra, Auger, Maude, Tihy, Frédérique, Mathonnet, Géraldine, Maftei, Catalina, Léveillé, France, Porteous, David, Davies, Gail, Redmond, Paul, Harris, Sarah E., Hill, W. David, Lemyre, Emmanuelle, Schumann, Gunter, Bourgeron, Thomas, Pausova, Zdenka, Paus, Tomas, Karama, Sherif, Lippe, Sarah, Deary, Ian J., Almasy, Laura, Labbe, Aurélie, Glahn, David, Greenwood, Celia M.T., and Jacquemont, Sébastien

Subjects
endocrine system diseases, mental disorders
Abstract

Rare genomic Copy Number Variants (CNVs) are major contributors to neurodevelopmental disorder. The vast majority of pathogenic CNVs reported back to patients are ultra-rare and their quantitative effects on traits such as intelligence are undocumented. Here, we identified all CNVs ≥ 50 kilobase in 24,092 individuals from unselected and autism cohorts. We developed statistical models to estimate the effect-size of CNVs on intelligence based on their coding and non-coding characteristics. Measures of intolerance to haploinsufficiency best explained the effect of any deletion or duplication on general intelligence. There was no heterogeneity across unselected and autism cohorts. Validation was performed using an intraclass concordance and showed that model estimates of general intelligence were 78% accurate with mean effect-sizes previously published for 47 CNVs. Inheritance data on 27,766 CNVs showed that deletions and duplications with the same large effect-size on intelligence occur de novo at the same frequency. Our first outline for the effect sizes of all coding genes on intelligence suggests that around 10,000 genes affect this trait.

Published
2020
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186. Early developmental EEG and seizure phenotypes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome

Author

Born, Heather A, Born, Heather A, Martinez, Luis A, Levine, Amber T, Harris, Sarah E, Mehra, Shubhangi, Lee, Wai Ling, Dindot, Scott V, Nash, Kevin R, Silverman, Jill L, Segal, David J, Weeber, Edwin J, Anderson, Anne E, Born, Heather A, Born, Heather A, Martinez, Luis A, Levine, Amber T, Harris, Sarah E, Mehra, Shubhangi, Lee, Wai Ling, Dindot, Scott V, Nash, Kevin R, Silverman, Jill L, Segal, David J, Weeber, Edwin J, and Anderson, Anne E

Published
2021

187. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Author

McCartney, Daniel L, McCartney, Daniel L, Min, Josine L, Richmond, Rebecca C, Lu, Ake T, Sobczyk, Maria K, Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R, Mishra, Pashupati P, Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M, Ratliff, Scott M, Richardson, Tom G, Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D, Walker, Rosie M, Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R, Gieger, Christian, Genetics of DNA Methylation Consortium, de Geus, Eco JC, Harris, Sarah E, Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon LR, Kresovich, Jacob K, Li, Shengxu, Lunetta, Kathryn L, Mangino, Massimo, Mason, Dan, McIntosh, Andrew M, Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Ollikainen, Miina, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Polidoro, Silvia, Porteous, David J, Raitakari, Olli, Rich, Stephen S, Sandler, Dale P, Sillanpää, Elina, Smith, Alicia K, Southey, Melissa C, Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G, Van Den Berg, David J, van Dongen, Jenny, Wilson, James G, Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T, Binder, Alexandra M, Boomsma, Dorret I, Chen, Wei, Christensen, Kaare, Conneely, Karen N, Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A, Lehtimäki, Terho, Lohoff, Falk W, Milani, Lili, Milne, Roger L, Probst-Hensch, Nicole, Reiner, Alex P, McCartney, Daniel L, McCartney, Daniel L, Min, Josine L, Richmond, Rebecca C, Lu, Ake T, Sobczyk, Maria K, Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R, Mishra, Pashupati P, Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M, Ratliff, Scott M, Richardson, Tom G, Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D, Walker, Rosie M, Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R, Gieger, Christian, Genetics of DNA Methylation Consortium, de Geus, Eco JC, Harris, Sarah E, Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon LR, Kresovich, Jacob K, Li, Shengxu, Lunetta, Kathryn L, Mangino, Massimo, Mason, Dan, McIntosh, Andrew M, Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Ollikainen, Miina, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Polidoro, Silvia, Porteous, David J, Raitakari, Olli, Rich, Stephen S, Sandler, Dale P, Sillanpää, Elina, Smith, Alicia K, Southey, Melissa C, Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G, Van Den Berg, David J, van Dongen, Jenny, Wilson, James G, Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T, Binder, Alexandra M, Boomsma, Dorret I, Chen, Wei, Christensen, Kaare, Conneely, Karen N, Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A, Lehtimäki, Terho, Lohoff, Falk W, Milani, Lili, Milne, Roger L, Probst-Hensch, Nicole, and Reiner, Alex P

