Citations 3
Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
McGregor, Tracy L., Yee, Elaine, Mason, Dan , Nioi, Paul , Ticau, Simina , Pelosi, Marissa, Loken, Perry R , Finer, Sarah , Lawlor, Deborah A, Fauman, Eric B. , Huang, Qin Qin , Griffiths, Chris , MacArthur, Daniel G. , Oglesbee, Devin , Erbe, David V., Heel, David A. van , Lawlor, Debbie A. , Finer, Sarah , Lieske, John C , van Heel, David A , Oglesbee, Devin , MacArthur, Daniel G , Hunt, Karen A. , Trembath, Richard C. , Lieske, John C. , Wright, John
eLife | March 24, 2020 | Volume: 9 | Issue: No issue available | Pages: No page available
By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.
DNA mismatch repair gene MSH6 implicated in determining age at natural menopause
Perry, John R. B. , Hsu, Yi-Hsiang, Johnson, Andrew D. , Elks, Cathy E., Albrecht, Eva, Andrulis, Irene L. , Berenson, Gerald S., Bojesen, Stig E. , Bolla, Manjeet K. , Brown, Judith, Buring, Julie E. , Campbell, Harry, Chang‐Claude, Jenny , Chenevix‐Trench, Georgia , Corre, Tanguy , Cox, Angela , Czene, Kamila , D’Adamo, Pio , Davies, Gail , Deary, Ian J. , Easton, Douglas F. , Engelhardt, Ellen G. , Eriksson, Johan G. , Fasching, Peter A. , Figueroa, Jonine D. , Flyger, Henrik, Fraser, Abigail , García‐Closas, Montserrat , Gasparini, Paolo , Gieger, Christian , Giles, Graham G. , Guénel, Pascal , Hägg, Sara , Hayward, Caroline , Hopper, John L. , investigators, kConFab, Kardia, Sharon L. R., Kasiman, Katherine, Knight, Julia A. , Lahti, Jari , Lawlor, Debbie A. , Magnusson, Patrik K. E. , Margolin, Sara , Marsh, Julie , Polašek, Ozren , Rahman, Iffat , Ridker, Paul M., Robino, Antonietta , Rudan, Igor , Salumets, Andres , Schmidt, Marjanka K. , Schoemaker, Minouk J. , Smith, Erin N. , Smith, Jennifer A. , Southey, Melissa C. , Stöckl, Doris, Swerdlow, Anthony J. , Thompson, Deborah J. , Truong, Thérèse , Ulivi, Sheila , Waldenberger, Mélanie , Wang, Qin , Wright, Alan F., Zgaga, Lina , Karasik, David , Murray, Anna , Uitterlinden, André G. , Hsu, Yi‐Hsiang , Chasman, Daniel I. , Beesley, Jonathan , Bergmann, Sven M. , Couch, Fergus J. , Dennis, Joe , Esko, Tõnu , Hall, Per N , Ingelsson, Erik , investigators, kConFab, Metspalu, Andres , Olson, Janet E. , Pennell, Craig Edward , Rudolph, Anja , Wild, Sarah H. , Wilson, James Fox , Ong, Ken K. , Murabito, Joanne M. , Giles, Graham G , Swerdlow, Anthony J , Smith, Jennifer A , Southey, Melissa C , Cox, Angela , Guénel, Pascal , García-Closas, Montserrat , Schmidt, Marjanka K , Chenevix-Trench, Georgia , Figueroa, Jonine D , Czene, Kamila , Bojesen, Stig E , Schoemaker, Minouk J , Truong, Therese
Human Molecular Genetics | December 20, 2013 | Volume: 23 | Issue: 9 | Pages: 2490-2497
GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment
Rietveld, Cornelius A. , Medland, Sarah E. , Derringer, Jaime , Esko, Tõnu , Martín, Nicolás W., Westra, Harm-Jan , Shakhbazov, Konstantin, Abdellaoui, Abdel , Albrecht, Eva, Alizadeh, Behrooz Z. , Amin, Najaf , Baumeister, Sebastian E. , Benke, Kelly S. , Bielak, Lawrence F. , Boatman, Jeffrey A. , Boyle, Patricia A. , Davies, Gail , Leeuw, Christiaan de , Eklund, Niina, Evans, Daniel S. , Ferhmann, Rudolf, Fischer, Krista , Gieger, Christian , Gjessing, Håkon K. , Hägg, Sara , Harris, Jennifer R. , Hayward, Caroline , Jacobsson, Bo , Joshi, Peter K. , Jugessur, Astanand , Kaakinen, Marika , Kanoni, Stavroula , Karjalainen, Juha, Kolčić, Ivana , Kristiansson, Kati , Kutalik, Zoltán , Lahti, Jari , Lee, Sang , Lin, Peng, Lind, Penelope A. , Lohman, Kurt, Loitfelder, Marisa, McMahon, George, Marques‐Vidal, Pedro , Meirelles, Osorio , Milani, Lili , Myhre, Ronny , Nuotio, Marja-Liisa , Oldmeadow, Christopher , Petrovic, Katja, Peyrot, Wouter J. , Polašek, Ozren , Quaye, Lydia, Reinmaa, Eva, Rice, John P. , Rizzi, Thais S., Schmidt, Helena , Schmidt, Reinhold, Smith, Albert V. , Smith, Jennifer A. , Terracciano, Antonio , Loos, Matthijs J. H. M. van der, Vitart, Véronique , Völzke, Henry , Wellmann, Jürgen , Yu, Lei , Zhao, Wei , Allïk, Jüri , Bandinelli, Stefania , Bastardot, François , Beauchamp, Jonathan , Bennett, David A. , Berger, Klaus, Bültmann, Ute , Campbell, Harry, Chabris, Christopher F., Cherkas, Lynn, Chung, Mina K. , Cucca, Francesco , Jager, Philip L. De , Neve, Jan-Emmanuel De, Deary, Ian J. , Dedoussis, George , Deloukas, Panos , Dimitriou, Maria , Eiríksdóttir, Guðný , Elderson, Martin F., Eriksson, Johan G. , Evans, David M. , Faul, Jessica D. , Ferrucci, Luigi , Garcia, Melissa E., Grönberg, Henrik , Guðnason, Vilmundur , Harris, Tamara B., Hastie, Nicholas D. , Hernández, Dena , Hoffmann, Wolfgang , Hofman, Adriaan, Holle, Rolf , Holliday, Elizabeth G., Hottenga, Jouke‐Jan , Illig, Thomas, Järvelin, Marjo‐Riitta , Kähönen, Mika , Kaprio, Jaakko , Kirkpatrick, Robert M. , Kowgier, Matthew , Latvala, Antti , Lawlor, Debbie A. , Lehtimäki, Terho , Li, Jingmei , Lichtenstein, Paul , Lichtner, Peter , Liewald, David C. , Madden, Pamela A. F., Magnusson, Patrik K. E. , Mäkinen, Tomi E., Masala, Marco , McGue, Matt , Mielck, Andreas, Miller, Michael B., Montgomery, Grant W. , Mukherjee, Sutapa , Nyholt, Dale R. , Oostra, Ben A., Palmer, Lyle J. , Palotie, Aarno , Perola, Markus, Peyser, Patricia A. , Preisig, Martin , Räikkönen, Katri , Rivadeneira, Fernando , Rudan, Igor , Rustichini, Aldo , Sarin, Antti-Pekka, Schlessinger, David, Scott, Rodney J. , Snieder, Harold , Pourcain, Beaté St , Starr, John M. , Sul, Jae Hoon , Surakka, Ida , Svento, Rauli , Teumer, Alexander , Study, The LifeLines Cohort, Tiemeier, Henning , Rooij, Frank J.A. van , Wagoner, David R. Van , Vartiainen, Erkki , Viikari, Jorma , Vollenweider, Péter , Vonk, Judith M. , Waeber, Gérard , Weir, David R. , Wichmann, H.‐Erich , Widén, Elisabeth , Willemsen, Gonneke , Wright, Alan F., Davey-Smith, George, Franke, Lude , Groenen, Patrick J. F. , Hofman, Albert , Johannesson, Magnus , Kardia, Sharon L. R., Krueger, Robert F., Laibson, David, Martin, Nicholas G. , Meyer, Michelle N., Posthuma, Daniëlle , Thurik, Roy , Timpson, Nicholas J. , Uitterlinden, André G. , Duijn, Cornelia M. van , Visscher, Peter M. , Benjamin, Daniel J. , Cesarini, David , Koellinger, Philipp , Bennett, David A. , Smith, George Davey , Meyer, Michelle N. , Westra, Harm-Jan , Yang, Jian , Agrawal, Arpana , Barnard, John , Holzapfel, Christina M. , Ibrahim‐Verbaas, Carla A. , Ingelsson, Erik , Lin, Peng, Liu, Ching‐Ti , Tanaka, Toshiko , Attia, John , Berger, Klaus, Bierut, Laura Jean , Boomsma, Dorret I , Andrade, Mariza de , Hall, Per N , Harris, Juliette , Heath, Andrew C. , Hofman, Adriaan, Holliday, Elizabeth G., Iacono, William G. , Launer, Lenore J. , Mäkinen, Tomi E., Metspalu, Andres , Palotie, Aarno V. , Penninx, Brenda W.J.H. , Raitakari, Olli Tuomas , Realo, Anu , Ring, Susan M. , Ripatti, Samuli , Salomaa, Veikko , Study, The LifeLines Cohort, Wilson, James Fox , Conley, Dalton , Davey-Smith, George, Smith, Jennifer A , Hottenga, Jouke-Jan , Martin, Nicholas G , Posthuma, Danielle , St Pourcain, Beate , Medland, Sarah E , Li, Jingmei , Teumer, Alexander , van Duijn, Cornelia M , Smith, Albert V , Ferrucci, Luigi , Davey Smith, George , Vonk, Judith M , Kanoni, Stavroula , Surakka, Ida
Science | May 31, 2013 | Volume: 340 | Issue: 6139 | Pages: 1467-1471
Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.