3,188 results on '"Loos, Ruth"'
Search Results
202. Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes
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Yu, Mengyao, primary, Aguirre, Matthew, additional, Jia, Meiwen, additional, Gjoni, Ketrin, additional, Cordova-Palomera, Aldo, additional, Munger, Chad, additional, Amgalan, Dulguun, additional, Rosa Ma, X., additional, Pereira, Alexandre, additional, Tcheandjieu, Catherine, additional, Seidman, Christine, additional, Seidman, Jonathan, additional, Tristani-Firouzi, Martin, additional, Chung, Wendy, additional, Goldmuntz, Elizabeth, additional, Srivastava, Deepak, additional, Loos, Ruth J.F., additional, Chami, Nathalie, additional, Cordell, Heather, additional, Dreßen, Martina, additional, Mueller-Myhsok, Bertram, additional, Lahm, Harald, additional, Krane, Markus, additional, Pollard, Katherine S., additional, Engreitz, Jesse M., additional, Gagliano Taliun, Sarah A., additional, Gelb, Bruce D., additional, and Priest, James R., additional
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- 2023
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203. Supplementary Figures S1-S11 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing
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Beauchamp, Ellen M., primary, Leventhal, Matthew, primary, Bernard, Elsa, primary, Hoppe, Emma R., primary, Todisco, Gabriele, primary, Creignou, Maria, primary, Gallì, Anna, primary, Castellano, Cecilia A., primary, McConkey, Marie, primary, Tarun, Akansha, primary, Wong, Waihay, primary, Schenone, Monica, primary, Stanclift, Caroline, primary, Tanenbaum, Benjamin, primary, Malolepsza, Edyta, primary, Nilsson, Björn, primary, Bick, Alexander G., primary, Weinstock, Joshua S., primary, Miller, Mendy, primary, Niroula, Abhishek, primary, Dunford, Andrew, primary, Taylor-Weiner, Amaro, primary, Wood, Timothy, primary, Barbera, Alex, primary, Anand, Shankara, primary, Psaty, Bruce M., primary, Desai, Pinkal, primary, Cho, Michael H., primary, Johnson, Andrew D., primary, Loos, Ruth, primary, MacArthur, Daniel G., primary, Lek, Monkol, primary, Neuberg, Donna S., primary, Lage, Kasper, primary, Carr, Steven A., primary, Hellstrom-Lindberg, Eva, primary, Malcovati, Luca, primary, Papaemmanuil, Elli, primary, Stewart, Chip, primary, Getz, Gad, primary, Bradley, Robert K., primary, Jaiswal, Siddhartha, primary, and Ebert, Benjamin L., primary
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- 2023
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204. Data from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing
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Beauchamp, Ellen M., primary, Leventhal, Matthew, primary, Bernard, Elsa, primary, Hoppe, Emma R., primary, Todisco, Gabriele, primary, Creignou, Maria, primary, Gallì, Anna, primary, Castellano, Cecilia A., primary, McConkey, Marie, primary, Tarun, Akansha, primary, Wong, Waihay, primary, Schenone, Monica, primary, Stanclift, Caroline, primary, Tanenbaum, Benjamin, primary, Malolepsza, Edyta, primary, Nilsson, Björn, primary, Bick, Alexander G., primary, Weinstock, Joshua S., primary, Miller, Mendy, primary, Niroula, Abhishek, primary, Dunford, Andrew, primary, Taylor-Weiner, Amaro, primary, Wood, Timothy, primary, Barbera, Alex, primary, Anand, Shankara, primary, Psaty, Bruce M., primary, Desai, Pinkal, primary, Cho, Michael H., primary, Johnson, Andrew D., primary, Loos, Ruth, primary, MacArthur, Daniel G., primary, Lek, Monkol, primary, Neuberg, Donna S., primary, Lage, Kasper, primary, Carr, Steven A., primary, Hellstrom-Lindberg, Eva, primary, Malcovati, Luca, primary, Papaemmanuil, Elli, primary, Stewart, Chip, primary, Getz, Gad, primary, Bradley, Robert K., primary, Jaiswal, Siddhartha, primary, and Ebert, Benjamin L., primary
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- 2023
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205. Supplementary Tables S1-S19 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing
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Beauchamp, Ellen M., primary, Leventhal, Matthew, primary, Bernard, Elsa, primary, Hoppe, Emma R., primary, Todisco, Gabriele, primary, Creignou, Maria, primary, Gallì, Anna, primary, Castellano, Cecilia A., primary, McConkey, Marie, primary, Tarun, Akansha, primary, Wong, Waihay, primary, Schenone, Monica, primary, Stanclift, Caroline, primary, Tanenbaum, Benjamin, primary, Malolepsza, Edyta, primary, Nilsson, Björn, primary, Bick, Alexander G., primary, Weinstock, Joshua S., primary, Miller, Mendy, primary, Niroula, Abhishek, primary, Dunford, Andrew, primary, Taylor-Weiner, Amaro, primary, Wood, Timothy, primary, Barbera, Alex, primary, Anand, Shankara, primary, Psaty, Bruce M., primary, Desai, Pinkal, primary, Cho, Michael H., primary, Johnson, Andrew D., primary, Loos, Ruth, primary, MacArthur, Daniel G., primary, Lek, Monkol, primary, Neuberg, Donna S., primary, Lage, Kasper, primary, Carr, Steven A., primary, Hellstrom-Lindberg, Eva, primary, Malcovati, Luca, primary, Papaemmanuil, Elli, primary, Stewart, Chip, primary, Getz, Gad, primary, Bradley, Robert K., primary, Jaiswal, Siddhartha, primary, and Ebert, Benjamin L., primary
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- 2023
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206. Abstract 3507: Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing
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Jakubek, Yasminka A., primary, Zhou, Ying, additional, Stilp, Adrienne, additional, Bacon, Jason, additional, Wong, Justin, additional, Ozcan, Zuhal, additional, Arnett, Donna, additional, Barnes, Kathleen, additional, Bis, Josh, additional, Boerwinkle, Eric, additional, Carson, April, additional, Chasman, Daniel, additional, Cho, Michael, additional, Conomos, Matthew, additional, Cox, Nancy, additional, Doyle, Margaret, additional, Fornage, Myriam, additional, Guo, Xiuqing, additional, Kardia, Sharon, additional, Lewis, Joshua, additional, Loos, Ruth, additional, Ma, Xiaolong, additional, Machiela, Mitchell, additional, Mack, Taralynn, additional, Mathias, Rasika, additional, Mitchell, Braxton, additional, North, Kari, additional, Pankratz, Nathan, additional, Peyser, Patricia, additional, Preuss, Michael, additional, Psaty, Bruce, additional, Raffield, Laura, additional, Vasan, Ramachandran, additional, Redline, Susan, additional, Rich, Stephen, additional, Rotter, Jerome, additional, Silverman, Edwin, additional, Smith, Jennifer, additional, Taub, Margaret, additional, Yun, Jeong, additional, Li, Yun, additional, Desai, Pinkal, additional, Bick, Alexander, additional, Reiner, Alexander, additional, Scheet, Paul, additional, and Auer, Paul, additional
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- 2023
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207. The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits
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Costanzo, Maria C., primary, von Grotthuss, Marcin, additional, Massung, Jeffrey, additional, Jang, Dongkeun, additional, Caulkins, Lizz, additional, Koesterer, Ryan, additional, Gilbert, Clint, additional, Welch, Ryan P., additional, Kudtarkar, Parul, additional, Hoang, Quy, additional, Boughton, Andrew P., additional, Singh, Preeti, additional, Sun, Ying, additional, Duby, Marc, additional, Moriondo, Annie, additional, Nguyen, Trang, additional, Smadbeck, Patrick, additional, Alexander, Benjamin R., additional, Brandes, MacKenzie, additional, Carmichael, Mary, additional, Dornbos, Peter, additional, Green, Todd, additional, Huellas-Bruskiewicz, Kenneth C., additional, Ji, Yue, additional, Kluge, Alexandria, additional, McMahon, Aoife C., additional, Mercader, Josep M., additional, Ruebenacker, Oliver, additional, Sengupta, Sebanti, additional, Spalding, Dylan, additional, Taliun, Daniel, additional, Smith, Philip, additional, Thomas, Melissa K., additional, Akolkar, Beena, additional, Brosnan, M. Julia, additional, Cherkas, Andriy, additional, Chu, Audrey Y., additional, Fauman, Eric B., additional, Fox, Caroline S., additional, Kamphaus, Tania Nayak, additional, Miller, Melissa R., additional, Nguyen, Lynette, additional, Parsa, Afshin, additional, Reilly, Dermot F., additional, Ruetten, Hartmut, additional, Wholley, David, additional, Zaghloul, Norann A., additional, Abecasis, Gonçalo R., additional, Altshuler, David, additional, Keane, Thomas M., additional, McCarthy, Mark I., additional, Gaulton, Kyle J., additional, Florez, Jose C., additional, Boehnke, Michael, additional, Burtt, Noël P., additional, Flannick, Jason, additional, Abecasis, Gonçalo, additional, Allred, Nicholette D., additional, Below, Jennifer E., additional, Bergman, Richard, additional, Beulens, Joline W.J., additional, Blangero, John, additional, Bokvist, Krister, additional, Bottinger, Erwin, additional, Bowden, Donald, additional, Brown, Christopher, additional, Bruskiewicz, Kenneth, additional, Cebola, Inês, additional, Chambers, John, additional, Ida Chen, Yii-Der, additional, Clark, Christopher, additional, Claussnitzer, Melina, additional, Costanzo, Maria C., additional, Cox, Nancy J., additional, Hoed, Marcel den, additional, Dong, Duc, additional, Duggirala, Ravindranath, additional, Dupuis, Josée, additional, Elders, Petra J.M., additional, Engreitz, Jesse M., additional, Fauman, Eric, additional, Ferrer, Jorge, additional, Flicek, Paul, additional, Flickinger, Matthew, additional, Frayling, Timothy M., additional, Frazer, Kelly A., additional, Gloyn, Anna L., additional, Hanis, Craig L., additional, Hanson, Robert, additional, Hattersley, Andrew T., additional, Im, Hae Kyung, additional, Iqbal, Sidra, additional, Jacobs, Suzanne B.R., additional, Jang, Dong-Keun, additional, Jordan, Tad, additional, Kamphaus, Tania, additional, Karpe, Fredrik, additional, Kim, Seung K., additional, Lage, Kasper, additional, Lange, Leslie A., additional, Lazar, Mitchell, additional, Lehman, Donna, additional, Liu, Ching-Ti, additional, Loos, Ruth J.F., additional, Ma, Ronald Ching-wan, additional, MacDonald, Patrick, additional, Maurano, Matthew T., additional, McVean, Gil, additional, Meigs, James B., additional, Mitchell, Braxton, additional, Mohlke, Karen L., additional, Morabito, Samuel, additional, Morgan, Claire, additional, Mullican, Shannon, additional, Narendra, Sharvari, additional, Ng, Maggie C.Y., additional, Palmer, Colin N.A., additional, Parker, Stephen C.J., additional, Parrado, Antonio, additional, Pawlyk, Aaron C., additional, Pearson, Ewan R., additional, Plump, Andrew, additional, Province, Michael, additional, Quertermous, Thomas, additional, Redline, Susan, additional, Ren, Bing, additional, Rich, Stephen S., additional, Richards, J. Brent, additional, Rotter, Jerome I., additional, Salem, Rany M., additional, Sander, Maike, additional, Sanders, Michael, additional, Sanghera, Dharambir, additional, Scott, Laura J., additional, Siedzik, David, additional, Sim, Xueling, additional, Sladek, Robert, additional, Small, Kerrin, additional, Stein, Peter, additional, Stringham, Heather M., additional, Susztak, Katalin, additional, ’t Hart, Leen M., additional, Taylor, Kent, additional, Todd, Jennifer A., additional, Udler, Miriam S., additional, Voight, Benjamin, additional, Wan, Andre, additional, and Yuksel, Kaan, additional
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- 2023
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208. Returning integrated genomic risk and clinical recommendations: The eMERGE study
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Linder, Jodell E., primary, Allworth, Aimee, additional, Bland, Sarah T., additional, Caraballo, Pedro J., additional, Chisholm, Rex L., additional, Clayton, Ellen Wright, additional, Crosslin, David R., additional, Dikilitas, Ozan, additional, DiVietro, Alanna, additional, Esplin, Edward D., additional, Forman, Sophie, additional, Freimuth, Robert R., additional, Gordon, Adam S., additional, Green, Richard, additional, Harden, Maegan V., additional, Holm, Ingrid A., additional, Jarvik, Gail P., additional, Karlson, Elizabeth W., additional, Labrecque, Sofia, additional, Lennon, Niall J., additional, Limdi, Nita A., additional, Mittendorf, Kathleen F., additional, Murphy, Shawn N., additional, Orlando, Lori, additional, Prows, Cynthia A., additional, Rasmussen, Luke V., additional, Rasmussen-Torvik, Laura, additional, Rowley, Robb, additional, Sawicki, Konrad Teodor, additional, Schmidlen, Tara, additional, Terek, Shannon, additional, Veenstra, David, additional, Velez Edwards, Digna R., additional, Absher, Devin, additional, Abul-Husn, Noura S., additional, Alsip, Jorge, additional, Bangash, Hana, additional, Beasley, Mark, additional, Below, Jennifer E., additional, Berner, Eta S., additional, Booth, James, additional, Chung, Wendy K., additional, Cimino, James J., additional, Connolly, John, additional, Davis, Patrick, additional, Devine, Beth, additional, Fullerton, Stephanie M., additional, Guiducci, Candace, additional, Habrat, Melissa L., additional, Hain, Heather, additional, Hakonarson, Hakon, additional, Harr, Margaret, additional, Haverfield, Eden, additional, Hernandez, Valentina, additional, Hoell, Christin, additional, Horike-Pyne, Martha, additional, Hripcsak, George, additional, Irvin, Marguerite R., additional, Kachulis, Christopher, additional, Karavite, Dean, additional, Kenny, Eimear E., additional, Khan, Atlas, additional, Kiryluk, Krzysztof, additional, Korf, Bruce, additional, Kottyan, Leah, additional, Kullo, Iftikhar J., additional, Larkin, Katie, additional, Liu, Cong, additional, Malolepsza, Edyta, additional, Manolio, Teri A., additional, May, Thomas, additional, McNally, Elizabeth M., additional, Mentch, Frank, additional, Miller, Alexandra, additional, Mooney, Sean D., additional, Murali, Priyanka, additional, Mutai, Brenda, additional, Muthu, Naveen, additional, Namjou, Bahram, additional, Perez, Emma F., additional, Puckelwartz, Megan J., additional, Rakhra-Burris, Tejinder, additional, Roden, Dan M., additional, Rosenthal, Elisabeth A., additional, Saadatagah, Seyedmohammad, additional, Sabatello, Maya, additional, Schaid, Dan J., additional, Schultz, Baergen, additional, Seabolt, Lynn, additional, Shaibi, Gabriel Q., additional, Sharp, Richard R., additional, Shirts, Brian, additional, Smith, Maureen E., additional, Smoller, Jordan W., additional, Sterling, Rene, additional, Suckiel, Sabrina A., additional, Thayer, Jeritt, additional, Tiwari, Hemant K., additional, Trinidad, Susan B., additional, Walunas, Theresa, additional, Wei, Wei-Qi, additional, Wells, Quinn S., additional, Weng, Chunhua, additional, Wiesner, Georgia L., additional, Wiley, Ken, additional, Peterson, Josh F., additional, Gordon, Adam, additional, Sobowale, Agboade, additional, Patel, Akshar, additional, Strong, Alanna, additional, Sherafati, Alborz, additional, Sherfati, Alborz, additional, Bick, Alex, additional, Chandel, Alka, additional, Rosenthal, Alyssa, additional, Khera, Amit, additional, Kontorovich, Amy, additional, Beck, Andrew, additional, Beck, Andy, additional, Espinoza, Angelica, additional, Lewis, Anna, additional, Prince, Anya, additional, Iverson, Ayuko, additional, Khales, Bahram Namjou, additional, Benoit, Barbara, additional, Hernan, Becca, additional, Kallman, Ben, additional, Kerman, Ben, additional, Shoemaker, Ben, additional, Satterfield, Benjamin, additional, Etheridge, Bethany, additional, Goff, Blake, additional, Freimuth, Bob, additional, Grundmeier, Bob, additional, Collier, Brenae, additional, Harnett, Brett, additional, Chang, Brian, additional, Piening, Brian, additional, Davis, Brittney, additional, Patterson, Candace, additional, Demetriou, Carmen, additional, Ta, Casey, additional, Hammack, Catherine, additional, Nelson, Catrina, additional, Gascoigne, Caytie, additional, Dorn, Chad, additional, Moretz, Chad, additional, Kachulis, Chris, additional, Hoell, Christie, additional, Cowles, Christine, additional, Lange, Christoph, additional, Prows, Cindy, additional, Brokamp, Cole, additional, Scherr, Courtney, additional, Gonzalez, Crystal, additional, Ramirez, Cynthia, additional, Shimbo, Daichi, additional, Roden, Dan, additional, Schaid, Daniel, additional, Kaufman, Dave, additional, Crosslin, David, additional, Kochan, David, additional, Singh, Davinder, additional, Abrams, Debbie, additional, Edwards, Digna