Abstract

BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Published
2021

188. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Author

de Las Fuentes, Lisa, de Las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F, Schwander, Karen, Bentley, Amy R, Brown, Michael R, Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P, Horimoto, ARVR, Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K, Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V, Tajuddin, Salman M, Tayo, Bamidele O, Vojinovic, Dina, Warren, Helen R, Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E, He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-Ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B, Weiss, Stefan, Yanek, Lisa R, Amin, Najaf, Arking, Dan E, Arnett, Donna K, Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A, Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P, Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H Janaka, de Vries, Paul S, Eiriksdottir, Gudny, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Fox, Ervin F, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M Arfan, Irvin, Marguerite R, Kähönen, Mika, Kavousi, Maryam, de Las Fuentes, Lisa, de Las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F, Schwander, Karen, Bentley, Amy R, Brown, Michael R, Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P, Horimoto, ARVR, Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K, Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V, Tajuddin, Salman M, Tayo, Bamidele O, Vojinovic, Dina, Warren, Helen R, Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E, He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-Ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B, Weiss, Stefan, Yanek, Lisa R, Amin, Najaf, Arking, Dan E, Arnett, Donna K, Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A, Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P, Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H Janaka, de Vries, Paul S, Eiriksdottir, Gudny, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Fox, Ervin F, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M Arfan, Irvin, Marguerite R, Kähönen, Mika, and Kavousi, Maryam

Abstract

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Published
2021

189. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Author

Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., McRae, Allan F., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle study, Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., McRae, Allan F., the Alzheimer's Disease Neuroimaging Initiative, and the Australian Imaging Biomarkers and Lifestyle study

Abstract

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

Published
2021

190. Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Author

Tin, Adrienne, Schlosser, Pascal, Matias-Garcia, Pamela R., Thio, Chris H. L., Joehanes, Roby, Liu, Hongbo, Yu, Zhi, Weihs, Antoine, Hoppmann, Anselm, Grundner-Culemann, Franziska, Min, Josine L., Kuhns, Victoria L. Halperin, Adeyemo, Adebowale A., Agyemang, Charles, arnlov, Johan, Aziz, Nasir A., Baccarelli, Andrea, Bochud, Murielle, Brenner, Hermann, Bressler, Jan, Breteler, Monique M. B., Carmeli, Cristian, Chaker, Layal, Coresh, Josef, Corre, Tanguy, Correa, Adolfo, Cox, Simon R., Delgado, Graciela E., Eckardt, Kai-Uwe, Ekici, Arif B., Endlich, Karlhans, Floyd, James S., Fraszczyk, Eliza, Gao, Xu, Gao, Xin, Gelber, Allan C., Ghanbari, Mohsen, Ghasemi, Sahar, Gieger, Christian, Greenland, Philip, Grove, Megan L., Harris, Sarah E., Hemani, Gibran, Henneman, Peter, Herder, Christian, Horvath, Steve, Hou, Lifang, Hurme, Mikko A., Hwang, Shih-Jen, Kardia, Sharon L. R., Kasela, Silva, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Kronenberg, Florian, Kuehnel, Brigitte, Ladd-Acosta, Christine, Lehtimaki, Terho, Lind, Lars, Liu, Dan, Lloyd-Jones, Donald M., Lorkowski, Stefan, Lu, Ake T., Marioni, Riccardo E., Marz, Winfried, McCartney, Daniel L., Meeks, Karlijn A. C., Milani, Lili, Mishra, Pashupati P., Nauck, Matthias, Nowak, Christoph, Peters, Annette, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ratliff, Scott M., Reiner, Alex P., Schottker, Ben, Schwartz, Joel, Sedaghat, Sanaz, Smith, Jennifer A., Sotoodehnia, Nona, Stocker, Hannah R., Stringhini, Silvia, Sundström, Johan, Swenson, Brenton R., van Meurs, Joyce B. J., van Vliet-Ostaptchouk, Jana V., Venema, Andrea, Volker, Uwe, Winkelmann, Juliane, Wolffenbuttel, Bruce H. R., Zhao, Wei, Zheng, Yinan, Loh, Marie, Snieder, Harold, Waldenberger, Melanie, Levy, Daniel, Akilesh, Shreeram, Woodward, Owen M., Susztak, Katalin, Teumer, Alexander, Kottgen, Anna, Tin, Adrienne, Schlosser, Pascal, Matias-Garcia, Pamela R., Thio, Chris H. L., Joehanes, Roby, Liu, Hongbo, Yu, Zhi, Weihs, Antoine, Hoppmann, Anselm, Grundner-Culemann, Franziska, Min, Josine L., Kuhns, Victoria L. Halperin, Adeyemo, Adebowale A., Agyemang, Charles, arnlov, Johan, Aziz, Nasir A., Baccarelli, Andrea, Bochud, Murielle, Brenner, Hermann, Bressler, Jan, Breteler, Monique M. B., Carmeli, Cristian, Chaker, Layal, Coresh, Josef, Corre, Tanguy, Correa, Adolfo, Cox, Simon R., Delgado, Graciela E., Eckardt, Kai-Uwe, Ekici, Arif B., Endlich, Karlhans, Floyd, James S., Fraszczyk, Eliza, Gao, Xu, Gao, Xin, Gelber, Allan C., Ghanbari, Mohsen, Ghasemi, Sahar, Gieger, Christian, Greenland, Philip, Grove, Megan L., Harris, Sarah E., Hemani, Gibran, Henneman, Peter, Herder, Christian, Horvath, Steve, Hou, Lifang, Hurme, Mikko A., Hwang, Shih-Jen, Kardia, Sharon L. R., Kasela, Silva, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Kronenberg, Florian, Kuehnel, Brigitte, Ladd-Acosta, Christine, Lehtimaki, Terho, Lind, Lars, Liu, Dan, Lloyd-Jones, Donald M., Lorkowski, Stefan, Lu, Ake T., Marioni, Riccardo E., Marz, Winfried, McCartney, Daniel L., Meeks, Karlijn A. C., Milani, Lili, Mishra, Pashupati P., Nauck, Matthias, Nowak, Christoph, Peters, Annette, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ratliff, Scott M., Reiner, Alex P., Schottker, Ben, Schwartz, Joel, Sedaghat, Sanaz, Smith, Jennifer A., Sotoodehnia, Nona, Stocker, Hannah R., Stringhini, Silvia, Sundström, Johan, Swenson, Brenton R., van Meurs, Joyce B. J., van Vliet-Ostaptchouk, Jana V., Venema, Andrea, Volker, Uwe, Winkelmann, Juliane, Wolffenbuttel, Bruce H. R., Zhao, Wei, Zheng, Yinan, Loh, Marie, Snieder, Harold, Waldenberger, Melanie, Levy, Daniel, Akilesh, Shreeram, Woodward, Owen M., Susztak, Katalin, Teumer, Alexander, and Kottgen, Anna

