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1. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Author: Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack A, Cirulli, Elizabeth T, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyun, Stockwell, Amy D, Sloofman, Laura G, Jordan, Daniel M, Thompson, Ryan C, Del Valle, Diane, Simons, Nicole, Cheng, Esther, Sebra, Robert, Schadt, Eric E, Kim-Schulze, Seunghee, Gnjatic, Sacha, Merad, Miriam, Buxbaum, Joseph D, Beckmann, Noam D, Charney, Alexander W, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess D, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, J Kenneth, Stuckey, Alex, Salas, Antonio, Bello, Xabier, Pardo-Seco, Jacobo, Gómez-Carballa, Alberto, Rivero-Calle, Irene, Martinón-Torres, Federico, Ganna, Andrea, Karczewski, Konrad J, Veerapen, Kumar, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert Jm, Forgetta, Vincenzo, Morrison, David, Langlais, David, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklos, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Schiabor Barrett, Kelly M, Lee, William, Bolze, Alexandre, White, Simon, Riffle, Stephen, Tanudjaja, Francisco, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Casadei, Nicolas, Motameny, Susanne, Alaamery, Manal, Massadeh, Salam, Aljawini, Nora, Almutairi, Mansour S, Arabi, Yaseen M, Alqahtani, Saleh A, Al Harthi, Fawz S, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal A, El Bardisy, Hadeel, Fawzy, Mohammad, Cai, Fang, Soranzo, Nicole, Butterworth, Adam, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study (Italy), Mount Sinai Clinical Intelligence Center, GEN-COVID Consortium (Spain), GenOMICC Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, Geschwind, Daniel H, Arteaga, Stephanie, Stephens, Alexis, Butte, Manish J, Boutros, Paul C, Yamaguchi, Takafumi N, Tao, Shu, Eng, Stefan, Sanders, Timothy, Tung, Paul J, Broudy, Michael E, Pan, Yu, Gonzalez, Alfredo, Chavan, Nikhil, Johnson, Ruth, Pasaniuc, Bogdan, Yaspan, Brian, Smieszek, Sandra, Rivolta, Carlo, Bibert, Stephanie, Bochud, Pierre-Yves, Dabrowski, Maciej, Zawadzki, Pawel, Sypniewski, Mateusz, Kaja, Elżbieta, Chariyavilaskul, Pajaree, Nilaratanakul, Voraphoj, Hirankarn, Nattiya, Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat, Chetruengchai, Wanna, Tokunaga, Katsushi, Sugiyama, Masaya, Kawai, Yosuke, Hasegawa, Takanori, Naito, Tatsuhiko, Namkoong, Ho, Edahiro, Ryuya, Kimura, Akinori, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, Okada, Yukinori, Imoto, Seiya, Miyano, Satoru, Mangul, Serghei, Abedalthagafi, Malak S, Zeberg, Hugo, Grzymski, Joseph J, Washington, Nicole L, Ossowski, Stephan, Ludwig, Kerstin U, Schulte, Eva C, Riess, Olaf, Moniuszko, Marcin, Kwasniewski, Miroslaw, Mbarek, Hamdi, Ismail, Said I, Verma, Anurag, Goldstein, David B, Kiryluk, Krzysztof, Renieri, Alessandra, Ferreira, Manuel AR, Richards, J Brent, Butler-Laporte, Guillaume [0000-0001-5388-0396], Povysil, Gundula [0000-0003-4625-5909], Kosmicki, Jack A [0000-0003-1252-6192], Cirulli, Elizabeth T [0000-0001-7808-2809], Drivas, Theodore [0000-0002-8717-0111], Saad, Chadi [0000-0001-6963-9126], Olszewski, Pawel [0000-0003-1010-8843], Korotko, Urszula [0000-0002-1779-8368], Quinodoz, Mathieu [0000-0002-9841-4433], Çelik, Elifnaz [0000-0002-0324-5228], Kundu, Kousik [0000-0002-1019-8351], Walter, Klaudia [0000-0003-4448-0301], Sloofman, Laura G [0000-0001-7628-4378], Jordan, Daniel M [0000-0002-5318-8225], Thompson, Ryan C [0000-0002-0450-8181], Del Valle, Diane [0000-0001-6983-5362], Simons, Nicole [0000-0002-3952-1458], Chang, Timothy [0000-0002-9225-9874], Brand, Fabian [0000-0003-1885-7021], Chwialkowska, Karolina [0000-0001-8053-8959], Niemira, Magdalena [0000-0002-0701-4961], Pula, Szymon [0000-0002-5684-5358], Stuckey, Alex [0000-0001-8636-737X], Bello, Xabier [0000-0002-4990-8496], Karczewski, Konrad J [0000-0003-2878-4671], Bourgey, Mathieu [0000-0002-8432-834X], Bourque, Guillaume [0000-0002-3933-9656], Eveleigh, Robert Jm [0000-0002-4147-382X], Morrison, David [0000-0001-8380-3615], Langlais, David [0000-0003-4429-0110], Mooser, Vincent [0000-0002-8632-0448], Nakanishi, Tomoko [0000-0001-9510-5646], Frithiof, Robert [0000-0003-2278-7951], Hultström, Michael [0000-0003-4675-1099], Lipcsey, Miklos [0000-0002-1976-4129], Nordlund, Jessica [0000-0001-8699-9959], Schiabor Barrett, Kelly M [0000-0001-6194-787X], Bolze, Alexandre [0000-0001-7399-2766], White, Simon [0000-0001-6375-2363], Dabe, Shaun [0000-0002-2494-962X], Casadei, Nicolas [0000-0003-2209-0580], Motameny, Susanne [0000-0003-1186-1108], Massadeh, Salam [0000-0001-9193-0008], Almutairi, Mansour S [0000-0003-2736-8991], Arabi, Yaseen M [0000-0001-5735-6241], Fawzy, Mohammad [0000-0002-1318-9979], Arteaga, Stephanie [0000-0003-1441-8849], Stephens, Alexis [0000-0002-5979-6838], Yamaguchi, Takafumi N [0000-0003-1082-3871], Eng, Stefan [0000-0002-5245-6507], Gonzalez, Alfredo [0000-0001-8963-3135], Johnson, Ruth [0000-0002-1929-0998], Yaspan, Brian [0000-0002-3787-2510], Smieszek, Sandra [0000-0002-8006-0454], Rivolta, Carlo [0000-0002-0733-9950], Bochud, Pierre-Yves [0000-0002-2208-4757], Dabrowski, Maciej [0000-0003-4150-3985], Zawadzki, Pawel [0000-0002-9032-2315], Kaja, Elżbieta [0000-0003-1277-6140], Chariyavilaskul, Pajaree [0000-0003-1096-6020], Nilaratanakul, Voraphoj [0000-0002-3964-5477], Hirankarn, Nattiya [0000-0003-2224-6856], Shotelersuk, Vorasuk [0000-0002-1856-0589], Pongpanich, Monnat [0000-0003-3228-3351], Phokaew, Chureerat [0000-0002-4246-2604], Chetruengchai, Wanna [0000-0003-2495-6595], Sugiyama, Masaya [0000-0002-9084-7197], Kawai, Yosuke [0000-0003-0666-1224], Hasegawa, Takanori [0000-0001-7251-9950], Namkoong, Ho [0000-0001-6181-4284], Miyano, Satoru [0000-0002-1753-6616], Mangul, Serghei [0000-0003-4770-3443], Zeberg, Hugo [0000-0001-7118-1249], Grzymski, Joseph J [0000-0003-2646-8958], Ossowski, Stephan [0000-0002-7416-9568], Ludwig, Kerstin U [0000-0002-8541-2519], Schulte, Eva C [0000-0003-3105-5672], Verma, Anurag [0000-0002-5063-9107], Goldstein, David B [0000-0001-7627-0259], Kiryluk, Krzysztof [0000-0002-5047-6715], Renieri, Alessandra [0000-0002-0846-9220], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository
Subjects: Medicine and health sciences, Research and analysis methods, Physical sciences, Toll-Like Receptor 7, Biology and life sciences, SARS-CoV-2, FOS: Physical sciences, Humans, COVID-19, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Research Article
Abstract: Acknowledgements: We thank the patients who volunteered to all participating cohorts, and the researchers and clinicians who enrolled them into the respective studies. A full list of acknowledgments can be found in S1 and S2 Tables., Funder: Lady Davis Institute of the Jewish General Hospital, Funder: Canadian Foundation for Innovation, Funder: NIH Foundation, Funder: Fonds de Recherche Québec Santé (FRQS), Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4), Funder: Jewish General Hospital Foundation, Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062, Funder: Public Health Agency of Canada, Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582, Funder: Calcul Québec and Compute Canada, Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020, Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380, Funder: State of Saarland, Funder: Dr. Rolf M. Schwiete Foundation, Funder: Munich Clinician Scientist Programm, Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021, Funder: Federal Ministry of Education and Research, Funder: Leenaards Foundation, Funder: Santos-Suarez Foundation, Funder: Carigest, Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”, Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency), Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
Published: 2022

2. Additional file 1 of INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG)

Author: Lam, Lyn Ley, Pavlakis, Nick, Shitara, Kohei, Sjoquist, Katrin M., Martin, Andrew J., Yip, Sonia, Kang, Yoon-Koo, Bang, Yung-Jue, Chen, Li-Tzong, Moehler, Markus, Bekaii-Saab, Tanios, Alcindor, Thierry, O’Callaghan, Christopher J., Tebbutt, Niall C., Hague, Wendy, Chan, Howard, Rha, Sun Young, Lee, Keun-Wook, Gebski, Val, Jaworski, Anthony, Zalcberg, John, Price, Timothy, Simes, John, and Goldstein, David
Abstract: Additional file 1: Spirit Checklist.
Published: 2023
Full Text: View/download PDF

3. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Author: Guillaume, Butler-Laporte, Gundula, Povysil, Kosmicki, Jack A., Cirulli, Elizabeth T., Theodore, Drivas, Furini, Simone, Chadi, Saad, Axel, Schmidt, Pawel, Olszewski, Urszula, Korotko, Mathieu, Quinodoz, Elifnaz, Çelik, Kousik, Kundu, Klaudia, Walter, Junghyun, Jung, Stockwell, Amy D., Sloofman, Laura G., Jordan, Daniel M., Thompson, Ryan C., Diane Del Valle, Nicole, Simons, Esther, Cheng, Robert, Sebra, Schadt, Eric E., Seunghee, Kim-Schulze, Sacha, Gnjatic, Miriam, Merad, Buxbaum, Joseph D., Beckmann, Noam D., Charney, Alexander W., Bartlomiej, Przychodzen, Timothy, Chang, Pottinger, Tess D., Ning, Shang, Fabian, Brand, Fava, Francesca, Mari, Francesca, Karolina, Chwialkowska, Magdalena, Niemira, Szymon, Pula, J Kenneth Baillie, Alex, Stuckey, Antonio, Salas, Xabier, Bello, Jacobo, Pardo-Seco, Alberto, Gómez-Carballa, Irene, Rivero-Calle, Federico, Martinón-Torres, Andrea, Ganna, Karczewski, Konrad J., Kumar, Veerapen, Mathieu, Bourgey, Guillaume, Bourque, Robert JM Eveleigh, Vincenzo, Forgetta, David, Morrison, David, Langlais, Mark, Lathrop, Vincent, Mooser, Tomoko, Nakanishi, Robert, Frithiof, Michael, Hultström, Miklos, Lipcsey, Yanara, Marincevic-Zuniga, Jessica, Nordlund, Schiabor Barrett, Kelly M., William, Lee, Alexandre, Bolze, Simon, White, Stephen, Riffle, Francisco, Tanudjaja, Efren, Sandoval, Iva, Neveux, Shaun, Dabe, Nicolas, Casadei, Susanne, Motameny, Manal, Alaamery, Salam, Massadeh, Nora, Aljawini, Almutairi, Mansour S., Arabi, Yaseen M., Alqahtani, Saleh A., Al Harthi, Fawz S., Amal, Almutairi, Fatima, Alqubaishi, Sarah, Alotaibi, Albandari, Binowayn, Alsolm, Ebtehal A., Hadeel El Bardisy, Mohammad, Fawzy, Fang, Cai, Nicole, Soranzo, Adam, Butterworth, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study (Italy), Daga, Sergio, Meloni, Ilaria, Mount Sinai Clinical Intelligence Center, GEN-COVID consortium (Spain), Genomicc, Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, Geschwind, Daniel H., Stephanie, Arteaga, Alexis, Stephens, Butte, Manish J., Boutros, Paul C., Yamaguchi, Takafumi N., Shu, Tao, Stefan, Eng, Timothy, Sanders, Tung, Paul J., Broudy, Michael E., Pan, Yu, Alfredo, Gonzalez, Nikhil, Chavan, Ruth, Johnson, Bogdan, Pasaniuc, Brian, Yaspan, Sandra, Smieszek, Carlo, Rivolta, Stephanie, Bibert, Pierre-Yves, Bochud, Maciej, Dabrowski, Pawel, Zawadzki, Mateusz, Sypniewski, Elżbieta, Kaja, Pajaree, Chariyavilaskul, Voraphoj, Nilaratanakul, Nattiya, Hirankarn, Vorasuk, Shotelersuk, Monnat, Pongpanich, Chureerat, Phokaew, Wanna, Chetruengchai, Katsushi, Tokunaga, Masaya, Sugiyama, Yosuke, Kawai, Takanori, Hasegawa, Tatsuhiko, Naito, Namkoong, Ho, Ryuya, Edahiro, Akinori, Kimura, Seishi, Ogawa, Takanori, Kanai, Koichi, Fukunaga, Yukinori, Okada, Seiya, Imoto, Satoru, Miyano, Serghei, Mangul, Abedalthagafi, Malak S., Hugo, Zeberg, Grzymski, Joseph J., Washington, Nicole L., Stephan, Ossowski, Ludwig, Kerstin U., Schulte, Eva C., Olaf, Riess, Marcin, Moniuszko, Miroslaw, Kwasniewski, Hamdi, Mbarek, Ismail, Said I., Anurag, Verma, Goldstein, David B., Krzysztof, Kiryluk, Renieri, Alessandra, Ferreira, Manuel A. R., J Brent Richards, Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack A, Cirulli, Elizabeth T, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyun, Stockwell, Amy D, Sloofman, Laura G, Jordan, Daniel M, Thompson, Ryan C, Del Valle, Diane, Simons, Nicole, Cheng, Esther, Sebra, Robert, Schadt, Eric E, Kim-Schulze, Seunghee, Gnjatic, Sacha, Merad, Miriam, Buxbaum, Joseph D, Beckmann, Noam D, Charney, Alexander W, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess D, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, J Kenneth, Stuckey, Alex, Salas, Antonio, Bello, Xabier, Pardo-Seco, Jacobo, Gómez-Carballa, Alberto, Rivero-Calle, Irene, Martinón-Torres, Federico, Ganna, Andrea, Karczewski, Konrad J, Veerapen, Kumar, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert Jm, Forgetta, Vincenzo, Morrison, David, Langlais, David, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Schiabor Barrett, Kelly M, Lee, William, Bolze, Alexandre, White, Simon, Riffle, Stephen, Tanudjaja, Francisco, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Casadei, Nicola, Motameny, Susanne, Alaamery, Manal, Massadeh, Salam, Aljawini, Nora, Almutairi, Mansour S, Arabi, Yaseen M, Alqahtani, Saleh A, Al Harthi, Fawz S, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal A, El Bardisy, Hadeel, Fawzy, Mohammad, Cai, Fang, Soranzo, Nicole, Butterworth, Adam, Geschwind, Daniel H, Arteaga, Stephanie, Stephens, Alexi, Butte, Manish J, Boutros, Paul C, Yamaguchi, Takafumi N, Tao, Shu, Eng, Stefan, Sanders, Timothy, Tung, Paul J, Broudy, Michael E, Pan, Yu, Gonzalez, Alfredo, Chavan, Nikhil, Johnson, Ruth, Pasaniuc, Bogdan, Yaspan, Brian, Smieszek, Sandra, Rivolta, Carlo, Bibert, Stephanie, Bochud, Pierre-Yve, Dabrowski, Maciej, Zawadzki, Pawel, Sypniewski, Mateusz, Kaja, Elżbieta, Chariyavilaskul, Pajaree, Nilaratanakul, Voraphoj, Hirankarn, Nattiya, Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat, Chetruengchai, Wanna, Tokunaga, Katsushi, Sugiyama, Masaya, Kawai, Yosuke, Hasegawa, Takanori, Naito, Tatsuhiko, Namkoong, Ho, Edahiro, Ryuya, Kimura, Akinori, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, Okada, Yukinori, Imoto, Seiya, Miyano, Satoru, Mangul, Serghei, Abedalthagafi, Malak S, Zeberg, Hugo, Grzymski, Joseph J, Washington, Nicole L, Ossowski, Stephan, Ludwig, Kerstin U, Schulte, Eva C, Riess, Olaf, Moniuszko, Marcin, Kwasniewski, Miroslaw, Mbarek, Hamdi, Ismail, Said I, Verma, Anurag, Goldstein, David B, Kiryluk, Krzysztof, Renieri, Alessandra, Ferreira, Manuel A R, Richards, J Brent, Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, University of Helsinki, and Helsinki Institute of Life Science HiLIFE
Subjects: Infectious Medicine, Cancer Research, Host genetics is a key determinant of COVID-19 outcomes. Previously, Infektionsmedicin, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights, Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, Genetics, Humans, Exome, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, SARS-CoV-2, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, 1184 Genetics, developmental biology, physiology, COVID-19, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5, 737 controls, Toll-Like Receptor 7, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, 085 severe disease cases and 571, thereby informing therapeutics development. Here, Medical Genetics, Genome-Wide Association Study
Abstract: Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
Published: 2022
Full Text: View/download PDF

4. The All of Us Research Program: Data quality, utility, and diversity

Author: Ramirez, Andrea H, Sulieman, Lina, Schlueter, David J, Halvorson, Alese, Qian, Jun, Ratsimbazafy, Francis, Loperena, Roxana, Mayo, Kelsey, Basford, Melissa, Deflaux, Nicole, Muthuraman, Karthik N, Natarajan, Karthik, Kho, Abel, Xu, Hua, Wilkins, Consuelo, Anton-Culver, Hoda, Boerwinkle, Eric, Cicek, Mine, Clark, Cheryl R, Cohn, Elizabeth, Ohno-Machado, Lucila, Schully, Sheri D, Ahmedani, Brian K, Argos, Maria, Cronin, Robert M, O'Donnell, Christopher, Fouad, Mona, Goldstein, David B, Greenland, Philip, Hebbring, Scott J, Karlson, Elizabeth W, Khatri, Parinda, Korf, Bruce, Smoller, Jordan W, Sodeke, Stephen, Wilbanks, John, Hentges, Justin, Mockrin, Stephen, Lunt, Christopher, Devaney, Stephanie A, Gebo, Kelly, Denny, Joshua C, Carroll, Robert J, Glazer, David, Harris, Paul A, Hripcsak, George, Philippakis, Anthony, Roden, Dan M, and All of Us Research Program
Subjects: All of Us Research Program, electronic health records, Good Health and Well Being, Networking and Information Technology R&D (NITRD), Clinical Research, precision medicine, cohort study, Generic health relevance, cloud-based analytics, Cardiovascular, Cancer
Abstract: The All of Us Research Program seeks to engage at least one million diverse participants to advance precision medicine and improve human health. We describe here the cloud-based Researcher Workbench that uses a data passport model to democratize access to analytical tools and participant information including survey, physical measurement, and electronic health record (EHR) data. We also present validation study findings for several common complex diseases to demonstrate use of this novel platform in 315,000 participants, 78% of whom are from groups historically underrepresented in biomedical research, including 49% self-reporting non-White races. Replication findings include medication usage pattern differences by race in depression and type 2 diabetes, validation of known cancer associations with smoking, and calculation of cardiovascular risk scores by reported race effects. The cloud-based Researcher Workbench represents an important advance in enabling secure access for a broad range of researchers to this large resource and analytical tools.
Published: 2022

5. Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop

Author: Mehra, Reena, Tjurmina, Olga A, Ajijola, Olujimi A, Arora, Rishi, Bolser, Donald C, Chapleau, Mark W, Chen, Peng-Sheng, Clancy, Colleen E, Delisle, Brian P, Gold, Michael R, Goldberger, Jeffrey J, Goldstein, David S, Habecker, Beth A, Handoko, M Louis, Harvey, Robert, Hummel, James P, Hund, Thomas, Meyer, Christian, Redline, Susan, Ripplinger, Crystal M, Simon, Marc A, Somers, Virend K, Stavrakis, Stavros, Taylor-Clark, Thomas, Undem, Bradley Joel, Verrier, Richard L, Zucker, Irving H, Sopko, George, and Shivkumar, Kalyanam
Subjects: rapid eye movement, HF, sympathetic nerve activity, long QT, HRV, heart failure, autonomic dysregulation, PV, Cardiorespiratory Medicine and Haematology, SDB, Cardiovascular, central sleep apnea, sleep disordered breathing, angiotensin-converting enzyme, cardiovascular disease, pulmonary arterial hypertension, atrial fibrillation, heart failure with reduced ejection fraction, Lung, obstructive sleep apnea, non-rapid eye movement, pulmonary vein, heart rate variability, ganglionated plexi, CVD, sleep apnea, and Blood Institute, myocardial infarction, Heart Disease, GP, ANS, SNA, CNS, Sleep Research, heart failure with preserved ejection fraction, neuropeptide Y, NREM, NE, cardiopulmonary, Clinical Sciences, TLD, RV, NPY, SNSA, electrocardiogram, CSA, sudden cardiac death, chronic obstructive pulmonary disease, norepinephrine, OSA, COPD, Ach, right ventricular, ACE, ventricular arrhythmia, MI, LQT, ECG, targeted lung denervation, autonomic nervous system, Neurosciences, AD, HFrEF, National Heart, PAH, AF, NHLBI, asthma, central nervous system, HFpEF, acetylcholine, SCD, circadian, REM, &nbsp, sympathetic nervous system activity, extracellular vesicle, EV
Abstract: This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.
Published: 2022

6. Contralateral nodal failures in oropharyngeal cancers after TORS and unilateral neck management: a retrospective study

