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1. “PMS2CL interference leading to erroneous identification of a pathogenic PMS2 variant in Black Patients”

Author

Cappadocia, Jacqueline, primary, Aiello, Lisa B., additional, Kelley, Michael J., additional, Katona, Bryson W., additional, Maxwell, Kara N., additional, Verma, Anurag, additional, Verma, Shefali S., additional, Bradford, Yuki, additional, Brock, Ashlei, additional, DerOhannessian, Stephanie, additional, Dudek, Scott, additional, Dunn, Joseph, additional, Drivas, Theodore, additional, Haubein, Ned, additional, Hu-Sain, Khadijah, additional, Judy, Renae, additional, Kloter, Ashley, additional, Ko, Yi-An, additional, Livingstone, Meghan, additional, Morrel, Linda, additional, Morse, Colleen, additional, Poindexter, Afiya, additional, Risman, Marjorie, additional, Tran, Teo, additional, Vadivieso, Fred, additional, Weaver, JoEllen, additional, Rader, Daniel J., additional, Ritchie, Marylyn D., additional, Feldman, Michael D., additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Overton, John D., additional, Padilla, Maria Sotiropoulos, additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Schleicher, Thomas D., additional, Widom, Louis, additional, Wolf, Sarah E., additional, Ulloa, Ricardo H., additional, Averitt, Amelia, additional, Banerjee, Nilanjana, additional, Cantor, Michael, additional, Li, Dadong, additional, Malhotra, Sameer, additional, Sharma, Deepika, additional, Staples, Jeffrey, additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Bao, Suying, additional, Boutkov, Boris, additional, Chen, Siying, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Mitra, George, additional, Nafde, Mona, additional, O’Keeffe, Sean, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Reid, Jeffrey G., additional, Salerno, William, additional, Staples, Jeffrey C., additional, Sun, Kathie, additional, Abecasis, Goncalo, additional, Backman, Joshua, additional, Damask, Amy, additional, Dobbyn, Lee, additional, Revez Ferreira, Manuel Allen, additional, Ghosh, Arkopravo, additional, Gillies, Christopher, additional, Gurski, Lauren, additional, Jorgenson, Eric, additional, Kang, Hyun Min, additional, Kessler, Michael, additional, Kosmicki, Jack, additional, Li, Alexander, additional, Lin, Nan, additional, Liu, Daren, additional, Locke, Adam, additional, Marchini, Jonathan, additional, Marcketta, Anthony, additional, Mbatchou, Joelle, additional, Moscati, Arden, additional, Paulding, Charles, additional, Sidore, Carlo, additional, Stahl, Eli, additional, Watanabe, Kyoko, additional, Ye, Bin, additional, Zhang, Blair, additional, Ziyatdinov, Andrey, additional, Ayer, Ariane, additional, Guvenek, Aysegul, additional, Hindy, George, additional, Coppola, Giovanni, additional, Freudenberg, Jan, additional, Bovijn, Jonas, additional, Siminovitch, Katherine, additional, Praveen, Kavita, additional, Lotta, Luca A., additional, Kapoor, Manav, additional, Haas, Mary, additional, Riaz, Moeen, additional, Verweij, Niek, additional, Sosina, Olukayode, additional, Akbari, Parsa, additional, Nakka, Priyanka, additional, Gelfman, Sahar, additional, Gokhale, Sujit, additional, De, Tanima, additional, Rajagopal, Veera, additional, Shuldiner, Alan, additional, Tzoneva, Gannie, additional, Rodriguez-Flores, Juan, additional, Chen, Esteban, additional, Jones, Marcus B., additional, LeBlanc, Michelle G., additional, Mighty, Jason, additional, Mitnaul, Lyndon J., additional, Nishtala, Nirupama, additional, Rana, Nadia, additional, Hernandez, Jaimee, additional, Baras, Aris, additional, Deubler, Andrew, additional, and Economides, Aris, additional

Published
2024
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4. PMS2CL interference leading to erroneous identification of a pathogenic PMS2 variant in Black patients

Author

Verma, Anurag, Verma, Shefali S., Bradford, Yuki, Brock, Ashlei, DerOhannessian, Stephanie, Dudek, Scott, Dunn, Joseph, Drivas, Theodore, Haubein, Ned, Hu-Sain, Khadijah, Judy, Renae, Kloter, Ashley, Ko, Yi-An, Livingstone, Meghan, Morrel, Linda, Morse, Colleen, Poindexter, Afiya, Risman, Marjorie, Tran, Teo, Vadivieso, Fred, Weaver, JoEllen, Rader, Daniel J., Ritchie, Marylyn D., Feldman, Michael D., Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Overton, John D., Padilla, Maria Sotiropoulos, Pradhan, Manasi, Manoochehri, Kia, Schleicher, Thomas D., Widom, Louis, Wolf, Sarah E., Ulloa, Ricardo H., Averitt, Amelia, Banerjee, Nilanjana, Cantor, Michael, Li, Dadong, Malhotra, Sameer, Sharma, Deepika, Staples, Jeffrey, Bai, Xiaodong, Balasubramanian, Suganthi, Bao, Suying, Boutkov, Boris, Chen, Siying, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Krasheninina, Olga, Lanche, Rouel, Mansfield, Adam J., Maxwell, Evan K., Mitra, George, Nafde, Mona, O’Keeffe, Sean, Orelus, Max, Panea, Razvan, Polanco, Tommy, Rasool, Ayesha, Reid, Jeffrey G., Salerno, William, Staples, Jeffrey C., Sun, Kathie, Abecasis, Goncalo, Backman, Joshua, Damask, Amy, Dobbyn, Lee, Ferreira, Manuel Allen Revez, Ghosh, Arkopravo, Gillies, Christopher, Gurski, Lauren, Jorgenson, Eric, Kang, Hyun Min, Kessler, Michael, Kosmicki, Jack, Li, Alexander, Lin, Nan, Liu, Daren, Locke, Adam, Marchini, Jonathan, Marcketta, Anthony, Mbatchou, Joelle, Moscati, Arden, Paulding, Charles, Sidore, Carlo, Stahl, Eli, Watanabe, Kyoko, Ye, Bin, Zhang, Blair, Ziyatdinov, Andrey, Ayer, Ariane, Guvenek, Aysegul, Hindy, George, Coppola, Giovanni, Freudenberg, Jan, Bovijn, Jonas, Siminovitch, Katherine, Praveen, Kavita, Lotta, Luca A., Kapoor, Manav, Haas, Mary, Riaz, Moeen, Verweij, Niek, Sosina, Olukayode, Akbari, Parsa, Nakka, Priyanka, Gelfman, Sahar, Gokhale, Sujit, De, Tanima, Rajagopal, Veera, Shuldiner, Alan, Tzoneva, Gannie, Rodriguez-Flores, Juan, Chen, Esteban, Jones, Marcus B., LeBlanc, Michelle G., Mighty, Jason, Mitnaul, Lyndon J., Nishtala, Nirupama, Rana, Nadia, Hernandez, Jaimee, Baras, Aris, Deubler, Andrew, Economides, Aris, Cappadocia, Jacqueline, Aiello, Lisa B., Kelley, Michael J., Katona, Bryson W., and Maxwell, Kara N.