Abstract

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits. Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

Published
2021
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191. Meta-analyses identify DNA methylation associated with kidney function and damage

Author

Schlosser, Pascal, Tin, Adrienne, Matias-Garcia, Pamela R., Thio, Chris H. L., Joehanes, Roby, Liu, Hongbo, Weihs, Antoine, Yu, Zhi, Hoppmann, Anselm, Grundner-Culemann, Franziska, Min, Josine L., Adeyemo, Adebowale A., Agyemang, Charles, Arnlov, Johan, Aziz, Nasir A., Baccarelli, Andrea, Bochud, Murielle, Brenner, Hermann, Breteler, Monique M. B., Carmeli, Cristian, Chaker, Layal, Chambers, John C., Cole, Shelley A., Coresh, Josef, Corre, Tanguy, Correa, Adolfo, Cox, Simon R., de Klein, Niek, Delgado, Graciela E., Domingo-Relloso, Arce, Eckardt, Kai-Uwe, Ekici, Arif B., Endlich, Karlhans, Evans, Kathryn L., Floyd, James S., Fornage, Myriam, Franke, Lude, Fraszczyk, Eliza, Gao, Xu, Gao, Xin, Ghanbari, Mohsen, Ghasemi, Sahar, Gieger, Christian, Greenland, Philip, Grove, Megan L., Harris, Sarah E., Hemani, Gibran, Henneman, Peter, Herder, Christian, Horvath, Steve, Hou, Lifang, Hurme, Mikko A., Hwang, Shih-Jen, Jarvelin, Marjo-Riitta, Kardia, Sharon L. R., Kasela, Silva, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Kramer, Holly, Kronenberg, Florian, Kuhnel, Brigitte, Lehtimaki, Terho, Lind, Lars, Liu, Dan, Liu, Yongmei, Lloyd-Jones, Donald M., Lohman, Kurt, Lorkowski, Stefan, Lu, Ake T., Marioni, Riccardo E., Marz, Winfried, McCartney, Daniel L., Meeks, Karlijn A. C., Milani, Lili, Mishra, Pashupati P., Nauck, Matthias, Navas-Acien, Ana, Nowak, Christoph, Peters, Annette, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ratliff, Scott M., Reiner, Alex P., Rosas, Sylvia E., Schottker, Ben, Schwartz, Joel, Sedaghat, Sanaz, Smith, Jennifer A., Sotoodehnia, Nona, Stocker, Hannah R., Stringhini, Silvia, Sundström, Johan, Swenson, Brenton R., Tellez-Plaza, Maria, van Meurs, Joyce B. J., van Vliet-Ostaptchouk, Jana V., Venema, Andrea, Verweij, Niek, Walker, Rosie M., Wielscher, Matthias, Winkelmann, Juliane, Wolffenbuttel, Bruce H. R., Zhao, Wei, Zheng, Yinan, Loh, Marie, Snieder, Harold, Levy, Daniel, Waldenberger, Melanie, Susztak, Katalin, Kottgen, Anna, Teumer, Alexander, Schlosser, Pascal, Tin, Adrienne, Matias-Garcia, Pamela R., Thio, Chris H. L., Joehanes, Roby, Liu, Hongbo, Weihs, Antoine, Yu, Zhi, Hoppmann, Anselm, Grundner-Culemann, Franziska, Min, Josine L., Adeyemo, Adebowale A., Agyemang, Charles, Arnlov, Johan, Aziz, Nasir A., Baccarelli, Andrea, Bochud, Murielle, Brenner, Hermann, Breteler, Monique M. B., Carmeli, Cristian, Chaker, Layal, Chambers, John C., Cole, Shelley A., Coresh, Josef, Corre, Tanguy, Correa, Adolfo, Cox, Simon R., de Klein, Niek, Delgado, Graciela E., Domingo-Relloso, Arce, Eckardt, Kai-Uwe, Ekici, Arif B., Endlich, Karlhans, Evans, Kathryn L., Floyd, James S., Fornage, Myriam, Franke, Lude, Fraszczyk, Eliza, Gao, Xu, Gao, Xin, Ghanbari, Mohsen, Ghasemi, Sahar, Gieger, Christian, Greenland, Philip, Grove, Megan L., Harris, Sarah E., Hemani, Gibran, Henneman, Peter, Herder, Christian, Horvath, Steve, Hou, Lifang, Hurme, Mikko A., Hwang, Shih-Jen, Jarvelin, Marjo-Riitta, Kardia, Sharon L. R., Kasela, Silva, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Kramer, Holly, Kronenberg, Florian, Kuhnel, Brigitte, Lehtimaki, Terho, Lind, Lars, Liu, Dan, Liu, Yongmei, Lloyd-Jones, Donald M., Lohman, Kurt, Lorkowski, Stefan, Lu, Ake T., Marioni, Riccardo E., Marz, Winfried, McCartney, Daniel L., Meeks, Karlijn A. C., Milani, Lili, Mishra, Pashupati P., Nauck, Matthias, Navas-Acien, Ana, Nowak, Christoph, Peters, Annette, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ratliff, Scott M., Reiner, Alex P., Rosas, Sylvia E., Schottker, Ben, Schwartz, Joel, Sedaghat, Sanaz, Smith, Jennifer A., Sotoodehnia, Nona, Stocker, Hannah R., Stringhini, Silvia, Sundström, Johan, Swenson, Brenton R., Tellez-Plaza, Maria, van Meurs, Joyce B. J., van Vliet-Ostaptchouk, Jana V., Venema, Andrea, Verweij, Niek, Walker, Rosie M., Wielscher, Matthias, Winkelmann, Juliane, Wolffenbuttel, Bruce H. R., Zhao, Wei, Zheng, Yinan, Loh, Marie, Snieder, Harold, Levy, Daniel, Waldenberger, Melanie, Susztak, Katalin, Kottgen, Anna, and Teumer, Alexander

