Literature DB >> 25199842

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

Adam C Naj1, Gyungah Jun2, Christiane Reitz3, Brian W Kunkle4, William Perry4, Yo Son Park5, Gary W Beecham6, Ruchita A Rajbhandary4, Kara L Hamilton-Nelson4, Li-San Wang7, John S K Kauwe8, Matthew J Huentelman9, Amanda J Myers10, Thomas D Bird11, Bradley F Boeve12, Clinton T Baldwin13, Gail P Jarvik14, Paul K Crane15, Ekaterina Rogaeva16, M Michael Barmada17, F Yesim Demirci17, Carlos Cruchaga18, Patricia L Kramer19, Nilufer Ertekin-Taner20, John Hardy21, Neill R Graff-Radford20, Robert C Green22, Eric B Larson23, Peter H St George-Hyslop24, Joseph D Buxbaum25, Denis A Evans26, Julie A Schneider27, Kathryn L Lunetta28, M Ilyas Kamboh29, Andrew J Saykin30, Eric M Reiman31, Philip L De Jager32, David A Bennett33, John C Morris34, Thomas J Montine35, Alison M Goate18, Deborah Blacker36, Debby W Tsuang37, Hakon Hakonarson38, Walter A Kukull39, Tatiana M Foroud40, Eden R Martin6, Jonathan L Haines41, Richard P Mayeux42, Lindsay A Farrer43, Gerard D Schellenberg7, Margaret A Pericak-Vance6, Marilyn S Albert44, Roger L Albin45, Liana G Apostolova46, Steven E Arnold47, Robert Barber48, Lisa L Barnes49, Thomas G Beach50, James T Becker51, Duane Beekly52, Eileen H Bigio53, James D Bowen54, Adam Boxer55, James R Burke56, Nigel J Cairns57, Laura B Cantwell7, Chuanhai Cao58, Chris S Carlson59, Regina M Carney10, Minerva M Carrasquillo60, Steven L Carroll61, Helena C Chui62, David G Clark63, Jason Corneveaux9, David H Cribbs64, Elizabeth A Crocco10, Charles DeCarli65, Steven T DeKosky66, Malcolm Dick67, Dennis W Dickson60, Ranjan Duara68, Kelley M Faber40, Kenneth B Fallon61, Martin R Farlow69, Steven Ferris70, Matthew P Frosch71, Douglas R Galasko72, Mary Ganguli73, Marla Gearing74, Daniel H Geschwind75, Bernardino Ghetti76, John R Gilbert6, Jonathan D Glass77, John H Growdon78, Ronald L Hamilton79, Lindy E Harrell63, Elizabeth Head80, Lawrence S Honig81, Christine M Hulette82, Bradley T Hyman78, Gregory A Jicha83, Lee-Way Jin84, Anna Karydas55, Jeffrey A Kaye85, Ronald Kim86, Edward H Koo72, Neil W Kowall87, Joel H Kramer88, Frank M LaFerla89, James J Lah77, James B Leverenz35, Allan I Levey77, Ge Li90, Andrew P Lieberman91, Chiao-Feng Lin7, Oscar L Lopez92, Constantine G Lyketsos93, Wendy J Mack94, Frank Martiniuk95, Deborah C Mash96, Eliezer Masliah97, Wayne C McCormick15, Susan M McCurry98, Andrew N McDavid59, Ann C McKee87, Marsel Mesulam99, Bruce L Miller55, Carol A Miller100, Joshua W Miller84, Jill R Murrell101, John M Olichney65, Vernon S Pankratz102, Joseph E Parisi103, Henry L Paulson104, Elaine Peskind90, Ronald C Petersen12, Aimee Pierce64, Wayne W Poon67, Huntington Potter58, Joseph F Quinn105, Ashok Raj58, Murray Raskind90, Barry Reisberg106, John M Ringman46, Erik D Roberson63, Howard J Rosen55, Roger N Rosenberg107, Mary Sano108, Lon S Schneider109, William W Seeley55, Amanda G Smith58, Joshua A Sonnen35, Salvatore Spina76, Robert A Stern110, Rudolph E Tanzi78, Tricia A Thornton-Wells111, John Q Trojanowski7, Juan C Troncoso112, Otto Valladares7, Vivianna M Van Deerlin7, Linda J Van Eldik113, Badri N Vardarajan114, Harry V Vinters115, Jean Paul Vonsattel116, Sandra Weintraub117, Kathleen A Welsh-Bohmer118, Jennifer Williamson81, Sarah Wishnek4, Randall L Woltjer119, Clinton B Wright120, Steven G Younkin60, Chang-En Yu15, Lei Yu121.   

