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CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
J.-M. Lee, E.M. Ramos, J.-H. Lee, Tammy Gillis, Jayalakshmi Srinidhi Mysore, Michael R. Hayden, Simon C. Warby, PJ Morrison, Martha Nance, Christopher A. Ross, Russell L. Margolis, Ferdinando Squitieri, S. Orobello, Stefano Di Donato, Estrella Gómez‐Tortosa, Carmen Ayuso, Oksana Suchowersky, R J Trent, Elizabeth McCusker, Andrea Novelletto, Marina Frontali, Randi Jones, Tetsuo Ashizawa, Samuel Frank, Marie Saint‐Hilaire, Steven M. Hersch, H. Diana Rosas, Diane Lucente, Madeline Harrison, Andrea Zanko, Ruth K. Abramson, Karen Marder, Jorge Sequeiros, Jane S. Paulsen, G. Bernhard Landwehrmeyer, Richard H. Myers, Marcy E. MacDonald, James F. Gusella, Alexandra Dürr, Adam Rosenblatt, Luigi Frati, Susan B. Perlman, P. M. Conneally, Mary Lou Klimek, Melissa Diggin, Tiffany C. Hadzi, Ayana Duckett, Anwar Ahmed, Paul Allen, David Ames, Karla J. Anderson, Karen Anderson, Thomasin Andrews, John Ashburner, Eric Axelson, Elizabeth Aylward, Roger A. Barker, Katrin Barth, Stacey K. Barton, Kathleen Baynes, Alexandra Bea, Erik B. Beall, Mirza Faisal Beg, Leigh J. Beglinger, Kevin Biglan, K. Björk, Steve Blanchard, Jeremy Bockholt, Sudharshan Reddy Bommu, Bradley G. Brossman, Maggie Burrows, Vince D. Calhoun, Noelle E. Carlozzi, Amy M. Chesire, Edmond Chiu, Phyllis Chua, R.J. Connell, Carmela Connor, Jody Corey‐Bloom, David Craufurd, Stephen Cross, Lucette A. Cysique, Rachelle Dar Santos, Jennifer Davis, Joji Decolongon, A. Dipietro, Nicholas Doucette, Nancy R. Downing, Ann Dudler, Steve Dunn, Daniel Ecker, Eric A. Epping, Diane Erickson, Cheryl Erwin, Kenneth Evans, Stewart A. Factor, Sarah Tomaszewski Farias, Marta Fatas, Jess G. Fiedorowicz, Ruth Fullam, Sarah Furtado, Mónica Bascuñana Garde, Carissa Gehl, Michael D. Geschwind, Anita Goh, Jon Gooblar, Anna Goodman, Jane Griffith, Mark Groves, Mark Guttman, Joanne M. Hamilton, Deborah L. Harrington, Greg Harris, Robert K. Heaton, Karl Helmer, Machelle Henneberry, Tamara Hershey, Kelly Herwig, Elizabeth Howard, Christine Hunter, Joseph Jankovic, Hans J. Johnson, Kathy Jones, Andrew R. Juhl, Eun Young Kim, Mycah Kimble, Pamela King, Stefan Klöppel, Katherine Koenig, Angela Komiti, Rajeev Kumar, Douglas R. Langbehn, Anne Leserman, Kelvin O. Lim, Hillary Lipe, Mark J. Lowe, Vincent A. Magnotta, William Mallonee, Nicole Mans, Jacquie Marietta, Frederick J. Marshall, W. R. Wayne Martin, Kirsty Matheson, Wayne R. Matson, Pietro Mazzoni, William McDowell, Zosia Miedzybrodzka, Michael I. Miller, James A. Mills, Dawn Miracle, Kelsey Montross, David D. Moore, S. Mori, David J. Moser, Carol Moskowitz, Emily R. Newman, Peg Nopoulos, Marianne Novak, Justin J. F. O’Rourke, David Oakes, William G. Ondo, Peter K. Panegyres, Karen R. Pease, Asa Peterson, Michael Phillips, Ron Pierson, Steven G. Potkin, J. Samuel Preston, Kimberly A. Quaid, Dawn Radtke, D. O. Rae, Stephen M. Rao, Lynn A. Raymond, Sarah Reading, Rebecca E. Ready, Christine Reece, Ralf Reilmann, Norm Reynolds, Kylie