Author: Sahovaler, Axel, Lee, John J. W., Xu, Wei, Su, Susie, Hosni, Ali, Bayley, Andrew, Goldstein, David P., and de Almeida, John R.
Subjects: Oropharyngeal cancer, Oropharyngeal Neoplasms, RD1-811, Robotic Surgical Procedures, Otorhinolaryngology, Carcinoma, Squamous Cell, Humans, Neck Dissection, Surgery, Original Research Article, TORS, Contralateral nodal failure, Retrospective Studies
Abstract: Background Report the incidence of contralateral nodal failure rates in well-lateralized oropharyngeal carcinoma treated with upfront surgery and unilateral neck management. Methods Lateralized oropharyngeal carcinomas treated with upfront surgery using transoral robotic surgery (TORS) and unilateral neck management (unilateral neck dissection ± unilateral radiation treatment) were identified. Primary endpoint was contralateral regional control (CRC). Secondary endpoints were local control (LC), and overall survival (OS). Results Thirty-two patients were included. Pathologic T categories included 66% pT1, 31% pT2 and 3% pT3. Nodal diseases comprised 41% N0 and 47% N1 (AJCC 8th). Twenty-three (72%) patients had HPV related tumors. 3-years CRC, LC and OS were 100%, 96% (89–100) and 96% (CI 89–100). One patient developed a second primary with contralateral nodal disease. Only one patient died from another primary cancer. Conclusion In selected patients with lateralized oropharyngeal cancer, treatment with TORS and ipsilateral management of the neck may be oncologically safe without significant risk of contralateral failure. Level of evidence: Level 2. Graphical abstract
Published: 2021
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7. Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

Author: Zazuli, Zulfan, Jong, Corine de de, Xu, Wei, Vijverberg, Susanne J. H., Masereeuw, Rosalinde, Patel, Devalben, Mirshams, Maryam, Khan, Khaleeq, Cheng, Dangxiao, Ordonez-Perez, Bayardo, Huang, Shao Hui, Spreafico, Anna, Hansen, Aaron R., Goldstein, David P., Almeida, John R. de de, Bratman, Scott V., Hope, Andrew, Knox, Jennifer J., Wong, Rebecca K. S., Darling, Gail E., Kitchlu, Abhijat, Haarlem, Simone W. A. van van, Meer, Femke van der, Lindert, Anne S. R. van, Heuvel, Alexandra ten ten, Brouwer, Jan, Ross, Colin J. D., Carleton, Bruce C., Egberts, Toine C. G., Herder, Gerarda J. M., Deneer, Vera H. M., Zee, Anke H. Maitland-van der, Liu, Geoffrey, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, APH - Personalized Medicine, CCA - Cancer biology and immunology, and Pulmonology
Subjects: Oncology, pharmacogenomics, Candidate gene, medicine.medical_specialty, genome-wide association study, business.industry, nephrotoxicity, Medicine (miscellaneous), cisplatin, Single-nucleotide polymorphism, Genome-wide association study, Article, Nephrotoxicity, Minor allele frequency, genetic polymorphisms, Internal medicine, Cohort, Genetic predisposition, kidney injury, Medicine, platinum, Allele, business
Abstract: This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.
Published: 2021

8. Whole-genome sequencing of patients with rare diseases in a national health system

Author: Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V.V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B.A., Saleem, Moin A., Smith, Kenneth G.C., Stark, Hannah, Tan, Rhea Y.Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Abbs, Stephen, Abulhoul, Lara, Adlard, Julian, Ahmed, Munaza, Alachkar, Hana, Allsup, David J., Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Attwood, Anthony, Aurora, Paul, Babbs, Christian, Bacchelli, Chiara, Bakchoul, Tamam, Banka, Siddharth, Bariana, Tadbir, Barwell, Julian, Batista, Joana, Baxendale, Helen E., Beales, Phil L., Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Black, Graeme C., Bleda, Marta, Blesneac, Iulia, Bockenhauer, Detlef, Bogaard, Harm, Bourne, Christian J., Boyce, Sara, Bradley, John R., Bragin, Eugene, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Andrew C., Browning, Michael J., Buchan, Rachel J., Buckland, Matthew S., Bueser, Teofila, Diz, Carmen Bugarin, Burn, John, Burns, Siobhan O., Burrows, Nigel, Campbell, Carolyn, Carr-White, Gerald, Casey, Ruth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Cheah, Calvin, Cheng, Floria, Chitre, Manali, Christian, Martin T., Church, Colin, Clayton-Smith, Jill, Cleary, Maureen, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine, Collins, Peter W., Colombo, Camilla, Compton, Cecilia J., Condliffe, Robin, Cook, Stuart, Cook, H. Terence, Cooper, Nichola, Corris, Paul A A., Furnell, Abigail, Cunningham, Fiona, Curry, Nicola S., Cutler, Antony J., Daniels, Matthew J., Dattani, Mehul, Daugherty, Louise C., Davis, John, De Soyza, Anthony, Dent, Timothy, Deshpande, Charu, Dewhurst, Eleanor F., Douzgou, Sofia, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edgar, J. David M., Edwards, Karen, Egner, William, Ekani, Melanie N., Elliott, Perry, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Fassihi, Hiva, Favier, Remi, Findhammer, Jack, Fletcher, Debra, Flinter, Frances A., Floto, R. Andres, Fowler, Tom, Fox, James, Frary, Amy J., French, Courtney E., Freson, Kathleen, Gall, Henning, Ganesan, Vijeya, Gattens, Michael, Geoghegan, Claire, Gerighty, Terence S.A., Gharavi, Ali G., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Gibbs, J. Simon R., Gibson, Kate, Gilmour, Kimberly C., Girerd, Barbara, Gleadall, Nicholas S., Goddard, Sarah, Goldstein, David B., Gomez, Keith, Gordins, Pavels, Gosal, David, Graham, Jodie, Grassi, Luigi, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell J., Grozeva, Detelina, Gurnell, Mark, Hackett, Scott, Hadinnapola, Charaka, Hague, William M., Hague, Rosie, Hall, Matthew, Hanson, Helen L., Haque, Eshika, Harkness, Kirsty, Harper, Andrew R., Harris, Claire L L., Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Herwadkar, Archana, Hoffman, Jonathan, Holden, Simon, Horvath, Rita, Houlden, Henry, Houweling, Arjan C C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud P., Humbert, Marc, Hunter, Sarah, Hurles, Matthew, Irving, Melita, Izatt, Louise, Johnson, Sally A., Jolles, Stephen, Jolley, Jennifer, Josifova, Dragana, Jurkute, Neringa, Karten, Tim, Karten, Johannes, Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kelly, Anne M., Kelsall, Wilf, Kempster, Carly, Kiely, David G., Kingston, Nathalie, Klima, Robert, Koelling, Nils, Kostadima, Myrto, Kovacs, Gabor, Kreuzhuber, Roman, Kuijpers, Taco W., Kumar, Ajith, Kumararatne, Dinakantha, Kurian, Manju A., Lalloo, Fiona, Lambert, Michele, Lawrie, Allan, Layton, D. Mark, Lench, Nick, Lentaigne, Claire, Lester, Tracy, Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Lyons, Paul A., Machado, Rajiv D., MacKenzie Ross, Robert V., Madan, Bella, Maimaris, Jesmeen, Malka, Samantha, Mangles, Sarah, Marchbank, Kevin J., Marks, Stephen, Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McKinney, Harriet, McMahon, Aoife, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Mehta, Sarju G G., Michaelides, Michel, Millar, Carolyn, Mohammed, Shehla N., Moledina, Shahin, Montani, David, Moore, Anthony T., Mozere, Monika, Muir, Keith W., Nemeth, Andrea H., Newman, William G., Newnham, Michael, Noorani, Sadia, Nurden, Paquita, O’Sullivan, Jennifer, Obaji, Samya, Odhams, Chris, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Oram, S. Helen, Ouwehand, Willem H., Palles, Claire, Papadia, Sofia, Park, Soo Mi, Parry, David, Patel, Smita, Paterson, Joan, Peacock, Andrew, Pearce, Simon H H., Peden, John, Peerlinck, Kathelijne, Penkett, Christopher J., Pepke-Zaba, Joanna, Petersen, Romina, Pilkington, Clarissa, Poole, Kenneth E.S., Prathalingam, Radhika, Psaila, Bethan, Pyle, Angela, Quinton, Richard, Rahman, Shamima, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthews, Paula J., Rees, Christine, Renton, Tara, Rhodes, Christopher J., Rice, Andrew S.C., Richter, Alex, Robert, Leema, Rogers, Anthony, Rose, Sarah J., Ross-Russell, Robert, Roughley, Catherine, Roy, Noemi B. A, Ruddy, Deborah M., Sadeghi-Alavijeh, Omid, Samani, Nilesh, Samarghitean, Crina, Sargur, Ravishankar B., Sarkany, Robert N., Satchell, Simon, Savic, Sinisa, Sayer, John A., Sayer, Genevieve, Scelsi, Laura, Schaefer, Andrew M., Schulman, Sol, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sen, Arjune, Sewell, W. A.Carrock, Seyres, Denis, Shah, Neil, Shapiro, Susan E., Shaw, Adam C., Short, Patrick J., Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael A A., Sims, Matthew C., Sivapalaratnam, Suthesh, Smedley, Damian, Smith, Katherine R., Snape, Katie, Soranzo, Nicole, Soubrier, Florent, Southgate, Laura, Spasic-Boskovic, Olivera, Staines, Simon, Staples, Emily, Steward, Charles, Stirrups, Kathleen E., Stuckey, Alex, Suntharalingam, Jay, Swietlik, Emilia M., Syrris, Petros, Tait, R. Campbell, Talks, Kate, Tate, Katie, Taylor, John M., Taylor, Jenny C., Thaventhiran, James E., Thomas, Ellen, Thomas, David, Thomas, Moira J., Thomas, Patrick, Thomson, Kate, Threadgold, Glen, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tolhuis, Bas, Tomlinson, Ian P., Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Treadaway, Paul, Trembath, Richard, Turek, Wojciech, Twiss, Philip, Vale, Tom, Geet, Chris Van, Zuydam, Natalie van, Vandekuilen, Maarten, Vandersteen, Anthony M., Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Vonk Noordegraaf, Anton, Wagner, Annette, Waisfisz, Quinten, Walker, Suellen M., Walker, Neil, Walter, Klaudia, Ware, James S., Watt, Christopher, Wedderburn, Lucy, Wei, Wei, Welch, Steven B., Wessels, Julie, Westbury, Sarah K., Westwood, John Paul, Wharton, John, Whitehorn, Deborah, Wilkie, Andrew O. M, Wilson, Brian T., Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R R., Wort, Stephen J., Worth, Austen, Wright, Michael, Yates, Katherine, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, University of Cambridge [UK] (CAM), John Wyeth & Brother Limited, Medical Research Council (MRC), Wellcome Trust, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, and Project, NIHR BioResource for the 100,000 Genomes
Subjects: 0301 basic medicine, Erythrocytes, Internationality, Databases, Factual, National Health Programs, [SDV]Life Sciences [q-bio], Disease, VARIANTS, Genome, State Medicine, NIHR BioResource for the 100,000 Genomes Project, 0302 clinical medicine, Medicine, GATA1 Transcription Factor, Genetics, Multidisciplinary, Translational bioinformatics, ASSOCIATION, 3. Good health, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, disease genetics, Medical genetics, Science & Technology - Other Topics, Receptors, Thrombopoietin, medicine.medical_specialty, General Science & Technology, Quantitative Trait Loci, Genomics, Computational biology, Biology, DIAGNOSIS, computational biology and bioinformatics, Actin-Related Protein 2-3 Complex, Article, LRBA, LINKS, 03 medical and health sciences, Rare Diseases, Humans, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, National health, Science & Technology, Whole Genome Sequencing, MUTATIONS, business.industry, THROMBOCYTOPENIA, United Kingdom, MACROTHROMBOCYTOPENIA, genetics research, 030104 developmental biology, business, Rare disease
Abstract: Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Published: 2021
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9. Exosphere-mediated migration of volatile species on airless bodies across the solar system