Velez, additional, Morales, Eduardo, additional, Esplin, Edward, additional, Alipour, Ehsan, additional, Kenny, Eimear, additional, Rosenthal, Elisabeth, additional, Duvall, Eliza, additional, McNally, Elizabeth, additional, Bhoj, Elizabeth, additional, Cohn, Elizabeth, additional, Hibler, Elizabeth, additional, Karlson, Elizabeth, additional, Clayton, Ellen, additional, Chesnut, Emily, additional, DeFranco, Emily, additional, Gallagher, Emily, additional, Soper, Emily, additional, Perez, Emma, additional, Cash, Erin, additional, Berner, Eta, additional, Wang, Fei, additional, Wehbe, Firas, additional, Ricci, Francisco, additional, Shaibi, Gabriel, additional, Jarvik, Gail, additional, Hahn, George, additional, Wiesner, Georgia, additional, Belbin, Gillian, additional, Davogustto, Gio, additional, Nadkarni, Girish, additional, Qiu, Haijun, additional, Beasley, Hannah, additional, Liu, Hao, additional, Aungst, Heide, additional, Tiwari, Hemant, additional, Duckham, Hillary, additional, Thomas, Hope, additional, Kullo, Iftikhar, additional, Holm, Ingrid, additional, Allen, Isabelle, additional, Ionita-Laza, Iuliana, additional, Hellwege, Jacklyn, additional, Petrzelka, Jacob, additional, Odgis, Jacqueline, additional, Narula, Jahnavi, additional, Petrzelka, Jake, additional, Patel, Jalpa, additional, Cimino, James, additional, Meigs, James, additional, Snyder, James, additional, Olson, Janet, additional, Zahner, Janet, additional, Pennington, Jeff, additional, Pacheco, Jen, additional, Pacheco, Jennifer Allen, additional, Morse, Jennifer, additional, Corsmo, Jeremy, additional, Cimino, Jim, additional, Chen, Jingheng, additional, Fournier, Jocelyn, additional, Jackson, Jodell, additional, Glessner, Joe, additional, Pacyna, Joel, additional, Smith, Johanna, additional, Lynch, John, additional, Shelley, John, additional, Mosley, Jonathan, additional, Nestor, Jordan, additional, Smoller, Jordan, additional, Kannry, Joseph, additional, Sutton, Joseph, additional, Peterson, Josh, additional, Smith, Joshua, additional, Galasso, Julia, additional, Smith, Julia, additional, Wynn, Julia, additional, Gundelach, Justin, additional, Starren, Justin, additional, Choi, Karmel, additional, Mittendorf, Kate, additional, Anderson, Katherine, additional, Bonini, Katherine, additional, Leppig, Kathleen, additional, Muenzen, Kathleen, additional, Stuttgen, Kelsey, additional, Nguyen, Kenny, additional, Dufendach, Kevin, additional, Atkins, Kiley, additional, Sawicki, Konrad, additional, Norland, Kristjan, additional, Beskow, Laura, additional, Hsu, Li, additional, Tian, Lifeng, additional, Mahanta, Lisa, additional, Martin, Lisa, additional, Wang, Lisa, additional, Gomez, Lizbeth, additional, Thompson, Lorenzo, additional, Richter, Lucas, additional, Rasmussen, Luke, additional, Petukhova, Lynn, additional, O’Brien, Madison, additional, Harden, Maegan, additional, Fullerton, Malia, additional, Guindo, Marta, additional, Horike, Martha, additional, Abdalla, Marwah, additional, Hamed, Marwan, additional, Terry, Mary Beth, additional, Maradik, Mary, additional, Wyatt, Matt, additional, Davis, Matthew, additional, Lebo, Matthew, additional, Smith, Maureen, additional, Rosario, Maya del, additional, Behr, Meckenzie, additional, Roy-Puckelwartz, Meg, additional, Habrat, Mel, additional, Myers, Melanie, additional, Yetisgen, Meliha, additional, Iris, Merve, additional, DaSilva, Michael, additional, Preuss, Michael, additional, McGowan, Michelle, additional, Shi, Mingjian, additional, Perera, Minoli, additional, Thomas, Minta, additional, Elkind, Mitch, additional, Abbass, Mohammad, additional, Saadatagah, Mohammad, additional, Hess, Molly, additional, Maradik, Molly, additional, Vaitinadin, Nataraja “RJ”, additional, Vaitinadin, Nataraja, additional, Netherly, Neil, additional, Lennon, Niall, additional, Shang, Ning, additional, Limdi, Nita, additional, Forrest, Noah, additional, Romero, Noheli, additional, Robinson, Nora, additional, Abul-Husn, Noura, additional, Elsekaily, Omar, additional, Kovatch, Patricia, additional, Appelbaum, Paul, additional, Francaviglia, Paul, additional, O’Reilly, Paul, additional, Chandler, Paulette, additional, Caraballo, Pedro, additional, Tarczy-Hornoch, Peter, additional, Shum, Pierre, additional, Marathe, Priya, additional, Feng, Qiping, additional, Wells, Quinn, additional, Atchley, Rachel, additional, Narla, Radhika, additional, Barton, Rene, additional, Chisholm, Rex, additional, Sharp, Richard, additional, Peters, Riki, additional, Kukafka, Rita, additional, Freimuth, Robert, additional, Green, Robert, additional, Winter, Robert, additional, Mueller, Roger, additional, Loos, Ruth, additional, Irvin, Ryan, additional, Suckiel, Sabrina, additional, Hussain, Sajjad, additional, Sharba, Samer, additional, Aronson, Sandy, additional, Jones, Sarah, additional, Knerr, Sarah, additional, Nigbur, Scott, additional, Weiss, Scott, additional, Mooney, Sean, additional, Aufox, Sharon, additional, Nirenberg, Sharon, additional, Murphy, Shawn, additional, O’Byrne, Sheila, additional, Wang (Sam) Choi, Shing, additional, Aguilar, Sienna, additional, Bland, S.T., additional, Rodrigues, Stefanie, additional, Ledbetter, Stephanie, additional, Rutledge, Stephanie, additional, Booth, Stuart James, additional, Xian, Su, additional, Trinidad, Susan Brown, additional, Bakken, Suzanne, additional, Manolio, Teri, additional, Mersha, Tesfaye, additional, Chandereng, Thevaa, additional, Ge, Tian, additional, Edwards, Todd, additional, Kaszemacher, Tom, additional, Willis, Valerie, additional, Desai, Vemi, additional, Desai, Vimi, additional, Lorenzi, Virginia, additional, Gainer, Vivian, additional, Chung, Wendy, additional, Su, Wu-Chen, additional, Chang, Xiao, additional, Zhao, Yiqing, additional, Luo, Yuan, additional, and Shen, Yufeng, additional
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- 2023
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209. Supplementary Table 6 from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk
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Vachon, Celine M., primary, Scott, Christopher G., primary, Fasching, Peter A., primary, Hall, Per, primary, Tamimi, Rulla M., primary, Li, Jingmei, primary, Stone, Jennifer, primary, Apicella, Carmel, primary, Odefrey, Fabrice, primary, Gierach, Gretchen L., primary, Jud, Sebastian M., primary, Heusinger, Katharina, primary, Beckmann, Matthias W., primary, Pollan, Marina, primary, Fernández-Navarro, Pablo, primary, Gonzalez-Neira, Anna, primary, Benitez, Javier, primary, van Gils, Carla H., primary, Lokate, Mariëtte, primary, Onland-Moret, N. Charlotte, primary, Peeters, Petra H.M., primary, Brown, Judith, primary, Leyland, Jean, primary, Varghese, Jajini S., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, Luben, Robert N., primary, Warren, Ruth M.L., primary, Wareham, Nicholas J., primary, Loos, Ruth J.F., primary, Khaw, Kay-Tee, primary, Ursin, Giske, primary, Lee, Eunjung, primary, Gayther, Simon A., primary, Ramus, Susan J., primary, Eeles, Rosalind A., primary, Leach, Martin O., primary, Kwan-Lim, Gek, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Baglietto, Laura, primary, Krishnan, Kavitha, primary, Southey, Melissa C., primary, Le Marchand, Loic, primary, Kolonel, Laurence N., primary, Woolcott, Christy, primary, Maskarinec, Gertraud, primary, Haiman, Christopher A., primary, Walker, Kate, primary, Johnson, Nichola, primary, McCormack, Valeria A., primary, Biong, Margarethe, primary, Alnaes, Grethe I.G., primary, Gram, Inger Torhild, primary, Kristensen, Vessela N., primary, Børresen-Dale, Anne-Lise, primary, Lindström, Sara, primary, Hankinson, Susan E., primary, Hunter, David J., primary, Andrulis, Irene L., primary, Knight, Julia A., primary, Boyd, Norman F., primary, Figuero, Jonine D., primary, Lissowska, Jolanta, primary, Wesolowska, Ewa, primary, Peplonska, Beata, primary, Bukowska, Agnieszka, primary, Reszka, Edyta, primary, Liu, JianJun, primary, Eriksson, Louise, primary, Czene, Kamila, primary, Audley, Tina, primary, Wu, Anna H., primary, Pankratz, V. Shane, primary, Hopper, John L., primary, and dos-Santos-Silva, Isabel, primary
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- 2023
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210. Supplementary Tables 1 - 4 from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk
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Vachon, Celine M., primary, Scott, Christopher G., primary, Fasching, Peter A., primary, Hall, Per, primary, Tamimi, Rulla M., primary, Li, Jingmei, primary, Stone, Jennifer, primary, Apicella, Carmel, primary, Odefrey, Fabrice, primary, Gierach, Gretchen L., primary, Jud, Sebastian M., primary, Heusinger, Katharina, primary, Beckmann, Matthias W., primary, Pollan, Marina, primary, Fernández-Navarro, Pablo, primary, Gonzalez-Neira, Anna, primary, Benitez, Javier, primary, van Gils, Carla H., primary, Lokate, Mariëtte, primary, Onland-Moret, N. Charlotte, primary, Peeters, Petra H.M., primary, Brown, Judith, primary, Leyland, Jean, primary, Varghese, Jajini S., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, Luben, Robert N., primary, Warren, Ruth M.L., primary, Wareham, Nicholas J., primary, Loos, Ruth J.F., primary, Khaw, Kay-Tee, primary, Ursin, Giske, primary, Lee, Eunjung, primary, Gayther, Simon A., primary, Ramus, Susan J., primary, Eeles, Rosalind A., primary, Leach, Martin O., primary, Kwan-Lim, Gek, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Baglietto, Laura, primary, Krishnan, Kavitha, primary, Southey, Melissa C., primary, Le Marchand, Loic, primary, Kolonel, Laurence N., primary, Woolcott, Christy, primary, Maskarinec, Gertraud, primary, Haiman, Christopher A., primary, Walker, Kate, primary, Johnson, Nichola, primary, McCormack, Valeria A., primary, Biong, Margarethe, primary, Alnaes, Grethe I.G., primary, Gram, Inger Torhild, primary, Kristensen, Vessela N., primary, Børresen-Dale, Anne-Lise, primary, Lindström, Sara, primary, Hankinson, Susan E., primary, Hunter, David J., primary, Andrulis, Irene L., primary, Knight, Julia A., primary, Boyd, Norman F., primary, Figuero, Jonine D., primary, Lissowska, Jolanta, primary, Wesolowska, Ewa, primary, Peplonska, Beata, primary, Bukowska, Agnieszka, primary, Reszka, Edyta, primary, Liu, JianJun, primary, Eriksson, Louise, primary, Czene, Kamila, primary, Audley, Tina, primary, Wu, Anna H., primary, Pankratz, V. Shane, primary, Hopper, John L., primary, and dos-Santos-Silva, Isabel, primary
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- 2023
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211. Supplementary Table 5 from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk
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Vachon, Celine M., primary, Scott, Christopher G., primary, Fasching, Peter A., primary, Hall, Per, primary, Tamimi, Rulla M., primary, Li, Jingmei, primary, Stone, Jennifer, primary, Apicella, Carmel, primary, Odefrey, Fabrice, primary, Gierach, Gretchen L., primary, Jud, Sebastian M., primary, Heusinger, Katharina, primary, Beckmann, Matthias W., primary, Pollan, Marina, primary, Fernández-Navarro, Pablo, primary, Gonzalez-Neira, Anna, primary, Benitez, Javier, primary, van Gils, Carla H., primary, Lokate, Mariëtte, primary, Onland-Moret, N. Charlotte, primary, Peeters, Petra H.M., primary, Brown, Judith, primary, Leyland, Jean, primary, Varghese, Jajini S., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, Luben, Robert N., primary, Warren, Ruth M.L., primary, Wareham, Nicholas J., primary, Loos, Ruth J.F., primary, Khaw, Kay-Tee, primary, Ursin, Giske, primary, Lee, Eunjung, primary, Gayther, Simon A., primary, Ramus, Susan J., primary, Eeles, Rosalind A., primary, Leach, Martin O., primary, Kwan-Lim, Gek, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Baglietto, Laura, primary, Krishnan, Kavitha, primary, Southey, Melissa C., primary, Le Marchand, Loic, primary, Kolonel, Laurence N., primary, Woolcott, Christy, primary, Maskarinec, Gertraud, primary, Haiman, Christopher A., primary, Walker, Kate, primary, Johnson, Nichola, primary, McCormack, Valeria A., primary, Biong, Margarethe, primary, Alnaes, Grethe I.G., primary, Gram, Inger Torhild, primary, Kristensen, Vessela N., primary, Børresen-Dale, Anne-Lise, primary, Lindström, Sara, primary, Hankinson, Susan E., primary, Hunter, David J., primary, Andrulis, Irene L., primary, Knight, Julia A., primary, Boyd, Norman F., primary, Figuero, Jonine D., primary, Lissowska, Jolanta, primary, Wesolowska, Ewa, primary, Peplonska, Beata, primary, Bukowska, Agnieszka, primary, Reszka, Edyta, primary, Liu, JianJun, primary, Eriksson, Louise, primary, Czene, Kamila, primary, Audley, Tina, primary, Wu, Anna H., primary, Pankratz, V. Shane, primary, Hopper, John L., primary, and dos-Santos-Silva, Isabel, primary
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- 2023
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212. Data from Mammographic Breast Density and Breast Cancer: Evidence of a Shared Genetic Basis
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Varghese, Jajini S., primary, Thompson, Deborah J., primary, Michailidou, Kyriaki, primary, Lindström, Sara, primary, Turnbull, Clare, primary, Brown, Judith, primary, Leyland, Jean, primary, Warren, Ruth M.L., primary, Luben, Robert N., primary, Loos, Ruth J., primary, Wareham, Nicholas J., primary, Rommens, Johanna, primary, Paterson, Andrew D., primary, Martin, Lisa J., primary, Vachon, Celine M., primary, Scott, Christopher G., primary, Atkinson, Elizabeth J., primary, Couch, Fergus J., primary, Apicella, Carmel, primary, Southey, Melissa C., primary, Stone, Jennifer, primary, Li, Jingmei, primary, Eriksson, Louise, primary, Czene, Kamila, primary, Boyd, Norman F., primary, Hall, Per, primary, Hopper, John L., primary, Tamimi, Rulla M., primary, Rahman, Nazneen, primary, and Easton, Douglas F., primary
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- 2023
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213. Supplementary Figure 1 from Mammographic Breast Density and Breast Cancer: Evidence of a Shared Genetic Basis
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Varghese, Jajini S., primary, Thompson, Deborah J., primary, Michailidou, Kyriaki, primary, Lindström, Sara, primary, Turnbull, Clare, primary, Brown, Judith, primary, Leyland, Jean, primary, Warren, Ruth M.L., primary, Luben, Robert N., primary, Loos, Ruth J., primary, Wareham, Nicholas J., primary, Rommens, Johanna, primary, Paterson, Andrew D., primary, Martin, Lisa J., primary, Vachon, Celine M., primary, Scott, Christopher G., primary, Atkinson, Elizabeth J., primary, Couch, Fergus J., primary, Apicella, Carmel, primary, Southey, Melissa C., primary, Stone, Jennifer, primary, Li, Jingmei, primary, Eriksson, Louise, primary, Czene, Kamila, primary, Boyd, Norman F., primary, Hall, Per, primary, Hopper, John L., primary, Tamimi, Rulla M., primary, Rahman, Nazneen, primary, and Easton, Douglas F., primary
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- 2023
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214. Assessing efficiency of fine-mapping obesity associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB Cohorts
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Anwar, Mohammad Yaser, primary, Graff, Mariaelisa, additional, Highland, Heather M., additional, Smit, Roelof, additional, Wang, Zhe, additional, Buchanan, Victoria L., additional, Young, Kristina L., additional, Kenny, Eimear E., additional, Fernandez-Rhodes, Lindsay, additional, Liu, Simin, additional, Assimes, Themistocles, additional, Garcia, David O., additional, Daeeun, Kim, additional, Gignoux, Christopher R., additional, Justice, Anne E., additional, Haiman, Christopher A., additional, Buyske, Steve, additional, Peters, Ulrike, additional, Loos, Ruth, additional, Kooperberg, Charles, additional, and North, Kari E., additional
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- 2023
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215. Precision medicine in complex diseases-Molecular subgrouping for improved prediction and treatment stratification.