Richardson, Hugh Rickards, Eunyoe Ro, Robert A. Robinson, Robert L. Rodnitzky, Benedict D. Rogers, Elisabeth Rosser, Pat Ryan, David P. Salmon, Ali Samii, Jamy Schumacher, Jessica R. Schumacher, Jose Luis Lópenz Sendon, Paula K. Shear, Alanna Sheinberg, Barnett Shpritz, Karen L. Siedlecki, Sheila A. Simpson, Adam D. Singer, Jim Q. Smith, Megan M. Smith, Glenn E. Smith, Pete Snyder, Allen W. Song, Satwinder Sran, Klaas Ε. Stephan, Janice Stober, Sigurd Sü muth, Greg Suter, Sarah J. Tabrizi, Terry Tempkin, Claudia Testa, Sean Thompson, Teri Thomsen, Kelli Thumma, Arthur W. Toga, Sonja Trautmann, Geoff Tremont, Jessica A. Turner, Anthony L. Vaccarino, E. van Duijn, Marleen van Walsem, Stacie Vik, Jean Paul Vonsattel, Elizabeth J. Vuletich, Paula Wasserman, Thomas H. Wassink, Elijah Waterman, Kurt E. Weaver, David Weir, Claire Welsh, Chris Werling-Witkoske, Melissa Wesson, Holly James Westervelt, Patrick Weydt, Vicki Wheelock, Kent C. Williams, Janet K. Williams, Mary Wodarski, Joanne Wojcieszek, Jessica Wood, Cathy Wood‐Siverio, Shuhua Wu, Olga Yastrubetskaya, Justo García de Yébenes, Yong Qiang Zhao, Janice L. Zimbelman, Roland Zschiegner, Olaf Aaserud, Giovanni Abbruzzese, Jurgin Andrich, Jakub Antczak, Natalie Arran, María José Saiz Artiga, Anne‐Catherine Bachoud‐Lévi, Krysztof Banaszkiewicz, M. Poggio, Oliver Bandmann, Miguel Aguilar Barberá, Francisco Javier Barrero, Jordi Bas, Antoine Beister, Anna Rita Bentivoglio, Elisabetta Bertini, Ida Biunno, Kathrine Bjørgo, Inga Bjørnevoll, Stefan Bohlen, Raphael M. Bonelli, Reineke Bos, Colin Bourne, Alyson Bradbury, Peter Brockie, Felicity Brown, Stefania Bruno, Anna Bryl, Andrea Buck, Sabrina Burg, Jean‐Marc Burgunder, Peter Burns, Liz Burrows, Núria Busquets, Monica Busse, Matilde Calopa, Gemma Tome Carruesco, Ana Gonzalez Casado, Judit López Catena, Carol Chu, Anna Ciesielska, Jackie Clapton, Carole Clayton, Catherine Clenaghan, Miguel Coelho, Julia Connemann, Jenny Crooks, Patricia Trigo Cubillo, Esther Cubo, Adrienne Curtis, Giuseppe De Michele, Antonio De Nicola, Jenny de Souza, A. Marit de Weert, M. Dekker, Asunción Martínez Descals, Luigi Di Maio, Anna Di Pietro, Heather Dipple, M. Dose, Eve M. Dumas, Stephen B. Dunnett, Francesca Elifani, Lynda Ellison-Rose, Marina D. Elorza, Carolin Eschenbach, Carole Evans, Helen Fairtlough, Madelein Fannemel, Alfonso Fasano, María del Mar Fenollar, Giovanna Ferrandes, Jaoquim J. Ferreira, Kay Fillingham, Ana Maria Finisterra, Kate Fisher, Amy Fletcher, Jillian Foster, Isabella Foustanos, Fernando Alonso Frech, Robert Fullam, Ruth Fullham, Miguel Gago, R. de Francisco García, Socorro S. García, Carolina Garrett, Cinzia Gellera, Paul R. Gill, Andrea Ginestroni, Charlotte Golding, Per F. Gørvell, Janet Grant, Anna Maria Griguoli, Diana Gross, Leonor Correia Guedes, Monica BascuñanaGuerra, Maria Rosália Guerra, Rosa Guerrero, D. Badenes Guía, Arianna Guidubaldi, Caroline Hallam, Stephanie Hamer, K. Hammer, Olivia Handley, Alison Harding, Lis Hasholt, R.M. Hedge, Arvid Heiberg, Walburgis Heinicke, Christine