622 results on '"Thornton, Timothy A"'
Search Results
2. A deep catalogue of protein-coding variation in 983,578 individuals
- Author
-
Sun, Kathie Y., Bai, Xiaodong, Chen, Siying, Bao, Suying, Zhang, Chuanyi, Kapoor, Manav, Backman, Joshua, Joseph, Tyler, Maxwell, Evan, Mitra, George, Gorovits, Alexander, Mansfield, Adam, Boutkov, Boris, Gokhale, Sujit, Habegger, Lukas, Marcketta, Anthony, Locke, Adam E., Ganel, Liron, Hawes, Alicia, Kessler, Michael D., Sharma, Deepika, Staples, Jeffrey, Bovijn, Jonas, Gelfman, Sahar, Di Gioia, Alessandro, Rajagopal, Veera M., Lopez, Alexander, Varela, Jennifer Rico, Alegre-Díaz, Jesús, Berumen, Jaime, Tapia-Conyer, Roberto, Kuri-Morales, Pablo, Torres, Jason, Emberson, Jonathan, Collins, Rory, Cantor, Michael, Thornton, Timothy, Kang, Hyun Min, Overton, John D., Shuldiner, Alan R., Cremona, M. Laura, Nafde, Mona, Baras, Aris, Abecasis, Gonçalo, Marchini, Jonathan, Reid, Jeffrey G., Salerno, William, and Balasubramanian, Suganthi more...
- Published
- 2024
- Full Text
- View/download PDF
Catalog
3. Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI
- Author
-
Sun, Quan, Rowland, Bryce T., Chen, Jiawen, Mikhaylova, Anna V., Avery, Christy, Peters, Ulrike, Lundin, Jessica, Matise, Tara, Buyske, Steve, Tao, Ran, Mathias, Rasika A., Reiner, Alexander P., Auer, Paul L., Cox, Nancy J., Kooperberg, Charles, Thornton, Timothy A., Raffield, Laura M., and Li, Yun more...
- Published
- 2024
- Full Text
- View/download PDF
4. An Exploration of Augmented Reality in an Introductory Engineering Graphics Course
- Author
-
Thornton, Timothy and Lammi, Matthew
- Abstract
The purpose of the study was to explore the effects of augmented reality (AR) in an introductory engineering graphics course. The study specifically examined the potential for AR to affect the spatial visualization ability of students and influence student motivation. This study included 50 students from an introductory engineering graphics course at a large southeastern US public university. The AR intervention consisted of six weekly sessions in which students were required to complete an assignment with the assistance of AR. Two quantitative measurements were employed to measure the results of the implementation. The Purdue Spatial Visualization Test: Rotations (PSVT-R) was used to measure spatial visualization ability, and the Motivated Strategies for Learning Questionnaire (MSLQ) was used to measure student motivation. Both instruments used a pre- and post-test format and were analyzed with paired t-tests. The results of the PSVT-R (p < 0.01) showed a significant difference between the pre- and post-test scores; however, this could not be solely attributed to the implementation of AR. The results of the overall MSLQ (p = 0.57) showed no significant difference between pre- and post-test scores. more...
- Published
- 2021
5. The PRIMED Consortium: Reducing disparities in polygenic risk assessment
- Author
-
Adebamowo, Sally, Adebamowo, Clement, Allred, Nicholette, Auer, Paul, Below, Jennifer, Boua, Palwende Romuald, Boulier, Kristin, Bowers, Michael, Breeyear, Joseph, Chatterjee, Nilanjan, Chikowore, Tinashe, Choi, Jaewon, Choudhury, Ananyo, Conomos, Matthew, Conti, David, Cox, Nancy, Cullina, Sinead, Darst, Burcu, Deutsch, Aaron, Ding, Yi, Edwards, Todd, Eskin, Eleazar, Fatumo, Segun, Florez, Jose, Freimer, Nelson, Fullerton, Stephanie, Ge, Tian, Geschwind, Daniel, Gignoux, Chris, Gogarten, Stephanie, Goodarzi, Mark, Guo, Xiuqing, Haiman, Christopher, Hanchard, Neil, Hazelhurst, Scott, Heavner, Ben, Heckbert, Susan, Hirbo, Jibril, Hornsby, Whitney, Hou, Kangcheng, Huang, Qinqin, Huerta, Alicia, Jiang, Guoqian, Johnston, Katherine, Kachuri, Linda, Kadowaki, Takashi, Kamiza, Abram Bunya, Kenny, Eimear, Kerns, Sarah, Khan, Alyna, Kim, Joohyun, Konigsberg, Iain, Kooperberg, Charles, Kosel, Matt, Kraft, Peter, Kullo, Iftikhar, Kwak, Soo-Heon, Lange, Leslie, Lange, Ethan, Le Marchand, Loic, Lee, Hyunsuk, Leong, Aaron, Li, Yun, Lin, Meng, Lohmueller, Kirk, Loos, Ruth, Lu, Kevin, Mandia, Ravi, Manning, Alisa, Martin, Alicia, Martin, Iman, Martin, Hilary, Mathias, Rasika, Meigs, James, Mercader, Josep, Mester, Rachel, Meyer, Mariah, Miller-Fleming, Tyne, Mitchell, Braxton, Mulder, Nicola, Na, Jie, Natarajan, Pradeep, Nelson, Sarah, Ng, Maggie, Norland, Kristjan, Loohuis, Loes Olde, Onengut-Gumuscu, Suna, Oneyobi, Ebuka, Ophoff, Roel, Pajukanta, Paivi, Pasaniuc, Bogdan, Patel, Aniruddh, Peters, Ulrike, Phuong, Jimmy, Preuss, Michael, Psaty, Bruce, Raffield, Laura, Ramsay, Michele, Reiner, Alexander, Rice, Kenneth, Rich, Stephen, Rotter, Jerome, Rowan, Bryce, Rowley, Robb, Ruan, Yunfeng, Sakoda, Lori, Sankararaman, Siram, Schaid, Dan, Schrider, Dan, Schroeder, Philip, Shemirani, Ruhoilah, Shortt, Jonathan, Shuey, Megan, Sim, Xueling, Smit, Roelof A.J., Smith, Johanna, Sobrin, Lucia, Stalbow, Lauren, Stilp, Adrienne, Stram, Daniel, Suzuki, Ken, Szczerbinski, Lukasz, Tao, Ran, Tayo, Bamidele, Thornton, Timothy, Truong, Buu, Tusie, Teresa, Udler, Miriam, van Heel, David, Vargas, Luciana B., Venkateswaran, Vidhya, Wang, Ying, Wessel, Jennifer, Wiley, Laura, Wilkens, Lynne, Wilson, Riley, Witte, John, Wojcik, Genevieve, Wong, Quenna, Yamauchi, Toshimasa, Yanek, Lisa, Yu, Yue, Zhang, Haoyu, Zhang, Yuji, Zhong, Michael, Kullo, Iftikhar J., Conomos, Matthew P., Nelson, Sarah C., Adebamowo, Sally N., Fullerton, Stephanie M., Gogarten, Stephanie M., Hornsby, Whitney E., Kenny, Eimear E., Khera, Amit V., Mercader, Josep M., Raffield, Laura M., Reiner, Alex, Schaid, Daniel, Wiley, Ken, and Witte, John S. more...
- Published
- 2024
- Full Text
- View/download PDF
6. Joint testing of rare variant burden scores using non-negative least squares
- Author
-
Ziyatdinov, Andrey, Mbatchou, Joelle, Marcketta, Anthony, Backman, Joshua, Gaynor, Sheila, Zou, Yuxin, Joseph, Tyler, Geraghty, Benjamin, Herman, Joseph, Watanabe, Kyoko, Ghosh, Arkopravo, Kosmicki, Jack, Locke, Adam, Thornton, Timothy, Kang, Hyun Min, Ferreira, Manuel, Baras, Aris, Abecasis, Goncalo, and Marchini, Jonathan more...
- Published
- 2024
- Full Text
- View/download PDF
7. Genotyping, sequencing and analysis of 140,000 adults from Mexico City
- Author
-
Ziyatdinov, Andrey, Torres, Jason, Alegre-Díaz, Jesús, Backman, Joshua, Mbatchou, Joelle, Turner, Michael, Gaynor, Sheila M., Joseph, Tyler, Zou, Yuxin, Liu, Daren, Wade, Rachel, Staples, Jeffrey, Panea, Razvan, Popov, Alex, Bai, Xiaodong, Balasubramanian, Suganthi, Habegger, Lukas, Lanche, Rouel, Lopez, Alex, Maxwell, Evan, Jones, Marcus, García-Ortiz, Humberto, Ramirez-Reyes, Raul, Santacruz-Benítez, Rogelio, Nag, Abhishek, Smith, Katherine R., Damask, Amy, Lin, Nan, Paulding, Charles, Reppell, Mark, Zöllner, Sebastian, Jorgenson, Eric, Salerno, William, Petrovski, Slavé, Overton, John, Reid, Jeffrey, Thornton, Timothy A., Abecasis, Gonçalo, Berumen, Jaime, Orozco-Orozco, Lorena, Collins, Rory, Baras, Aris, Hill, Michael R., Emberson, Jonathan R., Marchini, Jonathan, Kuri-Morales, Pablo, and Tapia-Conyer, Roberto more...
- Published
- 2023
- Full Text
- View/download PDF
8. An Examination of Skill Requirements for Augmented Reality and Virtual Reality Job Advertisements
- Author
-
Verma, Amit, Purohit, Pratibha, Thornton, Timothy, and Lamsal, Kamal
- Abstract
The fields of augmented reality (AR) and virtual reality (VR) have seen massive growth in recent years. Numerous degree programs have started to redesign their curricula to meet the high market demand for people qualified to fill related job positions. In this paper, the authors perform a content analysis of online job postings hosted on Indeed.com and provide a skill classification framework for AR/VR job positions. Furthermore, they present a ranking of the relevant skills for such positions. The paper contributes to the extant literature on curriculum design in degree programs by presenting the popular skills in the AR/VR domain. more...