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Johansson, Åsa, Andreassen, Ole A, Brunak, Søren, Franks, Paul W, Hedman, Harald, Loos, Ruth J F, Meder, Benjamin, Melén, Erik, Wheelock, Craig E, Jacobsson, Bo, Johansson, Åsa, Andreassen, Ole A, Brunak, Søren, Franks, Paul W, Hedman, Harald, Loos, Ruth J F, Meder, Benjamin, Melén, Erik, Wheelock, Craig E, and Jacobsson, Bo
- Abstract
Complex diseases are caused by a combination of genetic, lifestyle, and environmental factors and comprise common noncommunicable diseases, including allergies, cardiovascular disease, and psychiatric and metabolic disorders. More than 25% of Europeans suffer from a complex disease, and together these diseases account for 70% of all deaths. The use of genomic, molecular, or imaging data to develop accurate diagnostic tools for treatment recommendations and preventive strategies, and for disease prognosis and prediction, is an important step toward precision medicine. However, for complex diseases, precision medicine is associated with several challenges. There is a significant heterogeneity between patients of a specific disease-both with regards to symptoms and underlying causal mechanisms-and the number of underlying genetic and nongenetic risk factors is often high. Here, we summarize precision medicine approaches for complex diseases and highlight the current breakthroughs as well as the challenges. We conclude that genomic-based precision medicine has been used mainly for patients with highly penetrant monogenic disease forms, such as cardiomyopathies. However, for most complex diseases-including psychiatric disorders and allergies-available polygenic risk scores are more probabilistic than deterministic and have not yet been validated for clinical utility. However, subclassifying patients of a specific disease into discrete homogenous subtypes based on molecular or phenotypic data is a promising strategy for improving diagnosis, prediction, treatment, prevention, and prognosis. The availability of high-throughput molecular technologies, together with large collections of health data and novel data-driven approaches, offers promise toward improved individual health through precision medicine.
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- 2023
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216. Genetic insights into resting heart rate and its role in cardiovascular disease
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van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
- Abstract
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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- 2023
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217. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.
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Weinstock, Joshua S, Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O'Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Weinstock, Joshua S, Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O'Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, and NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Abstract
Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
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- 2023
218. GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
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Lagou, Vasiliki, Jiang, Longda, Ulrich, Anna, Zudina, Liudmila, Gonzalez, Karla Sofia Gutierrez, Balkhiyarova, Zhanna, Faggian, Alessia, Maina, Jared G., Chen, Shiqian, Todorov, Petar V., Sharapov, Sodbo, David, Alessia, Marullo, Letizia, Magi, Reedik, Rujan, Roxana-Maria, Ahlqvist, Emma, Thorleifsson, Gudmar, Gao, He, Evangelou, Evangelos, Benyamin, Beben, Scott, Robert A., Isaacs, Aaron, Zhao, Jing Hua, Willems, Sara M., Johnson, Toby, Gieger, Christian, Grallert, Harald, Meisinger, Christa, Mueller-Nurasyid, Martina, Strawbridge, Rona J., Goel, Anuj, Rybin, Denis, Albrecht, Eva, Jackson, Anne U., Stringham, Heather M., Correa, Ivan R., Jr., Farber-Eger, Eric, Steinthorsdottir, Valgerdur, Uitterlinden, Andre G., Munroe, Patricia B., Brown, Morris J., Schmidberger, Julian, Holmen, Oddgeir, Thorand, Barbara, Hveem, Kristian, Wilsgaard, Tom, Mohlke, Karen L., Wang, Zhe, Shmeliov, Aleksey, den Hoed, Marcel, Loos, Ruth J. F., Kratzer, Wolfgang, Haenle, Mark, Koenig, Wolfgang, Boehm, Bernhard O., Tan, Tricia M., Tomas, Alejandra, Salem, Victoria, Barroso, Ines, Tuomilehto, Jaakko, Boehnke, Michael, Florez, Jose C., Hamsten, Anders, Watkins, Hugh, Njolstad, Inger, Wichmann, H. -Erich, Caulfield, Mark J., Khaw, Kay-Tee, van Duijn, Cornelia M., Hofman, Albert, Wareham, Nicholas J., Langenberg, Claudia, Whitfield, John B., Martin, Nicholas G., Montgomery, Grant, Scapoli, Chiara, Tzoulaki, Ioanna, Elliott, Paul, Thorsteinsdottir, Unnur, Stefansson, Kari, Brittain, Evan L., McCarthy, Mark I., Froguel, Philippe, Sexton, Patrick M., Wootten, Denise, Groop, Leif, Dupuis, Josee, Meigs, James B., Deganutti, Giuseppe, Demirkan, Ayse, Pers, Tune H., Reynolds, Christopher A., Aulchenko, Yurii S., Kaakinen, Marika A., Jones, Ben, Prokopenko, Inga, Lagou, Vasiliki, Jiang, Longda, Ulrich, Anna, Zudina, Liudmila, Gonzalez, Karla Sofia Gutierrez, Balkhiyarova, Zhanna, Faggian, Alessia, Maina, Jared G., Chen, Shiqian, Todorov, Petar V., Sharapov, Sodbo, David, Alessia, Marullo, Letizia, Magi, Reedik, Rujan, Roxana-Maria, Ahlqvist, Emma, Thorleifsson, Gudmar, Gao, He, Evangelou, Evangelos, Benyamin, Beben, Scott, Robert A., Isaacs, Aaron, Zhao, Jing Hua, Willems, Sara M., Johnson, Toby, Gieger, Christian, Grallert, Harald, Meisinger, Christa, Mueller-Nurasyid, Martina, Strawbridge, Rona J., Goel, Anuj, Rybin, Denis, Albrecht, Eva, Jackson, Anne U., Stringham, Heather M., Correa, Ivan R., Jr., Farber-Eger, Eric, Steinthorsdottir, Valgerdur, Uitterlinden, Andre G., Munroe, Patricia B., Brown, Morris J., Schmidberger, Julian, Holmen, Oddgeir, Thorand, Barbara, Hveem, Kristian, Wilsgaard, Tom, Mohlke, Karen L., Wang, Zhe, Shmeliov, Aleksey, den Hoed, Marcel, Loos, Ruth J. F., Kratzer, Wolfgang, Haenle, Mark, Koenig, Wolfgang, Boehm, Bernhard O., Tan, Tricia M., Tomas, Alejandra, Salem, Victoria, Barroso, Ines, Tuomilehto, Jaakko, Boehnke, Michael, Florez, Jose C., Hamsten, Anders, Watkins, Hugh, Njolstad, Inger, Wichmann, H. -Erich, Caulfield, Mark J., Khaw, Kay-Tee, van Duijn, Cornelia M., Hofman, Albert, Wareham, Nicholas J., Langenberg, Claudia, Whitfield, John B., Martin, Nicholas G., Montgomery, Grant, Scapoli, Chiara, Tzoulaki, Ioanna, Elliott, Paul, Thorsteinsdottir, Unnur, Stefansson, Kari, Brittain, Evan L., McCarthy, Mark I., Froguel, Philippe, Sexton, Patrick M., Wootten, Denise, Groop, Leif, Dupuis, Josee, Meigs, James B., Deganutti, Giuseppe, Demirkan, Ayse, Pers, Tune H., Reynolds, Christopher A., Aulchenko, Yurii S., Kaakinen, Marika A., Jones, Ben, and Prokopenko, Inga
- Abstract
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification. Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
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- 2023
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219. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
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Weinstock, Joshua, Weinstock, Joshua, Gopakumar, Jayakrishnan, Burugula, Bala, Uddin, Md, Jahn, Nikolaus, Belk, Julia, Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn, Luna, Sofia, Prothro, Katherine, Mitchell, Shaneice, Laurie, Cecelia, Broome, Jai, Taylor, Kent, Guo, Xiuqing, Sinner, Moritz, von Falkenhausen, Aenne, Kääb, Stefan, Shuldiner, Alan, OConnell, Jeffrey, Lewis, Joshua, Boerwinkle, Eric, Barnes, Kathleen, Chami, Nathalie, Kenny, Eimear, Loos, Ruth, Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald, Redline, Susan, Cade, Brian, Psaty, Bruce, Bis, Joshua, Brody, Jennifer, Silverman, Edwin, Yun, Jeong, Qiao, Dandi, Palmer, Nicholette, Freedman, Barry, Bowden, Donald, Cho, Michael, DeMeo, Dawn, Vasan, Ramachandran, Yanek, Lisa, Becker, Lewis, Kardia, Sharon, Peyser, Patricia, He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan, Smith, Nicholas, Wiggins, Kerri, Arnett, Donna, Irvin, Marguerite, Tiwari, Hemant, Cutler, Michael, Knight, Stacey, Muhlestein, J, Correa, Adolfo, Raffield, Laura, Gao, Yan, de Andrade, Mariza, Rotter, Jerome, Rich, Stephen, Tracy, Russell, Konkle, Barbara, Johnsen, Jill, Wheeler, Marsha, Smith, J, Melander, Olle, Nilsson, Peter, Custer, Brian, Duggirala, Ravindranath, Curran, Joanne, Blangero, John, McGarvey, Stephen, Williams, L, Xiao, Shujie, Yang, Mao, Gu, C, Chen, Yii-Der, Lee, Wen-Jane, Kane, John, Pullinger, Clive, Shoemaker, M, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn, Desai, Pinkal, Johnson, Andrew, Mathias, Rasika, Blackwell, Thomas, Weinstock, Joshua, Weinstock, Joshua, Gopakumar, Jayakrishnan, Burugula, Bala, Uddin, Md, Jahn, Nikolaus, Belk, Julia, Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn, Luna, Sofia, Prothro, Katherine, Mitchell, Shaneice, Laurie, Cecelia, Broome, Jai, Taylor, Kent, Guo, Xiuqing, Sinner, Moritz, von Falkenhausen, Aenne, Kääb, Stefan, Shuldiner, Alan, OConnell, Jeffrey, Lewis, Joshua, Boerwinkle, Eric, Barnes, Kathleen, Chami, Nathalie, Kenny, Eimear, Loos, Ruth, Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald, Redline, Susan, Cade, Brian, Psaty, Bruce, Bis, Joshua, Brody, Jennifer, Silverman, Edwin, Yun, Jeong, Qiao, Dandi, Palmer, Nicholette, Freedman, Barry, Bowden, Donald, Cho, Michael, DeMeo, Dawn, Vasan, Ramachandran, Yanek, Lisa, Becker, Lewis, Kardia, Sharon, Peyser, Patricia, He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan, Smith, Nicholas, Wiggins, Kerri, Arnett, Donna, Irvin, Marguerite, Tiwari, Hemant, Cutler, Michael, Knight, Stacey, Muhlestein, J, Correa, Adolfo, Raffield, Laura, Gao, Yan, de Andrade, Mariza, Rotter, Jerome, Rich, Stephen, Tracy, Russell, Konkle, Barbara, Johnsen, Jill, Wheeler, Marsha, Smith, J, Melander, Olle, Nilsson, Peter, Custer, Brian, Duggirala, Ravindranath, Curran, Joanne, Blangero, John, McGarvey, Stephen, Williams, L, Xiao, Shujie, Yang, Mao, Gu, C, Chen, Yii-Der, Lee, Wen-Jane, Kane, John, Pullinger, Clive, Shoemaker, M, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn, Desai, Pinkal, Johnson, Andrew, Mathias, Rasika, and Blackwell, Thomas
- Abstract
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
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- 2023
220. Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.