Published
2024
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5. Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female‐Specific Health Conditions

Author

Xiao, Brenda, primary, Velez Edwards, Digna R., additional, Lucas, Anastasia, additional, Drivas, Theodore, additional, Gray, Kathryn, additional, Keating, Brendan, additional, Weng, Chunhua, additional, Jarvik, Gail P., additional, Hakonarson, Hakon, additional, Kottyan, Leah, additional, Elhadad, Noemie, additional, Wei, Wei‐Qi, additional, Luo, Yuan, additional, Kim, Dokyoon, additional, Ritchie, Marylyn, additional, Verma, Shefali Setia, additional, Abecasis, Goncalo, additional, Baras, Aris, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Deubler, Andrew, additional, Economides, Aris, additional, Karalis, Katia, additional, Lotta, Luca A., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Siminovitch, Katherine, additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Padilla, Maria Sotiropoulos, additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Schleicher, Thomas D., additional, Widom, Louis, additional, Wolf, Sarah E., additional, Ulloa, Ricardo H., additional, Averitt, Amelia, additional, Banerjee, Nilanjana, additional, Li, Dadong, additional, Malhotra, Sameer, additional, Sharma, Deepika, additional, Staples, Jeffrey, additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Bao, Suying, additional, Boutkov, Boris, additional, Chen, Siying, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Mitra, George, additional, Nafde, Mona, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Salerno, William, additional, Staples, Jeffrey C., additional, Sun, Kathie, additional, Backman, Joshua, additional, Damask, Amy, additional, Dobbyn, Lee, additional, Ferreira, Manuel Allen Revez, additional, Ghosh, Arkopravo, additional, Gillies, Christopher, additional, Gurski, Lauren, additional, Jorgenson, Eric, additional, Kang, Hyun Min, additional, Kessler, Michael, additional, Kosmicki, Jack, additional, Li, Alexander, additional, Lin, Nan, additional, Liu, Daren, additional, Locke, Adam, additional, Marchini, Jonathan, additional, Marcketta, Anthony, additional, Mbatchou, Joelle, additional, Moscati, Arden, additional, Paulding, Charles, additional, Sidore, Carlo, additional, Stahl, Eli, additional, Watanabe, Kyoko, additional, Ye, Bin, additional, Zhang, Blair, additional, Ziyatdinov, Andrey, additional, Ayer, Ariane, additional, Guvenek, Aysegul, additional, Hindy, George, additional, Freudenberg, Jan, additional, Bovijn, Jonas, additional, Praveen, Kavita, additional, Kapoor, Manav, additional, Haas, Mary, additional, Riaz, Moeen, additional, Verweij, Niek, additional, Sosina, Olukayode, additional, Akbari, Parsa, additional, Nakka, Priyanka, additional, Gelfman, Sahar, additional, Gokhale, Sujit, additional, De, Tanima, additional, Rajagopal, Veera, additional, Tzoneva, Gannie, additional, Rodriguez‐Flores, Juan, additional, Chim, Shek Man, additional, Donato, Valerio, additional, Fernandez, Daniel, additional, Gatta, Giusy Della, additional, Di Gioia, Alessandro, additional, Howell, Kristen, additional, Khrimian, Lori, additional, Kim, Minhee, additional, Martinez, Hector, additional, Miloscio, Lawrence, additional, Nunez, Sheilyn, additional, Pavlopoulos, Elias, additional, Persaud, Trikaldarshi, additional, Chen, Esteban, additional, Jones, Marcus B., additional, LeBlanc, Michelle G., additional, Mighty, Jason, additional, Mitnaul, Lyndon J., additional, Nishtala, Nirupama, additional, and Rana, Nadia, additional

Published
2023
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6. Structural variation across 138,134 samples in the TOPMed consortium