Author: Steckloff, Jordan K., Goldstein, David, Trafton, Laurence, Varghese, Philip, and Prem, Parvathy
Subjects: Earth and Planetary Astrophysics (astro-ph.EP), Space and Planetary Science, FOS: Physical sciences, Astronomy and Astrophysics, Astrophysics - Earth and Planetary Astrophysics
Abstract: Surface-bound exospheres facilitate volatile migration across the surfaces of nearly airless bodies. However, such transport requires that the body can both form and retain an exosphere. To form a sublimation exosphere requires the surface of a body to be sufficiently warm for surface volatiles to sublime; to retain an exosphere, the ballistic escape and photodestruction rates and other loss mechanisms must be sufficiently low. Here we construct a simple free molecular model of exospheres formed by volatile desorption/sublimation. We consider the conditions for forming and retaining exospheres for common volatile species across the Solar System, and explore how three processes (desorption/sublimation, ballistic loss, and photodestruction) shape exospheric dynamics on airless bodies. Our model finds that the CO2 exosphere of Callisto is too dense to be sustained by impact-delivered volatiles, but could be maintained by only ~7 hectares of exposed CO2 ice. We predict the peak surface locations of Callisto's CO2 exosphere along with other Galilean moons, which could be tested by JUICE observations. Our model finds that to maintain Iapetus' two-tone appearance, its dark Cassini Regio likely has unresolved exposures of water ice, perhaps in sub-resolution impact craters, that amount to up to ~0.06% of its surface. In the Uranian system, we find that the CO2 deposits on Ariel, Umbriel, Titania, and Oberon are unlikely to have been delivered via impacts, but are consistent with both a magnetospheric origin or sourced endogenously. We suggest that exosphere-mediated volatile transport could produce these moons' leading/trailing CO2 asymmetries, and may be a seasonal equinox feature that could be largely erased by volatile migration during the Uranian solstices. We calculate that ~2.4-6.4 mm thick layer of CO2 could migrate about the surface of Uranus' large moons during a seasonal cycle.
Published: 2022
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10. Antibodies to SARS-CoV-2 in All of Us Research Program Participants, January 2-March 18, 2020

Author: Althoff, Keri N, Schlueter, David J, Anton-Culver, Hoda, Cherry, James, Denny, Joshua C, Thomsen, Isaac, Karlson, Elizabeth W, Havers, Fiona P, Cicek, Mine S, Thibodeau, Stephen N, Pinto, Ligia A, Lowy, Douglas, Malin, Bradley A, Ohno-Machado, Lucila, Williams, Carolyn, Goldstein, David, Kouame, Aymone, Ramirez, Andrea, Roman, Adrienne, Sharpless, Norman E, Gebo, Kelly A, and Schully, Sheri D
Subjects: Vaccine Related, All of Us Research Program, Emerging Infectious Diseases, SARS-CoV-2 antibodies, Clinical Research, Biodefense, Prevention, Biological Sciences, Microbiology, Medical and Health Sciences, United States
Abstract: BackgroundWith limited SARS-CoV-2 testing capacity in the US at the start of the epidemic (January - March), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic.MethodsAll of Us study participants in all 50 US states provided blood specimens during study visits from January 2 to March 18, 2020. A participant was considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies on the Abbott Architect SARS-CoV-2 IgG ELISA and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. Sensitivity and specificity of the Abbott and EUROIMMUNE ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated with 95% confidence intervals.ResultsThe estimated sensitivity of Abbott and EUROIMMUN was 100% (107/107 [96.6%, 100%]) and 90.7% (97/107 [83.5%, 95.4%]), respectively. The estimated specificity of Abbott and EUROIMMUN was 99.5% (995/1,000 [98.8%, 99.8%]) and 99.7% (997/1,000 [99.1%, 99.9%), respectively. The net sensitivity and specificity of our sequential testing algorithm was 90.7% (97/107 [83.5%, 95.4%]) and 100.0% (1,000/1,000 [99.6%, 100%]), respectively. Of the 24,079 study participants with blood specimens from January 2 to March 18, 2020, 9 were seropositive, 7 of whom were seropositive prior to the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi.ConclusionsOur findings indicate SARS-CoV-2 infections weeks prior to the first recognized cases in 5 US states.
Published: 2021

11. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author: Chia, Ruth, Sabir, Marya S, Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H, Gustavsson, Emil, Walton, Ronald L, Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B, Diez-Fairen, Monica, Portley, Makayla K, Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G, Blauwendraat, Cornelis, Stone, David J, Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J, Morris, John C, Halliday, Glenda M, Van Deerlin, Vivianna M, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, American Genome Center, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C, Caraway, Chad A, Monuki, Edwin S, Brunetti, Maura, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Flanagan, Margaret E, Mao, Qinwen, Bigio, Eileen H, Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, and Logroscino, Giancarlo
Subjects: Lewy Body Disease, Aging, Lewy Body Dementia, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, American Genome Center, Alzheimer Disease, Acquired Cognitive Impairment, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alzheimer's Disease Related Dementias (ADRD), Genome, Parkinson's Disease, Tumor Suppressor Proteins, Gene Expression Profiling, Prevention, Human Genome, Signal Transducing, Neurosciences, Adaptor Proteins, Nuclear Proteins, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Parkinson Disease, Single Nucleotide, Biological Sciences, Brain Disorders, Case-Control Studies, Neurological, alpha-Synuclein, Glucosylceramidase, Dementia, hormones, hormone substitutes, and hormone antagonists, Human, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract: The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
Published: 2021

12. sj-pdf-1-bmi-10.1177_11772719211005745 – Supplemental material for Moving with the Times: The Health Science Alliance (HSA) Biobank, Pathway to Sustainability

Author: Quinn, Carmel M, Porwal, Mamta, Meagher, Nicola S, Anusha Hettiaratchi, Power, Carl, Jitendra Jonnaggadala, McCullough, Sue, Macmillan, Stephanie, Tang, Katrina, Liauw, Winston, Goldstein, David, Zeps, Nikolajs, and Crowe, Philip J
Subjects: Biochemistry
Abstract: Supplemental material, sj-pdf-1-bmi-10.1177_11772719211005745 for Moving with the Times: The Health Science Alliance (HSA) Biobank, Pathway to Sustainability by Carmel M Quinn, Mamta Porwal, Nicola S Meagher, Anusha Hettiaratchi, Carl Power, Jitendra Jonnaggadala, Sue McCullough, Stephanie Macmillan, Katrina Tang, Winston Liauw, David Goldstein, Nikolajs Zeps and Philip J Crowe in Biomarker Insights
Published: 2021
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13. Additional file 5 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Author: Nichols, Anthony, Pencilla Lang, Prisman, Eitan, Berthelet, Eric, Tran, Eric, Hamilton, Sarah, Wu, Jonn, Fung, Kevin, Almeida, John, Bayley, Andrew, Goldstein, David, Eskander, Antoine, Zain Husain, Bahig, Houda, Christopoulous, Apostolos, Hier, Michael, Sultanem, Khalil, Richardson, Keith, Mlynarek, Alex, Krishnan, Suren, Le, Hien, Yoo, John, S. MacNeil, Mendez, Adrian, Winquist, Eric, Read, Nancy, Varagur Venkatesan, Kuruvilla, Sara, Warner, Andrew, Mitchell, Sylvia, Corsten, Martin, Murali Rajaraman, Johnson-Obaseki, Stephanie, Libni Eapen, Odell, Michael, Chandarana, Shamir, Banerjee, Robyn, Dort, Joseph, T. Matthews, Hart, Robert, Kerr, Paul, Dowthwaite, Samuel, Gupta, Michael, Zhang, Han, Wright, Jim, Parker, Christina, Wehrli, Bret, Kwan, Keith, Theurer, Julie, and Palma, David
Abstract: Additional file 5. Study Information and Informed Consent Form.
Published: 2020
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14. Additional file 4 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Author: Nichols, Anthony, Pencilla Lang, Prisman, Eitan, Berthelet, Eric, Tran, Eric, Hamilton, Sarah, Wu, Jonn, Fung, Kevin, Almeida, John, Bayley, Andrew, Goldstein, David, Eskander, Antoine, Zain Husain, Bahig, Houda, Christopoulous, Apostolos, Hier, Michael, Sultanem, Khalil, Richardson, Keith, Mlynarek, Alex, Krishnan, Suren, Le, Hien, Yoo, John, S. MacNeil, Mendez, Adrian, Winquist, Eric, Read, Nancy, Varagur Venkatesan, Kuruvilla, Sara, Warner, Andrew, Mitchell, Sylvia, Corsten, Martin, Murali Rajaraman, Johnson-Obaseki, Stephanie, Libni Eapen, Odell, Michael, Chandarana, Shamir, Banerjee, Robyn, Dort, Joseph, T. Matthews, Hart, Robert, Kerr, Paul, Dowthwaite, Samuel, Gupta, Michael, Zhang, Han, Wright, Jim, Parker, Christina, Wehrli, Bret, Kwan, Keith, Theurer, Julie, and Palma, David
Subjects: ComputingMilieux_COMPUTERSANDEDUCATION, Data_FILES
Abstract: Additional file 4. Lab Guidelines.
Published: 2020
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15. Additional file 6 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Author: Nichols, Anthony, Pencilla Lang, Prisman, Eitan, Berthelet, Eric, Tran, Eric, Hamilton, Sarah, Wu, Jonn, Fung, Kevin, Almeida, John, Bayley, Andrew, Goldstein, David, Eskander, Antoine, Zain Husain, Bahig, Houda, Christopoulous, Apostolos, Hier, Michael, Sultanem, Khalil, Richardson, Keith, Mlynarek, Alex, Krishnan, Suren, Le, Hien, Yoo, John, S. MacNeil, Mendez, Adrian, Winquist, Eric, Read, Nancy, Varagur Venkatesan, Kuruvilla, Sara, Warner, Andrew, Mitchell, Sylvia, Corsten, Martin, Murali Rajaraman, Johnson-Obaseki, Stephanie, Libni Eapen, Odell, Michael, Chandarana, Shamir, Banerjee, Robyn, Dort, Joseph, T. Matthews, Hart, Robert, Kerr, Paul, Dowthwaite, Samuel, Gupta, Michael, Zhang, Han, Wright, Jim, Parker, Christina, Wehrli, Bret, Kwan, Keith, Theurer, Julie, and Palma, David
Abstract: Additional file 6. World Health Organization Trial Registration Dataset.
Published: 2020
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16. Additional file 1 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Author: Nichols, Anthony, Pencilla Lang, Prisman, Eitan, Berthelet, Eric, Tran, Eric, Hamilton, Sarah, Wu, Jonn, Fung, Kevin, Almeida, John, Bayley, Andrew, Goldstein, David, Eskander, Antoine, Zain Husain, Bahig, Houda, Christopoulous, Apostolos, Hier, Michael, Sultanem, Khalil, Richardson, Keith, Mlynarek, Alex, Krishnan, Suren, Le, Hien, Yoo, John, S. MacNeil, Mendez, Adrian, Winquist, Eric, Read, Nancy, Varagur Venkatesan, Kuruvilla, Sara, Warner, Andrew, Mitchell, Sylvia, Corsten, Martin, Murali Rajaraman, Johnson-Obaseki, Stephanie, Libni Eapen, Odell, Michael, Chandarana, Shamir, Banerjee, Robyn, Dort, Joseph, T. Matthews, Hart, Robert, Kerr, Paul, Dowthwaite, Samuel, Gupta, Michael, Zhang, Han, Wright, Jim, Parker, Christina, Wehrli, Bret, Kwan, Keith, Theurer, Julie, and Palma, David
Abstract: Additional file 1. Treatment Planning Guidelines.
Published: 2020
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17. Additional file 1 of Hepatic transcriptome of the freeze-tolerant Cope’s gray treefrog, Dryophytes chrysoscelis: responses to cold acclimation and freezing