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Jakubek, Yasminka, Jakubek, Yasminka, Zhou, Ying, Stilp, Adrienne, Bacon, Jason, Wong, Justin, Ozcan, Zuhal, Arnett, Donna, Barnes, Kathleen, Bis, Joshua, Boerwinkle, Eric, Brody, Jennifer, Carson, April, Chasman, Daniel, Chen, Jiawen, Cho, Michael, Conomos, Matthew, Cox, Nancy, Doyle, Margaret, Fornage, Myriam, Guo, Xiuqing, Kardia, Sharon, Lewis, Joshua, Loos, Ruth, Ma, Xiaolong, Machiela, Mitchell, Mack, Taralynn, Mathias, Rasika, Mitchell, Braxton, Mychaleckyj, Josyf, North, Kari, Pankratz, Nathan, Peyser, Patricia, Preuss, Michael, Psaty, Bruce, Raffield, Laura, Vasan, Ramachandran, Redline, Susan, Rich, Stephen, Silverman, Edwin, Smith, Jennifer, Smith, Aaron, Taub, Margaret, Taylor, Kent, Yun, Jeong, Li, Yun, Desai, Pinkal, Bick, Alexander, Reiner, Alexander, Scheet, Paul, Auer, Paul, Rotter, Jerome, Jakubek, Yasminka, Jakubek, Yasminka, Zhou, Ying, Stilp, Adrienne, Bacon, Jason, Wong, Justin, Ozcan, Zuhal, Arnett, Donna, Barnes, Kathleen, Bis, Joshua, Boerwinkle, Eric, Brody, Jennifer, Carson, April, Chasman, Daniel, Chen, Jiawen, Cho, Michael, Conomos, Matthew, Cox, Nancy, Doyle, Margaret, Fornage, Myriam, Guo, Xiuqing, Kardia, Sharon, Lewis, Joshua, Loos, Ruth, Ma, Xiaolong, Machiela, Mitchell, Mack, Taralynn, Mathias, Rasika, Mitchell, Braxton, Mychaleckyj, Josyf, North, Kari, Pankratz, Nathan, Peyser, Patricia, Preuss, Michael, Psaty, Bruce, Raffield, Laura, Vasan, Ramachandran, Redline, Susan, Rich, Stephen, Silverman, Edwin, Smith, Jennifer, Smith, Aaron, Taub, Margaret, Taylor, Kent, Yun, Jeong, Li, Yun, Desai, Pinkal, Bick, Alexander, Reiner, Alexander, Scheet, Paul, Auer, Paul, and Rotter, Jerome
- Abstract
Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
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- 2023
221. The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes
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Huerta-Chagoya, Alicia, Schroeder, Prosper, Mandla, Ravi, Deutsch, Aaron J., Zhu, Wanying, Petty, Lauren, Yi, Xiaoyan, Cole, Joanne B., Udler, Miriam, Dornbos, Peter, Porneala, Bianca, DiCorpo, Daniel, Liu, Ching-Ti, Li, Josephine H., Szczerbiński, Lukasz, Kaur, Varinderpal, Kim, Joohyun, Lu, Yu, Martin, Alicia, Eizirik, Décio L, Marchetti, Piero, Marselli, Lorella, Chen, Hui Ling, Srinivasan, Shylaja, Todd, Jennifer, Flannick, Jason, Gubitosi-Klug, Rose, Levitsky, Lynne, Shah, Rachana, Kelsey, Megan, Burke, Brian, Dabelea, Dana, Divers, Jasmin, Marcovina, Santica, Stalbow, Lauren, Loos, Ruth J. F., Darst, Burcu, Kooperberg, Charles, Raffield, Laura, Haiman, Christopher, Sun, Quan, McCormick, Joseph B., Fisher-Hoch, Susan, Ordoñez, Maria, Meigs, James, Baier, Leslie, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Orozco, Lorena, García-García, Lourdes, Moreno-Estrada, Andrés, Aguilar-Salinas, Carlos, Tusié, Teresa, Dupuis, Josée, Ng, Maggie C. Y., Manning, Alisa, Highland, Heather, Cnop, Miriam, Hanson, Robert R.E., Below, Jennifer, Florez, Jose, Leong, Aaron, Mercader, Josep Maria, Huerta-Chagoya, Alicia, Schroeder, Prosper, Mandla, Ravi, Deutsch, Aaron J., Zhu, Wanying, Petty, Lauren, Yi, Xiaoyan, Cole, Joanne B., Udler, Miriam, Dornbos, Peter, Porneala, Bianca, DiCorpo, Daniel, Liu, Ching-Ti, Li, Josephine H., Szczerbiński, Lukasz, Kaur, Varinderpal, Kim, Joohyun, Lu, Yu, Martin, Alicia, Eizirik, Décio L, Marchetti, Piero, Marselli, Lorella, Chen, Hui Ling, Srinivasan, Shylaja, Todd, Jennifer, Flannick, Jason, Gubitosi-Klug, Rose, Levitsky, Lynne, Shah, Rachana, Kelsey, Megan, Burke, Brian, Dabelea, Dana, Divers, Jasmin, Marcovina, Santica, Stalbow, Lauren, Loos, Ruth J. F., Darst, Burcu, Kooperberg, Charles, Raffield, Laura, Haiman, Christopher, Sun, Quan, McCormick, Joseph B., Fisher-Hoch, Susan, Ordoñez, Maria, Meigs, James, Baier, Leslie, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Orozco, Lorena, García-García, Lourdes, Moreno-Estrada, Andrés, Aguilar-Salinas, Carlos, Tusié, Teresa, Dupuis, Josée, Ng, Maggie C. Y., Manning, Alisa, Highland, Heather, Cnop, Miriam, Hanson, Robert R.E., Below, Jennifer, Florez, Jose, Leong, Aaron, and Mercader, Josep Maria
- Abstract
Aims/hypothesis The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. Methods We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. Results Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p =3.4 × 10 −9 ). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. Conclusions/interpretation Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic s, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2023
222. Distilling causality between physical activity traits and obesity via Mendelian randomization
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Wang, Zhe, Davey Smith, George, Loos, Ruth J. F., den Hoed, Marcel, Wang, Zhe, Davey Smith, George, Loos, Ruth J. F., and den Hoed, Marcel
- Abstract
Background Whether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed. Methods Leveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education—defined by years of schooling—and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches. Results Univariable MR analyses suggest bidirectional causal effects of physical activity and sedentary behavior with BMI. However, multivariable MR analyses that take years of schooling into account suggest that more MV physical activity causes a lower BMI, and a higher BMI causes more screen time, but not vice versa. In addition, more years of schooling causes higher levels of MV physical activity, less screen time, and lower BMI. Conclusions In conclusion, our results highlight the beneficial effect of education on improved health and suggest that a more physically active lifestyle leads to lower BMI, while sedentary behavior is a consequence of higher BMI.
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- 2023
- Full Text
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223. Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing
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Jakubek, Yasminka A., Zhou, Ying, Stilp, Adrienne, Bacon, Jason, Wong, Justin W., Ozcan, Zuhal, Arnett, Donna, Barnes, Kathleen, Bis, Joshua C., Boerwinkle, Eric, Brody, Jennifer A., Carson, April P., Chasman, Daniel I., Chen, Jiawen, Cho, Michael, Conomos, Matthew P., Cox, Nancy, Doyle, Margaret F., Fornage, Myriam, Guo, Xiuqing, Kardia, Sharon L.R., Lewis, Joshua P., Loos, Ruth J.F., Ma, Xiaolong, Machiela, Mitchell J., Mack, Taralynn M., Mathias, Rasika A., Mitchell, Braxton D., Mychaleckyj, Josyf C., North, Kari, Pankratz, Nathan, Peyser, Patricia A., Preuss, Michael H., Psaty, Bruce, Raffield, Laura M., Vasan, Ramachandran S., Redline, Susan, Rich, Stephen S., Rotter, Jerome I., Silverman, Edwin K., Smith, Jennifer A., Smith, Aaron P., Taub, Margaret, Taylor, Kent D., Yun, Jeong, Li, Yun, Desai, Pinkal, Bick, Alexander G., Reiner, Alexander P., Scheet, Paul, Auer, Paul L., Jakubek, Yasminka A., Zhou, Ying, Stilp, Adrienne, Bacon, Jason, Wong, Justin W., Ozcan, Zuhal, Arnett, Donna, Barnes, Kathleen, Bis, Joshua C., Boerwinkle, Eric, Brody, Jennifer A., Carson, April P., Chasman, Daniel I., Chen, Jiawen, Cho, Michael, Conomos, Matthew P., Cox, Nancy, Doyle, Margaret F., Fornage, Myriam, Guo, Xiuqing, Kardia, Sharon L.R., Lewis, Joshua P., Loos, Ruth J.F., Ma, Xiaolong, Machiela, Mitchell J., Mack, Taralynn M., Mathias, Rasika A., Mitchell, Braxton D., Mychaleckyj, Josyf C., North, Kari, Pankratz, Nathan, Peyser, Patricia A., Preuss, Michael H., Psaty, Bruce, Raffield, Laura M., Vasan, Ramachandran S., Redline, Susan, Rich, Stephen S., Rotter, Jerome I., Silverman, Edwin K., Smith, Jennifer A., Smith, Aaron P., Taub, Margaret, Taylor, Kent D., Yun, Jeong, Li, Yun, Desai, Pinkal, Bick, Alexander G., Reiner, Alexander P., Scheet, Paul, and Auer, Paul L.
- Abstract
Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
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- 2023
224. Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
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Tobias, Deirdre K., Merino, Jordi, Ahmad, Abrar, Aiken, Catherine, Benham, Jamie L., Bodhini, Dhanasekaran, Clark, Amy L., Colclough, Kevin, Corcoy, Rosa, Cromer, Sara J., Duan, Daisy, Felton, Jamie L., Francis, Ellen C., Gillard, Pieter, Gingras, Véronique, Gaillard, Romy, Haider, Eram, Hughes, Alice, Ikle, Jennifer M., Jacobsen, Laura M., Kahkoska, Anna R., Kettunen, Jarno L.T., Kreienkamp, Raymond J., Lim, Lee Ling, Männistö, Jonna M.E., Massey, Robert, Mclennan, Niamh Maire, Miller, Rachel G., Morieri, Mario Luca, Most, Jasper, Naylor, Rochelle N., Ozkan, Bige, Patel, Kashyap Amratlal, Pilla, Scott J., Prystupa, Katsiaryna, Raghavan, Sridharan, Rooney, Mary R., Schön, Martin, Semnani-Azad, Zhila, Sevilla-Gonzalez, Magdalena, Svalastoga, Pernille, Takele, Wubet Worku, Tam, Claudia Ha ting, Thuesen, Anne Cathrine B., Tosur, Mustafa, Wallace, Amelia S., Wang, Caroline C., Wong, Jessie J., Yamamoto, Jennifer M., Young, Katherine, Amouyal, Chloé, Andersen, Mette K., Bonham, Maxine P., Chen, Mingling, Cheng, Feifei, Chikowore, Tinashe, Chivers, Sian C., Clemmensen, Christoffer, Dabelea, Dana, Dawed, Adem Y., Deutsch, Aaron J., Dickens, Laura T., DiMeglio, Linda A., Dudenhöffer-Pfeifer, Monika, Evans-Molina, Carmella, Fernández-Balsells, María Mercè, Fitipaldi, Hugo, Fitzpatrick, Stephanie L., Gitelman, Stephen E., Goodarzi, Mark O., Grieger, Jessica A., Guasch-Ferré, Marta, Habibi, Nahal, Hansen, Torben, Huang, Chuiguo, Harris-Kawano, Arianna, Ismail, Heba M., Hoag, Benjamin, Johnson, Randi K., Jones, Angus G., Koivula, Robert W., Leong, Aaron, Leung, Gloria K.W., Libman, Ingrid M., Liu, Kai, Long, S. Alice, Lowe, William L., Morton, Robert W., Motala, Ayesha A., Onengut-Gumuscu, Suna, Pankow, James S., Pathirana, Maleesa, Pazmino, Sofia, Perez, Dianna, Petrie, John R., Powe, Camille E., Quinteros, Alejandra, Jain, Rashmi, Ray, Debashree, Ried-Larsen, Mathias, Saeed, Zeb, Santhakumar, Vanessa, Kanbour, Sarah, Sarkar, Sudipa, Monaco, Gabriela S.F., Scholtens, Denise M., Selvin, Elizabeth, Sheu, Wayne Huey Herng, Speake, Cate, Stanislawski, Maggie A., Steenackers, Nele, Steck, Andrea K., Stefan, Norbert, Støy, Julie, Taylor, Rachael, Tye, Sok Cin, Ukke, Gebresilasea Gendisha, Urazbayeva, Marzhan, Van der Schueren, Bart, Vatier, Camille, Wentworth, John M., Hannah, Wesley, White, Sara L., Yu, Gechang, Zhang, Yingchai, Zhou, Shao J., Beltrand, Jacques, Polak, Michel, Aukrust, Ingvild, de Franco, Elisa, Flanagan, Sarah E., Maloney, Kristin A., McGovern, Andrew, Molnes, Janne, Nakabuye, Mariam, Njølstad, Pål Rasmus, Pomares-Millan, Hugo, Provenzano, Michele, Saint-Martin, Cécile, Zhang, Cuilin, Zhu, Yeyi, Auh, Sungyoung, de Souza, Russell, Fawcett, Andrea J., Gruber, Chandra, Mekonnen, Eskedar Getie, Mixter, Emily, Sherifali, Diana, Eckel, Robert H., Nolan, John J., Philipson, Louis H., Brown, Rebecca J., Billings, Liana K., Boyle, Kristen, Costacou, Tina, Dennis, John M., Florez, Jose C., Gloyn, Anna L., Gomez, Maria F., Gottlieb, Peter A., Greeley, Siri Atma W., Griffin, Kurt, Hattersley, Andrew T., Hirsch, Irl B., Hivert, Marie France, Hood, Korey K., Josefson, Jami L., Kwak, Soo Heon, Laffel, Lori M., Lim, Siew S., Loos, Ruth J.F., Ma, Ronald C.W., Mathieu, Chantal, Mathioudakis, Nestoras, Meigs, James B., Misra, Shivani, Mohan, Viswanathan, Murphy, Rinki, Oram, Richard, Owen, Katharine R., Ozanne, Susan E., Pearson, Ewan R., Perng, Wei, Pollin, Toni I., Pop-Busui, Rodica, Pratley, Richard E., Redman, Leanne M., Redondo, Maria J., Reynolds, Rebecca M., Semple, Robert K., Sherr, Jennifer L., Sims, Emily K., Sweeting, Arianne, Tuomi, Tiinamaija, Udler, Miriam S., Vesco, Kimberly K., Vilsbøll, Tina, Wagner, Robert, Rich, Stephen S., Franks, Paul W., Tobias, Deirdre K., Merino, Jordi, Ahmad, Abrar, Aiken, Catherine, Benham, Jamie L., Bodhini, Dhanasekaran, Clark, Amy L., Colclough, Kevin, Corcoy, Rosa, Cromer, Sara J., Duan, Daisy, Felton, Jamie L., Francis, Ellen C., Gillard, Pieter, Gingras, Véronique, Gaillard, Romy, Haider, Eram, Hughes, Alice, Ikle, Jennifer M., Jacobsen, Laura M., Kahkoska, Anna R., Kettunen, Jarno L.T., Kreienkamp, Raymond J., Lim, Lee Ling, Männistö, Jonna M.E., Massey, Robert, Mclennan, Niamh Maire, Miller, Rachel G., Morieri, Mario Luca, Most, Jasper, Naylor, Rochelle N., Ozkan, Bige, Patel, Kashyap Amratlal, Pilla, Scott J., Prystupa, Katsiaryna, Raghavan, Sridharan, Rooney, Mary R., Schön, Martin, Semnani-Azad, Zhila, Sevilla-Gonzalez, Magdalena, Svalastoga, Pernille, Takele, Wubet Worku, Tam, Claudia Ha ting, Thuesen, Anne Cathrine B., Tosur, Mustafa, Wallace, Amelia S., Wang, Caroline C., Wong, Jessie J., Yamamoto, Jennifer M., Young, Katherine, Amouyal, Chloé, Andersen, Mette K., Bonham, Maxine P., Chen, Mingling, Cheng, Feifei, Chikowore, Tinashe, Chivers, Sian C., Clemmensen, Christoffer, Dabelea, Dana, Dawed, Adem Y., Deutsch, Aaron J., Dickens, Laura T., DiMeglio, Linda A., Dudenhöffer-Pfeifer, Monika, Evans-Molina, Carmella, Fernández-Balsells, María Mercè, Fitipaldi, Hugo, Fitzpatrick, Stephanie L., Gitelman, Stephen E., Goodarzi, Mark O., Grieger, Jessica A., Guasch-Ferré, Marta, Habibi, Nahal, Hansen, Torben, Huang, Chuiguo, Harris-Kawano, Arianna, Ismail, Heba M., Hoag, Benjamin, Johnson, Randi K., Jones, Angus G., Koivula, Robert W., Leong, Aaron, Leung, Gloria K.W., Libman, Ingrid M., Liu, Kai, Long, S. Alice, Lowe, William L., Morton, Robert W., Motala, Ayesha A., Onengut-Gumuscu, Suna, Pankow, James S., Pathirana, Maleesa, Pazmino, Sofia, Perez, Dianna, Petrie, John R., Powe, Camille E., Quinteros, Alejandra, Jain, Rashmi, Ray, Debashree, Ried-Larsen, Mathias, Saeed, Zeb, Santhakumar, Vanessa, Kanbour, Sarah, Sarkar, Sudipa, Monaco, Gabriela S.F., Scholtens, Denise M., Selvin, Elizabeth, Sheu, Wayne Huey Herng, Speake, Cate, Stanislawski, Maggie A., Steenackers, Nele, Steck, Andrea K., Stefan, Norbert, Støy, Julie, Taylor, Rachael, Tye, Sok Cin, Ukke, Gebresilasea Gendisha, Urazbayeva, Marzhan, Van der Schueren, Bart, Vatier, Camille, Wentworth, John M., Hannah, Wesley, White, Sara L., Yu, Gechang, Zhang, Yingchai, Zhou, Shao J., Beltrand, Jacques, Polak, Michel, Aukrust, Ingvild, de Franco, Elisa, Flanagan, Sarah E., Maloney, Kristin A., McGovern, Andrew, Molnes, Janne, Nakabuye, Mariam, Njølstad, Pål Rasmus, Pomares-Millan, Hugo, Provenzano, Michele, Saint-Martin, Cécile, Zhang, Cuilin, Zhu, Yeyi, Auh, Sungyoung, de Souza, Russell, Fawcett, Andrea J., Gruber, Chandra, Mekonnen, Eskedar Getie, Mixter, Emily, Sherifali, Diana, Eckel, Robert H., Nolan, John J., Philipson, Louis H., Brown, Rebecca J., Billings, Liana K., Boyle, Kristen, Costacou, Tina, Dennis, John M., Florez, Jose C., Gloyn, Anna L., Gomez, Maria F., Gottlieb, Peter A., Greeley, Siri Atma W., Griffin, Kurt, Hattersley, Andrew T., Hirsch, Irl B., Hivert, Marie France, Hood, Korey K., Josefson, Jami L., Kwak, Soo Heon, Laffel, Lori M., Lim, Siew S., Loos, Ruth J.F., Ma, Ronald C.W., Mathieu, Chantal, Mathioudakis, Nestoras, Meigs, James B., Misra, Shivani, Mohan, Viswanathan, Murphy, Rinki, Oram, Richard, Owen, Katharine R., Ozanne, Susan E., Pearson, Ewan R., Perng, Wei, Pollin, Toni I., Pop-Busui, Rodica, Pratley, Richard E., Redman, Leanne M., Redondo, Maria J., Reynolds, Rebecca M., Semple, Robert K., Sherr, Jennifer L., Sims, Emily K., Sweeting, Arianne, Tuomi, Tiinamaija, Udler, Miriam S., Vesco, Kimberly K., Vilsbøll, Tina, Wagner, Robert, Rich, Stephen S., and Franks, Paul W.