Abstract

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs. Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Published
2021
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192. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author

Ahluwalia, Tarunveer S., Prins, Bram P., Abdollahi, Mohammadreza, Armstrong, Nicola J., Aslibekyan, Stella, Bain, Lisa, Jefferis, Barbara, Baumert, Jens, Beekman, Marian, Ben-Shlomo, Yoav, Bis, Joshua C., Mitchell, Braxton D., de Geus, Eco, Delgado, Graciela E., Marek, Diana, Eriksson, Joel, Kajantie, Eero, Kanoni, Stavroula, Kemp, John P., Lu, Chen, Marioni, Riccardo E., McLachlan, Stela, Milaneschi, Yuri, Nolte, Ilja M., Petrelis, Alexandros M., Porcu, Eleonora, Sabater-Lleal, Maria, Naderi, Elnaz, Seppala, Ilkka, Shah, Tina, Singhal, Gaurav, Standl, Marie, Teumer, Alexander, Thalamuthu, Anbupalam, Thiering, Elisabeth, Trompet, Stella, Ballantyne, Christie M., Benjamin, Emelia J., Casas, Juan P., Toben, Catherine, Dedoussis, George, Deelen, Joris, Durda, Peter, Engmann, Jorgen, Feitosa, Mary F., Grallert, Harald, Hammarstedt, Ann, Harris, Sarah E., Homuth, Georg, Hottenga, Jouke-Jan, Jalkanen, Sirpa, Jamshidi, Yalda, Jawahar, Magdalene C., Jess, Tine, Kivimaki, Mika, Kleber, Marcus E., Lahti, Jari, Liu, Yongmei, Marques-Vidal, Pedro, Mellstrom, Dan, Mooijaart, Simon P., Muller-Nurasyid, Martina, Penninx, Brenda, Revez, Joana A., Rossing, Peter, Raikkonen, Katri, Sattar, Naveed, Scharnagl, Hubert, Sennblad, Bengt, Silveira, Angela, St Pourcain, Beate, Timpson, Nicholas J., Trollor, Julian, van Dongen, Jenny, Van Heemst, Diana, Visvikis-Siest, Sophie, Vollenweider, Peter, Volker, Uwe, Waldenberger, Melanie, Willemsen, Gonneke, Zabaneh, Delilah, Morris, Richard W., Arnett, Donna K., Baune, Bernhard T., Boomsma, Dorret, I, Chang, Yen-Pei C., Deary, Ian J., Deloukas, Panos, Eriksson, Johan G., Evans, David M., Ferreira, Manuel A., Gaunt, Tom, Gudnason, Vilmundur, Hamsten, Anders, Heinrich, Joachim, Hingorani, Aroon, Humphries, Steve E., Jukema, J. Wouter, Koenig, Wolfgang, Kumari, Meena, Kutalik, Zoltan, Lawlor, Deborah A., Lehtimaki, Terho, Marz, Winfried, Mather, Karen A., Naitza, Silvia, Nauck, Matthias, Ohlsson, Claes, Price, Jackie F., Raitakari, Olli, Rice, Ken, Sachdev, Perminder S., Slagboom, Eline, Sorensen, Thorkild I. A., Spector, Tim, Stacey, David, Stathopoulou, Maria G., Tanaka, Toshiko, Wannamethee, S. Goya, Whincup, Peter, Rotter, Jerome, I, Dehghan, Abbas, Boerwinkle, Eric, Psaty, Bruce M., Snieder, Harold, Alizadeh, Behrooz Z., Ahluwalia, Tarunveer S., Prins, Bram P., Abdollahi, Mohammadreza, Armstrong, Nicola J., Aslibekyan, Stella, Bain, Lisa, Jefferis, Barbara, Baumert, Jens, Beekman, Marian, Ben-Shlomo, Yoav, Bis, Joshua C., Mitchell, Braxton D., de Geus, Eco, Delgado, Graciela E., Marek, Diana, Eriksson, Joel, Kajantie, Eero, Kanoni, Stavroula, Kemp, John P., Lu, Chen, Marioni, Riccardo E., McLachlan, Stela, Milaneschi, Yuri, Nolte, Ilja M., Petrelis, Alexandros M., Porcu, Eleonora, Sabater-Lleal, Maria, Naderi, Elnaz, Seppala, Ilkka, Shah, Tina, Singhal, Gaurav, Standl, Marie, Teumer, Alexander, Thalamuthu, Anbupalam, Thiering, Elisabeth, Trompet, Stella, Ballantyne, Christie M., Benjamin, Emelia J., Casas, Juan P., Toben, Catherine, Dedoussis, George, Deelen, Joris, Durda, Peter, Engmann, Jorgen, Feitosa, Mary F., Grallert, Harald, Hammarstedt, Ann, Harris, Sarah E., Homuth, Georg, Hottenga, Jouke-Jan, Jalkanen, Sirpa, Jamshidi, Yalda, Jawahar, Magdalene C., Jess, Tine, Kivimaki, Mika, Kleber, Marcus E., Lahti, Jari, Liu, Yongmei, Marques-Vidal, Pedro, Mellstrom, Dan, Mooijaart, Simon P., Muller-Nurasyid, Martina, Penninx, Brenda, Revez, Joana A., Rossing, Peter, Raikkonen, Katri, Sattar, Naveed, Scharnagl, Hubert, Sennblad, Bengt, Silveira, Angela, St Pourcain, Beate, Timpson, Nicholas J., Trollor, Julian, van Dongen, Jenny, Van Heemst, Diana, Visvikis-Siest, Sophie, Vollenweider, Peter, Volker, Uwe, Waldenberger, Melanie, Willemsen, Gonneke, Zabaneh, Delilah, Morris, Richard W., Arnett, Donna K., Baune, Bernhard T., Boomsma, Dorret, I, Chang, Yen-Pei C., Deary, Ian J., Deloukas, Panos, Eriksson, Johan G., Evans, David M., Ferreira, Manuel A., Gaunt, Tom, Gudnason, Vilmundur, Hamsten, Anders, Heinrich, Joachim, Hingorani, Aroon, Humphries, Steve E., Jukema, J. Wouter, Koenig, Wolfgang, Kumari, Meena, Kutalik, Zoltan, Lawlor, Deborah A., Lehtimaki, Terho, Marz, Winfried, Mather, Karen A., Naitza, Silvia, Nauck, Matthias, Ohlsson, Claes, Price, Jackie F., Raitakari, Olli, Rice, Ken, Sachdev, Perminder S., Slagboom, Eline, Sorensen, Thorkild I. A., Spector, Tim, Stacey, David, Stathopoulou, Maria G., Tanaka, Toshiko, Wannamethee, S. Goya, Whincup, Peter, Rotter, Jerome, I, Dehghan, Abbas, Boerwinkle, Eric, Psaty, Bruce M., Snieder, Harold, and Alizadeh, Behrooz Z.