Author

Jun, Goo, primary, English, Adam, additional, Metcalf, Ginger, additional, Yang, Jianzhi, additional, Chaisson, Mark, additional, Pankratz, Nathan, additional, Menon, Vipin, additional, Salerno, William, additional, Krasheninina, Olga, additional, Smith, Albert, additional, Lane, John, additional, Blackwell, Thomas, additional, Kang, Hyun Min, additional, Salvi, Sejal, additional, Meng, Qingchang, additional, Shen, Hua, additional, Pasham, Divya, additional, Bhamidipati, Sravya, additional, Kottapalli, Kavya, additional, Arnett, Donna, additional, Ashley-Koch, Allison, additional, Auer, Paul, additional, Beutel, KAthleen, additional, Bis, Joshua, additional, Blangero, John, additional, Bowden, Donald, additional, Brody, Jennifer, additional, Cade, Brian, additional, Chen, Yii-Der Ida, additional, Cho, Michael, additional, Curran, Joanne, additional, Fornage, Myriam, additional, Frredman, Barry, additional, Fingerlin, Tasha, additional, Gelb, Bruce, additional, Hou, Lifang, additional, Hung, Yi-Jen, additional, Kane, John P, additional, Kaplan, Robert, additional, Kim, Wonji, additional, Loos, Ruth, additional, Marcus, Gregory, additional, Mathias, Rasika, additional, McGarvey, Stephen, additional, Montgomery, Courtney, additional, Naseri, Take, additional, Nouraie, Seyed, additional, Preuss, Michael, additional, Palmer, Nicholette, additional, Peyser, Patricia, additional, Raffield, Laura, additional, Ratan, Aakrosh, additional, Redline, Susan, additional, Reupena, Muagututia, additional, Rotter, Jerome, additional, Rich, Stephen, additional, Rienstra, Michiel, additional, Ruczinski, Ingo, additional, Sankaran, Vijay, additional, Schwartz, David, additional, Seidman, Christine, additional, Seidman, Jonathan, additional, Silverman, Edwin, additional, Smith, Jennifer, additional, Stilp, Adrienne, additional, Taylor, Kent, additional, Telen, Marilyn, additional, Weiss, Scott, additional, Williams, L. Keoki, additional, Wu, Baojun, additional, Yanek, Lisa, additional, Zhang, Yingze, additional, Lasky-Su, Jessica, additional, Gingras, Marie-Claude, additional, Dutcher, Susan, additional, Eichler, Evan, additional, Gabriel, Stacey, additional, Germer, Soren, additional, Kim, Ryan, additional, Martinez, Karine, additional, Nickerson, Deborah, additional, Luo, James, additional, Reiner, Alexander, additional, Gibbs, Richard, additional, Boerwinkle, Eric, additional, Abecasis, Goncaol, additional, and Sedlazeck, Fritz, additional

Published
2023
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7. Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

Author

Jurgens, Sean J., Choi, Seung Hoan, Morrill, Valerie N., Chaffin, Mark, Pirruccello, James P., Halford, Jennifer L., Weng, Lu-Chen, Nauffal, Victor, Roselli, Carolina, Hall, Amelia W., Oetjens, Matthew T., Lagerman, Braxton, vanMaanen, David P., Abecasis, Goncalo, Bai, Xiaodong, Balasubramanian, Suganthi, Baras, Aris, Beechert, Christina, Boutkov, Boris, Cantor, Michael, Coppola, Giovanni, de, Tanima, Deubler, Andrew, Economides, Aris, Eom, Gisu, Ferreira, Manuel A. R., Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Habegger, Lukas, Hawes, Alicia, Jones, Marcus B., Karalis, Katia, Khalid, Shareef, Krasheninina, Olga, Lanche, Rouel, Lattari, Michael, Li, Dadong, Lopez, Alexander, Lotta, Luca A., Manoochehri, Kia, Mansfield, Adam J., Maxwell, Evan K., Mighty, Jason, Mitnaul, Lyndon J., Nafde, Mona, Nielsen, Jonas, O’Keeffe, Sean, Orelus, Max, Overton, John D., Padilla, Maria Sotiropoulos, Panea, Razvan, Polanco, Tommy, Pradhan, Manasi, Rasool, Ayesha, Reid, Jeffrey G., Salerno, William, Schleicher, Thomas D., Shuldiner, Alan, Siminovitch, Katherine, Staples, Jeffrey C., Ulloa, Ricardo H., Verweij, Niek, Widom, Louis, Wolf, Sarah E., Aragam, Krishna G., Lunetta, Kathryn L., Haggerty, Christopher M., Lubitz, Steven A., Ellinor, Patrick T., Cardiology, Graduate School, and ACS - Amsterdam Cardiovascular Sciences

Subjects
Genetics
Abstract

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.

Published
2022

8. Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank

Author

Gaynor, Sheila M., Joseph, Tyler, Bai, Xiaodong, Zou, Yuxin, Boutkov, Boris, Maxwell, Evan K., Delaneau, Olivier, Hofmeister, Robin J., Krasheninina, Olga, Balasubramanian, Suganthi, Marcketta, Anthony, Backman, Joshua, Reid, Jeffrey G., Overton, John D., Lotta, Luca A., Marchini, Jonathan, Salerno, William J., Baras, Aris, Abecasis, Goncalo R., and Thornton, Timothy A.

Abstract

Whole-genome sequencing (WGS), whole-exome sequencing (WES) and array genotyping with imputation (IMP) are common strategies for assessing genetic variation and its association with medically relevant phenotypes. To date, there has been no systematic empirical assessment of the yield of these approaches when applied to hundreds of thousands of samples to enable the discovery of complex trait genetic signals. Using data for 100 complex traits from 149,195 individuals in the UK Biobank, we systematically compare the relative yield of these strategies in genetic association studies. We find that WGS and WES combined with arrays and imputation (WES + IMP) have the largest association yield. Although WGS results in an approximately fivefold increase in the total number of assayed variants over WES + IMP, the number of detected signals differed by only 1% for both single-variant and gene-based association analyses. Given that WES + IMP typically results in savings of lab and computational time and resources expended per sample, we evaluate the potential benefits of applying WES + IMP to larger samples. When we extend our WES + IMP analyses to 468,169 UK Biobank individuals, we observe an approximately fourfold increase in association signals with the threefold increase in sample size. We conclude that prioritizing WES + IMP and large sample sizes rather than contemporary short-read WGS alternatives will maximize the number of discoveries in genetic association studies.