- Published
- 2023
- Full Text
- View/download PDF
9. Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program
- Author
-
Hu, Xiaowei, Qiao, Dandi, Kim, Wonji, Moll, Matthew, Balte, Pallavi P, Lange, Leslie A, Bartz, Traci M, Kumar, Rajesh, Li, Xingnan, Yu, Bing, Cade, Brian E, Laurie, Cecelia A, Sofer, Tamar, Ruczinski, Ingo, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Gabriel, Stacy, Gupta, Namrata, Dugan-Perez, Shannon, Cupples, L Adrienne, Loehr, Laura R, Jain, Deepti, Rotter, Jerome I, Wilson, James G, Psaty, Bruce M, Fornage, Myriam, Morrison, Alanna C, Vasan, Ramachandran S, Washko, George, Rich, Stephen S, O’Connor, George T, Bleecker, Eugene, Kaplan, Robert C, Kalhan, Ravi, Redline, Susan, Gharib, Sina A, Meyers, Deborah, Ortega, Victor, Dupuis, Josée, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Silverman, Edwin K, Barr, R Graham, Thornton, Timothy A, Wheeler, Heather E, Group, TOPMed Lung Working, Cho, Michael H, Im, Hae Kyung, and Manichaikul, Ani more...
- Subjects
Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Clinical Research ,Lung ,Prevention ,Tobacco ,Chronic Obstructive Pulmonary Disease ,Tobacco Smoke and Health ,Respiratory ,Good Health and Well Being ,Humans ,National Heart ,Lung ,and Blood Institute (U.S.) ,Pulmonary Disease ,Chronic Obstructive ,Risk Factors ,Transcriptome ,United States ,TOPMed Lung Working Group ,cross-ethnic portability ,gene expression ,integrative analysis ,polygenic transcriptome risk score ,pulmonary disease ,risk prediction ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p more...
- Published
- 2022
10. An examination of skill requirements for Augmented Reality and Virtual Reality job advertisements
- Author
-
Verma, Amit, Purohit, Pratibha, Thornton, Timothy, and Lamsal, Kamal
- Subjects
Computer Science - Computers and Society - Abstract
The field of Augmented Reality (AR) and Virtual Reality (VR) has seen massive growth in recent years. Numerous degree programs have started to redesign their curricula to meet the high market demand of such job positions. In this paper, we performed a content analysis of online job postings hosted on Indeed.com and provided a skill classification framework for AR/VR job positions. Furthermore, we present a ranking of the relevant skills for the job position. Overall, we noticed that technical skills like UI/UX design, software design, asset design and graphics rendering are highly desirable for AR/VR positions. Our findings regarding prominent skill categories could be beneficial for the human resource departments as well as enhancing existing course curricula to tailor to the high market demand., Comment: Preprint submitted to Sage more...
- Published
- 2021
11. A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels
- Author
-
Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C. more...
- Published
- 2024
- Full Text
- View/download PDF
12. Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative
- Author
-
Little, Amarise, Hu, Yao, Sun, Quan, Jain, Deepti, Broome, Jai, Chen, Ming-Huei, Thibord, Florian, McHugh, Caitlin, Surendran, Praveen, Blackwell, Thomas W, Brody, Jennifer A, Bhan, Arunoday, Chami, Nathalie, de Vries, Paul S, Ekunwe, Lynette, Heard-Costa, Nancy, Hobbs, Brian D, Manichaikul, Ani, Moon, Jee-Young, Preuss, Michael H, Ryan, Kathleen, Wang, Zhe, Wheeler, Marsha, Yanek, Lisa R, Abecasis, Goncalo R, Almasy, Laura, Beaty, Terri H, Becker, Lewis C, Blangero, John, Boerwinkle, Eric, Butterworth, Adam S, Choquet, Hélène, Correa, Adolfo, Curran, Joanne E, Faraday, Nauder, Fornage, Myriam, Glahn, David C, Hou, Lifang, Jorgenson, Eric, Kooperberg, Charles, Lewis, Joshua P, Lloyd-Jones, Donald M, Loos, Ruth JF, Min, Yuan-I, Mitchell, Braxton D, Morrison, Alanna C, Nickerson, Deborah A, North, Kari E, O'Connell, Jeffrey R, Pankratz, Nathan, Psaty, Bruce M, Vasan, Ramachandran S, Rich, Stephen S, Rotter, Jerome I, Smith, Albert V, Smith, Nicholas L, Tang, Hua, Tracy, Russell P, Conomos, Matthew P, Laurie, Cecelia A, Mathias, Rasika A, Li, Yun, Auer, Paul L, Consortium, NHLBI Trans-Omics for Precision Medicine, Thornton, Timothy, Reiner, Alexander P, Johnson, Andrew D, and Raffield, Laura M more...
- Subjects
Biological Sciences ,Genetics ,Hematology ,Biotechnology ,Clinical Research ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Blood Platelets ,Genome-Wide Association Study ,Humans ,National Heart ,Lung ,and Blood Institute (U.S.) ,Phenotype ,Polymorphism ,Single Nucleotide ,Precision Medicine ,United States ,NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits. more...
- Published
- 2022
13. Protein prediction for trait mapping in diverse populations
- Author
-
Schubert, Ryan, Geoffroy, Elyse, Gregga, Isabelle, Mulford, Ashley J, Aguet, Francois, Ardlie, Kristin, Gerszten, Robert, Clish, Clary, Van Den Berg, David, Taylor, Kent D, Durda, Peter, Johnson, W Craig, Cornell, Elaine, Guo, Xiuqing, Liu, Yongmei, Tracy, Russell, Conomos, Matthew, Blackwell, Tom, Papanicolaou, George, Lappalainen, Tuuli, Mikhaylova, Anna V, Thornton, Timothy A, Cho, Michael H, Gignoux, Christopher R, Lange, Leslie, Lange, Ethan, Rich, Stephen S, Rotter, Jerome I, Manichaikul, Ani, Im, Hae Kyung, and Wheeler, Heather E more...
- Subjects
Biological Sciences ,Genetics ,Atherosclerosis ,Biotechnology ,Human Genome ,Generic health relevance ,Good Health and Well Being ,Female ,Gene Frequency ,Genetic Association Studies ,Humans ,Male ,Models ,Genetic ,Pilot Projects ,Polymorphism ,Single Nucleotide ,Proteins ,Proteome ,Quantitative Trait Loci ,NHLBI TOPMed Consortium ,General Science & Technology - Abstract
Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises ∼50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10.5281/zenodo.4837327. more...
- Published
- 2022
14. Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program
- Author
-
Mikhaylova, Anna V, McHugh, Caitlin P, Polfus, Linda M, Raffield, Laura M, Boorgula, Meher Preethi, Blackwell, Thomas W, Brody, Jennifer A, Broome, Jai, Chami, Nathalie, Chen, Ming-Huei, Conomos, Matthew P, Cox, Corey, Curran, Joanne E, Daya, Michelle, Ekunwe, Lynette, Glahn, David C, Heard-Costa, Nancy, Highland, Heather M, Hobbs, Brian D, Ilboudo, Yann, Jain, Deepti, Lange, Leslie A, Miller-Fleming, Tyne W, Min, Nancy, Moon, Jee-Young, Preuss, Michael H, Rosen, Jonathon, Ryan, Kathleen, Smith, Albert V, Sun, Quan, Surendran, Praveen, de Vries, Paul S, Walter, Klaudia, Wang, Zhe, Wheeler, Marsha, Yanek, Lisa R, Zhong, Xue, Abecasis, Goncalo R, Almasy, Laura, Barnes, Kathleen C, Beaty, Terri H, Becker, Lewis C, Blangero, John, Boerwinkle, Eric, Butterworth, Adam S, Chavan, Sameer, Cho, Michael H, Choquet, Hélène, Correa, Adolfo, Cox, Nancy, DeMeo, Dawn L, Faraday, Nauder, Fornage, Myriam, Gerszten, Robert E, Hou, Lifang, Johnson, Andrew D, Jorgenson, Eric, Kaplan, Robert, Kooperberg, Charles, Kundu, Kousik, Laurie, Cecelia A, Lettre, Guillaume, Lewis, Joshua P, Li, Bingshan, Li, Yun, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani, Meyers, Deborah A, Mitchell, Braxton D, Morrison, Alanna C, Ngo, Debby, Nickerson, Deborah A, Nongmaithem, Suraj, North, Kari E, O’Connell, Jeffrey R, Ortega, Victor E, Pankratz, Nathan, Perry, James A, Psaty, Bruce M, Rich, Stephen S, Soranzo, Nicole, Rotter, Jerome I, Silverman, Edwin K, Smith, Nicholas L, Tang, Hua, Tracy, Russell P, Thornton, Timothy A, Vasan, Ramachandran S, Zein, Joe, Mathias, Rasika A, Consortium, NHLBI Trans-Omics for Precision Medicine, Reiner, Alexander P, and Auer, Paul L more...
- Subjects
Human Genome ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Good Health and Well Being ,Asthma ,Biomarkers ,Dermatitis ,Atopic ,Genetic Predisposition to Disease ,Genome ,Human ,Genome-Wide Association Study ,Humans ,Leukocytes ,National Heart ,Lung ,and Blood Institute (U.S.) ,Phenotype ,Polymorphism ,Single Nucleotide ,Prognosis ,Proteome ,Pulmonary Disease ,Chronic Obstructive ,Quantitative Trait Loci ,United Kingdom ,United States ,Whole Genome Sequencing ,NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ,blood-cell counts ,whole-genome sequencing ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs. more...
- Published
- 2021
15. Variant-specific inflation factors for assessing population stratification at the phenotypic variance level.
- Author
-
Sofer, Tamar, Zheng, Xiuwen, Laurie, Cecelia A, Gogarten, Stephanie M, Brody, Jennifer A, Conomos, Matthew P, Bis, Joshua C, Thornton, Timothy A, Szpiro, Adam, O'Connell, Jeffrey R, Lange, Ethan M, Gao, Yan, Cupples, L Adrienne, Psaty, Bruce M, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, and Rice, Kenneth M more...
- Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ,Humans ,Sample Size ,Gene Frequency ,Phenotype ,Algorithms ,Computer Simulation ,Genetic Variation ,Genome-Wide Association Study - Abstract
In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term 'variance stratification'. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We develop a procedure to compute variant-specific inflation factors, and show how it can be used for diagnosis of genetic association analyses on pooled individual level data from multiple studies. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We illustrate the variance stratification problem, its solutions, and the proposed diagnostic procedure, in simulations and in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI. more...