Abstract

IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.
RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Entities:  

Mesh:

Year:  2014        PMID: 25199842      PMCID: PMC4314944          DOI: 10.1001/jamaneurol.2014.1491

Source DB:  PubMed          Journal:  JAMA Neurol        ISSN: 2168-6149            Impact factor:   18.302


  34 in total

1.  Statistical tests for detection of misspecified relationships by use of genome-screen data.

Authors:  M S McPeek; L Sun
Journal:  Am J Hum Genet       Date:  2000-03       Impact factor: 11.025

2.  The number of trait loci in late-onset Alzheimer disease.

Authors:  E W Daw; H Payami; E J Nemens; D Nochlin; T D Bird; G D Schellenberg; E M Wijsman
Journal:  Am J Hum Genet       Date:  2000-01       Impact factor: 11.025

3.  Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

Authors:  Peter Holmans; Marian Hamshere; Paul Hollingworth; Frances Rice; Nigel Tunstall; Sue Jones; Pamela Moore; Fabienne Wavrant DeVrieze; Amanda Myers; Richard Crook; Danielle Compton; Helen Marshall; David Meyer; Shantia Shears; Jeremy Booth; Dzanan Ramic; Nigel Williams; Nadine Norton; Richard Abraham; Pat Kehoe; Hywel Williams; Varuni Rudrasingham; Mick O'Donovan; Lesley Jones; John Hardy; Alison Goate; Simon Lovestone; Michael Owen; Julie Williams
Journal:  Am J Med Genet B Neuropsychiatr Genet       Date:  2005-05-05       Impact factor: 3.568

4.  Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity.

Authors:  Yoonha Choi; Elizabeth E Marchani; Thomas D Bird; Ellen J Steinbart; Deborah Blacker; Ellen M Wijsman
Journal:  Am J Med Genet B Neuropsychiatr Genet       Date:  2011-08-02       Impact factor: 3.568

5.  Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported.

Authors:  D A Evans; H H Funkenstein; M S Albert; P A Scherr; N R Cook; M J Chown; L E Hebert; C H Hennekens; J O Taylor
Journal:  JAMA       Date:  1989-11-10       Impact factor: 56.272

6.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

Authors:  E H Corder; A M Saunders; W J Strittmatter; D E Schmechel; P C Gaskell; G W Small; A D Roses; J L Haines; M A Pericak-Vance
Journal:  Science       Date:  1993-08-13       Impact factor: 47.728

7.  Apolipoprotein E polymorphism and age at onset of Alzheimer's disease in a quadriethnic sample.

Authors:  Oh Dae Kwon; Aisha Khaleeq; Wenyaw Chan; Valory N Pavlik; Rachelle S Doody
Journal:  Dement Geriatr Cogn Disord       Date:  2011-01-20       Impact factor: 2.959