Author: M. Clara F. Do Amaral, Frisbie, James, Crum, Raphael J., Goldstein, David L., and Krane, Carissa M.
Subjects: sense organs
Abstract: Additional file 1: Table S1. genes differentially regulated in Dryophytes chrysoscelis compared to warm animals with corresponding gene symbol, UniprotID, Transcript ID, and fold-change in each treatment. Table S2. genes differentially expressed in frozen Dryophytes chrysoscelis, relative to cold animals, with corresponding gene symbol, UniprotID, Transcript ID, and fold-change.
Published: 2020
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18. Additional file 2 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Author: Nichols, Anthony, Pencilla Lang, Prisman, Eitan, Berthelet, Eric, Tran, Eric, Hamilton, Sarah, Wu, Jonn, Fung, Kevin, Almeida, John, Bayley, Andrew, Goldstein, David, Eskander, Antoine, Zain Husain, Bahig, Houda, Christopoulous, Apostolos, Hier, Michael, Sultanem, Khalil, Richardson, Keith, Mlynarek, Alex, Krishnan, Suren, Le, Hien, Yoo, John, S. MacNeil, Mendez, Adrian, Winquist, Eric, Read, Nancy, Varagur Venkatesan, Kuruvilla, Sara, Warner, Andrew, Mitchell, Sylvia, Corsten, Martin, Murali Rajaraman, Johnson-Obaseki, Stephanie, Libni Eapen, Odell, Michael, Chandarana, Shamir, Banerjee, Robyn, Dort, Joseph, T. Matthews, Hart, Robert, Kerr, Paul, Dowthwaite, Samuel, Gupta, Michael, Zhang, Han, Wright, Jim, Parker, Christina, Wehrli, Bret, Kwan, Keith, Theurer, Julie, and Palma, David
Abstract: Additional file 2. Surgical Credentialling Form.
Published: 2020
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19. Additional file 3 of Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

Author: Nichols, Anthony, Pencilla Lang, Prisman, Eitan, Berthelet, Eric, Tran, Eric, Hamilton, Sarah, Wu, Jonn, Fung, Kevin, Almeida, John, Bayley, Andrew, Goldstein, David, Eskander, Antoine, Zain Husain, Bahig, Houda, Christopoulous, Apostolos, Hier, Michael, Sultanem, Khalil, Richardson, Keith, Mlynarek, Alex, Krishnan, Suren, Le, Hien, Yoo, John, S. MacNeil, Mendez, Adrian, Winquist, Eric, Read, Nancy, Varagur Venkatesan, Kuruvilla, Sara, Warner, Andrew, Mitchell, Sylvia, Corsten, Martin, Murali Rajaraman, Johnson-Obaseki, Stephanie, Libni Eapen, Odell, Michael, Chandarana, Shamir, Banerjee, Robyn, Dort, Joseph, T. Matthews, Hart, Robert, Kerr, Paul, Dowthwaite, Samuel, Gupta, Michael, Zhang, Han, Wright, Jim, Parker, Christina, Wehrli, Bret, Kwan, Keith, Theurer, Julie, and Palma, David
Subjects: ComputingMilieux_THECOMPUTINGPROFESSION, Data_FILES, ComputingMilieux_COMPUTERSANDEDUCATION, ComputingMilieux_MISCELLANEOUS
Abstract: Additional file 3. Schedule of Enrolment, Interventions and Assessments.
Published: 2020
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20. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

Author: Kelly, McKenna, Park, Meredith, Mihalek, Ivana, Rochtus, Anne, Gramm, Marie, Perez-Palma, Eduardo, Axeen, Erika Takle, Hung, Christina Y, Olson, Heather, Swanson, Lindsay, Anselm, Irina, Briere, Lauren C, High, Frances A, Sweetser, David A, Kayani, Saima, Snyder, Molly, Calvert, Sophie, Scheffer, Ingrid E, Yang, Edward, Waugh, Jeff L, Lal, Dennis, Bodamer, Olaf, Poduri, Annapurna, Adams, David R, Aday, Aaron, Alejandro, Mercedes E, Allard, Patrick, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Baker, Eva, Balasubramanyam, Ashok, Barseghyan, Hayk, Batzli, Gabriel F, Beggs, Alan H, Behnam, Babak, Bellen, Hugo J, Bernstein, Jonathan A, Bican, Anna, Bick, David P, Birch, Camille L, Bonner, Devon, Boone, Braden E, Bostwick, Bret L, Brokamp, Elly, Brown, Donna M, Brush, Matthew, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Chen, Shan, Clark, Gary D, Coakley, Terra R, Cogan, Joy D, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, D'Souza, Precilla, Davids, Mariska, Davidson, Jean M, Dayal, Jyoti G, Dell'Angelica, Esteban C, Dhar, Shweta U, Dipple, Katrina M, Donnell-Fink, Laurel A, Dorrani, Naghmeh, Dorset, Daniel C, Douine, Emilie D, Draper, David D, Dries, Annika M, Eckstein, David J, Emrick, Lisa T, Eng, Christine M, Enns, Gre-Gory M, Eskin, Ascia, Esteves, Cecilia, Estwick, Tyra, Fairbrother, Laura, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L, Fisher, Paul G, Fogel, Brent L, Friedman, Noah D, Gahl, William A, Glanton, Emily, Godfrey, Rena A, Goldman, Alica M, Goldstein, David B, Gould, Sarah E, Gourdine, Jean-Philippe F, Groden, Catherine A, Gropman, Andrea L, Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A, High, Francis, Holm, Ingrid A, Horn, Jason, Howerton, Ellen M, Huang, Yong, Jamal, Fariha, Jiang, Yong-hui, Johnston, Jean M, Jones, Angela L, Karaviti, Lefkothea, Koeller, David M, Kohane, Isaac S, Kohler, Jennefer N, Konick, Susan, Koziura, Mary, Krasnewich, Donna M, Krier, Joel B, Kyle, Jennifer E, Lalani, Seema R, Lau, C Christopher, Lazar, Jozef, LeBlanc, Kimberly, Lee, Brendan H, Lee, Hane, Levy, Shawn E, Lewis, Richard A, Lincoln, Sharyn A, Loo, Sandra K, Loscalzo, Joseph, Maas, Richard L, Macnamara, Ellen F, MacRae, Calum A, Maduro, Valerie V, Majch-erska, Marta M, Malicdan, May Christine, Mamounas, Laura A, Manolio, Teri A, Markello, Thomas C, Marom, Ronit, Martin, Martin G, Martinez-Agosto, Julian A, Mar-waha, Shruti, May, Thomas, McConkie-Rosell, Allyn, McCormack, Colleen E, McCray, Alexa F, Merker, Jason D, Metz, Thomas O, Might, Matthew, Moretti, Paolo M, Morimoto, Marie, Mulvihill, John J, Murdock, David R, Murphy, Jennifer L, Muzny, Donna M, Nehrebecky, Michele E, Nelson, Stan F, Newberry, J Scott, Newman, John H, Nicholas, Sarah K, Novacic, Donna, Orange, Jordan S, Orengo, James P, Pallais, J Carl, Palmer, Christina GS, Papp, Jeanette C, Parker, Neil H, Pena, Loren DM, Phillips, John A, Posey, Jennifer E, Postlethwait, John H, Potocki, Lorraine, Pusey, Barbara N, Reuter, Chloe M, Rives, Lynette, Robertson, Amy K, Rodan, Lance H, Rosenfeld, Jill A, Sampson, Jacinda B, Samson, Susan L, Schoch, Kelly, Scott, Daryl A, Shakachite, Lisa, Sharma, Prashant, Shashi, Vandana, Signer, Rebecca, Silverman, Edwin K, Sinsheimer, Janet S, Smith, Kevin S, Spillmann, Rebecca C, Stoler, Joan M, Stong, Nicholas, Sullivan, Jennifer A, Tan, Queenie K-G, Tifft, Cynthia J, Toro, Camilo, Tran, Alyssa A, Urv, Tiina K, Vilain, Eric, Vogel, Tiphanie P, Waggott, Daryl M, Wahl, Colleen E, Walker, Melissa, Walley, Nicole M, Walsh, Chris A, Wan, Jijun, Wangler, Michael F, Ward, Patricia A, Waters, Katrina M, Webb-Robertson, Bobbie-Jo M, Westerfield, Monte, Wheeler, Matthew T, Wise, Anastasia L, Wolfe, Lynne A, Worthey, Elizabeth A, Yamamoto, Shinya, Yang, Yaping, Yoon, Amanda J, Yu, Guoyun, Zastrow, Diane B, Zhao, Chunli, and Zheng, Allison
Subjects: 0301 basic medicine, Male, Movement disorders, VARIANT, GTP-Binding Protein alpha Subunits, Gi-Go, Neurodegenerative, PHENOTYPE, Gi-Go, Epilepsy, GNAO1, developmental and epileptic encephalopathy, mosaicism, movement disorders, 0302 clinical medicine, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences. Human Genetics, Genomics and Proteomics, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics, Hypotonia, GTP-Binding Protein alpha Subunits, Neurology, Child, Preschool, Female, medicine.symptom, Life Sciences & Biomedicine, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti. Genetika, genomika i proteomika čovjeka, Ataxia, Adolescent, Encephalopathy, Clinical Sciences, Clinical Neurology, Biology, MOVEMENT-DISORDER, G-ALPHA(O), Article, 03 medical and health sciences, Young Adult, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Neurology, medicine, Humans, Genetic Predisposition to Disease, Preschool, Genetic Association Studies, Science & Technology, Neurology & Neurosurgery, EPILEPTIC ENCEPHALOPATHY, Neurosciences, Genetic Variation, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Neurologija, Chorea, Undiagnosed Diseases Network, medicine.disease, Brain Disorders, MODEL, 030104 developmental biology, Dyskinesia, DE-NOVO MUTATIONS, Neurodevelopmental Disorders, Case-Control Studies, Neurosciences & Neurology, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment. ispartof: EPILEPSIA vol:60 issue:3 pages:406-418 ispartof: location:United States status: published
Published: 2019
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21. IRF2BPL Is Associated with Neurological Phenotypes