- Published
- 2021
16. Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium
- Author
-
Lin, Bridget M, Grinde, Kelsey E, Brody, Jennifer A, Breeze, Charles E, Raffield, Laura M, Mychaleckyj, Josyf C, Thornton, Timothy A, Perry, James A, Baier, Leslie J, de las Fuentes, Lisa, Guo, Xiuqing, Heavner, Benjamin D, Hanson, Robert L, Hung, Yi-Jen, Qian, Huijun, Hsiung, Chao A, Hwang, Shih-Jen, Irvin, Margaret R, Jain, Deepti, Kelly, Tanika N, Kobes, Sayuko, Lange, Leslie, Lash, James P, Li, Yun, Liu, Xiaoming, Mi, Xuenan, Musani, Solomon K, Papanicolaou, George J, Parsa, Afshin, Reiner, Alex P, Salimi, Shabnam, Sheu, Wayne H-H, Shuldiner, Alan R, Taylor, Kent D, Smith, Albert V, Smith, Jennifer A, Tin, Adrienne, Vaidya, Dhananjay, Wallace, Robert B, Yamamoto, Kenichi, Sakaue, Saori, Matsuda, Koichi, Kamatani, Yoichiro, Momozawa, Yukihide, Yanek, Lisa R, Young, Betsi A, Zhao, Wei, Okada, Yukinori, Abecasis, Gonzalo, Psaty, Bruce M, Arnett, Donna K, Boerwinkle, Eric, Cai, Jianwen, Chen, Ida Yii-Der, Correa, Adolfo, Cupples, L Adrienne, He, Jiang, Kardia, Sharon LR, Kooperberg, Charles, Mathias, Rasika A, Mitchell, Braxton D, Nickerson, Deborah A, Turner, Steve T, Ramachandran, Vasan S, Rotter, Jerome I, Levy, Daniel, Kramer, Holly J, Köttgen, Anna, Consortium, NHLBI Trans-Omics for Precision Medicine, Group, TOPMed Kidney Working, Rich, Stephen S, Lin, Dan-Yu, Browning, Sharon R, and Franceschini, Nora more...
- Subjects
Epidemiology ,Health Sciences ,Biotechnology ,Human Genome ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Alleles ,Gene Frequency ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genomics ,Glomerular Filtration Rate ,Humans ,Male ,National Heart ,Lung ,and Blood Institute (U.S.) ,Polymorphism ,Single Nucleotide ,Precision Medicine ,Public Health Surveillance ,Quantitative Trait ,Heritable ,United States ,Whole Genome Sequencing ,Whole genome sequencing ,Kidney traits ,Rare variants ,Ancestry-specific variants ,Clinical Sciences ,Public Health and Health Services ,Clinical sciences - Abstract
BackgroundGenetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.MethodsWe combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.FindingsWhen testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.InterpretationThis study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry. more...
- Published
- 2021
17. Author Correction: Genotyping, sequencing and analysis of 140,000 adults from Mexico City
- Author
-
Ziyatdinov, Andrey, Torres, Jason, Alegre-Díaz, Jesús, Backman, Joshua, Mbatchou, Joelle, Turner, Michael, Gaynor, Sheila M., Joseph, Tyler, Zou, Yuxin, Liu, Daren, Wade, Rachel, Staples, Jeffrey, Panea, Razvan, Popov, Alex, Bai, Xiaodong, Balasubramanian, Suganthi, Habegger, Lukas, Lanche, Rouel, Lopez, Alex, Maxwell, Evan, Jones, Marcus, García-Ortiz, Humberto, Ramirez-Reyes, Raul, Santacruz-Benítez, Rogelio, Nag, Abhishek, Smith, Katherine R., Damask, Amy, Lin, Nan, Paulding, Charles, Reppell, Mark, Zöllner, Sebastian, Jorgenson, Eric, Salerno, William, Petrovski, Slavé, Overton, John, Reid, Jeffrey, Thornton, Timothy A., Abecasis, Gonçalo, Berumen, Jaime, Orozco-Orozco, Lorena, Collins, Rory, Baras, Aris, Hill, Michael R., Emberson, Jonathan R., Marchini, Jonathan, Kuri-Morales, Pablo, and Tapia-Conyer, Roberto more...
- Published
- 2024
- Full Text
- View/download PDF
18. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma
- Author
-
Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K., Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P., Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Daniel, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J.F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A., Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L., Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C., Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S., Pleiness, Jacob, Pollin, Toni, Post, Wendy, Powers Becker, Julia, Preethi Boorgula, Meher, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D.C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Sheu, Wayne Hui-Heng, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent, Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T., Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Williams, Scott, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Baojun, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Recto, Kathryn, Kachroo, Priyadarshini, Huan, Tianxiao, Lee, Gha Young, Bui, Helena, Lee, Dong Heon, Gereige, Jessica, Yao, Chen, Hwang, Shih-Jen, Joehanes, Roby, O’Connor, George T., and DeMeo, Dawn L. more...
- Published
- 2023
- Full Text
- View/download PDF
19. Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations
- Author
-
Horimoto, Andrea R.V.R., Boyken, Lisa A., Blue, Elizabeth E., Grinde, Kelsey E., Nafikov, Rafael A., Sohi, Harkirat K., Nato, Alejandro Q., Jr., Bis, Joshua C., Brusco, Luis I., Morelli, Laura, Ramirez, Alfredo, Dalmasso, Maria Carolina, Temple, Seth, Satizabal, Claudia, Browning, Sharon R., Seshadri, Sudha, Wijsman, Ellen M., and Thornton, Timothy A. more...
- Published
- 2023
- Full Text
- View/download PDF
20. On the cross-population generalizability of gene expression prediction models.
- Author
-
Keys, Kevin L, Mak, Angel CY, White, Marquitta J, Eckalbar, Walter L, Dahl, Andrew W, Mefford, Joel, Mikhaylova, Anna V, Contreras, María G, Elhawary, Jennifer R, Eng, Celeste, Hu, Donglei, Huntsman, Scott, Oh, Sam S, Salazar, Sandra, Lenoir, Michael A, Ye, Jimmie C, Thornton, Timothy A, Zaitlen, Noah, Burchard, Esteban G, and Gignoux, Christopher R more...
- Subjects
Humans ,Gene Expression Profiling ,Quantitative Trait Loci ,Models ,Genetic ,Reference Standards ,African Americans ,Genome-Wide Association Study ,Transcriptome ,RNA-Seq ,Models ,Genetic ,Genetics ,Developmental Biology - Abstract
The genetic control of gene expression is a core component of human physiology. For the past several years, transcriptome-wide association studies have leveraged large datasets of linked genotype and RNA sequencing information to create a powerful gene-based test of association that has been used in dozens of studies. While numerous discoveries have been made, the populations in the training data are overwhelmingly of European descent, and little is known about the generalizability of these models to other populations. Here, we test for cross-population generalizability of gene expression prediction models using a dataset of African American individuals with RNA-Seq data in whole blood. We find that the default models trained in large datasets such as GTEx and DGN fare poorly in African Americans, with a notable reduction in prediction accuracy when compared to European Americans. We replicate these limitations in cross-population generalizability using the five populations in the GEUVADIS dataset. Via realistic simulations of both populations and gene expression, we show that accurate cross-population generalizability of transcriptome prediction only arises when eQTL architecture is substantially shared across populations. In contrast, models with non-identical eQTLs showed patterns similar to real-world data. Therefore, generating RNA-Seq data in diverse populations is a critical step towards multi-ethnic utility of gene expression prediction. more...
- Published
- 2020
21. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
- Author
-
Kowalski, Madeline H, Qian, Huijun, Hou, Ziyi, Rosen, Jonathan D, Tapia, Amanda L, Shan, Yue, Jain, Deepti, Argos, Maria, Arnett, Donna K, Avery, Christy, Barnes, Kathleen C, Becker, Lewis C, Bien, Stephanie A, Bis, Joshua C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Buyske, Steve, Cai, Jianwen, Cho, Michael H, Choi, Seung Hoan, Choquet, Hélène, Cupples, L Adrienne, Cushman, Mary, Daya, Michelle, de Vries, Paul S, Ellinor, Patrick T, Faraday, Nauder, Fornage, Myriam, Gabriel, Stacey, Ganesh, Santhi K, Graff, Misa, Gupta, Namrata, He, Jiang, Heckbert, Susan R, Hidalgo, Bertha, Hodonsky, Chani J, Irvin, Marguerite R, Johnson, Andrew D, Jorgenson, Eric, Kaplan, Robert, Kardia, Sharon LR, Kelly, Tanika N, Kooperberg, Charles, Lasky-Su, Jessica A, Loos, Ruth JF, Lubitz, Steven A, Mathias, Rasika A, McHugh, Caitlin P, Montgomery, Courtney, Moon, Jee-Young, Morrison, Alanna C, Palmer, Nicholette D, Pankratz, Nathan, Papanicolaou, George J, Peralta, Juan M, Peyser, Patricia A, Rich, Stephen S, Rotter, Jerome I, Silverman, Edwin K, Smith, Jennifer A, Smith, Nicholas L, Taylor, Kent D, Thornton, Timothy A, Tiwari, Hemant K, Tracy, Russell P, Wang, Tao, Weiss, Scott T, Weng, Lu-Chen, Wiggins, Kerri L, Wilson, James G, Yanek, Lisa R, Zöllner, Sebastian, North, Kari E, Auer, Paul L, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Raffield, Laura M, Reiner, Alexander P, and Li, Yun more...
- Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ,TOPMed Hematology & Hemostasis Working Group ,Humans ,Genetic Predisposition to Disease ,Computational Biology ,Genetics ,Population ,Gene Frequency ,Linkage Disequilibrium ,Databases ,Genetic ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,African Americans ,Hispanic Americans ,United States ,Female ,Male ,Genome-Wide Association Study ,beta-Globins ,Genotyping Techniques ,Precision Medicine ,Whole Genome Sequencing ,Genetics ,Population ,Databases ,Genetic ,and over ,Developmental Biology - Abstract
Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations. more...