Abstract

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Published
2021
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193. Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

Author

Sun, Daokun, Sun, Daokun, Richard, Melissa, Musani, Solomon K, Sung, Yun Ju, Winkler, Thomas W, Schwander, Karen, Chai, Jin Fang, Guo, Xiuqing, Kilpeläinen, Tuomas O, Vojinovic, Dina, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Brown, Michael R, Chitrala, Kumaraswamy, Hartwig, Fernando P, Horimoto, Andrea RVR, Liu, Yongmei, Manning, Alisa K, Noordam, Raymond, Smith, Albert V, Harris, Sarah E, Kühnel, Brigitte, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Rauramaa, Rainer, van der Most, Peter J, Wang, Rujia, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Arking, Dan E, Arnett, Donna K, Barac, Ana, Boerwinkle, Eric, Broeckel, Ulrich, Chakravarti, Aravinda, Chen, Yii-Der Ida, Cupples, L Adrienne, Davigulus, Martha L, de Las Fuentes, Lisa, de Mutsert, Renée, de Vries, Paul S, Delaney, Joseph AC, Roux, Ana V Diez, Dörr, Marcus, Faul, Jessica D, Fretts, Amanda M, Gallo, Linda C, Grabe, Hans Jörgen, Gu, C Charles, Harris, Tamara B, Hartman, Catharina CA, Heikkinen, Sami, Ikram, M Arfan, Isasi, Carmen, Johnson, W Craig, Jonas, Jost Bruno, Kaplan, Robert C, Komulainen, Pirjo, Krieger, Jose E, Levy, Daniel, Lifelines Cohort Study, Liu, Jianjun, Lohman, Kurt, Luik, Annemarie I, Martin, Lisa W, Meitinger, Thomas, Milaneschi, Yuri, O'Connell, Jeff R, Palmas, Walter R, Peters, Annette, Peyser, Patricia A, Pulkki-Råback, Laura, Raffel, Leslie J, Reiner, Alex P, Rice, Kenneth, Robinson, Jennifer G, Rosendaal, Frits R, Schmidt, Carsten Oliver, Schreiner, Pamela J, Schwettmann, Lars, Shikany, James M, Shu, Xiao-Ou, Sidney, Stephen, Sims, Mario, Smith, Jennifer A, Sotoodehnia, Nona, Strauch, Konstantin, Tai, E Shyong, Taylor, Kent, Uitterlinden, André G, van Duijn, Cornelia M, Waldenberger, Melanie, Wee, Hwee-Lin, Wei, Wen-Bin, Wilson, Gregory, Xuan, Deng, Yao, Jie, Sun, Daokun, Sun, Daokun, Richard, Melissa, Musani, Solomon K, Sung, Yun Ju, Winkler, Thomas W, Schwander, Karen, Chai, Jin Fang, Guo, Xiuqing, Kilpeläinen, Tuomas O, Vojinovic, Dina, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Brown, Michael R, Chitrala, Kumaraswamy, Hartwig, Fernando P, Horimoto, Andrea RVR, Liu, Yongmei, Manning, Alisa K, Noordam, Raymond, Smith, Albert V, Harris, Sarah E, Kühnel, Brigitte, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Rauramaa, Rainer, van der Most, Peter J, Wang, Rujia, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Arking, Dan E, Arnett, Donna K, Barac, Ana, Boerwinkle, Eric, Broeckel, Ulrich, Chakravarti, Aravinda, Chen, Yii-Der Ida, Cupples, L Adrienne, Davigulus, Martha L, de Las Fuentes, Lisa, de Mutsert, Renée, de Vries, Paul S, Delaney, Joseph AC, Roux, Ana V Diez, Dörr, Marcus, Faul, Jessica D, Fretts, Amanda M, Gallo, Linda C, Grabe, Hans Jörgen, Gu, C Charles, Harris, Tamara B, Hartman, Catharina CA, Heikkinen, Sami, Ikram, M Arfan, Isasi, Carmen, Johnson, W Craig, Jonas, Jost Bruno, Kaplan, Robert C, Komulainen, Pirjo, Krieger, Jose E, Levy, Daniel, Lifelines Cohort Study, Liu, Jianjun, Lohman, Kurt, Luik, Annemarie I, Martin, Lisa W, Meitinger, Thomas, Milaneschi, Yuri, O'Connell, Jeff R, Palmas, Walter R, Peters, Annette, Peyser, Patricia A, Pulkki-Råback, Laura, Raffel, Leslie J, Reiner, Alex P, Rice, Kenneth, Robinson, Jennifer G, Rosendaal, Frits R, Schmidt, Carsten Oliver, Schreiner, Pamela J, Schwettmann, Lars, Shikany, James M, Shu, Xiao-Ou, Sidney, Stephen, Sims, Mario, Smith, Jennifer A, Sotoodehnia, Nona, Strauch, Konstantin, Tai, E Shyong, Taylor, Kent, Uitterlinden, André G, van Duijn, Cornelia M, Waldenberger, Melanie, Wee, Hwee-Lin, Wei, Wen-Bin, Wilson, Gregory, Xuan, Deng, and Yao, Jie