Published
2024
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10. xAtlas: scalable small variant calling across heterogeneous next-generation sequencing experiments

Author

Farek, Jesse, primary, Hughes, Daniel, additional, Salerno, William, additional, Zhu, Yiming, additional, Pisupati, Aishwarya, additional, Mansfield, Adam, additional, Krasheninina, Olga, additional, English, Adam C, additional, Metcalf, Ginger, additional, Boerwinkle, Eric, additional, Muzny, Donna M, additional, Gibbs, Richard, additional, Khan, Ziad, additional, and Sedlazeck, Fritz J, additional

Published
2022
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11. Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle‐aged and older adults: A population‐based cohort study

Author

Manderstedt, Eric, primary, Lind‐Halldén, Christina, additional, Halldén, Christer, additional, Elf, Johan, additional, Svensson, Peter J., additional, Engström, Gunnar, additional, Melander, Olle, additional, Baras, Aris, additional, Lotta, Luca A., additional, Zöller, Bengt, additional, Abecasis, Goncalo, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Economides, Aris, additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Schleicher, Thomas D., additional, Padilla, Maria Sotiropoulos, additional, Widom, Louis, additional, Wolf, Sarah E., additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Ulloa, Ricardo H., additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Blumenfeld, Andrew, additional, Boutkov, Boris, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Nafde, Mrunali, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Salerno, William, additional, Staples, Jeffrey C., additional, Jones, Marcus B., additional, Mighty, Jason, additional, and Mitnaul, Lyndon J., additional

Published
2022
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12. Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects

Author

Regier, Allison A., Farjoun, Yossi, Larson, David E., Krasheninina, Olga, Kang, Hyun Min, Howrigan, Daniel P., Chen, Bo-Juen, Kher, Manisha, Banks, Eric, Ames, Darren C., English, Adam C., Li, Heng, Xing, Jinchuan, Zhang, Yeting, Matise, Tara, Abecasis, Goncalo R., Salerno, Will, Zody, Michael C., Neale, Benjamin M., and Hall, Ira M.

Published
2018
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13. Thrombotic risk determined by rare and common SERPINA1 variants in a population‐based cohort study

Author

Manderstedt, Eric, primary, Halldén, Christer, additional, Lind‐Halldén, Christina, additional, Elf, Johan, additional, Svensson, Peter J., additional, Engström, Gunnar, additional, Melander, Olle, additional, Baras, Aris, additional, Lotta, Luca A., additional, Zöller, Bengt, additional, Abecasis, Goncalo, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Economides, Aris, additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Manoochehri, Kia, additional, Padilla, Maria Sotiropoulos, additional, Pradhan, Manasi, additional, Schleicher, Thomas D., additional, Ulloa, Ricardo H., additional, Widom, Louis, additional, Wolf, Sarah E., additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Blumenfeld, Andrew, additional, Boutkov, Boris, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Nafde, Mrunali, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Salerno, William, additional, Staples, Jeffrey C., additional, Jones, Marcus B., additional, Mighty, Jason, additional, and Mitnaul, Lyndon J., additional

Published
2022
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14. Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

Author

Wang, Louise, primary, Desai, Heena, additional, Verma, Shefali S., additional, Le, Anh, additional, Hausler, Ryan, additional, Verma, Anurag, additional, Judy, Renae, additional, Doucette, Abigail, additional, Gabriel, Peter E., additional, Nathanson, Katherine L., additional, Damrauer, Scott M., additional, Mowery, Danielle L., additional, Ritchie, Marylyn D., additional, Kember, Rachel L., additional, Maxwell, Kara N., additional, Abecasis, Goncalo, additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Baras, Aris, additional, Blumenfeld, Andrew, additional, Boutkov, Boris, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Economides, Aris, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Jones, Marcus B., additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Lotta, Luca A., additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Mighty, Jason, additional, Mitnaul, Lyndon J., additional, Nafde, Mrunali, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Overton, John D., additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Reid, Jeffrey G., additional, Salerno, William, additional, Staples, Jeffrey C., additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Manoochehri, Kia, additional, Pradhan, Manasi, additional, Schleicher, Thomas D., additional, Padilla, Maria Sotiropoulos, additional, Ulloa, Ricardo H., additional, Widom, Louis, additional, and Wolf, Sarah E., additional

Published
2022
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15. Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study

Author

Manderstedt, Eric, primary, Lind‐Halldén, Christina, additional, Halldén, Christer, additional, Elf, Johan, additional, Svensson, Peter J., additional, Dahlbäck, Björn, additional, Engström, Gunnar, additional, Melander, Olle, additional, Baras, Aris, additional, Lotta, Luca A., additional, Zöller, Bengt, additional, Abecasis, Goncalo, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Economides, Aris, additional, Lotta, Luca A, additional, Overton, John D, additional, Reid, Jeffrey G, additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D, additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Schleicher, Thomas D, additional, Padilla, Maria Sotiropoulos, additional, Widom, Louis, additional, Wolf, Sarah E, additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Ulloa, Ricardo H, additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Blumenfeld, Andrew, additional, Boutkov, Boris, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J, additional, Maxwell, Evan K, additional, Nafde, Mrunali, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Salerno, William, additional, Staples, Jeffrey C, additional, Jones, Marcus B, additional, Mighty, Jason, additional, and Mitnaul, Lyndon J, additional

Published
2022
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16. Crucial Roles of Two Hydrated Mg2+ Ions in Reaction Catalysis of the Pistol Ribozyme

Author

Teplova, Marianna, Falschlunger, Christoph, Krasheninina, Olga, Egger, Michaela, Ren, Aiming, Patel, Dinshaw J., and Micura, Ronald