- Published
- 2019
22. Genetic analyses of diverse populations improves discovery for complex traits.
- Author
-
Wojcik, Genevieve L, Graff, Mariaelisa, Nishimura, Katherine K, Tao, Ran, Haessler, Jeffrey, Gignoux, Christopher R, Highland, Heather M, Patel, Yesha M, Sorokin, Elena P, Avery, Christy L, Belbin, Gillian M, Bien, Stephanie A, Cheng, Iona, Cullina, Sinead, Hodonsky, Chani J, Hu, Yao, Huckins, Laura M, Jeff, Janina, Justice, Anne E, Kocarnik, Jonathan M, Lim, Unhee, Lin, Bridget M, Lu, Yingchang, Nelson, Sarah C, Park, Sung-Shim L, Poisner, Hannah, Preuss, Michael H, Richard, Melissa A, Schurmann, Claudia, Setiawan, Veronica W, Sockell, Alexandra, Vahi, Karan, Verbanck, Marie, Vishnu, Abhishek, Walker, Ryan W, Young, Kristin L, Zubair, Niha, Acuña-Alonso, Victor, Ambite, Jose Luis, Barnes, Kathleen C, Boerwinkle, Eric, Bottinger, Erwin P, Bustamante, Carlos D, Caberto, Christian, Canizales-Quinteros, Samuel, Conomos, Matthew P, Deelman, Ewa, Do, Ron, Doheny, Kimberly, Fernández-Rhodes, Lindsay, Fornage, Myriam, Hailu, Benyam, Heiss, Gerardo, Henn, Brenna M, Hindorff, Lucia A, Jackson, Rebecca D, Laurie, Cecelia A, Laurie, Cathy C, Li, Yuqing, Lin, Dan-Yu, Moreno-Estrada, Andres, Nadkarni, Girish, Norman, Paul J, Pooler, Loreall C, Reiner, Alexander P, Romm, Jane, Sabatti, Chiara, Sandoval, Karla, Sheng, Xin, Stahl, Eli A, Stram, Daniel O, Thornton, Timothy A, Wassel, Christina L, Wilkens, Lynne R, Winkler, Cheryl A, Yoneyama, Sachi, Buyske, Steven, Haiman, Christopher A, Kooperberg, Charles, Le Marchand, Loic, Loos, Ruth JF, Matise, Tara C, North, Kari E, Peters, Ulrike, Kenny, Eimear E, and Carlson, Christopher S more...
- Subjects
Humans ,Body Height ,Cohort Studies ,Genetics ,Medical ,Multifactorial Inheritance ,Minority Groups ,African Continental Ancestry Group ,Asian Continental Ancestry Group ,Hispanic Americans ,Women's Health ,United States ,Female ,Male ,Health Status Disparities ,Genome-Wide Association Study ,Health Equity ,Genetics ,Medical ,General Science & Technology - Abstract
Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities. more...
- Published
- 2019
23. Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans
- Author
-
Wang, Heming, Cade, Brian E, Sofer, Tamar, Sands, Scott A, Chen, Han, Browning, Sharon R, Stilp, Adrienne M, Louie, Tin L, Thornton, Timothy A, Johnson, W Craig, Below, Jennifer E, Conomos, Matthew P, Evans, Daniel S, Gharib, Sina A, Guo, Xiuqing, Wood, Alexis C, Mei, Hao, Yaffe, Kristine, Loredo, Jose S, Ramos, Alberto R, Barrett-Connor, Elizabeth, Ancoli-Israel, Sonia, Zee, Phyllis C, Arens, Raanan, Shah, Neomi A, Taylor, Kent D, Tranah, Gregory J, Stone, Katie L, Hanis, Craig L, Wilson, James G, Gottlieb, Daniel J, Patel, Sanjay R, Rice, Ken, Post, Wendy S, Rotter, Jerome I, Sunyaev, Shamil R, Cai, Jianwen, Lin, Xihong, Purcell, Shaun M, Laurie, Cathy C, Saxena, Richa, Redline, Susan, and Zhu, Xiaofeng more...
- Subjects
Biological Sciences ,Genetics ,Sleep Research ,Lung ,Aged ,Chromosome Mapping ,Female ,Ferrochelatase ,Genome-Wide Association Study ,Genotype ,Hispanic or Latino ,Humans ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Polysomnography ,Sleep Apnea ,Obstructive ,White People ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 more...
- Published
- 2019
24. Generalizing polygenic risk scores from Europeans to Hispanics/Latinos
- Author
-
Grinde, Kelsey E, Qi, Qibin, Thornton, Timothy A, Liu, Simin, Shadyab, Aladdin H, Chan, Kei Hang K, Reiner, Alexander P, and Sofer, Tamar
- Subjects
Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Human Genome ,Prevention ,Computer Simulation ,Genome-Wide Association Study ,Hispanic or Latino ,Humans ,Linkage Disequilibrium ,Models ,Genetic ,Multifactorial Inheritance ,Polymorphism ,Single Nucleotide ,Risk Factors ,White People ,admixed populations ,genetic diversity ,linkage disequilibrium ,Public Health and Health Services - Abstract
Polygenic risk scores (PRSs) are weighted sums of risk allele counts of single-nucleotide polymorphisms (SNPs) associated with a disease or trait. PRSs are typically constructed based on published results from Genome-Wide Association Studies (GWASs), and the majority of which has been performed in large populations of European ancestry (EA) individuals. Although many genotype-trait associations have generalized across populations, the optimal choice of SNPs and weights for PRSs may differ between populations due to different linkage disequilibrium (LD) and allele frequency patterns. We compare various approaches for PRS construction, using GWAS results from both large EA studies and a smaller study in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL, n=12,803 ). We consider multiple approaches for selecting SNPs and for computing SNP weights. We study the performance of the resulting PRSs in an independent study of Hispanics/Latinos from the Women's Health Initiative (WHI, n=3,582 ). We support our investigation with simulation studies of potential genetic architectures in a single locus. We observed that selecting variants based on EA GWASs generally performs well, except for blood pressure trait. However, the use of EA GWASs for weight estimation was suboptimal. Using non-EA GWAS results to estimate weights improved results. more...
- Published
- 2019
25. GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations
- Author
-
Swenson, Brenton R, Louie, Tin, Lin, Henry J, Méndez-Giráldez, Raúl, Below, Jennifer E, Laurie, Cathy C, Kerr, Kathleen F, Highland, Heather, Thornton, Timothy A, Ryckman, Kelli K, Kooperberg, Charles, Soliman, Elsayed Z, Seyerle, Amanda A, Guo, Xiuqing, Taylor, Kent D, Yao, Jie, Heckbert, Susan R, Darbar, Dawood, Petty, Lauren E, McKnight, Barbara, Cheng, Susan, Bello, Natalie A, Whitsel, Eric A, Hanis, Craig L, Nalls, Mike A, Evans, Daniel S, Rotter, Jerome I, Sofer, Tamar, Avery, Christy L, and Sotoodehnia, Nona more...
- Subjects
Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Cardiovascular ,Human Genome ,Heart Disease ,Good Health and Well Being ,Electrocardiography ,Genetic Loci ,Genome-Wide Association Study ,Hispanic or Latino ,Humans ,Middle Aged ,Molecular Sequence Annotation ,Phenotype ,Polymorphism ,Single Nucleotide ,General Science & Technology - Abstract
BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (P more...
- Published
- 2019
26. Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep
- Author
-
Cade, Brian E, Chen, Han, Stilp, Adrienne M, Louie, Tin, Ancoli-Israel, Sonia, Arens, Raanan, Barfield, Richard, Below, Jennifer E, Cai, Jianwen, Conomos, Matthew P, Evans, Daniel S, Frazier-Wood, Alexis C, Gharib, Sina A, Gleason, Kevin J, Gottlieb, Daniel J, Hillman, David R, Johnson, W Craig, Lederer, David J, Lee, Jiwon, Loredo, Jose S, Mei, Hao, Mukherjee, Sutapa, Patel, Sanjay R, Post, Wendy S, Purcell, Shaun M, Ramos, Alberto R, Reid, Kathryn J, Rice, Ken, Shah, Neomi A, Sofer, Tamar, Taylor, Kent D, Thornton, Timothy A, Wang, Heming, Yaffe, Kristine, Zee, Phyllis C, Hanis, Craig L, Palmer, Lyle J, Rotter, Jerome I, Stone, Katie L, Tranah, Gregory J, Wilson, James G, Sunyaev, Shamil R, Laurie, Cathy C, Zhu, Xiaofeng, Saxena, Richa, Lin, Xihong, and Redline, Susan more...
- Subjects
Genetics ,Lung ,Sleep Research ,Clinical Research ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Cell Adhesion Molecules ,Neuronal ,Computational Biology ,Extracellular Matrix Proteins ,Female ,Gene Regulatory Networks ,Genetic Variation ,Genome-Wide Association Study ,Hexokinase ,Humans ,Hypoxia ,Interleukin-18 Receptor alpha Subunit ,Male ,Middle Aged ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Nerve Tissue Proteins ,Oxygen ,Oxyhemoglobins ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Reelin Protein ,Serine Endopeptidases ,Sleep ,Sleep Apnea Syndromes ,Young Adult ,Developmental Biology - Abstract
Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia. more...
- Published
- 2019
27. Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort
- Author
-
Loesch, Douglas P., Horimoto, Andrea R.V.R., Sarihan, Elif Irem, Inca-Martinez, Miguel, Mason, Emily, Cornejo-Olivas, Mario, Torres, Luis, Mazzetti, Pilar, Cosentino, Carlos, Sarapura-Castro, Elison, Rivera-Valdivia, Andrea, Medina, Angel C., Dieguez, Elena, Raggio, Victor, Lescano, Andres, Tumas, Vitor, Borges, Vanderci, Ferraz, Henrique B., Rieder, Carlos R., Schumacher-Schuh, Artur, Santos-Lobato, Bruno L., Velez-Pardo, Carlos, Jimenez-Del-Rio, Marlene, Lopera, Francisco, Moreno, Sonia, Chana-Cuevas, Pedro, Fernandez, William, Arboleda, Gonzalo, Arboleda, Humberto, Arboleda-Bustos, Carlos E., Yearout, Dora, Zabetian, Cyrus P., Thornton, Timothy A., Mata, Ignacio F., and O'Connor, Timothy D. more...
- Published
- 2022
- Full Text
- View/download PDF
28. Associating sleep problems with advanced cancer diagnosis, and immune checkpoint treatment outcomes: a pilot study
- Author
-
Sillah, Arthur, Peters, Ulrike, Watson, Nathaniel F., Tykodi, Scott S., Hall, Evan T., Silverman, Allison, Malen, Rachel C., Thompson, John A., Lee, Sylvia M., Bhatia, Shailender, Veatch, Joshua, Warner, Jeannie, Thornton, Timothy, and Phipps, Amanda I. more...
- Published
- 2022
- Full Text
- View/download PDF
29. Adjusting for principal components can induce collider bias in genome-wide association studies.
- Author
-
Grinde, Kelsey E., Browning, Brian L., Reiner, Alexander P., Thornton, Timothy A., and Browning, Sharon R.