Author: Marcogliese, Paul C, Shashi, Vandana, Spillmann, Rebecca C, Stong, Nicholas, Rosenfeld, Jill A, Koenig, Mary Kay, Martínez-Agosto, Julián A, Herzog, Matthew, Chen, Agnes H, Dickson, Patricia I, Lin, Henry J, Vera, Moin U, Salamon, Noriko, Graham, John M, Ortiz, Damara, Infante, Elena, Steyaert, Wouter, Dermaut, Bart, Poppe, Bruce, Chung, Hyung-Lok, Zuo, Zhongyuan, Lee, Pei-Tseng, Kanca, Oguz, Xia, Fan, Yang, Yaping, Smith, Edward C, Jasien, Joan, Kansagra, Sujay, Spiridigliozzi, Gail, El-Dairi, Mays, Lark, Robert, Riley, Kacie, Koeberl, Dwight D, Golden-Grant, Katie, Program for Undiagnosed Diseases (UD-PrOZA), Undiagnosed Diseases Network, Yamamoto, Shinya, Wangler, Michael F, Mirzaa, Ghayda, Hemelsoet, Dimitri, Lee, Brendan, Nelson, Stanley F, Goldstein, David B, Bellen, Hugo J, and Pena, Loren DM
Subjects: Genetics & Heredity, ataxia, Human Genome, neurodegeneration, pits, Neurosciences, Undiagnosed Diseases Network, Neurodegenerative, Biological Sciences, CG11138, Medical and Health Sciences, Program for Undiagnosed Diseases, C3HC4 RING finger, Brain Disorders, developmental regression, EAP1, Neurological, Genetics, 2.1 Biological and endogenous factors, Drosophila, hypotonia, Aetiology, seizures, Biotechnology
Abstract: Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.
Published: 2018

22. Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium

Author: Sanders, Stephan J, Neale, Benjamin M, Huang, Hailiang, Werling, Donna M, An, Joon-Yong, Dong, Shan, Abecasis, Goncalo, Arguello, P Alexander, Blangero, John, Boehnke, Michael, Daly, Mark J, Eggan, Kevin, Geschwind, Daniel H, Glahn, David C, Goldstein, David B, Gur, Raquel E, Handsaker, Robert E, McCarroll, Steven A, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Sabatti, Chiara, State, Matthew W, Willsey, A Jeremy, Hyman, Steven E, Addington, Anjene M, Lehner, Thomas, Freimer, Nelson B, and Whole Genome Sequencing for Psychiatric Disorders (WGSPD)
Subjects: Mental Health, Neurology & Neurosurgery, Whole Genome Sequencing for Psychiatric Disorders, Neurosciences, Psychology, Cognitive Sciences
Abstract: In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article.
Published: 2018

23. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases

Author: Pena, Loren DM, Jiang, Yong-Hui, Schoch, Kelly, Spillmann, Rebecca C, Walley, Nicole, Stong, Nicholas, Rapisardo Horn, Sarah, Sullivan, Jennifer A, McConkie-Rosell, Allyn, Kansagra, Sujay, Smith, Edward C, El-Dairi, Mays, Bellet, Jane, Keels, Martha Ann, Jasien, Joan, Kranz, Peter G, Noel, Richard, Nagaraj, Shashi K, Lark, Robert K, Wechsler, Daniel SG, Del Gaudio, Daniela, Leung, Marco L, Hendon, Laura G, Parker, Collette C, Jones, Kelly L, Undiagnosed Diseases Network Members, Goldstein, David B, and Shashi, Vandana
Subjects: Genotype, Biopsy, Clinical Sciences, infantile neuroaxonal dystrophy, Whole Exome Sequencing, Rare Diseases, Clinical Research, Exome Sequencing, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Exome, whole-exome sequencing, Polymorphism, Aetiology, Child, Preschool, leukoencephalopathy with vanishing white matter, Alleles, Genetic Association Studies, Undiagnosed Diseases Network Members, Pediatric, Genetics & Heredity, Whole Genome Sequencing, Human Genome, Infant, Single Nucleotide, Undiagnosed Diseases Network, Brain Disorders, Inborn, Phenotype, Good Health and Well Being, Molecular Diagnostic Techniques, Genetic Diseases, Female, infantile systemic hyalinosis
Abstract: PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
Published: 2018

24. Whole genome sequencing in psychiatric disorders: the WGSPD consortium

Author: Sanders, Stephan J, Neale, Benjamin M, Huang, Hailiang, Werling, Donna M, An, Joon-Yong, Dong, Shan, Whole Genome Sequencing for Psychiatric Disorders (WGSPD), Abecasis, Goncalo, Arguello, P Alexander, Blangero, John, Boehnke, Michael, Daly, Mark J, Eggan, Kevin, Geschwind, Daniel H, Glahn, David C, Goldstein, David B, Gur, Raquel E, Handsaker, Robert E, McCarroll, Steven A, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Sabatti, Chiara, State, Matthew W, Willsey, A Jeremy, Hyman, Steven E, Addington, Anjene M, Lehner, Thomas, and Freimer, Nelson B
Subjects: Intellectual and Developmental Disabilities (IDD), Autism, 1.1 Normal biological development and functioning, Underpinning research, Genetics, Humans, 2.1 Biological and endogenous factors, Psychology, Aetiology, Biological Psychiatry, screening and diagnosis, Genome, Neurology & Neurosurgery, Whole Genome Sequencing, Mental Disorders, Whole Genome Sequencing for Psychiatric Disorders, Human Genome, Neurosciences, Genetic Variation, Serious Mental Illness, Brain Disorders, Detection, Mental Health, Schizophrenia, Cognitive Sciences, Human, Biotechnology, 4.2 Evaluation of markers and technologies
Abstract: As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome through pilot WGS projects will be critical to determining which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The Whole Genome Sequencing for Psychiatric Disorders Consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.
Published: 2017

25. Additional file 8: of The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes

Author: Gussow, Ayal, SlavĂŠ Petrovski, Quanli Wang, Allen, Andrew, and Goldstein, David
Abstract: A PDF containing the full results of the comparison to variant level predictors. (PDF 88 kb)
Published: 2016
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26. Additional file 6: of The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes

Author: Gussow, Ayal, SlavĂŠ Petrovski, Quanli Wang, Allen, Andrew, and Goldstein, David
Abstract: A PDF containing Figure S1 and Figure S2, which show the distribution of score effect sizes from random permutations. (PDF 195 kb)
Published: 2016
Full Text: View/download PDF

27. Additional file 6: of The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes

Author: Gussow, Ayal, SlavĂŠ Petrovski, Quanli Wang, Allen, Andrew, and Goldstein, David
Abstract: A PDF containing Figure S1 and Figure S2, which show the distribution of score effect sizes from random permutations. (PDF 195 kb)
Published: 2016
Full Text: View/download PDF

28. Additional file 1: of Unequal representation of genetic variation across ancestry groups creates healthcare inequalityÂ in the application of precision medicine

Author: SlavĂŠ Petrovski and Goldstein, David
Abstract: Supplementary methods that describe the variant calling quality control parameters adopted and the principal component ancestry predictions. (PDF 390Â kb)
Published: 2016
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29. Additional file 8: of The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes

Author: Gussow, Ayal, SlavĂŠ Petrovski, Quanli Wang, Allen, Andrew, and Goldstein, David
Abstract: A PDF containing the full results of the comparison to variant level predictors. (PDF 88 kb)
Published: 2016
Full Text: View/download PDF

30. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy

Author: Allen, Andrew S., Berkovic, Samuel F., Coe, Bradley P., Cook, Joseph, Cossette, Patrick, Delanty, Norman, Dlugos, Dennis, Eichler, Evan E., Epstein, Michael P., Glauser, Tracy, Goldstein, David B., Heinzen, Erin L., Johnson, Michael R., Krumm, Nik, Kuzniecky, Ruben, Lowenstein, Daniel H., Marson, Anthony G., Mefford, Heather C., Nelson, Ben, Esmaeeli Nieh, Sahar, O'Brien, Terence J., Ottman, Ruth, Petrou, Stephen, Petrovski, Slavé, Poduri, Annapurna, Raja, Archana, Ruzzo, Elizabeth K., Scheffer, Ingrid E., Sherr, Elliott, Abou‐Khalil, Bassel, Alldredge, Brian K., Andermann, Eva, Andermann, Frederick, Amron, Dina, Bautista, Jocelyn F., Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Fiol, Miguel, Fountain, Nathan B., French, Jacqueline, Friedman, Daniel, Geller, Eric B., Glynn, Simon, Haut, Sheryl R., Hayward, Jean, Helmers, Sandra L., Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Knowlton, Robert C., Kossoff, Eric H., Kuperman, Rachel, McGuire, Shannon M., Motika, Paul V., Novotny, Edward J., Paolicchi, Juliann M., Parent, Jack, Park, Kristen, Shellhaas, Renée A., Shih, Jerry J., Singh, Rani, Sirven, Joseph, Smith, Michael C., Sullivan, Joe, Thio, Liu Lin, Venkat, Anu, Vining, Eileen P.G., Von Allmen, Gretchen K., Weisenberg, Judith L., Widdess‐Walsh, Peter, Winawer, Melodie R., and Wellcome Trust
Subjects: Parents, Male, Epilepsy Phenome/Genome Project Epi4K Consortium, Neurodegenerative, Bioinformatics, Infantile, Spasms, Cohort Studies, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, Exome, Copy-number variation, Aetiology, Child, Exome sequencing, Genetics, Pediatric, 0303 health sciences, Neurology, Child, Preschool, Female, Brief Communications, Spasms, Infantile, Sequence Analysis, Adult, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Copy number analysis, Phenome, Biology, Brief Communication, 03 medical and health sciences, Clinical Research, mental disorders, medicine, Humans, Preschool, 030304 developmental biology, Neurology & Neurosurgery, Lennox Gastaut Syndrome, Human Genome, Infant, Newborn, Neurosciences, Infant, 1103 Clinical Sciences, Sequence Analysis, DNA, DNA, medicine.disease, Newborn, Brain Disorders, Human genome, Neurology (clinical), 1109 Neurosciences, 030217 neurology & neurosurgery, Lennox–Gastaut syndrome
Abstract: The epileptic encephalopathies (EEs) are a devastating group of epilepsies in which epileptic activity and seizures contribute to cognitive impairment or regression.1 Most EEs begin in infancy or early childhood and are associated with poor developmental outcome. Although the cause is unknown in the majority of cases, recent studies confirm that de novo mutations and copy number variants (CNVs) play an important role.2, 3 We recently reported exome sequencing data in 264 parent–proband trios with infantile spasms (n = 149) or Lennox–Gastaut syndrome (LGS; n = 115) without syndromic features or magnetic resonance imaging (MRI) abnormalities from the Epilepsy Phenome/Genome Project (EPGP) cohort, identifying likely pathogenic, de novo sequence changes in >10% of patients.2 Here we report results of copy number analysis derived from the exome data of this cohort and 85 additional patients to further elucidate the genetic architecture of these paradigmatic EEs. Our exome‐based CNV calling yields similar results to array‐based studies for confirmed, de novo, likely pathogenic CNVs.
Published: 2015

31. Additional file 1: of Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhoodâ a study of 155 patients

Author: Panagiotakaki, Eleni, Grandis, Elisa De, Stagnaro, Michela, Heinzen, Erin, Fons, Carmen, Sisodiya, Sanjay, Vries, Boukje De, Goubau, Christophe, Weckhuysen, Sarah, Kemlink, David, Scheffer, Ingrid, GaĂŤtan Lesca, Rabilloud, Muriel, Amna Klich, Ramirez-Camacho, Alia, Ulate-Campos, Adriana, Campistol, Jaume, Giannotta, Melania, Marie-Laure Moutard, Doummar, Diane, Hubsch-Bonneaud, Cecile, Jaffer, Fatima, Cross, Helen, Gurrieri, Fiorella, Tiziano, Danilo, Nevsimalova, Sona, Nicole, Sophie, Neville, Brian, Maagdenberg, Arn Van Den, Mikati, Mohamad, Goldstein, David, Vavassori, Rosaria, and Arzimanoglou, Alexis
Abstract: Table of ATP1A3 mutations (in this study and in previous studies). (DOCX 31Â kb)
Published: 2015
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32. Additional file 5: of Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhoodâ a study of 155 patients