Subjects
Ions, Models, Molecular, oligonucleotides, structure–function relationships, Water, Hydrogen Bonding, magnesium, Phosphates, reaction mechanisms, Biocatalysis, RNA, RNA, Catalytic, Research Articles, Research Article
Abstract

Pistol ribozymes constitute a new class of small self‐cleaving RNAs. Crystal structures have been solved, providing three‐dimensional snapshots along the reaction coordinate of pistol phosphodiester cleavage, corresponding to the pre‐catalytic state, a vanadate mimic of the transition state, and the product. The results led to the proposed underlying chemical mechanism. Importantly, a hydrated Mg2+ ion remains innersphere‐coordinated to N7 of G33 in all three states, and is consistent with its likely role as acid in general acid base catalysis (δ and β catalysis). Strikingly, the new structures shed light on a second hydrated Mg2+ ion that approaches the scissile phosphate from its binding site in the pre‐cleavage state to reach out for water‐mediated hydrogen bonding in the cyclophosphate product. The major role of the second Mg2+ ion appears to be the stabilization of product conformation. This study delivers a mechanistic understanding of ribozyme‐catalyzed backbone cleavage., Role play: Transition‐state mimic and product crystal structures suggest that two hydrated metal ions are involved in pistol ribozyme cleavage chemistry. One of them remains innersphere‐coordinated to N7 of a guanosine and plays a key role in catalysis.

Published
2020

17. xAtlas: scalable small variant calling across heterogeneous next-generation sequencing experiments.

Author

Farek, Jesse, Hughes, Daniel, Salerno, William, Zhu, Yiming, Pisupati, Aishwarya, Mansfield, Adam, Krasheninina, Olga, English, Adam C, Metcalf, Ginger, Boerwinkle, Eric, Muzny, Donna M, Gibbs, Richard, Khan, Ziad, and Sedlazeck, Fritz J

Subjects
NUCLEOTIDE sequencing, PRINCIPAL components analysis, SOURCE code
Abstract

Background The growing volume and heterogeneity of next-generation sequencing (NGS) data complicate the further optimization of identifying DNA variation, especially considering that curated high-confidence variant call sets frequently used to validate these methods are generally developed from the analysis of comparatively small and homogeneous sample sets. Findings We have developed xAtlas, a single-sample variant caller for single-nucleotide variants (SNVs) and small insertions and deletions (indels) in NGS data. xAtlas features rapid runtimes, support for CRAM and gVCF file formats, and retraining capabilities. xAtlas reports SNVs with 99.11% recall and 98.43% precision across a reference HG002 sample at 60× whole-genome coverage in less than 2 CPU hours. Applying xAtlas to 3,202 samples at 30× whole-genome coverage from the 1000 Genomes Project achieves an average runtime of 1.7 hours per sample and a clear separation of the individual populations in principal component analysis across called SNVs. Conclusions xAtlas is a fast, lightweight, and accurate SNV and small indel calling method. Source code for xAtlas is available under a BSD 3-clause license at https://github.com/jfarek/xatlas. [ABSTRACT FROM AUTHOR]

Published
2023
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18. Thrombotic Risk Determined by STAB 2 Variants in a Population-Based Cohort Study

Author

Manderstedt, Eric, primary, Halldén, Christer, additional, Lind-Halldén, Christina, additional, Elf, Johan, additional, Svensson, Peter J., additional, Engström, Gunnar, additional, Melander, Olle, additional, Baras, Aris, additional, Lotta, Luca A, additional, Zöller, Bengt, additional, Abecasis, Goncalo, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan, additional, Karalis, Katia, additional, Siminovitch, Katherine, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Schleicher, Thomas D., additional, Sotiropoulos Padilla, Maria, additional, Widom, Louis, additional, Wolf, Sarah E., additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Ulloa, Ricardo H., additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Blumenfeld, Andrew, additional, Boutkov, Boris, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Nafde, Mrunali, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Salerno, William, additional, Staples, Jeffrey C., additional, Verweij, Niek, additional, Nielsen, Jonas, additional, De, Tanima, additional, Jones, Marcus B., additional, Mighty, Jason, additional, LeBlanc, Michelle G., additional, and Mitnaul, Lyndon J., additional

Published
2021
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19. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Author