- Abstract
Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models. Author summary: Principal component analysis (PCA) is a widely used technique in human genetics research. One of its most frequent applications is in the context of genetic association studies, wherein researchers use PCA to infer, and then adjust for, the genetic ancestry of study participants. Although a powerful approach, prior work has shown that PCA sometimes captures other features or data quality issues, and pre-processing steps have been suggested to address these concerns. However, the utility and downstream implications of this recommended pre-processing are not fully understood, nor are these steps universally implemented. Moreover, the vast majority of prior work in this area was conducted in studies that exclusively included individuals of European ancestry. Here, we revisit this work in the context of admixed populations—populations with diverse, mixed ancestry that have been largely underrepresented in genetics research to date. We demonstrate the unique concerns that can arise in this context and illustrate the detrimental effects that including principal components in genetic association study models can have when not implemented carefully. Altogether, we hope our work serves as a reminder of the care that must be taken—including careful pre-processing, diagnostics, and modeling choices—when implementing PCA in admixed populations and beyond. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
- View/download PDF
30. Sleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS)
- Author
-
Sillah, Arthur, Watson, Nathaniel F., Peters, Ulrike, Biggs, Mary L., Nieto, F. Javier, Li, Christopher I., Gozal, David, Thornton, Timothy, Barrie, Sonnah, and Phipps, Amanda I.
- Published
- 2022
- Full Text
- View/download PDF
31. Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea–related Quantitative Trait Locus in Men
- Author
-
Chen, Han, Cade, Brian E, Gleason, Kevin J, Bjonnes, Andrew C, Stilp, Adrienne M, Sofer, Tamar, Conomos, Matthew P, Ancoli-Israel, Sonia, Arens, Raanan, Azarbarzin, Ali, Bell, Graeme I, Below, Jennifer E, Chun, Sung, Evans, Daniel S, Ewert, Ralf, Frazier-Wood, Alexis C, Gharib, Sina A, Haba-Rubio, José, Hagen, Erika W, Heinzer, Raphael, Hillman, David R, Johnson, W Craig, Kutalik, Zoltan, Lane, Jacqueline M, Larkin, Emma K, Lee, Seung Ku, Liang, Jingjing, Loredo, Jose S, Mukherjee, Sutapa, Palmer, Lyle J, Papanicolaou, George J, Penzel, Thomas, Peppard, Paul E, Post, Wendy S, Ramos, Alberto R, Rice, Ken, Rotter, Jerome I, Sands, Scott A, Shah, Neomi A, Shin, Chol, Stone, Katie L, Stubbe, Beate, Sul, Jae Hoon, Tafti, Mehdi, Taylor, Kent D, Teumer, Alexander, Thornton, Timothy A, Tranah, Gregory J, Wang, Chaolong, Wang, Heming, Warby, Simon C, Wellman, D Andrew, Zee, Phyllis C, Hanis, Craig L, Laurie, Cathy C, Gottlieb, Daniel J, Patel, Sanjay R, Zhu, Xiaofeng, Sunyaev, Shamil R, Saxena, Richa, Lin, Xihong, and Redline, Susan more...
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Genetics ,Sleep Research ,Clinical Research ,Human Genome ,Lung ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Aged ,Female ,Genome-Wide Association Study ,Humans ,Male ,Middle Aged ,Phosphatidylethanolamine N-Methyltransferase ,Quantitative Trait Loci ,Sex Characteristics ,Sleep Apnea ,Obstructive ,Sleep ,REM ,Sterol Regulatory Element Binding Protein 1 ,Trans-Activators ,Transcription Factors ,ras Proteins ,obstructive sleep apnea ,genetics ,genome-wide association studies ,multiethnic ,sexual dimorphism ,Cardiorespiratory Medicine and Haematology ,Respiratory System ,Biochemistry and cell biology ,Cardiovascular medicine and haematology - Abstract
Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism. more...
- Published
- 2018
32. RECENT DEVELOPMENTS IN INSURANCE COVERAGE
- Author
-
Arguello, Damian J., Reed, William, Mosley, Christopher, Gregory, Laura Meyer, and Thornton, Timothy M.
- Published
- 2020
33. Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts
- Author
-
Kerr, Kathleen F, Avery, Christy L, Lin, Henry J, Raffield, Laura M, Zhang, Qian S, Browning, Brian L, Browning, Sharon R, Conomos, Matthew P, Gogarten, Stephanie M, Laurie, Cathy C, Sofer, Tamar, Thornton, Timothy A, Hohensee, Chancellor, Jackson, Rebecca D, Kooperberg, Charles, Li, Yun, Méndez-Giráldez, Raúl, Perez, Marco V, Peters, Ulrike, Reiner, Alexander P, Zhang, Zhu-Ming, Yao, Jie, Sotoodehnia, Nona, Taylor, Kent D, Guo, Xiuqing, Lange, Leslie A, Soliman, Elsayed Z, Wilson, James G, Rotter, Jerome I, Heckbert, Susan R, Jain, Deepti, and Whitsel, Eric A more...
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Research ,Prevention ,Human Genome ,Heart Disease ,Cardiovascular ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Black or African American ,Arrhythmias ,Cardiac ,Autonomic Nervous System ,Electrocardiography ,Genome-Wide Association Study ,Genotype ,Heart Rate ,Hispanic or Latino ,Humans ,Phenotype ,Polymorphism ,Single Nucleotide ,United States ,Epidemiology ,Genetic association studies ,Electrocardiogram ,Autonomic nervous system ,Ion channels/membrane transport ,Biomedical Engineering ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology - Abstract
BackgroundAlthough time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized.ObjectiveThe purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767).MethodsWe estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P more...
- Published
- 2017
34. Transethnic genome‐wide scan identifies novel Alzheimer's disease loci
- Author
-
Jun, Gyungah R, Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W, Bennett, David A, Buxbaum, Joseph D, Byrd, Goldie S, Carrasquillo, Minerva M, Crane, Paul K, Cruchaga, Carlos, De Jager, Philip, Ertekin‐Taner, Nilufer, Evans, Denis, Fallin, M Danielle, Foroud, Tatiana M, Friedland, Robert P, Goate, Alison M, Graff‐Radford, Neill R, Hendrie, Hugh, Hall, Kathleen S, Hamilton‐Nelson, Kara L, Inzelberg, Rivka, Kamboh, M Ilyas, Kauwe, John SK, Kukull, Walter A, Kunkle, Brian W, Kuwano, Ryozo, Larson, Eric B, Logue, Mark W, Manly, Jennifer J, Martin, Eden R, Montine, Thomas J, Mukherjee, Shubhabrata, Naj, Adam, Reiman, Eric M, Reitz, Christiane, Sherva, Richard, St. George‐Hyslop, Peter H, Thornton, Timothy, Younkin, Steven G, Vardarajan, Badri N, Wang, Li‐San, Wendlund, Jens R, Winslow, Ashley R, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Barmada, Michjael M, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Green, Robert C, and Growdon, John H more...
- Subjects
Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Neurodegenerative ,Brain Disorders ,Human Genome ,Genetics ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease ,Prevention ,Biotechnology ,Aging ,Dementia ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Alzheimer Disease ,Apolipoprotein E4 ,GTPase-Activating Proteins ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Heparin-binding EGF-like Growth Factor ,Humans ,Membrane Glycoproteins ,Molecular Chaperones ,NFI Transcription Factors ,Peroxisomal Bifunctional Enzyme ,Polymorphism ,Single Nucleotide ,Receptors ,GABA ,Alzheimer's Disease Genetics Consortium ,APOE interaction ,Alzheimer's disease ,Genome-wide association ,Transethnic ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P more...
- Published
- 2017
35. Genome-wide association study of iron traits and relation to diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): potential genomic intersection of iron and glucose regulation?
- Author
-
Raffield, Laura M, Louie, Tin, Sofer, Tamar, Jain, Deepti, Ipp, Eli, Taylor, Kent D, Papanicolaou, George J, Avilés-Santa, Larissa, Lange, Leslie A, Laurie, Cathy C, Conomos, Matthew P, Thornton, Timothy A, Chen, Yii-Der Ida, Qi, Qibin, Cotler, Scott, Thyagarajan, Bharat, Schneiderman, Neil, Rotter, Jerome I, Reiner, Alex P, and Lin, Henry J more...
- Subjects
Genetics ,Diabetes ,Clinical Research ,Human Genome ,Hematology ,Prevention ,Nutrition ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Adult ,Anemia ,Iron-Deficiency ,Antigens ,CD ,Blood Glucose ,Diabetes Mellitus ,Fasting ,Female ,Ferritins ,Genetic Association Studies ,Genetic Variation ,Genome-Wide Association Study ,Genomics ,Glucose ,Hemochromatosis ,Hispanic or Latino ,Hospitals ,Community ,Humans ,Insulin ,Iron ,Male ,Membrane Proteins ,Middle Aged ,Phenotype ,Polymorphism ,Single Nucleotide ,Receptors ,Transferrin ,Risk Factors ,Serine Endopeptidases ,Transferrin ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Genetic variants contribute to normal variation of iron-related traits and may also cause clinical syndromes of iron deficiency or excess. Iron overload and deficiency can adversely affect human health. For example, elevated iron storage is associated with increased diabetes risk, although mechanisms are still being investigated. We conducted the first genome-wide association study of serum iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin in a Hispanic/Latino cohort, the Hispanic Community Health Study/Study of Latinos (>12 000 participants) and also assessed the generalization of previously known loci to this population. We then evaluated whether iron-associated variants were associated with diabetes and glycemic traits. We found evidence for a novel association between TIBC and a variant near the gene for protein phosphatase 1, regulatory subunit 3B (PPP1R3B; rs4841132, β = -0.116, P = 7.44 × 10-8). The effect strengthened when iron deficient individuals were excluded (β = -0.121, P = 4.78 × 10-9). Ten of sixteen variants previously associated with iron traits generalized to HCHS/SOL, including variants at the transferrin (TF), hemochromatosis (HFE), fatty acid desaturase 2 (FADS2)/myelin regulatory factor (MYRF), transmembrane protease, serine 6 (TMPRSS6), transferrin receptor (TFR2), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ABO blood group (ABO), and GRB2 associated binding protein 3 (GAB3) loci. In examining iron variant associations with glucose homeostasis, an iron-raising variant of TMPRSS6 was associated with lower HbA1c levels (P = 8.66 × 10-10). This association was attenuated upon adjustment for iron measures. In contrast, the iron-raising allele of PPP1R3B was associated with higher levels of fasting glucose (P = 7.70 × 10-7) and fasting insulin (P = 4.79 × 10-6), but these associations were not attenuated upon adjustment for TIBC-so iron is not likely a mediator. These results provide new genetic information on iron traits and their connection with glucose homeostasis. more...