Abstract

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

Published
2021

194. Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Author

Wang, Heming, Wang, Heming, Noordam, Raymond, Cade, Brian E, Schwander, Karen, Winkler, Thomas W, Lee, Jiwon, Sung, Yun Ju, Bentley, Amy R, Manning, Alisa K, Aschard, Hugues, Kilpeläinen, Tuomas O, Ilkov, Marjan, Brown, Michael R, Horimoto, Andrea R, Richard, Melissa, Bartz, Traci M, Vojinovic, Dina, Lim, Elise, Nierenberg, Jovia L, Liu, Yongmei, Chitrala, Kumaraswamynaidu, Rankinen, Tuomo, Musani, Solomon K, Franceschini, Nora, Rauramaa, Rainer, Alver, Maris, Zee, Phyllis C, Harris, Sarah E, van der Most, Peter J, Nolte, Ilja M, Munroe, Patricia B, Palmer, Nicholette D, Kühnel, Brigitte, Weiss, Stefan, Wen, Wanqing, Hall, Kelly A, Lyytikäinen, Leo-Pekka, O'Connell, Jeff, Eiriksdottir, Gudny, Launer, Lenore J, de Vries, Paul S, Arking, Dan E, Chen, Han, Boerwinkle, Eric, Krieger, Jose E, Schreiner, Pamela J, Sidney, Stephen, Shikany, James M, Rice, Kenneth, Chen, Yii-Der Ida, Gharib, Sina A, Bis, Joshua C, Luik, Annemarie I, Ikram, M Arfan, Uitterlinden, André G, Amin, Najaf, Xu, Hanfei, Levy, Daniel, He, Jiang, Lohman, Kurt K, Zonderman, Alan B, Rice, Treva K, Sims, Mario, Wilson, Gregory, Sofer, Tamar, Rich, Stephen S, Palmas, Walter, Yao, Jie, Guo, Xiuqing, Rotter, Jerome I, Biermasz, Nienke R, Mook-Kanamori, Dennis O, Martin, Lisa W, Barac, Ana, Wallace, Robert B, Gottlieb, Daniel J, Komulainen, Pirjo, Heikkinen, Sami, Mägi, Reedik, Milani, Lili, Metspalu, Andres, Starr, John M, Milaneschi, Yuri, Waken, RJ, Gao, Chuan, Waldenberger, Melanie, Peters, Annette, Strauch, Konstantin, Meitinger, Thomas, Roenneberg, Till, Völker, Uwe, Dörr, Marcus, Shu, Xiao-Ou, Mukherjee, Sutapa, Hillman, David R, Kähönen, Mika, Wagenknecht, Lynne E, Gieger, Christian, Grabe, Hans J, Zheng, Wei, Wang, Heming, Wang, Heming, Noordam, Raymond, Cade, Brian E, Schwander, Karen, Winkler, Thomas W, Lee, Jiwon, Sung, Yun Ju, Bentley, Amy R, Manning, Alisa K, Aschard, Hugues, Kilpeläinen, Tuomas O, Ilkov, Marjan, Brown, Michael R, Horimoto, Andrea R, Richard, Melissa, Bartz, Traci M, Vojinovic, Dina, Lim, Elise, Nierenberg, Jovia L, Liu, Yongmei, Chitrala, Kumaraswamynaidu, Rankinen, Tuomo, Musani, Solomon K, Franceschini, Nora, Rauramaa, Rainer, Alver, Maris, Zee, Phyllis C, Harris, Sarah E, van der Most, Peter J, Nolte, Ilja M, Munroe, Patricia B, Palmer, Nicholette D, Kühnel, Brigitte, Weiss, Stefan, Wen, Wanqing, Hall, Kelly A, Lyytikäinen, Leo-Pekka, O'Connell, Jeff, Eiriksdottir, Gudny, Launer, Lenore J, de Vries, Paul S, Arking, Dan E, Chen, Han, Boerwinkle, Eric, Krieger, Jose E, Schreiner, Pamela