Boer, Cindy G., primary, Hatzikotoulas, Konstantinos, additional, Southam, Lorraine, additional, Stefánsdóttir, Lilja, additional, Zhang, Yanfei, additional, Coutinho de Almeida, Rodrigo, additional, Wu, Tian T., additional, Zheng, Jie, additional, Hartley, April, additional, Teder-Laving, Maris, additional, Skogholt, Anne Heidi, additional, Terao, Chikashi, additional, Zengini, Eleni, additional, Alexiadis, George, additional, Barysenka, Andrei, additional, Bjornsdottir, Gyda, additional, Gabrielsen, Maiken E., additional, Gilly, Arthur, additional, Ingvarsson, Thorvaldur, additional, Johnsen, Marianne B., additional, Jonsson, Helgi, additional, Kloppenburg, Margreet, additional, Luetge, Almut, additional, Lund, Sigrun H., additional, Mägi, Reedik, additional, Mangino, Massimo, additional, Nelissen, Rob R.G.H.H., additional, Shivakumar, Manu, additional, Steinberg, Julia, additional, Takuwa, Hiroshi, additional, Thomas, Laurent F., additional, Tuerlings, Margo, additional, Babis, George C., additional, Cheung, Jason Pui Yin, additional, Kang, Jae Hee, additional, Kraft, Peter, additional, Lietman, Steven A., additional, Samartzis, Dino, additional, Slagboom, P. Eline, additional, Stefansson, Kari, additional, Thorsteinsdottir, Unnur, additional, Tobias, Jonathan H., additional, Uitterlinden, André G., additional, Winsvold, Bendik, additional, Zwart, John-Anker, additional, Davey Smith, George, additional, Sham, Pak Chung, additional, Thorleifsson, Gudmar, additional, Gaunt, Tom R., additional, Morris, Andrew P., additional, Valdes, Ana M., additional, Tsezou, Aspasia, additional, Cheah, Kathryn S.E., additional, Ikegawa, Shiro, additional, Hveem, Kristian, additional, Esko, Tõnu, additional, Wilkinson, J. Mark, additional, Meulenbelt, Ingrid, additional, Lee, Ming Ta Michael, additional, van Meurs, Joyce B.J., additional, Styrkársdóttir, Unnur, additional, Zeggini, Eleftheria, additional, Loughlin, John, additional, Arden, Nigel, additional, Birrell, Fraser, additional, Carr, Andrew, additional, Deloukas, Panos, additional, Doherty, Michael, additional, McCaskie, Andrew W., additional, Ollier, William E.R., additional, Rai, Ashok, additional, Ralston, Stuart H., additional, Spector, Tim D., additional, Wallis, Gillian A., additional, Martinsen, Amy E., additional, Willer, Cristen, additional, Fors, Egil Andreas, additional, Mundal, Ingunn, additional, Hagen, Knut, additional, Nilsen, Kristian Bernhard, additional, Lie, Marie Udnesseter, additional, Børte, Sigrid, additional, Brumpton, Ben, additional, Nielsen, Jonas Bille, additional, Fritsche, Lars G., additional, Zhou, Wei, additional, Heuch, Ingrid, additional, Storheim, Kjersti, additional, Tyrpenou, Evangelos, additional, Koukakis, Athanasios, additional, Chytas, Dimitrios, additional, Evangelopoulos, Dimitrios Stergios, additional, Efstathios, Chronopoulos, additional, Pneumaticos, Spiros, additional, Nikolaou, Vasileios S., additional, Malizos, Konstantinos, additional, Anastasopoulou, Lydia, additional, Abecasis, Goncalo, additional, Baras, Aris, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Deubler, Andrew, additional, Economides, Aris, additional, Lotta, Luca A., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan, additional, Karalis, Katia, additional, Siminovitch, Katherine, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Schleicher, Thomas D., additional, Padilla, Maria Sotiropoulos, additional, Widom, Louis, additional, Wolf, Sarah E., additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Boutkov, Boris, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Krasheninina, Olga, additional, Lanche, Rouel, additional, Mansfield, Adam J., additional, Maxwell, Evan K., additional, Nafde, Mona, additional, O’Keeffe, Sean, additional, Orelus, Max, additional, Panea, Razvan, additional, Polanco, Tommy, additional, Rasool, Ayesha, additional, Salerno, William, additional, Staples, Jeffrey C., additional, Li, Dadong, additional, Sharma, Deepika, additional, Banerjee, Ilanjana, additional, Bovijn, Jonas, additional, Locke, Adam, additional, Verweij, Niek, additional, Haas, Mary, additional, Hindy, George, additional, De, Tanima, additional, Akbari, Parsa, additional, Sosina, Olukayode, additional, Ferreira, Manuel A.R., additional, Jones, Marcus B., additional, Mighty, Jason, additional, LeBlanc, Michelle G., additional, and Mitnaul, Lyndon J., additional

Published
2021
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21. Multiethnic catalog of structural variants and their translational impact for disease phenotypes across 19,652 genomes

Author

Sedlazeck, Fritz J., Yu, Bing, Mansfield, Adam J., Chen, Han, Krasheninina, Olga, Tin, Adrienne, Qi, Qibin, Zarate, Samantha, Traynelis, Joshua L., Menon, Vipin, Hu, Jianhong, Doddapaneni, Harsha, Metcalf, Ginger A., Coresh, Josef, Kaplan, Robert C., Muzny, Donna M., Jun, Goo, Gibbs, Richard A., Salerno, William J., and Boerwinkle, Eric

Subjects
0303 health sciences, education.field_of_study, Population, Disease, Computational biology, Biology, Phenotype, Genome, DNA sequencing, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Endophenotype, education, Gene, 030304 developmental biology
Abstract

Genome sequencing at population scale provides unprecedented access to the genetic foundations of human phenotypic diversity, but genotype-phenotype association analyses limited to small variants have failed to comprehensively characterize the genetic architecture of human health and disease because they ignore structural variants (SVs) known to contribute to phenotypic variation and pathogenic conditions1–3. Here we demonstrate the significance of SVs when assessing genotype-phenotype associations and the importance of ethnic diversity in study design by analyzing SVs across 19,652 individuals and the translational impact on 4,156 aptamerbased proteomic measurements across 4,021 multi-ethnic samples. The majority of 304,533 SVs detected are rare, although we identified 2,336 protein-coding genes impacted by common SVs.\We identified 64 significant SV-protein associations that comprise 36 cis- and 28 trans-acting relationships, and 21 distinct SV regions overlapped with genome-wide association study loci. These findings represent a more comprehensive mapping of regulatory and translational endophenotypes underlying health and disease.

Published
2020
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23. Parliament2: Accurate structural variant calling at scale

Author

Zarate, Samantha, primary, Carroll, Andrew, additional, Mahmoud, Medhat, additional, Krasheninina, Olga, additional, Jun, Goo, additional, Salerno, William J, additional, Schatz, Michael C, additional, Boerwinkle, Eric, additional, Gibbs, Richard A, additional, and Sedlazeck, Fritz J, additional

Published
2020
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25. Advancing Human Genetics Research and Drug Discovery through Exome Sequencing of the UK Biobank