- Published
- 2017
36. A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium
- Author
-
Noordam, Raymond, Sitlani, Colleen M, Avery, Christy L, Stewart, James D, Gogarten, Stephanie M, Wiggins, Kerri L, Trompet, Stella, Warren, Helen R, Sun, Fangui, Evans, Daniel S, Li, Xiaohui, Li, Jin, Smith, Albert V, Bis, Joshua C, Brody, Jennifer A, Busch, Evan L, Caulfield, Mark J, Chen, Yii-Der I, Cummings, Steven R, Cupples, L Adrienne, Duan, Qing, Franco, Oscar H, Méndez-Giráldez, Rául, Harris, Tamara B, Heckbert, Susan R, van Heemst, Diana, Hofman, Albert, Floyd, James S, Kors, Jan A, Launer, Lenore J, Li, Yun, Li-Gao, Ruifang, Lange, Leslie A, Lin, Henry J, de Mutsert, Renée, Napier, Melanie D, Newton-Cheh, Christopher, Poulter, Neil, Reiner, Alexander P, Rice, Kenneth M, Roach, Jeffrey, Rodriguez, Carlos J, Rosendaal, Frits R, Sattar, Naveed, Sever, Peter, Seyerle, Amanda A, Slagboom, P Eline, Soliman, Elsayed Z, Sotoodehnia, Nona, Stott, David J, Stürmer, Til, Taylor, Kent D, Thornton, Timothy A, Uitterlinden, André G, Wilhelmsen, Kirk C, Wilson, James G, Gudnason, Vilmundur, Jukema, J Wouter, Laurie, Cathy C, Liu, Yongmei, Mook-Kanamori, Dennis O, Munroe, Patricia B, Rotter, Jerome I, Vasan, Ramachandran S, Psaty, Bruce M, Stricker, Bruno H, and Whitsel, Eric A more...
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Health Disparities ,Human Genome ,Minority Health ,Cardiovascular ,Heart Disease ,Good Health and Well Being ,Aged ,Aging ,Antidepressive Agents ,Tricyclic ,Electrocardiography ,Female ,Genetic Loci ,Genome-Wide Association Study ,Heart ,Humans ,Male ,Middle Aged ,Pharmacogenetics ,Genome-wide ,QT interval electrocardiography ,RR interval ,drug-gene interaction ,tri/tetracyclic antidepressants ,Medical and Health Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
BackgroundIncreased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.Methods and resultsWe conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e-8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.ConclusionsAmong Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results. more...
- Published
- 2017
37. Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.
- Author
-
Hodonsky, Chani J, Jain, Deepti, Schick, Ursula M, Morrison, Jean V, Brown, Lisa, McHugh, Caitlin P, Schurmann, Claudia, Chen, Diane D, Liu, Yong Mei, Auer, Paul L, Laurie, Cecilia A, Taylor, Kent D, Browning, Brian L, Li, Yun, Papanicolaou, George, Rotter, Jerome I, Kurita, Ryo, Nakamura, Yukio, Browning, Sharon R, Loos, Ruth JF, North, Kari E, Laurie, Cathy C, Thornton, Timothy A, Pankratz, Nathan, Bauer, Daniel E, Sofer, Tamar, and Reiner, Alex P more...
- Subjects
Erythrocytes ,Humans ,Proteasome Endopeptidase Complex ,Hemoglobins ,Homeodomain Proteins ,Tumor Suppressor Proteins ,Erythrocyte Count ,Polymorphism ,Single Nucleotide ,Hispanic Americans ,Female ,Male ,Genome-Wide Association Study ,alpha-Globins ,beta-Globins ,RNA ,Long Noncoding ,Solute Carrier Family 12 ,Member 2 ,Polymorphism ,Single Nucleotide ,RNA ,Long Noncoding ,Solute Carrier Family 12 ,Member 2 ,Genetics ,Developmental Biology - Abstract
Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos. more...
- Published
- 2017
38. Human whole-exome genotype data for Alzheimer’s disease
- Author
-
Leung, Yuk Yee, Naj, Adam C., Chou, Yi Fan, Valladares, Otto, Schmidt, Michael, Hamilton-Nelson, Kara, Wheeler, Nicholas, Lin, Honghuang, Gangadharan, Prabhakaran, Qu, Liming, Clark, Kaylyn, Kuzma, Amanda B., Lee, Wan Ping, Cantwell, Laura, Nicaretta, Heather, van der Lee, Sven, English, Adam, Kalra, Divya, Muzny, Donna, Skinner, Evette, Doddapeneni, Harsha, Dinh, Huyen, Hu, Jianhong, Santibanez, Jireh, Jayaseelan, Joy, Worley, Kim, Gibbs, Richard A., Lee, Sandra, Dugan-Perez, Shannon, Korchina, Viktoriya, Nasser, Waleed, Liu, Xiuping, Han, Yi, Zhu, Yiming, Liu, Yue, Khan, Ziad, Zhu, Congcong, Sun, Fangui Jenny, Jun, Gyungah R., Chung, Jaeyoon, Farrell, John, Zhang, Xiaoling, Banks, Eric, Gupta, Namrata, Gabriel, Stacey, Butkiewicz, Mariusz, Benchek, Penelope, Smieszek, Sandra, Song, Yeunjoo, Vardarajan, Badri, Reitz, Christiane, Reyes-Dumeyer, Dolly, Tosto, Giuseppe, De Jager, Phillip L., Barral, Sandra, Ma, Yiyi, Beiser, Alexa, Liu, Ching Ti, Dupuis, Josee, Lunetta, Kathy, Cupples, L. Adrienne, Choi, Seung Hoan, Chen, Yuning, Mez, Jesse, Vanderspek, Ashley, Ikram, M. Arfan, Ahmad, Shahzad, Faber, Kelley, Foroud, Tatiana, Mlynarski, Elisabeth, Schmidt, Helena, Schmidt, Reinhold, Kunkle, Brian, Rajabli, Farid, Beecham, Gary, Vance, Jeffrey M., Adams, Larry D., Cuccaro, Michael, Mena, Pedro, Booth, Briana M., Renton, Alan, Goate, Alison, Marcora, Edoardo, Stine, Adam, Feolo, Michael, Launer, Lenore J., Koboldt, Daniel C., Wilson, Richard K., van Duijn, Cornelia, Amin, Najaf, Kapoor, Manav, Salerno, William, Bennett, David A., Xia, Li Charlie, Malamon, John, Mosley, Thomas H., Satizabal, Claudia, Jan Bressler, Bressler, Jian, Xueqiu, Nato, Alejandro Q., Horimoto, Andrea R., Wang, Bowen, Psaty, Bruce, Witten, Daniela, Tsuang, Debby, Blue, Elizabeth, Wijsman, Ellen, Sohi, Harkirat, Nguyen, Hiep, Bis, Joshua C., Rice, Kenneth, Brown, Lisa, Dorschner, Michael, Saad, Mohamad, Navas, Pat, Nafikov, Rafael, Thornton, Timothy, Day, Tyler, Haut, Jacob, Sha, Jin, Zhang, Nancy, Iqbal, Taha, Zhao, Yi, Below, Jennifer E., Larson, David E., Appelbaum, Elizabeth, Waligorski, Jason, Antonacci-Fulton, Lucinda, Fulton, Robert S., Haines, Jonathan, Farrer, Lindsay, Seshadri, Sudha, Brkanac, Zoran, Cruchaga, Carlos, Pericak-Vance, Margaret, Mayeux, Richard P., Bush, William S., Destefano, Anita, Martin, Eden, Schellenberg, Gerard D., Wang, Li San, Leung, Yuk Yee, Naj, Adam C., Chou, Yi Fan, Valladares, Otto, Schmidt, Michael, Hamilton-Nelson, Kara, Wheeler, Nicholas, Lin, Honghuang, Gangadharan, Prabhakaran, Qu, Liming, Clark, Kaylyn, Kuzma, Amanda B., Lee, Wan Ping, Cantwell, Laura, Nicaretta, Heather, van der Lee, Sven, English, Adam, Kalra, Divya, Muzny, Donna, Skinner, Evette, Doddapeneni, Harsha, Dinh, Huyen, Hu, Jianhong, Santibanez, Jireh, Jayaseelan, Joy, Worley, Kim, Gibbs, Richard A., Lee, Sandra, Dugan-Perez, Shannon, Korchina, Viktoriya, Nasser, Waleed, Liu, Xiuping, Han, Yi, Zhu, Yiming, Liu, Yue, Khan, Ziad, Zhu, Congcong, Sun, Fangui Jenny, Jun, Gyungah R., Chung, Jaeyoon, Farrell, John, Zhang, Xiaoling, Banks, Eric, Gupta, Namrata, Gabriel, Stacey, Butkiewicz, Mariusz, Benchek, Penelope, Smieszek, Sandra, Song, Yeunjoo, Vardarajan, Badri, Reitz, Christiane, Reyes-Dumeyer, Dolly, Tosto, Giuseppe, De Jager, Phillip L., Barral, Sandra, Ma, Yiyi, Beiser, Alexa, Liu, Ching Ti, Dupuis, Josee, Lunetta, Kathy, Cupples, L. Adrienne, Choi, Seung Hoan, Chen, Yuning, Mez, Jesse, Vanderspek, Ashley, Ikram, M. Arfan, Ahmad, Shahzad, Faber, Kelley, Foroud, Tatiana, Mlynarski, Elisabeth, Schmidt, Helena, Schmidt, Reinhold, Kunkle, Brian, Rajabli, Farid, Beecham, Gary, Vance, Jeffrey M., Adams, Larry D., Cuccaro, Michael, Mena, Pedro, Booth, Briana M., Renton, Alan, Goate, Alison, Marcora, Edoardo, Stine, Adam, Feolo, Michael, Launer, Lenore J., Koboldt, Daniel C., Wilson, Richard K., van Duijn, Cornelia, Amin, Najaf, Kapoor, Manav, Salerno, William, Bennett, David A., Xia, Li Charlie, Malamon, John, Mosley, Thomas H., Satizabal, Claudia, Jan Bressler, Bressler, Jian, Xueqiu, Nato, Alejandro Q., Horimoto, Andrea R., Wang, Bowen, Psaty, Bruce, Witten, Daniela, Tsuang, Debby, Blue, Elizabeth, Wijsman, Ellen, Sohi, Harkirat, Nguyen, Hiep, Bis, Joshua C., Rice, Kenneth, Brown, Lisa, Dorschner, Michael, Saad, Mohamad, Navas, Pat, Nafikov, Rafael, Thornton, Timothy, Day, Tyler, Haut, Jacob, Sha, Jin, Zhang, Nancy, Iqbal, Taha, Zhao, Yi, Below, Jennifer E., Larson, David E., Appelbaum, Elizabeth, Waligorski, Jason, Antonacci-Fulton, Lucinda, Fulton, Robert S., Haines, Jonathan, Farrer, Lindsay, Seshadri, Sudha, Brkanac, Zoran, Cruchaga, Carlos, Pericak-Vance, Margaret, Mayeux, Richard P., Bush, William S., Destefano, Anita, Martin, Eden, Schellenberg, Gerard D., and Wang, Li San more...