- Abstract
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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- 2023
225. Ancestral diversity in lipoprotein(a) studies helps address evidence gaps
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Lee, Moa P., Dimos, Sofia F., Raffield, Laura M., Wang, Zhe, Ballou, Anna F., Downie, Carolina G., Arehart, Christopher H., Correa, Adolfo, De Vries, Paul S., Du, Zhaohui, Gignoux, Christopher R., Gordon-Larsen, Penny, Guo, Xiuqing, Haessler, Jeffrey, Howard, Annie Green, Hu, Yao, Kassahun, Helina, Kent, Shia T., Lopez, J. Antonio G., Monda, Keri L., North, Kari E., Peters, Ulrike, Preuss, Michael H., Rich, Stephen S., Rhodes, Shannon L., Yao, Jie, Yarosh, Rina, Tsai, Michael Y., Rotter, Jerome I., Kooperberg, Charles L., Loos, Ruth J.F., Ballantyne, Christie, Avery, Christy L., Graff, Mariaelisa, Lee, Moa P., Dimos, Sofia F., Raffield, Laura M., Wang, Zhe, Ballou, Anna F., Downie, Carolina G., Arehart, Christopher H., Correa, Adolfo, De Vries, Paul S., Du, Zhaohui, Gignoux, Christopher R., Gordon-Larsen, Penny, Guo, Xiuqing, Haessler, Jeffrey, Howard, Annie Green, Hu, Yao, Kassahun, Helina, Kent, Shia T., Lopez, J. Antonio G., Monda, Keri L., North, Kari E., Peters, Ulrike, Preuss, Michael H., Rich, Stephen S., Rhodes, Shannon L., Yao, Jie, Yarosh, Rina, Tsai, Michael Y., Rotter, Jerome I., Kooperberg, Charles L., Loos, Ruth J.F., Ballantyne, Christie, Avery, Christy L., and Graff, Mariaelisa
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Introduction The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations. Methods Here, we examined how ancestrally diverse studies could clarify Lp(a)’s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. Results Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a ‘rule out’ for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%– 99.9%) across PRS thresholds (80th–99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10−6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects. Conclusions Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps., Introduction The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations. Methods Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. Results Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R 2 =15% in East Asians) to high (R 2 =50% in Europeans) accuracy. For all populations, PRS showed promise as a 'rule out' for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%-99.9%) across PRS thresholds (80th-99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10 -6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects. Conclusions Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.
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- 2023
226. Genetic insights into resting heart rate and its role in cardiovascular disease
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van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne U., Bielak, Lawrence F., Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus E., Witte, Daniel R., Linneberg, Allan, Lind, Lars, Hansen, Torben, Grarup, Niels, Loos, Ruth J.F., van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne U., Bielak, Lawrence F., Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus E., Witte, Daniel R., Linneberg, Allan, Lind, Lars, Hansen, Torben, Grarup, Niels, and Loos, Ruth J.F.
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Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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- 2023
227. Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts
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Wang, Ying, Namba, Shinichi, Lopera-Maya, Esteban A., Kerminen, Sini, Tsuo, Kristin, Läll, Kristi, Kanai, Masahiro, Zhou, Wei, Wu, Kuan Han H., Favé, Marie Julie, Bhatta, Laxmi, Awadalla, Philip, Brumpton, Ben M., Deelen, Patrick, Hveem, Kristian, Lo Faro, Valeria, Mägi, Reedik, Murakami, Yoshinori, Sanna, Serena, Smoller, Jordan W., Uzunovic, Jasmina, Wolford, Brooke N., Rasheed, Humaira, Hirbo, Jibril B., Bhattacharya, Arjun, Zhao, Huiling, Surakka, Ida, Chapman, Sinéad B., Karjalainen, Juha, Kurki, Mitja, Mutaamba, Maasha, Partanen, Juulia J., Chavan, Sameer, Chen, Tzu Ting, Daya, Michelle, Ding, Yi, Feng, Yen Chen A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Loos, Ruth J.F., Wang, Ying, Namba, Shinichi, Lopera-Maya, Esteban A., Kerminen, Sini, Tsuo, Kristin, Läll, Kristi, Kanai, Masahiro, Zhou, Wei, Wu, Kuan Han H., Favé, Marie Julie, Bhatta, Laxmi, Awadalla, Philip, Brumpton, Ben M., Deelen, Patrick, Hveem, Kristian, Lo Faro, Valeria, Mägi, Reedik, Murakami, Yoshinori, Sanna, Serena, Smoller, Jordan W., Uzunovic, Jasmina, Wolford, Brooke N., Rasheed, Humaira, Hirbo, Jibril B., Bhattacharya, Arjun, Zhao, Huiling, Surakka, Ida, Chapman, Sinéad B., Karjalainen, Juha, Kurki, Mitja, Mutaamba, Maasha, Partanen, Juulia J., Chavan, Sameer, Chen, Tzu Ting, Daya, Michelle, Ding, Yi, Feng, Yen Chen A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., and Loos, Ruth J.F.
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Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.
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- 2023
228. Role of sociodemographic, clinical, behavioral, and molecular factors in precision prevention of type 2 diabetes:a systematic review
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Bodhini, Dhanasekaran, Morton, Robert W, Santhakumar, Vanessa, Nakabuye, Mariam, Pomares-Millan, Hugo, Clemmensen, Christoffer, Fitzpatrick, Stephanie L, Guasch-Ferre, Marta, Pankow, James S, Ried-Larsen, Mathias, Franks, Paul W, Tobias, Deirdre K, Merino, Jordi, Mohan, Viswanathan, Loos, Ruth J F, Bodhini, Dhanasekaran, Morton, Robert W, Santhakumar, Vanessa, Nakabuye, Mariam, Pomares-Millan, Hugo, Clemmensen, Christoffer, Fitzpatrick, Stephanie L, Guasch-Ferre, Marta, Pankow, James S, Ried-Larsen, Mathias, Franks, Paul W, Tobias, Deirdre K, Merino, Jordi, Mohan, Viswanathan, and Loos, Ruth J F
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The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular characteristics modify the efficacy of dietary or lifestyle interventions to prevent T2D. Among the 80 publications that met our criteria for inclusion, the evidence was low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. We found evidence, albeit low certainty, to support conclusions that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.
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- 2023
229. Genomic Disorders in CKD across the Lifespan
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Verbitsky, Miguel, Krishnamurthy, Sarathbabu, Krithivasan, Priya, Hughes, Daniel, Khan, Atlas, Marasà, Maddalena, Vena, Natalie, Khosla, Pavan, Zhang, Junying, Lim, Tze Y., Glessner, Joseph T., Weng, Chunhua, Shang, Ning, Shen, Yufeng, Hripcsak, George, Hakonarson, Hakon, Ionita-Laza, Iuliana, Levy, Brynn, Kenny, Eimear E., Loos, Ruth J.F., Kiryluk, Krzysztof, Sanna-Cherchi, Simone, Crosslin, David R., Furth, Susan, Warady, Bradley A., Igo, Robert P., Iyengar, Sudha K., Wong, Craig S., Parsa, Afshin, Feldman, Harold I., Gharavi, Ali G., Verbitsky, Miguel, Krishnamurthy, Sarathbabu, Krithivasan, Priya, Hughes, Daniel, Khan, Atlas, Marasà, Maddalena, Vena, Natalie, Khosla, Pavan, Zhang, Junying, Lim, Tze Y., Glessner, Joseph T., Weng, Chunhua, Shang, Ning, Shen, Yufeng, Hripcsak, George, Hakonarson, Hakon, Ionita-Laza, Iuliana, Levy, Brynn, Kenny, Eimear E., Loos, Ruth J.F., Kiryluk, Krzysztof, Sanna-Cherchi, Simone, Crosslin, David R., Furth, Susan, Warady, Bradley A., Igo, Robert P., Iyengar, Sudha K., Wong, Craig S., Parsa, Afshin, Feldman, Harold I., and Gharavi, Ali G.
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SIGNIFICANCE STATEMENT: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis. BACKGROUND: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility. METHODS: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort. RESULTS: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associ
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- 2023
230. Polygenic Scores Help Reduce Racial Disparities in Predictive Accuracy of Automated Type 1 Diabetes Classification Algorithms
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Deutsch, Aaron J., Stalbow, Lauren, Majarian, Timothy D., Mercader, Josep M., Manning, Alisa K., Florez, Jose C., Loos, Ruth J.F., Udler, Miriam S., Deutsch, Aaron J., Stalbow, Lauren, Majarian, Timothy D., Mercader, Josep M., Manning, Alisa K., Florez, Jose C., Loos, Ruth J.F., and Udler, Miriam S.
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OBJECTIVE: Automated algorithms to identify individuals with type 1 diabetes using electronic health records are increasingly used in biomedical research. It is not known whether the accuracy of these algorithms differs by self-reported race. We investigated whether polygenic scores improve identification of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: We investigated two large hospital-based biobanks (Mass General Brigham [MGB] and BioMe) and identified individuals with type 1 diabetes using an established automated algorithm. We performed medical record reviews to validate the diagnosis of type 1 diabetes. We implemented two published polygenic scores for type 1 diabetes (developed in individuals of European or African ancestry). We assessed the classification algorithm before and after incorporating polygenic scores. RESULTS: The automated algorithm was more likely to incorrectly assign a diagnosis of type 1 diabetes in self-reported non-White individuals than in self-reported White individuals (odds ratio 3.45; 95% CI 1.54-7.69; P = 0.0026). After incorporating polygenic scores into the MGB Biobank, the positive predictive value of the type 1 diabetes algorithm increased from 70 to 97% for self-reported White individuals (meaning that 97% of those predicted to have type 1 diabetes indeed had type 1 diabetes) and from 53 to 100% for self-reported non-White individuals. Similar results were found in BioMe. CONCLUSIONS: Automated phenotyping algorithms may exacerbate health disparities because of an increased risk of misclassification of individuals from underrepresented populations. Polygenic scores may be used to improve the performance of phenotyping algorithms and potentially reduce this disparity.
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- 2023
231. Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program
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Small, Aeron M., Peloso, Gina M., Linefsky, Jason, Aragam, Jayashri, Galloway, Ashley, Tanukonda, Vidisha, Wang, Lu Chen, Yu, Zhi, Sunitha Selvaraj, Margaret, Farber-Eger, Eric H., Baker, Michael T., Setia-Verma, Shefali, Lee, Simon S.K., Preuss, Michael, Ritchie, Marylyn D., Damrauer, Scott M., Rader, Daniel J., Wells, Quinn S., Loos, Ruth, Lubitz, Steven A., Thanassoulis, George, Cho, Kelly, Wilson, Peter W.F., Natarajan, Pradeep, O'Donnell, Christopher J., Small, Aeron M., Peloso, Gina M., Linefsky, Jason, Aragam, Jayashri, Galloway, Ashley, Tanukonda, Vidisha, Wang, Lu Chen, Yu, Zhi, Sunitha Selvaraj, Margaret, Farber-Eger, Eric H., Baker, Michael T., Setia-Verma, Shefali, Lee, Simon S.K., Preuss, Michael, Ritchie, Marylyn D., Damrauer, Scott M., Rader, Daniel J., Wells, Quinn S., Loos, Ruth, Lubitz, Steven A., Thanassoulis, George, Cho, Kelly, Wilson, Peter W.F., Natarajan, Pradeep, and O'Donnell, Christopher J.
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Background: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. Methods: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. Results: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting
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- 2023
232. Approaches to addressing the rise in obesity levels
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Apovian, Caroline M., Guo, Xi Rong, Hawley, John A., Karmali, Shahzeer, Loos, Ruth J.F., Waterlander, Wilma E., Apovian, Caroline M., Guo, Xi Rong, Hawley, John A., Karmali, Shahzeer, Loos, Ruth J.F., and Waterlander, Wilma E.
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Levels of obesity and overweight are increasing globally, with affected individuals often experiencing health issues and reduced quality of life. The pathogenesis of obesity is complex and multifactorial, and effective solutions have been elusive. In this Viewpoint, experts in the fields of medical therapy, adipocyte biology, exercise and muscle, bariatric surgery, genetics, and public health give their perspectives on current and future progress in addressing the rising prevalence of obesity.
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- 2023
233. Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus
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RWE/Causal inference, Child Health, Kwak, Soo Heon, Hernandez-Cancela, Ryan B, DiCorpo, Daniel A, Condon, David E, Merino, Jordi, Wu, Peitao, Brody, Jennifer A, Yao, Jie, Guo, Xiuqing, Ahmadizar, Fariba, Meyer, Mariah, Sincan, Murat, Mercader, Josep M, Lee, Sujin, Haessler, Jeffrey, Vy, Ha My T, Lin, Zhaotong, Armstrong, Nicole D, Gu, Shaopeng, Tsao, Noah L, Lange, Leslie A, Wang, Ningyuan, Wiggins, Kerri L, Trompet, Stella, Liu, Simin, Loos, Ruth J F, Judy, Renae, Schroeder, Philip H, Hasbani, Natalie R, Bos, Maxime M, Morrison, Alanna C, Jackson, Rebecca D, Reiner, Alexander P, Manson, JoAnn E, Chaudhary, Ninad S, Carmichael, Lynn K, Chen, Yii-Der Ida, Taylor, Kent D, Ghanbari, Mohsen, van Meurs, Joyce, Pitsillides, Achilleas N, Psaty, Bruce M, Noordam, Raymond, Do, Ron, Park, Kyong Soo, Jukema, J Wouter, Kavousi, Maryam, Correa, Adolfo, Rich, Stephen S, Damrauer, Scott M, Hajek, Catherine, Cho, Nam H, Irvin, Marguerite R, Pankow, James S, Nadkarni, Girish N, Sladek, Robert, Goodarzi, Mark O, Florez, Jose C, Chasman, Daniel I, Heckbert, Susan R, Kooperberg, Charles, Dupuis, Josée, Malhotra, Rajeev, de Vries, Paul S, Liu, Ching-Ti, Rotter, Jerome I, Meigs, James B, RWE/Causal inference, Child Health, Kwak, Soo Heon, Hernandez-Cancela, Ryan B, DiCorpo, Daniel A, Condon, David E, Merino, Jordi, Wu, Peitao, Brody, Jennifer A, Yao, Jie, Guo, Xiuqing, Ahmadizar, Fariba, Meyer, Mariah, Sincan, Murat, Mercader, Josep M, Lee, Sujin, Haessler, Jeffrey, Vy, Ha My T, Lin, Zhaotong, Armstrong, Nicole D, Gu, Shaopeng, Tsao, Noah L, Lange, Leslie A, Wang, Ningyuan, Wiggins, Kerri L, Trompet, Stella, Liu, Simin, Loos, Ruth J F, Judy, Renae, Schroeder, Philip H, Hasbani, Natalie R, Bos, Maxime M, Morrison, Alanna C, Jackson, Rebecca D, Reiner, Alexander P, Manson, JoAnn E, Chaudhary, Ninad S, Carmichael, Lynn K, Chen, Yii-Der Ida, Taylor, Kent D, Ghanbari, Mohsen, van Meurs, Joyce, Pitsillides, Achilleas N, Psaty, Bruce M, Noordam, Raymond, Do, Ron, Park, Kyong Soo, Jukema, J Wouter, Kavousi, Maryam, Correa, Adolfo, Rich, Stephen S, Damrauer, Scott M, Hajek, Catherine, Cho, Nam H, Irvin, Marguerite R, Pankow, James S, Nadkarni, Girish N, Sladek, Robert, Goodarzi, Mark O, Florez, Jose C, Chasman, Daniel I, Heckbert, Susan R, Kooperberg, Charles, Dupuis, Josée, Malhotra, Rajeev, de Vries, Paul S, Liu, Ching-Ti, Rotter, Jerome I, and Meigs, James B
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- 2023
234. Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study.