Held, Laura Casas Hernanz, Briggitte Herranhof, Carmen Herrera-Espiñeira, Ute Hidding, Heli Hiivola, Susan Hill, Lena E. Hjermind, Emma Hobson, Rainer Hoffmann, Anna Holl, Liz Livingston Howard, Sarah Hunt, Susan Huson, Tàmara Ialongo, Jesús Miguel Ruiz Idiago, Torsten Illmann, Katarzyna Jachińska, Gioia Jacopini, Oda Jakobsen, Stuart W. Jamieson, Zygmunt Jamrozik, Piotr Janik, Nicola Johns, Lesley Jones, Una Jones, Caroline K. Jurgens, Alain Kaelin‐Lang, Anna Kalbarczyk, Ann Kershaw, Hanan Khalil, Janina Kieni, Aneta Klimberg, Susana Pro Koivisto, Kerstin Koppers, Christoph M. Kosinski, Małgorzata Krawczyk, Berry Kremer, Wioletta Krysa, Hubert Kwieciński, Nayana Lahiri, Johann Lambeck, Herwig W. Lange, Fiona Laver, Klaus L. Leenders, Jamie Levey, Gabriele Leythaeuser, Franziska Lezius, Joan Roig Llesoy, Matthias Löhle, Cristobal Diez-Aja López, Fortuna Lorenza, G Loria, Markus Magnet, Paola Mandich, Roberta Marchese, T Marcinkowski, Caterina Mariotti, Natividad Mariscal, Ivana S. Marková, Ralf Marquard, Kirsti Martikainen, Isabel Haro Martínez, Asunción Martínez‐Descals, T. Martino, Sue McKenzie, Claudia Mechi, Tiago Mendes, Tiago Mestre, Julia Middleton, Eva Milkereit, J. Philip Miller, Julie Miller, Sara Minster, Jens Carsten Möller, Daniela Monza, Blas Morales, L. Vivancos, José Luis López-Sendón, Alexander Münchau, Ann Murch, Jørgen E. Nielsen, Anke Niess, Anne Nørremølle, Kristy O'Donovan, Daniela Otti, Michael J. Owen, Hélène Padieu, M. Paganini, Annamaria Painold, Markku Päivärinta, Lucy Partington-Jones, Laurent Paterski, Nicole D. Paterson, Dawn Freire- Patino, Michael J. Patton, Alexander Peinemann, Nadia Peppa, María Fuensanta Noguera Perea, Maria Peterson, Silvia Piacentini, Carla Piano, Regina Pons i Càrdenas, Christian Prehn, Kathleen Price, Daniela Probst, Oliver Quarrell, Purificacion Pin Quiroga, Tina Raab, Ashok Raman, Lucy Raymond, Gema Reinante, Karin Reisinger, Lars Retterstøl, Pascale Ribaı̈, Antonio Villa Riballo, Guillermo García Ribas, Sven Richter, Carlo Rinaldi, Ida Rissling, Stuart J. Ritchie, Susana Vázquez Rivera, Misericordia Floriach Robert, Elvira Roca, Silvia Romano, Anna Maria Romoli, Raymond A.C. Roos, Niini Røren, Sarah Rose, F. Rossi, Jean Rothery, Monika Rudzińska, Pedro Ruiz, Belan Garzon Ruíz, Cinzia Valeria Russo, Danuta Ryglewicz, Elena Salvatore, Vicenta Sánchez, Sigrid Botne Sando, Pavla Šašinková, Christian Saß, Monika Scheibl, Johannes Schiefer, Christiane Schlangen, Simone Schmidt, Helmut Schöggl, Caroline Schrenk, Michaël Schüpbach, Michele Schuierer, Ana Rojo Sebastián, Amina Selimbegovic-Turkovic, Justyna Sempołowicz, Mark Silva, Emilia J. Sitek, Jarosław Sławek, Julie S. Snowden, Francesco Soleti, Paola Soliveri, Andrea Sollom, Witold Sołtan, Sandro Sorbi, Sven Asger Sørensen, M. Spadaro, Michael Städtler, Christiane Stamm, Tanja Steiner, Jette Stokholm, Bodil Stokke, Cheryl Stopford, Alexander Storch, Katrin Straßburger, Lars Stubbe, Anna Sułek, Andrzej Szczudlik, Rachel Taylor, Santiago Duran-Sindreu Terol, Gareth Thomas, J. C. Thompson, Aileen