Author

Szustakowski, Joseph D., primary, Balasubramanian, Suganthi, additional, Sasson, Ariella, additional, Khalid, Shareef, additional, Bronson, Paola G., additional, Kvikstad, Erika, additional, Wong, Emily, additional, Liu, Daren, additional, Davis, J. Wade, additional, Haefliger, Carolina, additional, Loomis, A. Katrina, additional, Mikkilineni, Rajesh, additional, Noh, Hyun Ji, additional, Wadhawan, Samir, additional, Bai, Xiaodong, additional, Hawes, Alicia, additional, Krasheninina, Olga, additional, Ulloa, Ricardo, additional, Lopez, Alex, additional, Smith, Erin N., additional, Waring, Jeff, additional, Whelan, Christopher D., additional, Tsai, Ellen A., additional, Overton, John, additional, Salerno, William, additional, Jacob, Howard, additional, Szalma, Sandor, additional, Runz, Heiko, additional, Hinkle, Greg, additional, Nioi, Paul, additional, Petrovski, Slavé, additional, Miller, Melissa R., additional, Baras, Aris, additional, Mitnaul, Lyndon, additional, and Reid, Jeffrey G., additional

Published
2020
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28. Thrombotic risk determined by rare and common SERPINA1variants in a population‐based cohort study

Author

Manderstedt, Eric, Halldén, Christer, Lind‐Halldén, Christina, Elf, Johan, Svensson, Peter J., Engström, Gunnar, Melander, Olle, Baras, Aris, Lotta, Luca A., Zöller, Bengt, Abecasis, Goncalo, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Overton, John D., Reid, Jeffrey G., Shuldiner, Alan, Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Manoochehri, Kia, Overton, John D., Padilla, Maria Sotiropoulos, Pradhan, Manasi, Schleicher, Thomas D., Ulloa, Ricardo H., Widom, Louis, Wolf, Sarah E., Bai, Xiaodong, Balasubramanian, Suganthi, Blumenfeld, Andrew, Boutkov, Boris, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Krasheninina, Olga, Lanche, Rouel, Mansfield, Adam J., Maxwell, Evan K., Nafde, Mrunali, O’Keeffe, Sean, Orelus, Max, Panea, Razvan, Polanco, Tommy, Rasool, Ayesha, Reid, Jeffrey G., Salerno, William, Staples, Jeffrey C., Jones, Marcus B., Mighty, Jason, and Mitnaul, Lyndon J.

Abstract

Severe alpha‐1‐antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case‐control study.

Published
2022
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32. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank

Author

Szustakowski, Joseph D., Balasubramanian, Suganthi, Kvikstad, Erika, Khalid, Shareef, Bronson, Paola G., Sasson, Ariella, Wong, Emily, Liu, Daren, Wade Davis, J., Haefliger, Carolina, Katrina Loomis, A., Mikkilineni, Rajesh, Noh, Hyun Ji, Wadhawan, Samir, Bai, Xiaodong, Hawes, Alicia, Krasheninina, Olga, Ulloa, Ricardo, Lopez, Alex E., Smith, Erin N., Waring, Jeffrey F., Whelan, Christopher D., Tsai, Ellen A., Overton, John D., Salerno, William J., Jacob, Howard, Szalma, Sandor, Runz, Heiko, Hinkle, Gregory, Nioi, Paul, Petrovski, Slavé, Miller, Melissa R., Baras, Aris, Mitnaul, Lyndon J., and Reid, Jeffrey G.

Abstract

The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a private–public partnership between the UK Biobank (UKB) and eight biopharmaceutical companies that will complete the sequencing of exomes for all ~500,000 UKB participants. Here, we describe the early results from ~200,000 UKB participants and the features of this project that enabled its success. The biopharmaceutical industry has increasingly used human genetics to improve success in drug discovery. Recognizing the need for large-scale human genetics data, as well as the unique value of the data access and contribution terms of the UKB, the UKB-ESC was formed. As a result, exome data from 200,643 UKB enrollees are now available. These data include ~10 million exonic variants—a rich resource of rare coding variation that is particularly valuable for drug discovery. The UKB-ESC precompetitive collaboration has further strengthened academic and industry ties and has provided teams with an opportunity to interact with and learn from the wider research community.

Published
2021
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33. Crucial Roles of Two Hydrated Mg2+ Ions in Reaction Catalysis of the Pistol Ribozyme.

Author

Teplova, Marianna, Falschlunger, Christoph, Krasheninina, Olga, Egger, Michaela, Ren, Aiming, Patel, Dinshaw J., and Micura, Ronald

Subjects
ACID-base catalysis, HYDROGEN bonding, CATALYSIS, TRANSITION state theory (Chemistry), PISTOLS, IONS, NON-coding RNA
Abstract

Pistol ribozymes constitute a new class of small self‐cleaving RNAs. Crystal structures have been solved, providing three‐dimensional snapshots along the reaction coordinate of pistol phosphodiester cleavage, corresponding to the pre‐catalytic state, a vanadate mimic of the transition state, and the product. The results led to the proposed underlying chemical mechanism. Importantly, a hydrated Mg2+ ion remains innersphere‐coordinated to N7 of G33 in all three states, and is consistent with its likely role as acid in general acid base catalysis (δ and β catalysis). Strikingly, the new structures shed light on a second hydrated Mg2+ ion that approaches the scissile phosphate from its binding site in the pre‐cleavage state to reach out for water‐mediated hydrogen bonding in the cyclophosphate product. The major role of the second Mg2+ ion appears to be the stabilization of product conformation. This study delivers a mechanistic understanding of ribozyme‐catalyzed backbone cleavage. [ABSTRACT FROM AUTHOR]

Published
2020
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35. xAtlas: Scalable small variant calling across heterogeneous next-generation sequencing experiments

Author

Farek, Jesse, primary, Hughes, Daniel, additional, Mansfield, Adam, additional, Krasheninina, Olga, additional, Nasser, Waleed, additional, Sedlazeck, Fritz J, additional, Khan, Ziad, additional, Venner, Eric, additional, Metcalf, Ginger, additional, Boerwinkle, Eric, additional, Muzny, Donna M, additional, Gibbs, Richard A, additional, and Salerno, William, additional