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Wang, Yuxuan, Wang, Yuxuan, Selvaraj, Margaret, Li, Xihao, Li, Zilin, Holdcraft, Jacob, Arnett, Donna, Bis, Joshua, Blangero, John, Boerwinkle, Eric, Bowden, Donald, Cade, Brian, Carlson, Jenna, Carson, April, Chen, Yii-Der, Curran, Joanne, de Vries, Paul, Dutcher, Susan, Ellinor, Patrick, Floyd, James, Fornage, Myriam, Freedman, Barry, Gabriel, Stacey, Germer, Soren, Gibbs, Richard, Guo, Xiuqing, He, Jiang, Heard-Costa, Nancy, Hildalgo, Bertha, Hou, Lifang, Irvin, Marguerite, Joehanes, Roby, Kaplan, Robert, Kardia, Sharon, Kelly, Tanika, Kim, Ryan, Kooperberg, Charles, Kral, Brian, Levy, Daniel, Li, Changwei, Liu, Chunyu, Lloyd-Jone, Don, Loos, Ruth, Mahaney, Michael, Martin, Lisa, Mathias, Rasika, Minster, Ryan, Mitchell, Braxton, Montasser, May, Morrison, Alanna, Murabito, Joanne, Naseri, Take, OConnell, Jeffrey, Palmer, Nicholette, Preuss, Michael, Psaty, Bruce, Raffield, Laura, Rao, Dabeeru, Redline, Susan, Reiner, Alexander, Rich, Stephen, Ruepena, Muagututia, Sheu, Wayne, Smith, Jennifer, Smith, Albert, Tiwari, Hemant, Tsai, Michael, Viaud-Martinez, Karine, Wang, Zhe, Yanek, Lisa, Zhao, Wei, Lin, Xihong, Natarajan, Pradeep, Peloso, Gina, Rotter, Jerome, Wang, Yuxuan, Wang, Yuxuan, Selvaraj, Margaret, Li, Xihao, Li, Zilin, Holdcraft, Jacob, Arnett, Donna, Bis, Joshua, Blangero, John, Boerwinkle, Eric, Bowden, Donald, Cade, Brian, Carlson, Jenna, Carson, April, Chen, Yii-Der, Curran, Joanne, de Vries, Paul, Dutcher, Susan, Ellinor, Patrick, Floyd, James, Fornage, Myriam, Freedman, Barry, Gabriel, Stacey, Germer, Soren, Gibbs, Richard, Guo, Xiuqing, He, Jiang, Heard-Costa, Nancy, Hildalgo, Bertha, Hou, Lifang, Irvin, Marguerite, Joehanes, Roby, Kaplan, Robert, Kardia, Sharon, Kelly, Tanika, Kim, Ryan, Kooperberg, Charles, Kral, Brian, Levy, Daniel, Li, Changwei, Liu, Chunyu, Lloyd-Jone, Don, Loos, Ruth, Mahaney, Michael, Martin, Lisa, Mathias, Rasika, Minster, Ryan, Mitchell, Braxton, Montasser, May, Morrison, Alanna, Murabito, Joanne, Naseri, Take, OConnell, Jeffrey, Palmer, Nicholette, Preuss, Michael, Psaty, Bruce, Raffield, Laura, Rao, Dabeeru, Redline, Susan, Reiner, Alexander, Rich, Stephen, Ruepena, Muagututia, Sheu, Wayne, Smith, Jennifer, Smith, Albert, Tiwari, Hemant, Tsai, Michael, Viaud-Martinez, Karine, Wang, Zhe, Yanek, Lisa, Zhao, Wei, Lin, Xihong, Natarajan, Pradeep, Peloso, Gina, and Rotter, Jerome
- Abstract
Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.
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- 2023
235. Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development:a systematic review
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Bodhini, Dhanasekaran, Morton, Robert W, Santhakumar, Vanessa, Nakabuye, Mariam, Pomares-Millan, Hugo, Clemmensen, Christoffer, Fitzpatrick, Stephanie L, Guasch-Ferre, Marta, Pankow, James S, Ried-Larsen, Mathias, Franks, Paul W, Tobias, Deirdre K, Merino, Jordi, Mohan, Viswanathan, Loos, Ruth J F, Bodhini, Dhanasekaran, Morton, Robert W, Santhakumar, Vanessa, Nakabuye, Mariam, Pomares-Millan, Hugo, Clemmensen, Christoffer, Fitzpatrick, Stephanie L, Guasch-Ferre, Marta, Pankow, James S, Ried-Larsen, Mathias, Franks, Paul W, Tobias, Deirdre K, Merino, Jordi, Mohan, Viswanathan, and Loos, Ruth J F
- Abstract
BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D.METHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier.RESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition.CONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.
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- 2023
236. A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies
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Li, Xihao, Chen, Han, Selvaraj, Margaret Sunitha, Van Buren, Eric, Zhou, Hufeng, Wang, Yuxuan, Sun, Ryan, McCaw, Zachary R, Yu, Zhi, Arnett, Donna K, Bis, Joshua C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Carson, April P, Carlson, Jenna C, Chami, Nathalie, Chen, Yii-Der Ida, Curran, Joanne E, de Vries, Paul S, Fornage, Myriam, Franceschini, Nora, Freedman, Barry I, Gu, Charles, Heard-Costa, Nancy L, He, Jiang, Hou, Lifang, Hung, Yi-Jen, Irvin, Marguerite R, Kaplan, Robert C, Kardia, Sharon L R, Kelly, Tanika, Konigsberg, Iain, Kooperberg, Charles, Kral, Brian G, Li, Changwei, Loos, Ruth J F, Mahaney, Michael C, Martin, Lisa W, Mathias, Rasika A, Minster, Ryan L, Mitchell, Braxton D, Montasser, May E, Morrison, Alanna C, Palmer, Nicholette D, Peyser, Patricia A, Psaty, Bruce M, Raffield, Laura M, Li, Xihao, Chen, Han, Selvaraj, Margaret Sunitha, Van Buren, Eric, Zhou, Hufeng, Wang, Yuxuan, Sun, Ryan, McCaw, Zachary R, Yu, Zhi, Arnett, Donna K, Bis, Joshua C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Carson, April P, Carlson, Jenna C, Chami, Nathalie, Chen, Yii-Der Ida, Curran, Joanne E, de Vries, Paul S, Fornage, Myriam, Franceschini, Nora, Freedman, Barry I, Gu, Charles, Heard-Costa, Nancy L, He, Jiang, Hou, Lifang, Hung, Yi-Jen, Irvin, Marguerite R, Kaplan, Robert C, Kardia, Sharon L R, Kelly, Tanika, Konigsberg, Iain, Kooperberg, Charles, Kral, Brian G, Li, Changwei, Loos, Ruth J F, Mahaney, Michael C, Martin, Lisa W, Mathias, Rasika A, Minster, Ryan L, Mitchell, Braxton D, Montasser, May E, Morrison, Alanna C, Palmer, Nicholette D, Peyser, Patricia A, Psaty, Bruce M, and Raffield, Laura M
- Abstract
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of NIPSNAP3A and an intergenic region on chromosome 1.
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- 2023
237. Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores
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Hrytsenko, Yana, Shea, Benjamin, Elgart, Michael, Kurniansyah, Nuzulul, Lyons, Genevieve, Morrison, Alanna C, Carson, April P, Haring, Bernhard, Mitchel, Braxton D, Psaty, Bruce M, Jaeger, Byron C, Gu, C Charles, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald, Choi, Eunhee, Brody, Jennifer A, Smith, Jennifer A, Rotter, Jerome I, Moll, Matthew, Fornage, Myriam, Simon, Noah, Castaldi, Peter, Casanova, Ramon, Chung, Ren-Hua, Kaplan, Robert, Loos, Ruth J F, Kardia, Sharon L R, Rich, Stephen S, Redline, Susan, Kelly, Tanika, O'Connor, Timothy, Zhao, Wei, Kim, Wonji, Guo, Xiuqing, Chen, Yii Der Ida, Sofer, Tamar, Hrytsenko, Yana, Shea, Benjamin, Elgart, Michael, Kurniansyah, Nuzulul, Lyons, Genevieve, Morrison, Alanna C, Carson, April P, Haring, Bernhard, Mitchel, Braxton D, Psaty, Bruce M, Jaeger, Byron C, Gu, C Charles, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald, Choi, Eunhee, Brody, Jennifer A, Smith, Jennifer A, Rotter, Jerome I, Moll, Matthew, Fornage, Myriam, Simon, Noah, Castaldi, Peter, Casanova, Ramon, Chung, Ren-Hua, Kaplan, Robert, Loos, Ruth J F, Kardia, Sharon L R, Rich, Stephen S, Redline, Susan, Kelly, Tanika, O'Connor, Timothy, Zhao, Wei, Kim, Wonji, Guo, Xiuqing, Chen, Yii Der Ida, and Sofer, Tamar
- Abstract
We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1% to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8% to 5.1% (SBP) and 4.7% to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.
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- 2023
238. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
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Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J.F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., Sanna-Cherchi, Simone, Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J.F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., and Sanna-Cherchi, Simone
- Abstract
African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
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- 2023
239. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
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Wang, Anqi, Shen, Jiayi, Rodriguez, Alex A., Saunders, Edward J., Chen, Fei, Janivara, Rohini, Darst, Burcu F., Sheng, Xin, Xu, Yili, Chou, Alisha J., Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Plym, Anna, Sahimi, Ali, Hoffman, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Laisk, Triin, Figuerêdo, Jéssica, Muir, Kenneth, Ito, Shuji, Liu, Xiaoxi, Yamanashi, Yuji, Furukawa, Yoichi, Morisaki, Takayuki, Murakami, Yoshinori, Muto, Kaori, Nagai, Akiko, Obara, Wataru, Yamaji, Ken, Takahashi, Kazuhisa, Asai, Satoshi, Takahashi, Yasuo, Suzuki, Takao, Sinozaki, Nobuaki, Yamaguchi, Hiroki, Nordestgaard, Borge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Andreas, Stroomberg, Hein V., Sørensen, Karina Dalsgaard, Borre, Michael, Strom, Sara S., Wang, Ying, Loos, Ruth J.F., Wang, Anqi, Shen, Jiayi, Rodriguez, Alex A., Saunders, Edward J., Chen, Fei, Janivara, Rohini, Darst, Burcu F., Sheng, Xin, Xu, Yili, Chou, Alisha J., Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Plym, Anna, Sahimi, Ali, Hoffman, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Laisk, Triin, Figuerêdo, Jéssica, Muir, Kenneth, Ito, Shuji, Liu, Xiaoxi, Yamanashi, Yuji, Furukawa, Yoichi, Morisaki, Takayuki, Murakami, Yoshinori, Muto, Kaori, Nagai, Akiko, Obara, Wataru, Yamaji, Ken, Takahashi, Kazuhisa, Asai, Satoshi, Takahashi, Yasuo, Suzuki, Takao, Sinozaki, Nobuaki, Yamaguchi, Hiroki, Nordestgaard, Borge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Andreas, Stroomberg, Hein V., Sørensen, Karina Dalsgaard, Borre, Michael, Strom, Sara S., Wang, Ying, and Loos, Ruth J.F.
- Abstract
The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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- 2023
240. New insights in the mechanisms of weight-loss maintenance:Summary from a Pennington symposium
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Flanagan, Emily W., Spann, Redin, Berry, Sarah E., Berthoud, Hans Rudolf, Broyles, Stephanie, Foster, Gary D., Krakoff, Jonathan, Loos, Ruth J.F., Lowe, Michael R., Ostendorf, Danielle M., Powell-Wiley, Tiffany M., Redman, Leanne M., Rosenbaum, Michael, Schauer, Philip R., Seeley, Randy J., Swinburn, Boyd A., Hall, Kevin, Ravussin, Eric, Flanagan, Emily W., Spann, Redin, Berry, Sarah E., Berthoud, Hans Rudolf, Broyles, Stephanie, Foster, Gary D., Krakoff, Jonathan, Loos, Ruth J.F., Lowe, Michael R., Ostendorf, Danielle M., Powell-Wiley, Tiffany M., Redman, Leanne M., Rosenbaum, Michael, Schauer, Philip R., Seeley, Randy J., Swinburn, Boyd A., Hall, Kevin, and Ravussin, Eric
- Abstract
Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.
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- 2023
241. Editorial overview:Fat tissue in focus: Assembled deeply insightful perspectives on state-of-the-art explorations
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Gerhart-Hines, Zach, Loos, Ruth, Gerhart-Hines, Zach, and Loos, Ruth
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- 2023
242. Discrepancy between predicted and measured exercise intensity for eliciting the maximal rate of lipid oxidation
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Kittrell, Hannah D., DiMenna, Fred J., Arad, Avigdor D., Oh, Wonsuk, Hofer, Ira, Walker, Ryan W., Loos, Ruth J.F., Albu, Jeanine B., Nadkarni, Girish N., Kittrell, Hannah D., DiMenna, Fred J., Arad, Avigdor D., Oh, Wonsuk, Hofer, Ira, Walker, Ryan W., Loos, Ruth J.F., Albu, Jeanine B., and Nadkarni, Girish N.
- Abstract
Background and aims: Ectopic lipid storage is implicated in type 2 diabetes pathogenesis; hence, exercise to deplete stores (i.e., at the intensity that allows for maximal rate of lipid oxidation; MLO) might be optimal for restoring metabolic health. This intensity (“Fatmax”) is estimated during incremental exercise (“Fatmax test”). However, in “the field” general recommendations exist regarding a range of percentages of maximal heart rate (HR) to elicit MLO. The degree to which this range is aligned with measured Fatmax has not been investigated. We compared measured HR at Fatmax, with maximal HR percentages within the typically recommended range in a sample of 26 individuals (Female: n = 11, European ancestry: n = 17). Methods and results: Subjects completed a modified Fatmax test with a 5-min warmup, followed by incremental stages starting at 15 W with work rate increased by 15 W every 5 min until termination criteria were reached. Pulmonary gas exchange was recorded and average values for V˙ o2 and V˙ co2 for the final minute of each stage were used to estimate substrate-oxidation rates. We modeled lipid-oxidation kinetics using a sinusoidal model and expressed MLO relative to peak V˙ o2 and HR. Bland-Altman analysis demonstrated lack of concordance between HR at Fatmax and at 50%, 70%, and 80% of age-predicted maximum with a mean difference of 23 b·min−1. Conclusion: Our results indicate that estimated “fat-burning” heart rate zones are inappropriate for prescribing exercise to elicit MLO and we recommend direct individual exercise lipid oxidation measurements to elicit these values.