8.  Canadian study of health and aging: study methods and prevalence of dementia.

Authors: 
Journal:  CMAJ       Date:  1994-03-15       Impact factor: 8.262

9.  Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

Authors:  Adam C Naj; Gyungah Jun; Gary W Beecham; Li-San Wang; Badri Narayan Vardarajan; Jacqueline Buros; Paul J Gallins; Joseph D Buxbaum; Gail P Jarvik; Paul K Crane; Eric B Larson; Thomas D Bird; Bradley F Boeve; Neill R Graff-Radford; Philip L De Jager; Denis Evans; Julie A Schneider; Minerva M Carrasquillo; Nilufer Ertekin-Taner; Steven G Younkin; Carlos Cruchaga; John S K Kauwe; Petra Nowotny; Patricia Kramer; John Hardy; Matthew J Huentelman; Amanda J Myers; Michael M Barmada; F Yesim Demirci; Clinton T Baldwin; Robert C Green; Ekaterina Rogaeva; Peter St George-Hyslop; Steven E Arnold; Robert Barber; Thomas Beach; Eileen H Bigio; James D Bowen; Adam Boxer; James R Burke; Nigel J Cairns; Chris S Carlson; Regina M Carney; Steven L Carroll; Helena C Chui; David G Clark; Jason Corneveaux; Carl W Cotman; Jeffrey L Cummings; Charles DeCarli; Steven T DeKosky; Ramon Diaz-Arrastia; Malcolm Dick; Dennis W Dickson; William G Ellis; Kelley M Faber; Kenneth B Fallon; Martin R Farlow; Steven Ferris; Matthew P Frosch; Douglas R Galasko; Mary Ganguli; Marla Gearing; Daniel H Geschwind; Bernardino Ghetti; John R Gilbert; Sid Gilman; Bruno Giordani; Jonathan D Glass; John H Growdon; Ronald L Hamilton; Lindy E Harrell; Elizabeth Head; Lawrence S Honig; Christine M Hulette; Bradley T Hyman; Gregory A Jicha; Lee-Way Jin; Nancy Johnson; Jason Karlawish; Anna Karydas; Jeffrey A Kaye; Ronald Kim; Edward H Koo; Neil W Kowall; James J Lah; Allan I Levey; Andrew P Lieberman; Oscar L Lopez; Wendy J Mack; Daniel C Marson; Frank Martiniuk; Deborah C Mash; Eliezer Masliah; Wayne C McCormick; Susan M McCurry; Andrew N McDavid; Ann C McKee; Marsel Mesulam; Bruce L Miller; Carol A Miller; Joshua W Miller; Joseph E Parisi; Daniel P Perl; Elaine Peskind; Ronald C Petersen; Wayne W Poon; Joseph F Quinn; Ruchita A Rajbhandary; Murray Raskind; Barry Reisberg; John M Ringman; Erik D Roberson; Roger N Rosenberg; Mary Sano; Lon S Schneider; William Seeley; Michael L Shelanski; Michael A Slifer; Charles D Smith; Joshua A Sonnen; Salvatore Spina; Robert A Stern; Rudolph E Tanzi; John Q Trojanowski; Juan C Troncoso; Vivianna M Van Deerlin; Harry V Vinters; Jean Paul Vonsattel; Sandra Weintraub; Kathleen A Welsh-Bohmer; Jennifer Williamson; Randall L Woltjer; Laura B Cantwell; Beth A Dombroski; Duane Beekly; Kathryn L Lunetta; Eden R Martin; M Ilyas Kamboh; Andrew J Saykin; Eric M Reiman; David A Bennett; John C Morris; Thomas J Montine; Alison M Goate; Deborah Blacker; Debby W Tsuang; Hakon Hakonarson; Walter A Kukull; Tatiana M Foroud; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Gerard D Schellenberg
Journal:  Nat Genet       Date:  2011-04-03       Impact factor: 38.330