- Abstract
The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer’s Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community. more...
- Published
- 2024
39. Coagulation factor VIII: Relationship to cardiovascular disease risk and whole genome sequence and epigenome‐wide analysis in African Americans
- Author
-
Raffield, Laura M., Lu, Ake T., Szeto, Mindy D., Little, Amarise, Grinde, Kelsey E., Shaw, Jessica, Auer, Paul L., Cushman, Mary, Horvath, Steve, Irvin, Marguerite R., Lange, Ethan M., Lange, Leslie A., Nickerson, Deborah A., Thornton, Timothy A., Wilson, James G., Wheeler, Marsha M., Zakai, Neil A., and Reiner, Alex P. more...
- Published
- 2020
- Full Text
- View/download PDF
40. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program
- Author
-
Taliun, Daniel, Harris, Daniel N., Kessler, Michael D., Carlson, Jedidiah, Szpiech, Zachary A., Torres, Raul, Taliun, Sarah A. Gagliano, Corvelo, André, Gogarten, Stephanie M., Kang, Hyun Min, Pitsillides, Achilleas N., LeFaive, Jonathon, Lee, Seung-been, Tian, Xiaowen, Browning, Brian L., Das, Sayantan, Emde, Anne-Katrin, Clarke, Wayne E., Loesch, Douglas P., Shetty, Amol C., Blackwell, Thomas W., Smith, Albert V., Wong, Quenna, Liu, Xiaoming, Conomos, Matthew P., Bobo, Dean M., Aguet, François, Albert, Christine, Alonso, Alvaro, Ardlie, Kristin G., Arking, Dan E., Aslibekyan, Stella, Auer, Paul L., Barnard, John, Barr, R. Graham, Barwick, Lucas, Becker, Lewis C., Beer, Rebecca L., Benjamin, Emelia J., Bielak, Lawrence F., Blangero, John, Boehnke, Michael, Bowden, Donald W., Brody, Jennifer A., Burchard, Esteban G., Cade, Brian E., Casella, James F., Chalazan, Brandon, Chasman, Daniel I., Chen, Yii-Der Ida, Cho, Michael H., Choi, Seung Hoan, Chung, Mina K., Clish, Clary B., Correa, Adolfo, Curran, Joanne E., Custer, Brian, Darbar, Dawood, Daya, Michelle, de Andrade, Mariza, DeMeo, Dawn L., Dutcher, Susan K., Ellinor, Patrick T., Emery, Leslie S., Eng, Celeste, Fatkin, Diane, Fingerlin, Tasha, Forer, Lukas, Fornage, Myriam, Franceschini, Nora, Fuchsberger, Christian, Fullerton, Stephanie M., Germer, Soren, Gladwin, Mark T., Gottlieb, Daniel J., Guo, Xiuqing, Hall, Michael E., He, Jiang, Heard-Costa, Nancy L., Heckbert, Susan R., Irvin, Marguerite R., Johnsen, Jill M., Johnson, Andrew D., Kaplan, Robert, Kardia, Sharon L. R., Kelly, Tanika, Kelly, Shannon, Kenny, Eimear E., Kiel, Douglas P., Klemmer, Robert, Konkle, Barbara A., Kooperberg, Charles, Köttgen, Anna, Lange, Leslie A., Lasky-Su, Jessica, Levy, Daniel, Lin, Xihong, Lin, Keng-Han, Liu, Chunyu, Loos, Ruth J. F., Garman, Lori, Gerszten, Robert, Lubitz, Steven A., Lunetta, Kathryn L., Mak, Angel C. Y., Manichaikul, Ani, Manning, Alisa K., Mathias, Rasika A., McManus, David D., McGarvey, Stephen T., Meigs, James B., Meyers, Deborah A., Mikulla, Julie L., Minear, Mollie A., Mitchell, Braxton D., Mohanty, Sanghamitra, Montasser, May E., Montgomery, Courtney, Morrison, Alanna C., Murabito, Joanne M., Natale, Andrea, Natarajan, Pradeep, Nelson, Sarah C., North, Kari E., O’Connell, Jeffrey R., Palmer, Nicholette D., Pankratz, Nathan, Peloso, Gina M., Peyser, Patricia A., Pleiness, Jacob, Post, Wendy S., Psaty, Bruce M., Rao, D. C., Redline, Susan, Reiner, Alexander P., Roden, Dan, Rotter, Jerome I., Ruczinski, Ingo, Sarnowski, Chloé, Schoenherr, Sebastian, Schwartz, David A., Seo, Jeong-Sun, Seshadri, Sudha, Sheehan, Vivien A., Sheu, Wayne H., Shoemaker, M. Benjamin, Smith, Nicholas L., Smith, Jennifer A., Sotoodehnia, Nona, Stilp, Adrienne M., Tang, Weihong, Taylor, Kent D., Telen, Marilyn, Thornton, Timothy A., Tracy, Russell P., Van Den Berg, David J., Vasan, Ramachandran S., Viaud-Martinez, Karine A., Vrieze, Scott, Weeks, Daniel E., Weir, Bruce S., Weiss, Scott T., Weng, Lu-Chen, Willer, Cristen J., Zhang, Yingze, Zhao, Xutong, Arnett, Donna K., Ashley-Koch, Allison E., Barnes, Kathleen C., Boerwinkle, Eric, Gabriel, Stacey, Gibbs, Richard, Rice, Kenneth M., Rich, Stephen S., Silverman, Edwin K., Qasba, Pankaj, Gan, Weiniu, Papanicolaou, George J., Nickerson, Deborah A., Browning, Sharon R., Zody, Michael C., Zöllner, Sebastian, Wilson, James G., Cupples, L. Adrienne, Laurie, Cathy C., Jaquish, Cashell E., Hernandez, Ryan D., O’Connor, Timothy D., and Abecasis, Gonçalo R. more...
- Published
- 2021
- Full Text
- View/download PDF
41. Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans
- Author
-
Cade, Brian E, Chen, Han, Stilp, Adrienne M, Gleason, Kevin J, Sofer, Tamar, Ancoli-Israel, Sonia, Arens, Raanan, Bell, Graeme I, Below, Jennifer E, Bjonnes, Andrew C, Chun, Sung, Conomos, Matthew P, Evans, Daniel S, Johnson, W Craig, Frazier-Wood, Alexis C, Lane, Jacqueline M, Larkin, Emma K, Loredo, Jose S, Post, Wendy S, Ramos, Alberto R, Rice, Ken, Rotter, Jerome I, Shah, Neomi A, Stone, Katie L, Taylor, Kent D, Thornton, Timothy A, Tranah, Gregory J, Wang, Chaolong, Zee, Phyllis C, Hanis, Craig L, Sunyaev, Shamil R, Patel, Sanjay R, Laurie, Cathy C, Zhu, Xiaofeng, Saxena, Richa, Lin, Xihong, and Redline, Susan more...
- Subjects
Genetics ,Clinical Research ,Lung ,Aging ,Prevention ,Sleep Research ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,sleep apnea ,hypoxia ,genetics ,GWAS ,Prader-Willi syndrome ,Prader–Willi syndrome ,Medical and Health Sciences ,Respiratory System - Abstract
RationaleObstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability.ObjectivesTo define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts.MethodsGenome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration.Measurements and main resultsTwo novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 × 10-8 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 × 10-8 for respiratory event duration) and seven additional loci were identified with suggestive significance (P more...
- Published
- 2016
42. Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
- Author
-
Mahajan, Anubha, Rodan, Aylin R, Le, Thu H, Gaulton, Kyle J, Haessler, Jeffrey, Stilp, Adrienne M, Kamatani, Yoichiro, Zhu, Gu, Sofer, Tamar, Puri, Sanjana, Schellinger, Jeffrey N, Chu, Pei-Lun, Cechova, Sylvia, van Zuydam, Natalie, Consortium, the SUMMIT, Project, the BioBank Japan, Arnlov, Johan, Flessner, Michael F, Giedraitis, Vilmantas, Heath, Andrew C, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia M, Madden, Pamela AF, Montgomery, Grant W, Papanicolaou, George J, Reiner, Alex P, Sundström, Johan, Thornton, Timothy A, Lind, Lars, Ingelsson, Erik, Cai, Jianwen, Martin, Nicholas G, Kooperberg, Charles, Matsuda, Koichi, Whitfield, John B, Okada, Yukinori, Laurie, Cathy C, Morris, Andrew P, and Franceschini, Nora more...
- Subjects
Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Kidney Disease ,Biotechnology ,Human Genome ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Renal and urogenital ,Alleles ,Animals ,Deoxyribonuclease I ,Diabetes Mellitus ,Disease Models ,Animal ,Drosophila melanogaster ,Ethnicity ,Female ,Genome-Wide Association Study ,Glomerular Filtration Rate ,Humans ,Kidney ,Linkage Disequilibrium ,Male ,NFATC Transcription Factors ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,RGS Proteins ,Racial Groups ,Renal Insufficiency ,Chronic ,Salt Tolerance ,Sodium Chloride ,Sodium-Phosphate Cotransporter Proteins ,Type IIa ,Stress ,Physiological ,SUMMIT Consortium ,BioBank Japan Project ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans. more...