Author: Panagiotakaki, Eleni, Grandis, Elisa De, Stagnaro, Michela, Heinzen, Erin, Fons, Carmen, Sisodiya, Sanjay, Vries, Boukje De, Goubau, Christophe, Weckhuysen, Sarah, Kemlink, David, Scheffer, Ingrid, GaĂŤtan Lesca, Rabilloud, Muriel, Amna Klich, Ramirez-Camacho, Alia, Ulate-Campos, Adriana, Campistol, Jaume, Giannotta, Melania, Marie-Laure Moutard, Doummar, Diane, Hubsch-Bonneaud, Cecile, Jaffer, Fatima, Cross, Helen, Gurrieri, Fiorella, Tiziano, Danilo, Nevsimalova, Sona, Nicole, Sophie, Neville, Brian, Maagdenberg, Arn Van Den, Mikati, Mohamad, Goldstein, David, Vavassori, Rosaria, and Arzimanoglou, Alexis
Abstract: Clinical phenotype of patients with the three most common mutations, and of patients without and with mutations, in the ATP1A3 gene. (DOCX 46Â kb)
Published: 2015
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33. Additional file 2: of Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhoodâ a study of 155 patients

Author: Panagiotakaki, Eleni, Grandis, Elisa De, Stagnaro, Michela, Heinzen, Erin, Fons, Carmen, Sisodiya, Sanjay, Vries, Boukje De, Goubau, Christophe, Weckhuysen, Sarah, Kemlink, David, Scheffer, Ingrid, GaĂŤtan Lesca, Rabilloud, Muriel, Amna Klich, Ramirez-Camacho, Alia, Ulate-Campos, Adriana, Campistol, Jaume, Giannotta, Melania, Marie-Laure Moutard, Doummar, Diane, Hubsch-Bonneaud, Cecile, Jaffer, Fatima, Cross, Helen, Gurrieri, Fiorella, Tiziano, Danilo, Nevsimalova, Sona, Nicole, Sophie, Neville, Brian, Maagdenberg, Arn Van Den, Mikati, Mohamad, Goldstein, David, Vavassori, Rosaria, and Arzimanoglou, Alexis
Abstract: Clinical Information included in the Questionnaire. (DOCX 14Â kb)
Published: 2015
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34. Additional file 4: of Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhoodâ a study of 155 patients

Author: Panagiotakaki, Eleni, Grandis, Elisa De, Stagnaro, Michela, Heinzen, Erin, Fons, Carmen, Sisodiya, Sanjay, Vries, Boukje De, Goubau, Christophe, Weckhuysen, Sarah, Kemlink, David, Scheffer, Ingrid, GaĂŤtan Lesca, Rabilloud, Muriel, Amna Klich, Ramirez-Camacho, Alia, Ulate-Campos, Adriana, Campistol, Jaume, Giannotta, Melania, Marie-Laure Moutard, Doummar, Diane, Hubsch-Bonneaud, Cecile, Jaffer, Fatima, Cross, Helen, Gurrieri, Fiorella, Tiziano, Danilo, Nevsimalova, Sona, Nicole, Sophie, Neville, Brian, Maagdenberg, Arn Van Den, Mikati, Mohamad, Goldstein, David, Vavassori, Rosaria, and Arzimanoglou, Alexis
Abstract: Taqman-based genotyping assays used to establish unique patient identities. (DOCX 17Â kb)
Published: 2015
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35. Additional file 3: of Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhoodâ a study of 155 patients

Author: Panagiotakaki, Eleni, Grandis, Elisa De, Stagnaro, Michela, Heinzen, Erin, Fons, Carmen, Sisodiya, Sanjay, Vries, Boukje De, Goubau, Christophe, Weckhuysen, Sarah, Kemlink, David, Scheffer, Ingrid, GaĂŤtan Lesca, Rabilloud, Muriel, Amna Klich, Ramirez-Camacho, Alia, Ulate-Campos, Adriana, Campistol, Jaume, Giannotta, Melania, Marie-Laure Moutard, Doummar, Diane, Hubsch-Bonneaud, Cecile, Jaffer, Fatima, Cross, Helen, Gurrieri, Fiorella, Tiziano, Danilo, Nevsimalova, Sona, Nicole, Sophie, Neville, Brian, Maagdenberg, Arn Van Den, Mikati, Mohamad, Goldstein, David, Vavassori, Rosaria, and Arzimanoglou, Alexis
Abstract: Primers used to sequence the ATP1A3 exons and adjacent splice sites. (DOCX 18Â kb)
Published: 2015
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36. Genetic epidemiology of motor neuron disease-associated variants in the Scottish population

Author: Black, Holly A., Leighton, Danielle J., Cleary, Elaine M., Rose, Elaine, Stephenson, Laura, Colville, Shuna, Ross, David, Warner, Jon, Porteous, Mary, Gorrie, George H., Swingler, Robert, Goldstein, David, Harms, Matthew B., Connick, Peter, Pal, Suvankar, Aitman, Timothy J., and Chandran, Siddharthan
Subjects: Ageing, Neuroscience(all), Clinical Neurology, Geriatrics and Gerontology, Developmental Biology
Abstract: Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population.
Published: 2017
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37. Evaluation of a school-to-work internship pilot program for high-school seniors with special needs

Author: Goldstein, David S.
Subjects: ComputingMilieux_COMPUTERSANDEDUCATION
Abstract: Students with disabilities face a variety of challenges that extend beyond the classroom, as they are often behind their peers in social and life skills. As they exit their secondary education programs they are often ill prepared to meet the multi-dimensional demands of the work place. According to the United States Department of Labor(2011), only 34% of adults with disabilities ages 18–64 years work full time, when compared with 82% of those without disabilities. The current study examined a specialized School-to-Work Internship Pilot Program designed for high school seniors with disabilities that was developed and implemented by a school district in central New Jersey. Twenty four students from the 2009-2010 and 2010-2011 graduating classes participated in this study. Of those 24 participants, 10 participated in the School-to-Work Internship Pilot Programand 14 participated as the matched control group in this quasi-experimental study. Participants reported on their post-high school experiences of employment and post-high school education enrollment. In addition, these participants self-appraised their job knowledge/skills, socialization/emotional coping skills, task flexibility, dependability, motivation, and job satisfactionon a questionnaire pertaining to their employment experiences. These participants also appraised theirlife satisfaction, feelings of competence,empowerment, and social belongingon a questionnaire pertaining to their quality of life. Results indicated that the School-to-Work and Case Control participant groups did not statistically differ with respect to securing or maintaining employment, or the measures of employment experiences or quality of life. However, participants in the School-to-Work group enrolled in post-secondary education at a statistically significant higher rate when compared to the Case Control group. The School-to-Work Internship Pilot Program may have empowered these student participants to gain the necessary insight that further training would be necessary to obtain a full time job that is both rewarding and providesfull time benefits. Furthermore, although there were no statistical group differences due to small sample size, the School-to-Work Internship Pilot Program appeared to have generally positive influences on quality of life for participants as indicated by consistently favorable outcomes.
Published: 2012
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38. Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes

Author: Goldstein, David S., Bentho, Oladi, Park, Mee-Yeong, and Sharabi, Yehonatan
Subjects: Norepinephrine, Sympathetic Nervous System, Heart Rate, Positron-Emission Tomography, cardiovascular system, Humans, Arrhythmias, Cardiac, Blood Pressure, Heart, Baroreflex, Autonomic Nervous System, Article, circulatory and respiratory physiology
Abstract: Power spectral analysis of heart rate variability has often been used to assess cardiac autonomic function; however, the relationship of low-frequency (LF) power of heart rate variability to cardiac sympathetic tone has been unclear. With or without adjustment for high-frequency (HF) power, total power or respiration, LF power seems to provide an index not of cardiac sympathetic tone but of baroreflex function. Manipulations and drugs that change LF power or LF:HF may do so not by affecting cardiac autonomic outflows directly but by affecting modulation of those outflows by baroreflexes.
Published: 2011

39. Using a Delphi process to determine optimal care for patients with pancreatic cancer

Author: Gooden Helen, Neale Rachel, Susan J. Jordan, Elizabeth Burmeister, Dianne L. O'Connell, Goldstein David, Merrett Neil, Wyld David, Janda Monka, and Beesley Vanessa
Subjects: medicine.medical_specialty, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Pancreatic cancer, Gastroenterology, medicine, Delphi method, Intensive care medicine, business, medicine.disease
Published: 2015
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40. Development of a Light-Weight, Reliable, Booster System for SHELS-Launched Payloads

Author: Nowinski, Lt. Arnold, Hampsten, Ken, Buckley, Steven, Goldstein, David, and Cohen, Dan
Abstract: Small satellite missions are often used to support low-cost space missions demonstrating new technologies. An economical source of low-cost space lift is to fly these satellites as secondary payloads aboard the Space Shuttle. The Shuttle has accommodations for flying these payloads using the Shuttle Hitchhiker Experiment Launch System (SHELS). While the relative costs for a Shuttle launch are at least an order of magnitude below the cost of a dedicated Expendable Launch Vehicle (ELV), final orbit altitude selection is limited to Shuttle mission goals. The Air Force Space Test Program (STP) is responsible for flying the Space Experiments Review Board (SERB) recommended experiments on a level-of-effort basis. Low-cost space lift is crucial to maximizing the number of SERB payloads that STP can support. Unfortunately, the typical Shuttle orbit does not provide a high enough orbit to guarantee the oneyear orbital lifetime required to meet STP mission objectives. A low-cost, autonomous STP Transfer Upper stage, Guided (TUG) that can boost an STP payload from a typical Shuttle orbit to a higher, longer duration orbit would allow STP to take advantage of the low-cost space lift provided by the Shuttle and still meet their mission requirements. The Air Force Research Laboratory Space Vehicles Directorate (AFRL/VS) is pursuing a solution to fulfill STP’s satellite lifting requirements by developing a low-cost, lightweight, reliable, strap-on propulsion module using several Small Business Innovative Research (SBIR) contracts focused on various parts of the TUG system. The Shuttle Expendable Rocket for Payload Augmentation (SHERPA) program will integrate all of these SBIR programs to meet the STP TUG requirement. The TUG system would be composed of several technologies being developed or already developed by AFRL/VS such as separation systems, guidance systems, propulsion modules, and modular bus architecture. The TUG would be re-startable for multiple orbit changes, station keeping, or deorbiting at the completion of a mission. Three versions of the TUG are envisioned. The first is a simple propulsion module that uses the satellite's Attitude Control System (ACS) and Guidance, Navigation, and Control (GN&C) to provide stack guidance. The second is a fully autonomous TUG that lifts the payload to the higher orbit as cargo, separates from the payload, and then accomplishes a collision avoidance maneuver and propellant burn after payload separation. The third configuration is an autonomous TUG with a long duration module that allow experiments to use the TUG's ACS, GN&C, and power systems in the intended final orbit. There are many challenges in the development of this vehicle. The most difficult of these is meeting the man-rating requirements of the Shuttle. All critical systems must have triple redundancy to ensure that the system does not threaten the Shuttle, its crew, or its mission. Another complication is producing a structure that meets the strict mass and volume restrictions of the SHELS system. Integration is als o a challenge, as many contractors and technologies are brought together under this program.
Published: 2002

41. The Small Payload ORbit Transfer (SPORT™) Vehicle and The Business Environment for the Next Generation of Piggyback Launch Options