Published
2018
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38. Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Author

Ihnatsyeu-Kachan, Aliaksei, primary, Dzmitruk, Volha, additional, Apartsin, Evgeny, additional, Krasheninina, Olga, additional, Ionov, Maksim, additional, Loznikova, Svetlana, additional, Venyaminova, Alya, additional, Miłowska, Katarzyna, additional, Shcharbin, Dzmitry, additional, Mignani, Serge, additional, Muñoz-Fernández, Maria, additional, Majoral, Jean-Pierre, additional, and Bryszewska, Maria, additional

Published
2017
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42. Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (A). Mechanisms of interaction

Author

Rafael Gomez-Ramirez, Francisco Javier de la Mata, Svetlana Loznikova, Alya G. Venyaminova, Inessa Halets, Jean-Pierre Majoral, Dzmitry Shcharbin, Katarzyna Milowska, D. S. Novopashina, Volha Dzmitruk, Maksim Ionov, Joanna Lazniewska, Olga A. Krasheninina, Maria Bryszewska, Evgeny K. Apartsin, Olga Nowacka, Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, University of Lódź, Institute of Biophysics and Cell Engineering, NASB, Minsk, National Academy of Sciences of Belarus (NASB), Institute of of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Institute of Chemical Biology and Fundamental Medicine, Departamento Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares, Universidad de Alcalá - University of Alcalá (UAH), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III [Madrid] (ISC)-ministerio de ciencia e innovacion, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Ionov, Maksim, Lazniewska, Joanna, Dzmitruk, Volha, Halets, Inessa, Loznikova, Svetlana, Novopashina, Darya, Apartsin, Evgeny, Krasheninina, Olga, Venyaminova, Alya, Milowska, Katarzyna, Nowacka, Olga, Gomez-Ramirez, Rafael, Javier de la Mata, Francisco, Majoral, Jean-Pierre, Shcharbin, Dzmitry, and Bryszewska, Maria

Subjects
Dendrimers, Small interfering RNA, Circular dichroism, Light, RNase P, Stereochemistry, anticancer siRNA, biophysical characteristics, bcl-X Protein, Pharmaceutical Science, 02 engineering and technology, dendrimer, Transfection, 03 medical and health sciences, Microscopy, Electron, Transmission, complex formation, Neoplasms, Dendrimer, Zeta potential, Humans, Scattering, Radiation, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Pharmacology & Pharmacy, Particle Size, RNA, Small Interfering, 030304 developmental biology, Electrophoresis, Agar Gel, 0303 health sciences, Heparin, Chemistry, Circular Dichroism, Phosphorus, Silanes, 021001 nanoscience & nanotechnology, 3. Good health, Gene Expression Regulation, Neoplastic, RNAi Therapeutics, Spectrometry, Fluorescence, Proto-Oncogene Proteins c-bcl-2, Cell culture, Cancer cell, Biophysics, Myeloid Cell Leukemia Sequence 1 Protein, Nucleic Acid Conformation, Nanocarriers, 0210 nano-technology, nano-drug-delivery
Abstract

International audience; This paper examines a perspective on the use of newly engineered nanomaterials as effective and safe carriers of genes for the therapy of cancer. Three different groups of cationic dendrimers (PAMAM, phosphorus and carbosilane) were complexed with anticancer siRNA and their biophysical properties of the dendriplexes analyzed. The potential of the dendrimers as nanocarriers for anticancer siBcl-xl, siBcl-2, siMcl-1 siRNAs and a siScrambled sequence was explored. Dendrimer/siRNA complexes were characterized by methods including fluorescence, zeta potential, dynamic light scattering, circular dichroism, gel electrophoresis and transmission electron microscopy. Some of the experiments were done with heparin to check if siRNA can be easily disassociated from the complexes, and whether released siRNA maintains its structure after interaction with the dendrimer. The results indicate that siRNAs form complexes with all the dendrimers tested. Oligoribonucleotide duplexes can be released from dendriplexes after heparin treatment and the structure of siRNA is maintained in the case of PAMAM or carbosilane dendrimers. The dendrimers were also effective in protecting siRNA from RNase A activity. The selection of the best siRNA carrier will be made based on cell culture studies (Part B).

Published
2015

43. Structural variation across 138,134 samples in the TOPMed consortium.

Author

Jun G, English AC, Metcalf GA, Yang J, Chaisson MJ, Pankratz N, Menon VK, Salerno WJ, Krasheninina O, Smith AV, Lane JA, Blackwell T, Kang HM, Salvi S, Meng Q, Shen H, Pasham D, Bhamidipati S, Kottapalli K, Arnett DK, Ashley-Koch A, Auer PL, Beutel KM, Bis JC, Blangero J, Bowden DW, Brody JA, Cade BE, Chen YI, Cho MH, Curran JE, Fornage M, Freedman BI, Fingerlin T, Gelb BD, Hou L, Hung YJ, Kane JP, Kaplan R, Kim W, Loos RJF, Marcus GM, Mathias RA, McGarvey ST, Montgomery C, Naseri T, Nouraie SM, Preuss MH, Palmer ND, Peyser PA, Raffield LM, Ratan A, Redline S, Reupena S, Rotter JI, Rich SS, Rienstra M, Ruczinski I, Sankaran VG, Schwartz DA, Seidman CE, Seidman JG, Silverman EK, Smith JA, Stilp A, Taylor KD, Telen MJ, Weiss ST, Williams LK, Wu B, Yanek LR, Zhang Y, Lasky-Su J, Gingras MC, Dutcher SK, Eichler EE, Gabriel S, Germer S, Kim R, Viaud-Martinez KA, Nickerson DA, Luo J, Reiner A, Gibbs RA, Boerwinkle E, Abecasis G, and Sedlazeck FJ

Abstract

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hematologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

Published
2023
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