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- 2023
243. PFAS Exposures and the Human Metabolome:A Systematic Review of Epidemiological Studies
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India-Aldana, Sandra, Yao, Meizhen, Midya, Vishal, Colicino, Elena, Chatzi, Leda, Chu, Jaime, Gennings, Chris, Jones, Dean P., Loos, Ruth J.F., Setiawan, Veronica W., Smith, Mathew Ryan, Walker, Ryan W., Barupal, Dinesh, Walker, Douglas I., Valvi, Damaskini, India-Aldana, Sandra, Yao, Meizhen, Midya, Vishal, Colicino, Elena, Chatzi, Leda, Chu, Jaime, Gennings, Chris, Jones, Dean P., Loos, Ruth J.F., Setiawan, Veronica W., Smith, Mathew Ryan, Walker, Ryan W., Barupal, Dinesh, Walker, Douglas I., and Valvi, Damaskini
- Abstract
Purpose of Review: There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In this systematic review, we aimed to identify consistent findings between PFAS and metabolomic signatures. We conducted a search matching specific keywords that was independently reviewed by two authors on two databases (EMBASE and PubMed) from their inception through July 19, 2022 following PRISMA guidelines. Recent Findings: We identified a total of 28 eligible observational studies that evaluated the associations between 31 different PFAS exposures and metabolomics in humans. The most common exposure evaluated was legacy long-chain PFAS. Population sample sizes ranged from 40 to 1,105 participants at different stages across the lifespan. A total of 19 studies used a non-targeted metabolomics approach, 7 used targeted approaches, and 2 included both. The majority of studies were cross-sectional (n = 25), including four with prospective analyses of PFAS measured prior to metabolomics. Summary: Most frequently reported associations across studies were observed between PFAS and amino acids, fatty acids, glycerophospholipids, glycerolipids, phosphosphingolipids, bile acids, ceramides, purines, and acylcarnitines. Corresponding metabolic pathways were also altered, including lipid, amino acid, carbohydrate, nucleotide, energy metabolism, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. We found consistent evidence across studies indicating PFAS-induced alterations in lipid and amino acid metabolites, which may be involved in energy and cell membrane disruption.
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- 2023
244. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy
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Kiryluk, Krzysztof, Sanchez-Rodriguez, Elena, Zhou, Xu Jie, Zanoni, Francesca, Liu, Lili, Mladkova, Nikol, Khan, Atlas, Marasa, Maddalena, Zhang, Jun Y., Balderes, Olivia, Sanna-Cherchi, Simone, Bomback, Andrew S., Canetta, Pietro A., Appel, Gerald B., Radhakrishnan, Jai, Trimarchi, Hernan, Sprangers, Ben, Cattran, Daniel C., Reich, Heather, Pei, York, Ravani, Pietro, Galesic, Kresimir, Maixnerova, Dita, Tesar, Vladimir, Stengel, Benedicte, Metzger, Marie, Canaud, Guillaume, Maillard, Nicolas, Berthoux, Francois, Berthelot, Laureline, Pillebout, Evangeline, Monteiro, Renato, Nelson, Raoul, Wyatt, Robert J., Smoyer, William, Mahan, John, Samhar, Al Akash, Hidalgo, Guillermo, Quiroga, Alejandro, Weng, Patricia, Sreedharan, Raji, Selewski, David, Davis, Keefe, Kallash, Mahmoud, Vasylyeva, Tetyana L., Rheault, Michelle, Chishti, Aftab, Ranch, Daniel, Wenderfer, Scott E., Samsonov, Dmitry, Claes, Donna J., Akchurin, Oleh, Goumenos, Dimitrios, Stangou, Maria, Nagy, Judit, Kovacs, Tibor, Fiaccadori, Enrico, Amoroso, Antonio, Barlassina, Cristina, Cusi, Daniele, Del Vecchio, Lucia, Battaglia, Giovanni Giorgio, Bodria, Monica, Boer, Emanuela, Bono, Luisa, Boscutti, Giuliano, Caridi, Gianluca, Lugani, Francesca, Ghiggeri, Gian Marco, Coppo, Rosanna, Peruzzi, Licia, Esposito, Vittoria, Esposito, Ciro, Feriozzi, Sandro, Polci, Rosaria, Frasca, Giovanni, Galliani, Marco, Garozzo, Maurizio, Mitrotti, Adele, Gesualdo, Loreto, Granata, Simona, Zaza, Gianluigi, Londrino, Francesco, Magistroni, Riccardo, Pisani, Isabella, Magnano, Andrea, Marcantoni, Carmelita, Messa, Piergiorgio, Mignani, Renzo, Pani, Antonello, Ponticelli, Claudio, Roccatello, Dario, Salvadori, Maurizio, Salvi, Erica, Santoro, Domenico, Gembillo, Guido, Savoldi, Silvana, Spotti, Donatella, Zamboli, Pasquale, Izzi, Claudia, Alberici, Federico, Delbarba, Elisa, Florczak, Michał, Krata, Natalia, Mucha, Krzysztof, Pączek, Leszek, Niemczyk, Stanisław, Moszczuk, Barbara, Pańczyk-Tomaszewska, Malgorzata, Mizerska-Wasiak, Malgorzata, Perkowska-Ptasińska, Agnieszka, Bączkowska, Teresa, Durlik, Magdalena, Pawlaczyk, Krzysztof, Sikora, Przemyslaw, Zaniew, Marcin, Kaminska, Dorota, Krajewska, Magdalena, Kuzmiuk-Glembin, Izabella, Heleniak, Zbigniew, Bullo-Piontecka, Barbara, Liberek, Tomasz, Dębska-Slizien, Alicja, Hryszko, Tomasz, Materna-Kiryluk, Anna, Miklaszewska, Monika, Szczepańska, Maria, Dyga, Katarzyna, Machura, Edyta, Siniewicz-Luzeńczyk, Katarzyna, Pawlak-Bratkowska, Monika, Tkaczyk, Marcin, Runowski, Dariusz, Kwella, Norbert, Drożdż, Dorota, Habura, Ireneusz, Kronenberg, Florian, Prikhodina, Larisa, van Heel, David, Fontaine, Bertrand, Cotsapas, Chris, Wijmenga, Cisca, Franke, Andre, Annese, Vito, Gregersen, Peter K., Parameswaran, Sreeja, Weirauch, Matthew, Kottyan, Leah, Harley, John B., Suzuki, Hitoshi, Narita, Ichiei, Goto, Shin, Lee, Hajeong, Kim, Dong Ki, Kim, Yon Su, Park, Jin Ho, Cho, Be Long, Choi, Murim, Van Wijk, Ans, Huerta, Ana, Ars, Elisabet, Ballarin, Jose, Lundberg, Sigrid, Vogt, Bruno, Mani, Laila Yasmin, Caliskan, Yasar, Barratt, Jonathan, Abeygunaratne, Thilini, Kalra, Philip A., Gale, Daniel P., Panzer, Ulf, Rauen, Thomas, Floege, Jürgen, Schlosser, Pascal, Ekici, Arif B., Eckardt, Kai Uwe, Chen, Nan, Xie, Jingyuan, Lifton, Richard P., Loos, Ruth J.F., Kenny, Eimear E., Ionita-Laza, Iuliana, Köttgen, Anna, Julian, Bruce A., Novak, Jan, Scolari, Francesco, Zhang, Hong, Gharavi, Ali G., Kiryluk, Krzysztof, Sanchez-Rodriguez, Elena, Zhou, Xu Jie, Zanoni, Francesca, Liu, Lili, Mladkova, Nikol, Khan, Atlas, Marasa, Maddalena, Zhang, Jun Y., Balderes, Olivia, Sanna-Cherchi, Simone, Bomback, Andrew S., Canetta, Pietro A., Appel, Gerald B., Radhakrishnan, Jai, Trimarchi, Hernan, Sprangers, Ben, Cattran, Daniel C., Reich, Heather, Pei, York, Ravani, Pietro, Galesic, Kresimir, Maixnerova, Dita, Tesar, Vladimir, Stengel, Benedicte, Metzger, Marie, Canaud, Guillaume, Maillard, Nicolas, Berthoux, Francois, Berthelot, Laureline, Pillebout, Evangeline, Monteiro, Renato, Nelson, Raoul, Wyatt, Robert J., Smoyer, William, Mahan, John, Samhar, Al Akash, Hidalgo, Guillermo, Quiroga, Alejandro, Weng, Patricia, Sreedharan, Raji, Selewski, David, Davis, Keefe, Kallash, Mahmoud, Vasylyeva, Tetyana L., Rheault, Michelle, Chishti, Aftab, Ranch, Daniel, Wenderfer, Scott E., Samsonov, Dmitry, Claes, Donna J., Akchurin, Oleh, Goumenos, Dimitrios, Stangou, Maria, Nagy, Judit, Kovacs, Tibor, Fiaccadori, Enrico, Amoroso, Antonio, Barlassina, Cristina, Cusi, Daniele, Del Vecchio, Lucia, Battaglia, Giovanni Giorgio, Bodria, Monica, Boer, Emanuela, Bono, Luisa, Boscutti, Giuliano, Caridi, Gianluca, Lugani, Francesca, Ghiggeri, Gian Marco, Coppo, Rosanna, Peruzzi, Licia, Esposito, Vittoria, Esposito, Ciro, Feriozzi, Sandro, Polci, Rosaria, Frasca, Giovanni, Galliani, Marco, Garozzo, Maurizio, Mitrotti, Adele, Gesualdo, Loreto, Granata, Simona, Zaza, Gianluigi, Londrino, Francesco, Magistroni, Riccardo, Pisani, Isabella, Magnano, Andrea, Marcantoni, Carmelita, Messa, Piergiorgio, Mignani, Renzo, Pani, Antonello, Ponticelli, Claudio, Roccatello, Dario, Salvadori, Maurizio, Salvi, Erica, Santoro, Domenico, Gembillo, Guido, Savoldi, Silvana, Spotti, Donatella, Zamboli, Pasquale, Izzi, Claudia, Alberici, Federico, Delbarba, Elisa, Florczak, Michał, Krata, Natalia, Mucha, Krzysztof, Pączek, Leszek, Niemczyk, Stanisław, Moszczuk, Barbara, Pańczyk-Tomaszewska, Malgorzata, Mizerska-Wasiak, Malgorzata, Perkowska-Ptasińska, Agnieszka, Bączkowska, Teresa, Durlik, Magdalena, Pawlaczyk, Krzysztof, Sikora, Przemyslaw, Zaniew, Marcin, Kaminska, Dorota, Krajewska, Magdalena, Kuzmiuk-Glembin, Izabella, Heleniak, Zbigniew, Bullo-Piontecka, Barbara, Liberek, Tomasz, Dębska-Slizien, Alicja, Hryszko, Tomasz, Materna-Kiryluk, Anna, Miklaszewska, Monika, Szczepańska, Maria, Dyga, Katarzyna, Machura, Edyta, Siniewicz-Luzeńczyk, Katarzyna, Pawlak-Bratkowska, Monika, Tkaczyk, Marcin, Runowski, Dariusz, Kwella, Norbert, Drożdż, Dorota, Habura, Ireneusz, Kronenberg, Florian, Prikhodina, Larisa, van Heel, David, Fontaine, Bertrand, Cotsapas, Chris, Wijmenga, Cisca, Franke, Andre, Annese, Vito, Gregersen, Peter K., Parameswaran, Sreeja, Weirauch, Matthew, Kottyan, Leah, Harley, John B., Suzuki, Hitoshi, Narita, Ichiei, Goto, Shin, Lee, Hajeong, Kim, Dong Ki, Kim, Yon Su, Park, Jin Ho, Cho, Be Long, Choi, Murim, Van Wijk, Ans, Huerta, Ana, Ars, Elisabet, Ballarin, Jose, Lundberg, Sigrid, Vogt, Bruno, Mani, Laila Yasmin, Caliskan, Yasar, Barratt, Jonathan, Abeygunaratne, Thilini, Kalra, Philip A., Gale, Daniel P., Panzer, Ulf, Rauen, Thomas, Floege, Jürgen, Schlosser, Pascal, Ekici, Arif B., Eckardt, Kai Uwe, Chen, Nan, Xie, Jingyuan, Lifton, Richard P., Loos, Ruth J.F., Kenny, Eimear E., Ionita-Laza, Iuliana, Köttgen, Anna, Julian, Bruce A., Novak, Jan, Scolari, Francesco, Zhang, Hong, and Gharavi, Ali G.
- Abstract
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.
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- 2023
245. Role of sociodemographic, clinical, behavioral, and molecular factors in precision prevention of type 2 diabetes: a systematic review
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Bodhini, Dhanasekaran, Morton, Robert W., Santhakumar, Vanessa, Nakabuye, Mariam, Pomares-Millan, Hugo, Clemmensen, Christoffer, Fitzpatrick, Stephanie L., Guasch-Ferre, Marta, Pankow, James S., Ried-Larsen, Mathias, Franks, Paul W., Tobias, Deirdre K., Merino, Jordi, Mohan, Viswanathan, and Loos, Ruth J.F.
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Article - Abstract
The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular characteristics modify the efficacy of dietary or lifestyle interventions to prevent T2D. Among the 80 publications that met our criteria for inclusion, the evidence was low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. We found evidence, albeit low certainty, to support conclusions that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.