- Published
- 2016
43. Genome-wide association study of dental caries in the Hispanic Communities Health Study/Study of Latinos (HCHS/SOL)
- Author
-
Morrison, Jean, Laurie, Cathy C, Marazita, Mary L, Sanders, Anne E, Offenbacher, Steven, Salazar, Christian R, Conomos, Matthew P, Thornton, Timothy, Jain, Deepti, Laurie, Cecelia A, Kerr, Kathleen F, Papanicolaou, George, Taylor, Kent, Kaste, Linda M, Beck, James D, and Shaffer, John R more...
- Subjects
Biological Sciences ,Genetics ,Dental/Oral and Craniofacial Disease ,Clinical Research ,Behavioral and Social Science ,Prevention ,Basic Behavioral and Social Science ,Infectious Diseases ,Human Genome ,Oral and gastrointestinal ,Good Health and Well Being ,Adult ,Aged ,Community Health Centers ,Dental Caries ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Hispanic or Latino ,Humans ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Dental caries is the most common chronic disease worldwide, and exhibits profound disparities in the USA with racial and ethnic minorities experiencing disproportionate disease burden. Though heritable, the specific genes influencing risk of dental caries remain largely unknown. Therefore, we performed genome-wide association scans (GWASs) for dental caries in a population-based cohort of 12 000 Hispanic/Latino participants aged 18-74 years from the HCHS/SOL. Intra-oral examinations were used to generate two common indices of dental caries experience which were tested for association with 27.7 M genotyped or imputed single-nucleotide polymorphisms separately in the six ancestry groups. A mixed-models approach was used, which adjusted for age, sex, recruitment site, five principal components of ancestry and additional features of the sampling design. Meta-analyses were used to combine GWAS results across ancestry groups. Heritability estimates ranged from 20-53% in the six ancestry groups. The most significant association observed via meta-analysis for both phenotypes was in the region of the NAMPT gene (rs190395159; P-value = 6 × 10(-10)), which is involved in many biological processes including periodontal healing. Another significant association was observed for rs72626594 (P-value = 3 × 10(-8)) downstream of BMP7, a tooth development gene. Other associations were observed in genes lacking known or plausible roles in dental caries. In conclusion, this was the largest GWAS of dental caries, to date and was the first to target Hispanic/Latino populations. Understanding the factors influencing dental caries susceptibility may lead to improvements in prediction, prevention and disease management, which may ultimately reduce the disparities in oral health across racial, ethnic and socioeconomic strata. more...
- Published
- 2016
44. Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans
- Author
-
Schick, Ursula M, Jain, Deepti, Hodonsky, Chani J, Morrison, Jean V, Davis, James P, Brown, Lisa, Sofer, Tamar, Conomos, Matthew P, Schurmann, Claudia, McHugh, Caitlin P, Nelson, Sarah C, Vadlamudi, Swarooparani, Stilp, Adrienne, Plantinga, Anna, Baier, Leslie, Bien, Stephanie A, Gogarten, Stephanie M, Laurie, Cecelia A, Taylor, Kent D, Liu, Yongmei, Auer, Paul L, Franceschini, Nora, Szpiro, Adam, Rice, Ken, Kerr, Kathleen F, Rotter, Jerome I, Hanson, Robert L, Papanicolaou, George, Rich, Stephen S, Loos, Ruth JF, Browning, Brian L, Browning, Sharon R, Weir, Bruce S, Laurie, Cathy C, Mohlke, Karen L, North, Kari E, Thornton, Timothy A, and Reiner, Alex P more...
- Subjects
Biological Sciences ,Genetics ,Human Genome ,Clinical Research ,Hematology ,Underpinning research ,1.1 Normal biological development and functioning ,Blood ,Actinin ,Adolescent ,Adult ,Aged ,Alleles ,Gene Frequency ,Genetic Association Studies ,Genetic Loci ,Genotype ,Genotyping Techniques ,Hispanic or Latino ,Humans ,MEF2 Transcription Factors ,Membrane Proteins ,Middle Aged ,Phenotype ,Platelet Count ,Polymorphism ,Single Nucleotide ,Receptors ,GABA-B ,Young Adult ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10(-28)) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits. more...
- Published
- 2016
45. Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos
- Author
-
Conomos, Matthew P, Laurie, Cecelia A, Stilp, Adrienne M, Gogarten, Stephanie M, McHugh, Caitlin P, Nelson, Sarah C, Sofer, Tamar, Fernández-Rhodes, Lindsay, Justice, Anne E, Graff, Mariaelisa, Young, Kristin L, Seyerle, Amanda A, Avery, Christy L, Taylor, Kent D, Rotter, Jerome I, Talavera, Gregory A, Daviglus, Martha L, Wassertheil-Smoller, Sylvia, Schneiderman, Neil, Heiss, Gerardo, Kaplan, Robert C, Franceschini, Nora, Reiner, Alex P, Shaffer, John R, Barr, R Graham, Kerr, Kathleen F, Browning, Sharon R, Browning, Brian L, Weir, Bruce S, Avilés-Santa, M Larissa, Papanicolaou, George J, Lumley, Thomas, Szpiro, Adam A, North, Kari E, Rice, Ken, Thornton, Timothy A, and Laurie, Cathy C more...
- Subjects
Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Health Disparities ,Clinical Research ,Human Genome ,Minority Health ,Generic health relevance ,Good Health and Well Being ,Genetic Variation ,Genome-Wide Association Study ,Hispanic or Latino ,Humans ,United States ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a "genetic-analysis group" variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness. more...
- Published
- 2016
46. RECENT DEVELOPMENTS IN INSURANCE COVERAGE
- Author
-
Arguello, Damian, Ward, Jeffrey J., Chotvacs, Charles W., Reichlyn, Jason C., Giometti, Gregory R., Seibel, Taylor R., Thornton, Timothy M., and Yetka, Christopher
- Published
- 2019
47. Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer’s disease in Caribbean Hispanics
- Author
-
Horimoto, Andréa R. V. R., Xue, Diane, Thornton, Timothy A., and Blue, Elizabeth E.
- Published
- 2021
- Full Text
- View/download PDF
48. Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics
- Author
-
Blue, Elizabeth E., Horimoto, Andréa R.V.R., Mukherjee, Shubhabrata, Wijsman, Ellen M., and Thornton, Timothy A.
- Published
- 2019
- Full Text
- View/download PDF
49. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
- Author
-
Abe, Namiko, Abecasis, Goncalo, Albert, Christine, Palmer Allred, Nicholette (Nichole), Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Arking, Dan, Arnett, Donna K., Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Beaty, Terri, Becker, Diane, Becker, Lewis, Beer, Rebecca, Begum, Ferdouse, Beitelshees, Amber, Benjamin, Emelia, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Boerwinkle, Eric, Borecki, Ingrid, Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Bunting, Karen, Burchard, Esteban, Cardwell, Jonathan, Carty, Cara, Casaburi, Richard, Casella, James, Chaffin, Mark, Chang, Christy, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Chen, Yii-Der Ida, Cho, Michael H., Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, Das, Sayantan, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Do, Ron, Duan, Qing, Duggirala, Ravi, Durda, Peter, Dutcher, Susan, Eaton, Charles, Ekunwe, Lynette, Ellinor, Patrick, Emery, Leslie, Farber, Charles, Farnam, Leanna, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Yan, Gass, Margery, Gelb, Bruce, Geng, Xiaoqi (Priscilla), Germer, Soren, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Haessler, Jeff, Hall, Michael, Harris, Daniel, Hawley, Nicola, He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hokanson, John, Holly, Kramer, Hong, Elliott, Hoth, Karin, (Agnes) Hsiung, Chao, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Jhun, Min A., Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kachroo, Priyadarshini, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kathiresan, Sekar, Kaufman, Laura, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Krauter, Stephanie, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Seunggeun Shawn, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Yun, Lin, Honghuang, Lin, Keng Han, Liu, Simin, Liu, Yongmei, Loos, Ruth, Lubitz, Steven, Lunetta, Kathryn, Luo, James, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manson, JoAnn, Margolin, Lauren, Martin, Lisa, Mathai, Susan, Mathias, Rasika, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, Mei, Hao, Meyers, Deborah A., Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L., Mitchell, Braxton, Montasser, May E., Musani, Solomon, Mwasongwe, Stanford, Mychaleckyj, Josyf C., Nadkarni, Girish, Naik, Rakhi, Natarajan, Pradeep, Nekhai, Sergei, Nickerson, Deborah, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Pankow, James, Papanicolaou, George, Parker, Margaret, Parsa, Afshin, Penchev, Sara, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S., Phillips, Sam, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Prokopenko, Dmitry, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Ramachandran, Vasan, Rao, D.C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Regan, Elizabeth, Reiner, Alex, Rice, Ken, Rich, Stephen, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sakornsakolpat, Phuwanat, Salimi, Shabnam, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay, Scheller, Christopher, Schmidt, Ellen, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sheehan, Vivien, Shetty, Amol, Shetty, Aniket, Sheu, Wayne Hui-Heng, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne, Streeten, Elizabeth, Sung, Yun Ju, Su-Lasky, Jessica, Sylvia, Jody, Szpiro, Adam, Sztalryd, Carole, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Tinker, Lesley, Tirschwell, David, Tiwari, Hemant, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wan, Emily, Wang, Fei Fei, Watson, Karol, Weeks, Daniel E., Weir, Bruce, Weiss, Scott, Weng, Lu-Chen, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Wong, Quenna, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yang, Rongze, Zaghloul, Norann, Zekavat, Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zheng, Xiuwen, Zhi, Degui, Zhou, Xiang, Zody, Michael, Zoellner, Sebastian, Hecker, Julian, Chawes, Bo L., Ahluwalia, Tarunveer S., Kelly, Rachel S., Chu, Su H., Virkud, Yamini V., Huang, Mengna, Barnes, Kathleen C., Burchard, Esteban G., Eng, Celeste, Hu, Donglei, Celedón, Juan C., Levin, Albert M., Gui, Hongsheng, Forno, Erick, Mak, Angel C.Y., Avila, Lydiana, Soto-Quiros, Manuel E., Cloutier, Michelle M., Acosta-Pérez, Edna, Canino, Glorisa, Bønnelykke, Klaus, Bisgaard, Hans, Raby, Benjamin A., Weiss, Scott T., and Lasky-Su, Jessica A. more...
- Published
- 2019
- Full Text
- View/download PDF
50. Genome-wide Significance Thresholds for Admixture Mapping Studies
- Author
-
Grinde, Kelsey E., Brown, Lisa A., Reiner, Alexander P., Thornton, Timothy A., and Browning, Sharon R.
- Published
- 2019
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.