Thomson, Katherine Tidswell, María Martirio Antequera Torres, Jean Toscano, Jenny Townhill, Tecla Tucci, Katri Tuuha, Tereza Uhrová, Anabela Valadas, Monique S.E. van Hout, Joost C.H. van Oostrom, Jeroen P.P. van Vugt, Walsem Marleen R. vanm, Wim Vandenberghe, Christine Verellen‐Dumoulin, M Vergara, C.C.P. Verstappen, Nichola Verstraelen, Cèlia Mareca Viladrich, Clara Villanueva, Jan Wahlström, Thomas T. Warner, R. Wehus, A. Weindl, Cornelius J. Werner, Leann Westmoreland, Alexandra Wiedemann, Edward J. Wild, Sue Wild, Marie‐Noëlle W. Witjes‐Ané, Grzegorz Witkowski, Magdalena Wójcik-Pędziwiatr, Martin Wolz, Annett Wolz, Jan Wright, Pam Yardumian, Shona Yates, Elizaveta Yudina, Jacek Zaremba, Sabine Weber Zaugg, Elżbieta Zdzienicka, Daniel Zielonka, Euginiusz Zielonka, Paola Zinzi, Simone Zittel, B. Zucker, John Adams, Pinky Agarwal, Irina Antonijevic, Christopher A. Beck, Andrew Churchyard, Amy Colcher, Ray Dorsey, Carolyn Drazinic, Richard Dubinsky, Tatiana Foroud, Joe Giuliano, Donald S. Higgins, Dana Jennings, Un Jung Kang, Sandra K. Kostyk, Mark S. LeDoux, Eric Mohlo, John C. Morgan, Michel Panisset, Fredy J. Revilla, Suzanne Robertson, B. Robottom, Juan Sanchez‐Ramos, B.L. Scott, Kathleen M. Shannon, Ira Shoulson, Carlos Singer, Samer D. Tabbal, Kammen Dan van, Louise Vetter, Francis O. Walker, John Harley Warner, illiam Weiner, Janice Broyles, Ronda Clouse, Allison Coleman, Robert E. Davis, J.-L. de-la-Rosa, Lisa M. Deuel, Susan Dietrich, Hilary Dubinsky, Ken Eaton, Mary Jane Fitzpatrick, Steven J. Frucht, Maureen Gartner, Jody Goldstein, Charlyne Hickey, Victoria Hunt, Jeana Jaglin, Pat Lindsay, Elan D. Louis, Clemet Loy, N. Lucarelli, Keith Malarick, Amanda Martin, Robert McInnis, Lisa M. Muratori, Frederick C. Nucifora, Christine J. O’Neill, Alicia Palao, Guerry M. Peavy, Mónica Quesada, Amy P. Schmidt, Vicki Segro, Elaine Sperin, Kalo Tanev, Teresa Tempkin, Curtis Thiede, Elizabeth Zauber
Bibliographic record
VenueNeurology · 2012
Typearticle
Languageen
FieldNeuroscience
TopicGenetic Neurodegenerative Diseases
Canadian institutionsHôtel-Dieu de MontréalUniversity of AlbertaUniversity of TorontoCentre for Addiction and Mental HealthSimon Fraser UniversityUniversity of CalgaryUniversity of British Columbia
FundersNational Center for Advancing Translational SciencesNational Center for Research ResourcesNational Institute of Neurological Disorders and StrokeNational Institutes of HealthNational Institute for Health and Care ResearchWellcome TrustNorthwestern University
KeywordsAlleleAge of onsetHuntington's diseaseTrinucleotide repeat expansionAnalysis of varianceBiologyDiseaseAllele frequencyGeneticsMedicineInternal medicineGene
Abstract
OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.004
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.003
Threshold uncertainty score0.008
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.026
GPT teacher head0.272
Teacher spread0.246 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations391
Published2012
Admission routes1
Has abstractyes