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- 2023
246. Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications
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Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry J., Yin, Xianyong, Lorenz, Kim M., Mandla, Ravi, Huerta-Chagoya, Alicia, Rayner, Nigel W., Bocher, Ozvan, Ana Luiza de, S. V. Arruda, Sonehara, Kyuto, Namba, Shinichi, Lee, Simon S. K., Preuss, Michael H., Petty, Lauren E., Schroeder, Philip, Vanderwerff, Brett, Kals, Mart, Bragg, Fiona, Lin, Kuang, Guo, Xiuqing, Zhang, Weihua, Yao, Jie, Kim, Young Jin, Graff, Mariaelisa, Takeuchi, Fumihiko, Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Moon, Sanghoon, Scott, Robert A., Cook, James P., Lee, Jung-Jin, Pan, Ian, Taliun, Daniel, Parra, Esteban J., Chai, Jin-Fang, Bielak, Lawrence F., Tabara, Yasuharu, Hai, Yang, Thorleifsson, Gudmar, Grarup, Niels, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloé, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Kwak, Soo-Heon, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Nongmaithem, Suraj S., Noordam, Raymond, Lim, Victor J. Y., Tam, Claudia H. T., Joo, Yoonjung Yoonie, Chen, Chien-Hsiun, Raffield, Laura M., Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R., Chen, Guanjie, Brody, Jennifer A., Kabagambe, Edmond, An, Ping, Xiang, Anny H., Choi, Hyeok Sun, Cade, Brian E., Tan, Jingyi, Alaine Broadaway, K., Williamson, Alice, Kamali, Zoha, Cui, Jinrui, Adair, Linda S., Adeyemo, Adebowale, Aguilar-Salinas, Carlos A., Ahluwalia, Tarunveer S., Anand, Sonia S., Bertoni, Alain, Bork-Jensen, Jette, Brandslund, Ivan, Buchanan, Thomas A., Burant, Charles F., Butterworth, Adam S., Canouil, Mickaël, Chan, Juliana C. N., Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, Cushman, Mary, Danesh, John, Das, Swapan K., Janaka de Silva, H., Dedoussis, George, Dimitrov, Latchezar, Doumatey, Ayo P., Du, Shufa, Duan, Qing, Eckardt, Kai-Uwe, Emery, Leslie S., Evans, Daniel S., Evans, Michele K., Fischer, Krista, Floyd, James S., Ford, Ian, Franco, Oscar H., Frayling, Timothy M., Freedman, Barry I., Genter, Pauline, Gerstein, Hertzel C., Giedraitis, Vilmantas, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Gordon-Larsen, Penny, Gross, Myron, Guare, Lindsay A., Hackinger, Sophie, Han, Sohee, Hattersley, Andrew T., Herder, Christian, Horikoshi, Momoko, Howard, Annie-Green, Hsueh, Willa, Huang, Mengna, Huang, Wei, Hung, Yi-Jen, Hwang, Mi Yeong, Hwu, Chii-Min, Ichihara, Sahoko, Ikram, Mohammad Arfan, Ingelsson, Martin, Islam, Md. Tariqul, Isono, Masato, Jang, Hye-Mi, Jasmine, Farzana, Jiang, Guozhi, Jonas, Jost B., Jørgensen, Torben, Kandeel, Fouad R., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kaur, Varinderpal, Kawaguchi, Takahisa, Keaton, Jacob M., Kho, Abel N., Khor, Chiea-Chuen, Kibriya, Muhammad G., Kim, Duk-Hwan, Kronenberg, Florian, Kuusisto, Johanna, Läll, Kristi, Lange, Leslie A., Lee, Kyung Min, Lee, Myung-Shik, Lee, Nanette R., Leong, Aaron, Li, Liming, Li, Yun, Li-Gao, Ruifang, Lithgart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Locke, Adam E., Louie, Tin, Luan, Jian’an, Luk, Andrea O., Luo, Xi, Lv, Jun, Lynch, Julie A., Lyssenko, Valeriya, Maeda, Shiro, Mamakou, Vasiliki, Mansuri, Sohail Rafik, Matsuda, Koichi, Meitinger, Thomas, Metspalu, Andres, Mo, Huan, Morris, Andrew D., Nadler, Jerry L., Nalls, Michael A., Nayak, Uma, Ntalla, Ioanna, Okada, Yukinori, Orozco, Lorena, Patel, Sanjay R., Patil, Snehal, Pei, Pei, Pereira, Mark A, Peters, Annette, Pirie, Fraser J., Polikowsky, Hannah G., Porneala, Bianca, Prasad, Gauri, Rasmussen-Torvik, Laura J., Reiner, Alexander P., Roden, Michael, Rohde, Rebecca, Roll, Katheryn, Sabanayagam, Charumathi, Sandow, Kevin, Sankareswaran, Alagu, Sattar, Naveed, Schönherr, Sebastian, Shahriar, Mohammad, Shen, Botong, Shi, Jinxiu, Shin, Dong Mun, Shojima, Nobuhiro, Smith, Jennifer A., So, Wing Yee, Stančáková, Alena, Steinthorsdottir, Valgerdur, Stilp, Adrienne M., Strauch, Konstantin, Taylor, Kent D., Thorand, Barbara, Thorsteinsdottir, Unnur, Tomlinson, Brian, Tran, Tam C., Tsai, Fuu-Jen, Tuomilehto, Jaakko, Tusie-Luna, Teresa, Udler, Miriam S., Valladares-Salgado, Adan, van Dam, Rob M., van Klinken, Jan B., Varma, Rohit, Wacher-Rodarte, Niels, Wheeler, Eleanor, Wickremasinghe, Ananda R., van Dijk, Ko Willems, Witte, Daniel R., Yajnik, Chittaranjan S., Yamamoto, Ken, Yamamoto, Kenichi, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-Min, Yusuf, Salim, Zawistowski, Matthew, Zhang, Liang, Zheng, Wei, Project, Biobank Japan, BioBank, Penn Medicine, Center, Regeneron Genetics, Consortium, eMERGE, Raffel, Leslie J, Igase, Michiya, Ipp, Eli, Redline, Susan, Cho, Yoon Shin, Lind, Lars, Province, Michael A., Fornage, Myriam, Hanis, Craig L., Ingelsson, Erik, Zonderman, Alan B., Psaty, Bruce M., Wang, Ya-Xing, Rotimi, Charles N., Becker, Diane M., Matsuda, Fumihiko, Liu, Yongmei, Yokota, Mitsuhiro, Kardia, Sharon L. R., Peyser, Patricia A., Pankow, James S., Engert, James C., Bonnefond, Amélie, Froguel, Philippe, Wilson, James G., Sheu, Wayne H. H., Wu, Jer-Yuarn, Geoffrey Hayes, M., Ma, Ronald C. W., Wong, Tien-Yin, Mook-Kanamori, Dennis O., Tuomi, Tiinamaija, Chandak, Giriraj R., Collins, Francis S., Bharadwaj, Dwaipayan, Paré, Guillaume, Sale, Michèle M., Ahsan, Habibul, Motala, Ayesha A., Shu, Xiao-Ou, Park, Kyong-Soo, Jukema, J Wouter, Cruz, Miguel, Chen, Yii-Der Ida, Rich, Stephen S., McKean-Cowdin, Roberta, Grallert, Harald, Cheng, Ching-Yu, Ghanbari, Mohsen, Tai, E-Shyong, Dupuis, Josee, Kato, Norihiro, Laakso, Markku, Köttgen, Anna, Koh, Woon-Puay, Bowden, Donald W., Palmer, Colin N. A., Kooner, Jaspal S., Kooperberg, Charles, Liu, Simin, North, Kari E., Saleheen, Danish, Hansen, Torben, Pedersen, Oluf, Wareham, Nicholas J., Lee, Juyoung, Kim, Bong-Jo, Millwood, Iona Y., Walters, Robin G., Stefansson, Kari, Goodarzi, Mark O., Mohlke, Karen L., Langenberg, Claudia, Haiman, Christopher A., Loos, Ruth J. F., Florez, Jose C., Rader, Daniel J., Ritchie, Marylyn D., Zöllner, Sebastian, Mägi, Reedik, Denny, Joshua C., Yamauchi, Toshimasa, Kadowaki, Takashi, Chambers, John C., Ng, Maggie C. Y., Sim, Xueling, Below, Jennifer E., Tsao, Philip S., Chang, Kyong-Mi, McCarthy, Mark I., Meigs, James B., Mahajan, Anubha, Spracklen, Cassandra N., Mercader, Josep M., Boehnke, Michael, Rotter, Jerome I., Vujkovic, Marijana, Voight, Benjamin F., Morris, Andrew P., and Zeggini, Eleftheria
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Article - Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P
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- 2023
247. Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease
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Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H, Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B, Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N, Lo Faro, Valeria, Lopera-Maya, Esteban A, Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J, Chapman, Sinéad B, Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M, Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A, Guare, Lindsay A, Gignoux, Christopher R, Graham, Sarah E, Hornsby, Whitney E, Ingold, Nathan, Ismail, Said I, Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y, Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H, Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M, Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, De Bock, Geertruida H, Damrauer, Scott M, Douville, Nicholas J, Finer, Sarah, Fritsche, Lars G, Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J, Guo, Yu, Hunt, Karen A, Ioannidis, Alexander, Jansonius, Nomdo M, Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E, Moatamed, Babak, Nava-Aguilar, Marco A, Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Muñoz, Agustin, Shortt, Jonathan A, Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C, Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K, Franke, Lude, Gamazon, Eric R, Ganna, Andrea, Gaunt, Tom R, Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T, Lajonchere, Clara, Law, Matthew H, Li, Liming, Lindgren, Cecilia M, Loos, Ruth JF, MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M, Porteous, David J, Shavit, Jordan A, Snieder, Harold, Takano, Tomohiro, Trembath, Richard C, Vonk, Judith M, Whiteman, David C, Wicks, Stephen J, Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D, Cox, Nancy J, Fatumo, Segun, Geschwind, Daniel H, Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E, Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Mägi, Reedik, Martin, Hilary C, Medland, Sarah E, Okada, Yukinori, Palotie, Aarno V, Pasaniuc, Bogdan, Rader, Daniel J, Ritchie, Marylyn D, Sanna, Serena, Smoller, Jordan W, Stefansson, Kari, Van Heel, David A, Walters, Robin G, Zöllner, Sebastian, Biobank Of The Americas, Biobank Japan Project, BioMe, BioVU, CanPath-Ontario Health Study, China Kadoorie Biobank Collaborative Group, Colorado Center For Personalized Medicine, DeCODE Genetics, Estonian Biobank, FinnGen, Generation Scotland, Genes & Health Research Team, LifeLines, Mass General Brigham Biobank, Michigan Genomics Initiative, National Biobank Of Korea, Penn Medicine BioBank, Qatar Biobank, QSkin Sun And Health Study, Taiwan Biobank, HUNT Study, UCLA ATLAS Community Health Initiative, Uganda Genome Resource, UK Biobank, Martin, Alicia R, Willer, Cristen J, Daly, Mark J, Neale, Benjamin M, Namba, Shinichi [0000-0002-7486-3146], Guare, Lindsay A [0000-0001-6988-5319], Palta, Priit [0000-0001-9320-7008], de Bock, Geertruida H [0000-0003-3104-4471], Finer, Sarah [0000-0002-2684-4653], Jansonius, Nomdo M [0000-0002-6495-6568], Rojas-Muñoz, Agustin [0000-0001-7594-0599], Gamazon, Eric R [0000-0003-4204-8734], Ganna, Andrea [0000-0002-8147-240X], Koskela, Jukka T [0000-0002-0154-7222], MacGregor, Stuart [0000-0001-6731-8142], Palotie, Aarno V [0000-0002-2527-5874], and Apollo - University of Cambridge Repository
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biobank ,meta-analysis ,genetic association studies ,GWAS ,ancestry diversity ,phenotype harmonization - Abstract
Funder: Biogen, Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
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- 2023
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248. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
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Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Søren Karl, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Swertz, Morris, Wijmenga, Tjitske Nienke, van der Harst, Pim, Navis, Gerjan, Rots, Marianne, Wolffenbuttel, Bruce H. R., Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., Hoed, Marcel den, Epidemiology, Internal Medicine, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J, Moore, Tim, Hyppönen, Elina, den Hoed, Marcel, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Swertz, M., Wijmenga, C., van der Harst, P., Navis, G., Rots, M., Wolffenbuttel, BHR, Wang, Zhe [0000-0002-8046-4969], Emmerich, Andrew [0000-0002-0908-9924], Pillon, Nicolas J [0000-0003-1107-9490], Moore, Tim [0000-0003-4250-3370], Ameur, Adam [0000-0001-6085-6749], Bis, Joshua C [0000-0002-3409-1110], Boehnke, Michael [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Chasman, Daniel I [0000-0003-3357-0862], Smith, George Davey [0000-0002-1407-8314], de Geus, Eco JC [0000-0001-6022-2666], Dörr, Marcus [0000-0001-7471-475X], Ferrucci, Luigi [0000-0002-6273-1613], Fornage, Myriam [0000-0003-0677-8158], Garland, Theodore [0000-0002-7916-3552], Gyllensten, Ulf [0000-0002-6316-3355], Hansen, Torben [0000-0001-8748-3831], Horta, Bernardo L [0000-0001-9843-412X], Hyppönen, Elina [0000-0003-3670-9399], Johnson, W Craig [0000-0002-3161-3753], Kiemeney, Lambertus A [0000-0002-2368-1326], Laakso, Markku [0000-0002-3394-7749], Langenberg, Claudia [0000-0002-5017-7344], Lehtimäki, Terho [0000-0002-2555-4427], Magnusson, Patrik KE [0000-0002-7315-7899], Martin, Nicholas G [0000-0003-4069-8020], Melbye, Mads [0000-0001-8264-6785], Metspalu, Andres [0000-0002-3718-796X], Meyre, David [0000-0003-4850-7444], North, Kari E [0000-0002-8903-0366], Ohlsson, Claes [0000-0002-9633-2805], Oldehinkel, Albertine J [0000-0003-3925-3913], Orho-Melander, Marju [0000-0002-3578-2503], Pare, Guillaume [0000-0002-6795-4760], Park, Taesung [0000-0002-8294-590X], Pedersen, Oluf [0000-0002-3321-3972], Pers, Tune H [0000-0003-0207-4831], Polasek, Ozren [0000-0002-5765-1862], Prokopenko, Inga [0000-0003-1624-7457], Rotimi, Charles N [0000-0001-5759-053X], Sim, Xueling [0000-0002-1233-7642], Snieder, Harold [0000-0003-1949-2298], Sørensen, Thorkild IA [0000-0003-4821-430X], Spector, Tim D [0000-0002-9795-0365], Timpson, Nicholas J [0000-0002-7141-9189], Voortman, Trudy [0000-0003-2830-6813], Waeber, Gérard [0000-0003-4193-788X], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Wilson, James F [0000-0001-5751-9178], Krook, Anna [0000-0002-0891-0258], Zierath, Juleen R [0000-0001-6891-7497], Thomis, Martine AI [0000-0001-9093-2191], Loos, Ruth JF [0000-0002-8532-5087], Hoed, Marcel den [0000-0001-8081-428X], Apollo - University of Cambridge Repository, Center for Liver, Digestive and Metabolic Diseases (CLDM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Geriatrics, AMS - Ageing & Vitality, APH - Aging & Later Life, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, and AMS - Sports
- Subjects
Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,631/208/205/2138 ,610 Medicine & health ,heritability ,Actinin/genetics ,Cross-Sectional Studies ,Exercise/physiology ,Genome-Wide Association Study ,Humans ,Leisure Activities ,Sedentary Behavior ,apolipoprotein-e genotype ,Lifelines Cohort Study ,360 Social problems & social services ,692/308/575 ,Genetics ,Actinin ,Exercise ,Medicinsk genetik ,exercise ,APOLIPOPROTEIN-E GENOTYPE ,LD SCORE REGRESSION ,GENE-EXPRESSION ,EXERCISE ,COMPLEX ,PERFORMANCE ,GWAS ,HERITABILITY ,MORTALITY ,FITNESS ,360 Soziale Probleme, Sozialdienste ,692/308/2056 ,article ,gwas ,gene-expression ,mortality ,3142 Public health care science, environmental and occupational health ,fitness ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,LD score regression ,3111 Biomedicine ,610 Medizin und Gesundheit ,Medical Genetics ,complex ,performance - Abstract
Funder: Kjell och Märta Beijers Stiftelse (Kjell and Marta Beijer Foundation); doi: https://doi.org/10.13039/501100006353, Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
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- 2022
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249. Author Correction: The genomics of childhood eating behaviours
- Author
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Herle, Moritz, Abdulkadir, Mohamed, Hübel, Christopher, Ferreira, Diana Santos, Bryant-Waugh, Rachel, Loos, Ruth J. F., Bulik, Cynthia M., De Stavola, Bianca, and Micali, Nadia
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- 2021
- Full Text
- View/download PDF
250. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference
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Meng, Xiangrui, Navoly, Georgina, Giannakopoulou, Olga, Levey, Daniel F., Koller, Dora, Pathak, Gita A., Koen, Nastassja, Lin, Kuang, Adams, Mark J., Rentería, Miguel E., Feng, Yanzhe, Gaziano, J. Michael, Stein, Dan J., Zar, Heather J., Campbell, Megan L., van Heel, David A., Trivedi, Bhavi, Finer, Sarah, McQuillin, Andrew, Bass, Nick, Chundru, V. Kartik, Martin, Hilary C., Huang, Qin Qin, Valkovskaya, Maria, Chu, Chia-Yi, Kanjira, Susan, Kuo, Po-Hsiu, Chen, Hsi-Chung, Tsai, Shih-Jen, Liu, Yu-Li, Kendler, Kenneth S., Peterson, Roseann E., Cai, Na, Fang, Yu, Sen, Srijan, Scott, Laura J., Burmeister, Margit, Loos, Ruth J. F., Preuss, Michael H., Actkins, Ky’Era V., Davis, Lea K., Uddin, Monica, Wani, Agaz H., Wildman, Derek E., Aiello, Allison E., Ursano, Robert J., Kessler, Ronald C., Kanai, Masahiro, Okada, Yukinori, Sakaue, Saori, Rabinowitz, Jill A., Maher, Brion S., Uhl, George, Eaton, William, Cruz-Fuentes, Carlos S., Martinez-Levy, Gabriela A., Campos, Adrian I., Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wassertheil-Smoller, Sylvia, Jiang, Yunxuan, Tian, Chao, Martin, Nicholas G., Mitchell, Brittany L., Byrne, Enda M., Awasthi, Swapnil, Coleman, Jonathan R. I., Ripke, Stephan, Sofer, Tamar, Walters, Robin G., McIntosh, Andrew M., Polimanti, Renato, Dunn, Erin C., Stein, Murray B., Gelernter, Joel, Lewis, Cathryn M., and Kuchenbaecker, Karoline
- Abstract
Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.
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- 2024
- Full Text
- View/download PDF
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