Author: Sabirin Arshad, Ahmad, Jacobovits, Aaron, Ahmad, Yasser, and Goldstein, David
Abstract: AeroAstro and Astronautic Technology Sdn. Bhd. (ATSB) are developing the Small Payload ORbit Transfer (SPORT) Vehicle. Primarily designed to take advantage of the many auxiliary launch opportunities to Geosynchronous Transfer Orbit (GTO), SPORT acts as a small upper stage by moving a small payload from GTO to Low Earth Orbit (LEO), which is typically a much more desirable orbit. An innovative combination of aerobraking and chemical propulsion allows SPORT to accomplish this mission while keeping costs low. This paper provides an overview of the growing market for auxiliary launches, which also includes a discussion of launch brokering, SPORT, competing decommissioned ICBMs, as well as the needs of different user segments. The SPORT team’s bilateral business arrangements with a Dr. Ahmad Sabirin 2 15th AIAA/USU Conference on Small Satellites primary launch vehicle operator bring an additional point of view to the paper. SPORT’s pioneer mission is planned for 2003, for this first mission, a Malaysian satellite mounted on top of SPORT will be launched into GTO on an Ariane 5 Structure for Auxiliary Payloads (ASAP) micro launch slot. SPORT will then place its payload, a low earth orbit satellite, into a 9° inclination, 700 km altitude orbit.
Published: 2001

42. Small Payload ORbit Transfer (SPORT™) System: An Innovative Approach to Lowering Missions Costs Without Increased Risk

Author: Gloyer, Paul and Goldstein, David
Abstract: The past decade has seen efforts to lower costs by "doing more with less," instead of making innovative changes in the way missions are designed and implemented. Now, the industry is turning towards more intelligent approaches to mission design. AeroAstro has developed the Small Payload ORbit Transfer (SPORT™) system to provide a flexible low-cost orbit transfer capability, enabling small payloads to use low-cost secondary launch opportunities and still reach their desired final orbits. This capability allows small payloads to effectively use a wider variety of launch opportunities, including numerous under-utilized GTO slots. Its use, in conjunction with growing opportunities for secondary launches, enable "better, cheaper, faster" missions through innovative mission design and lower cost access to space, not increased risk. SPORT uses a suite of innovative technologies that are packaged in a simple, reliable, modular system. The command, control and data handling of SPORT is provided by AeroAstro's Bitsy™ Kernel, which will be demonstrated on the Shuttle under a NASA MSFC-sponsored program in late 2001 and is available for very low cost due to its highly repeatable nature. SPORT achieves its orbit transfer capability through a combination of chemical propulsion and aerobraking technology. This paper will discuss the SPORT design and its application to overall small satellite mission development.
Published: 2000

43. The Bitsy Spacecraft Kernel: Reducing Nanosatellite Mission Cost in the MSFC Future-X Program through Miniaturized Technologies

Author: McDermott, Scott and Goldstein, David
Subjects: ComputerApplications_COMPUTERSINOTHERSYSTEMS
Abstract: A team led by AeroAstro Incorporated was selected under the Future-X program to fly an experiment in late 2000 to demonstrate key elements of reducing space mission cost utilizing Bitsy™ Spacecraft Kernel technology. The Small Payload Access to Space Experiment (SPASE) is funded through the Future-X program, and is to be launched in late 2000 using the Space Shuttle. The mission will also carry a small microgravity payload. The entire first mission, including space and ground systems and launch interfaces, will cost under $2M. The recurring cost for follow-on microgravity spacecraft will be under $1M. Achieving on-orbit science missions with a cost comparable or below that of suborbital flights is made possible by: 1. Creation of a standardized core of spacecraft capabilities, not a standard bus, based on commercial-off-the-shelf (COTS) technologies, which the science team uses to manage spacecraft functions (patent pending); 2. Miniaturization, which both reduces recurring costs (fabrication and parts) and makes a minimal demand on launch vehicle services with very high reliability. The spacecraft “kernel”, as opposed to bus, does not have a traditional division into discrete subsystems, but rather manages power, thermal control, ACDS, C&DH, and communications in a package of a few kilograms. Its small size, light weight, and unique extensible architecture enables a variety of customizations to be added as needed to greatly expand the range of achievable missions. These added capabilities include modest in-space propulsion, which enables missions including those requiring large V for spacecraft inspection, orbit initialization or station keeping, or achieving unusual or energetic orbits without requiring very expensive launch capability. While Bitsy™ technology enables flying significant science, communications, and remote sensing missions with total mass of 10-60 kg forcosts similar to suborbital flights, there is in principle no limit to the size or complexity of payloads it can accommodate. The spacecraft program currently underway will demonstrate the capabilities provided by the combination of miniaturization and nanospacecraft architectures. It will perform a flight demonstration of the spacecraft, ground station, and flight operations control software offering standard interfaces to payloads and to launch systems, to be launched in late 2000 on the Shuttle Hitchhiker accommodation. The Bitsy™ kernel concept, progress to date on the SPASE mission, and the fundamental design and architecture decisions for each will be discussed in this paper.
Published: 1999

44. Q & A

Author: Goldstein, David
Subjects: Agricultural and Biological Sciences(all), Biochemistry, Genetics and Molecular Biology(all), education, General Agricultural and Biological Sciences, humanities, General Biochemistry, Genetics and Molecular Biology
Abstract: David B. Goldstein is Professor of Genetics in the Galton Laboratory, Department of Biology, at University College London. His training is in population genetics, and his primary contributions have been in assessing the medical and evolutionary implications of human genetic diversity. His work currently focuses on pharmacogenetics, the genetics of complex disease, and human evolution. He received his PhD from Stanford University in 1994 and moved to the UK in 1996.
Published: 2003
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45. The Student Government Experience at The University of Texas at Austin, 1932-1933 to 1982-1983

Author: Goldstein, David Scott
Subjects: ComputingMilieux_THECOMPUTINGPROFESSION, ComputingMilieux_COMPUTERSANDEDUCATION, ComputingMilieux_PERSONALCOMPUTING, ComputingMilieux_LEGALASPECTSOFCOMPUTING, GeneralLiterature_MISCELLANEOUS
Abstract: A study of student government at The University of Texas at Austin from 1932 to 1983.
Published: 1983
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46. Additional file 1: of Patient perspectives on molecular tumor profiling: â Why wouldnâ t you?â

Author: Best, Megan, Bartley, Nicole, Jacobs, Chris, Juraskova, Ilona, Goldstein, David, Newson, Ainsley, Savard, Jacqueline, Meiser, Bettina, Ballinger, Mandy, Napier, Christine, Thomas, David, Biesecker, Barbara, and Butow, Phyllis
Subjects: 3. Good health
Abstract: Interview Schedule. 18 questions which asked of each interviewee. (DOCX 14 kb)

47. Additional file 1: of Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial

Author: Reichardt, Peter, Demetri, George, Gelderblom, Hans, Rutkowski, Piotr, Seock-Ah Im, Sudeep Gupta, Yoon-Koo Kang, SchĂśffski, Patrick, Schuette, Jochen, SouliĂ¨Res, Denis, Jean-Yves Blay, Goldstein, David, Kolette Fly, Huang, Xin, Corsaro, Massimo, Lechuga, Maria, Jean-Francois Martini, and Heinrich, Michael
Subjects: 3. Good health
Abstract: Supplementary Methods and Results. (DOC 64 kb)

48. Evaluating the Impact of Functional Genetic Variation on HIV-1 Control

Author: McLaren, Paul J, Pulit, Sara L, Gurdasani, Deepti, Bartha, Istvan, Shea, Patrick R, Pomilla, Cristina, Gupta, Namrata, Gkrania-Klotsas, Effrossyni, Young, Elizabeth H, Bannert, Norbert, Del Amo, Julia, Gill, M John, Gilmour, Jill, Kellam, Paul, Kelleher, Anthony D, Sönnerborg, Anders, Zangerle, Robert, Post, Frank A, Fisher, Martin, Haas, David W, Walker, Bruce D, Porter, Kholoud, Goldstein, David B, Sandhu, Manjinder S, De Bakker, Paul IW, and Fellay, Jacques
Subjects: Adult, Male, Genotype, HIV host dependency factors, Genetic Variation, HIV Infections, Middle Aged, Viral Load, Polymorphism, Single Nucleotide, Whole Exome Sequencing, 3. Good health, HIV-1 progression, Host-Pathogen Interactions, HIV-1, host genetics of infection, Humans, Female, Genetic Predisposition to Disease, exome sequencing, HIV-1 control
Abstract: Background: Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods: We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. Results: Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. Conclusions: These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.

49. Role of human leukocyte antigen class I alleles in progressive multifocal leukoencephalopathy

Author: Gheuens, Sarah, Fellay, Jacques, Goldstein, David B., and Koralnik, Igor J.
Abstract: Because human leukocyte antigen (HLA) associations with various infectious diseases have recently been reported, we examined the role of HLA class I alleles in the development of progressive multifocal leukoencephalopathy (PML) or its outcome in 152 patients, including 123 Caucasians and 29 African Americans. Compared to a human immunodeficiency virus positive (HIV+) control population, we observed decreased frequency of HLA-A3 (P = 0.03) in the Caucasian PML group, whereas B18 (P = 0.02), was more frequent. No such difference was found among African American PML patients. We then sought to characterize differences in HLA between PML progressors, whose survival doesn't exceed 1 year, and survivors. Caucasian survivors were less likely to harbor A68 (P = 0.01), whereas African American survivors less frequently displayed Cw4 (P = .01). However, none of these differences reached statistical significance after Bonferroni correction for multiple testing. Further investigations are needed to assess the role of genetics in the incidence of PML or its outcome. Physicians may exercise caution in the use of immunomodulatory medications in patients whose genetic background is associated with an increased risk of PML.

50. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

Author: Allen, Andrew S., Bellows, Susannah T., Berkovic, Samuel F., Bridgers, Joshua, Burgess, Rosemary, Cavalleri, Gianpiero, Chung, Seo-Kyung, Cossette, Patrick, Delanty, Norman, Dlugos, Dennis, Epstein, Michael P., Freyer, Catharine, Goldstein, David B., Heinzen, Erin L., Hildebrand, Michael S., Johnson, Michael R., Kuzniecky, Ruben, Lowenstein, Daniel H., Marson, Anthony G., Mayeux, Richard, Mebane, Caroline, Mefford, Heather C., O Brien, Terence J., Ruth Ottman, Petrou, Steven, Petrovski, Slave, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Scheffer, Ingrid E., Sills, Graeme J., Thomas, Rhys H., Wang, Quanli, Abou-Khalil, Bassel, Alldredge, Brian K., Amrom, Dina, Andermann, Eva, Andermann, Frederick, Bautista, Jocelyn F., Bluvstein, Judith, Boro, Alex, Cascino, Gregory D., Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Fiol, Miguel, Fountain, Nathan B., French, Jacqueline, Friedman, Daniel, Geller, Eric B., Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R., Hayward, Jean, Helmers, Sandra L., Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Knowlton, Robert C., Kossoff, Eric H., Kuperman, Rachel, Motika, Paul V., Novotny, Edward J., Paolicchi, Juliann M., Parent, Jack M., Park, Kristen, Sadleir, Lynette G., Shellhaas, Renee A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Singh, Rani K., Sirven, Joseph, Smith, Michael C., Sullivan, Joseph, Thio, Liu Lin, Venkat, Anu, Vining, Eileen P. G., Allmen, Gretchen K., Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Consortium, Epi K., and Epilepsy Phenome-Genome Proj

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