J, Sidney, Stephen, Shikany, James M, Rice, Kenneth, Chen, Yii-Der Ida, Gharib, Sina A, Bis, Joshua C, Luik, Annemarie I, Ikram, M Arfan, Uitterlinden, André G, Amin, Najaf, Xu, Hanfei, Levy, Daniel, He, Jiang, Lohman, Kurt K, Zonderman, Alan B, Rice, Treva K, Sims, Mario, Wilson, Gregory, Sofer, Tamar, Rich, Stephen S, Palmas, Walter, Yao, Jie, Guo, Xiuqing, Rotter, Jerome I, Biermasz, Nienke R, Mook-Kanamori, Dennis O, Martin, Lisa W, Barac, Ana, Wallace, Robert B, Gottlieb, Daniel J, Komulainen, Pirjo, Heikkinen, Sami, Mägi, Reedik, Milani, Lili, Metspalu, Andres, Starr, John M, Milaneschi, Yuri, Waken, RJ, Gao, Chuan, Waldenberger, Melanie, Peters, Annette, Strauch, Konstantin, Meitinger, Thomas, Roenneberg, Till, Völker, Uwe, Dörr, Marcus, Shu, Xiao-Ou, Mukherjee, Sutapa, Hillman, David R, Kähönen, Mika, Wagenknecht, Lynne E, Gieger, Christian, Grabe, Hans J, and Zheng, Wei

Abstract

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Published
2021

195. Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Author

Yang, Tianzhong, Jackson, Victoria E., Smith, Albert V., Chen, Han, Bartz, Traci M., Sitlani, Colleen M., Psaty, Bruce M., Gharib, Sina A., O’Connor, George T., Dupuis, Josée, Xu, Jiayi, Lohman, Kurt, Liu, Yongmei, Kritchevsky, Stephen B., Cassano, Patricia A., Flexeder, Claudia, Gieger, Christian, Karrasch, Stefan, Peters, Annette, Schulz, Holger, Harris, Sarah E., Starr, John M., Deary, Ian J., Manichaikul, Ani, Oelsner, Elizabeth C., Barr, R. G., Taylor, Kent D., Rich, Stephen S., Bonten, Tobias N., Mook-Kanamori, Dennis O., Noordam, Raymond, Li-Gao, Ruifang, Jarvelin, Marjo Riitta, Wielscher, Matthias, Terzikhan, Natalie, Lahousse, Lies, Brusselle, Guy, Weiss, Stefan, Ewert, Ralf, Gläser, Sven, Homuth, Georg, Shrine, Nick, Hall, Ian P., Tobin, Martin, London, Stephanie J., Wei, Peng, Morrison, Alanna C., Yang, Tianzhong, Jackson, Victoria E., Smith, Albert V., Chen, Han, Bartz, Traci M., Sitlani, Colleen M., Psaty, Bruce M., Gharib, Sina A., O’Connor, George T., Dupuis, Josée, Xu, Jiayi, Lohman, Kurt, Liu, Yongmei, Kritchevsky, Stephen B., Cassano, Patricia A., Flexeder, Claudia, Gieger, Christian, Karrasch, Stefan, Peters, Annette, Schulz, Holger, Harris, Sarah E., Starr, John M., Deary, Ian J., Manichaikul, Ani, Oelsner, Elizabeth C., Barr, R. G., Taylor, Kent D., Rich, Stephen S., Bonten, Tobias N., Mook-Kanamori, Dennis O., Noordam, Raymond, Li-Gao, Ruifang, Jarvelin, Marjo Riitta, Wielscher, Matthias, Terzikhan, Natalie, Lahousse, Lies, Brusselle, Guy, Weiss, Stefan, Ewert, Ralf, Gläser, Sven, Homuth, Georg, Shrine, Nick, Hall, Ian P., Tobin, Martin, London, Stephanie J., Wei, Peng, and Morrison, Alanna C.

Abstract

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Published
2021

197. Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Author

Robertson, Neil A., primary, Latorre-Crespo, Eric, additional, Terradas-Terradas, Maria, additional, Purcell, Alison C., additional, Livesey, Benjamin J, additional, Marsh, Joseph A., additional, Murphy, Lee, additional, Fawkes, Angie, additional, MacGillivray, Louise, additional, Copland, Mhairi, additional, Marioni, Riccardo E., additional, Harris, Sarah E., additional, Cox, Simon R., additional, Deary, Ian J., additional, Schumacher, Linus J., additional, Kirschner, Kristina, additional, and Chandra, Tamir, additional

Published
2021
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198. Blood-based epigenome-wide analyses of cognitive abilities

Author

McCartney, Daniel L., primary, Hillary, Robert F., additional, Conole, Eleanor L. S., additional, Banos, Daniel Trejo, additional, Gadd, Danni A., additional, Walker, Rosie M., additional, Nangle, Cliff, additional, Flaig, Robin, additional, Campbell, Archie, additional, Murray, Alison D. D., additional, Maniega, Susana Muñoz, additional, Valdés-Hernández, María del. C, additional, Harris, Mathew A., additional, Bastin, Mark E., additional, Wardlaw, Joanna M., additional, Harris, Sarah E., additional, Porteous, David J., additional, Tucker-Drob, Elliot M., additional, McIntosh, Andrew M., additional, Evans, Kathryn L., additional, Deary, Ian J., additional, Cox, Simon R., additional, Robinson, Matthew R., additional, and Marioni, Riccardo E., additional

Published
2021
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199. Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage

Author

Chung, Jaeyoon, primary, Hamilton, Graham, additional, Kim, Minsup, additional, Marini, Sandro, additional, Montgomery, Bailey, additional, Henry, Jonathan, additional, Cho, Art E., additional, Brown, Devin L., additional, Worrall, Bradford B., additional, Meschia, James F., additional, Silliman, Scott L., additional, Selim, Magdy, additional, Tirschwell, David L., additional, Kidwell, Chelsea S., additional, Kissela, Brett, additional, Greenberg, Steven M., additional, Viswanathan, Anand, additional, Goldstein, Joshua N., additional, Langefeld, Carl D., additional, Rannikmae, Kristiina, additional, Sudlow, Catherine L.M., additional, Samarasekera, Neshika, additional, Rodrigues, Mark, additional, Al-Shahi Salman, Rustam, additional, Prendergast, James G.D., additional, Harris, Sarah E., additional, Deary, Ian, additional, Woo, Daniel, additional, Rosand, Jonathan, additional, Van Agtmael, Tom, additional, and Anderson, Christopher D., additional

Published
2021
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200. Variants associated with HHIP expression have sex-differential effects on lung function

Author

Fawcett, Katherine A., primary, Obeidat, Ma'en, additional, Melbourne, Carl A., additional, Shrine, Nick, additional, Guyatt, Anna L., additional, John, Catherine, additional, Luan, Jian'an, additional, Richmond, Anne, additional, Moksnes, Marta R., additional, Granell, Raquel, additional, Weiss, Stefan, additional, Imboden, Medea, additional, May-Wilson, Sebastian, additional, Hysi, Pirro, additional, Boutin, Thibaud S., additional, Portas, Laura, additional, Flexeder, Claudia, additional, Harris, Sarah E., additional, Wang, Carol A., additional, Lyytikäinen, Leo-Pekka, additional, Palviainen, Teemu, additional, Foong, Rachel E., additional, Keidel, Dirk, additional, Minelli, Cosetta, additional, Langenberg, Claudia, additional, Bossé, Yohan, additional, Van den Berge, Maarten, additional, Sin, Don D., additional, Hao, Ke, additional, Campbell, Archie, additional, Porteous, David, additional, Padmanabhan, Sandosh, additional, Smith, Blair H., additional, Evans, David M., additional, Ring, Sue, additional, Langhammer, Arnulf, additional, Hveem, Kristian, additional, Willer, Cristen, additional, Ewert, Ralf, additional, Stubbe, Beate, additional, Pirastu, Nicola, additional, Klaric, Lucija, additional, Joshi, Peter K., additional, Patasova, Karina, additional, Massimo, Mangino, additional, Polasek, Ozren, additional, Starr, John M., additional, Karrasch, Stefan, additional, Strauch, Konstantin, additional, Meitinger, Thomas, additional, Rudan, Igor, additional, Rantanen, Taina, additional, Pietiläinen, Kirsi, additional, Kähönen, Mika, additional, Raitakari, Olli T., additional, Hall, Graham L., additional, Sly, Peter D., additional, Pennell, Craig E., additional, Kaprio, Jaakko, additional, Lehtimäki, Terho, additional, Vitart, Veronique, additional, Deary, Ian J., additional, Jarvis, Debbie, additional, Wilson, James F., additional, Spector, Tim, additional, Probst-Hensch, Nicole, additional, Wareham, Nicholas J., additional, Völzke, Henry, additional, Henderson, John, additional, Strachan, David P., additional, Brumpton, Ben M., additional, Hayward, Caroline, additional, Hall, Ian P., additional, Tobin, Martin D., additional, and Wain, Louise V., additional

Published
2021
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