10.  Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Authors:  Paul Hollingworth; Denise Harold; Rebecca Sims; Amy Gerrish; Jean-Charles Lambert; Minerva M Carrasquillo; Richard Abraham; Marian L Hamshere; Jaspreet Singh Pahwa; Valentina Moskvina; Kimberley Dowzell; Nicola Jones; Alexandra Stretton; Charlene Thomas; Alex Richards; Dobril Ivanov; Caroline Widdowson; Jade Chapman; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K Lupton; Carol Brayne; David C Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kristelle S Brown; Peter A Passmore; David Craig; Bernadette McGuinness; Stephen Todd; Clive Holmes; David Mann; A David Smith; Helen Beaumont; Donald Warden; Gordon Wilcock; Seth Love; Patrick G Kehoe; Nigel M Hooper; Emma R L C Vardy; John Hardy; Simon Mead; Nick C Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Eckart Rüther; Britta Schürmann; Reiner Heun; Heike Kölsch; Hendrik van den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Frölich; Harald Hampel; John Gallacher; Michael Hüll; Dan Rujescu; Ina Giegling; Alison M Goate; John S K Kauwe; Carlos Cruchaga; Petra Nowotny; John C Morris; Kevin Mayo; Kristel Sleegers; Karolien Bettens; Sebastiaan Engelborghs; Peter P De Deyn; Christine Van Broeckhoven; Gill Livingston; Nicholas J Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Ammar Al-Chalabi; Christopher E Shaw; Magda Tsolaki; Andrew B Singleton; Rita Guerreiro; Thomas W Mühleisen; Markus M Nöthen; Susanne Moebus; Karl-Heinz Jöckel; Norman Klopp; H-Erich Wichmann; V Shane Pankratz; Sigrid B Sando; Jan O Aasly; Maria Barcikowska; Zbigniew K Wszolek; Dennis W Dickson; Neill R Graff-Radford; Ronald C Petersen; Cornelia M van Duijn; Monique M B Breteler; M Arfan Ikram; Anita L DeStefano; Annette L Fitzpatrick; Oscar Lopez; Lenore J Launer; Sudha Seshadri; Claudine Berr; Dominique Campion; Jacques Epelbaum; Jean-François Dartigues; Christophe Tzourio; Annick Alpérovitch; Mark Lathrop; Thomas M Feulner; Patricia Friedrich; Caterina Riehle; Michael Krawczak; Stefan Schreiber; Manuel Mayhaus; S Nicolhaus; Stefan Wagenpfeil; Stacy Steinberg; Hreinn Stefansson; Kari Stefansson; Jon Snaedal; Sigurbjörn Björnsson; Palmi V Jonsson; Vincent Chouraki; Benjamin Genier-Boley; Mikko Hiltunen; Hilkka Soininen; Onofre Combarros; Diana Zelenika; Marc Delepine; Maria J Bullido; Florence Pasquier; Ignacio Mateo; Ana Frank-Garcia; Elisa Porcellini; Olivier Hanon; Eliecer Coto; Victoria Alvarez; Paolo Bosco; Gabriele Siciliano; Michelangelo Mancuso; Francesco Panza; Vincenzo Solfrizzi; Benedetta Nacmias; Sandro Sorbi; Paola Bossù; Paola Piccardi; Beatrice Arosio; Giorgio Annoni; Davide Seripa; Alberto Pilotto; Elio Scarpini; Daniela Galimberti; Alexis Brice; Didier Hannequin; Federico Licastro; Lesley Jones; Peter A Holmans; Thorlakur Jonsson; Matthias Riemenschneider; Kevin Morgan; Steven G Younkin; Michael J Owen; Michael O'Donovan; Philippe Amouyel; Julie Williams
Journal:  Nat Genet       Date:  2011-04-03       Impact factor: 38.330

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  82 in total

Review 1.  Impact of late-onset Alzheimer's genetic risk factors on beta-amyloid endocytic production.

Authors:  Cláudia Guimas Almeida; Farzaneh Sadat Mirfakhar; Catarina Perdigão; Tatiana Burrinha
Journal:  Cell Mol Life Sci       Date:  2018-04-27       Impact factor: 9.261

2.  Fast Algorithms for Conducting Large-Scale GWAS of Age-at-Onset Traits Using Cox Mixed-Effects Models.

Authors:  Liang He; Alexander M Kulminski
Journal:  Genetics       Date:  2020-03-04       Impact factor: 4.562

3.  Association of the CX3CR1-V249I Variant with Neurofibrillary Pathology Progression in Late-Onset Alzheimer's Disease.

Authors:  Alan López-López; Ellen Gelpi; Diana Maria Lopategui; Jose M Vidal-Taboada
Journal:  Mol Neurobiol       Date:  2017-03-25       Impact factor: 5.590

4.  Identification of genetic heterogeneity of Alzheimer's disease across age.

Authors:  Min-Tzu Lo; Karolina Kauppi; Chun-Chieh Fan; Nilotpal Sanyal; Emilie T Reas; V S Sundar; Wen-Chung Lee; Rahul S Desikan; Linda K McEvoy; Chi-Hua Chen
Journal:  Neurobiol Aging       Date:  2019-03-12       Impact factor: 4.673

5.  Family-based genome scan for age at onset of late-onset Alzheimer's disease in whole exome sequencing data.

Authors:  M Saad; Z Brkanac; E M Wijsman
Journal:  Genes Brain Behav       Date:  2015-09-23       Impact factor: 3.449

6.  Traumatic brain injury history is associated with earlier age of onset of Alzheimer disease.

Authors:  Christian LoBue; Hannah Wadsworth; Kristin Wilmoth; Matthew Clem; John Hart; Kyle B Womack; Nyaz Didehbani; Laura H Lacritz; Heidi C Rossetti; C Munro Cullum
Journal:  Clin Neuropsychol       Date:  2016-11-18       Impact factor: 3.535

Review 7.  Genomic variants, genes, and pathways of Alzheimer's disease: An overview.

Authors:  Adam C Naj; Gerard D Schellenberg
Journal:  Am J Med Genet B Neuropsychiatr Genet       Date:  2017-01       Impact factor: 3.568

Review 8.  Clinical exome sequencing in neurogenetic and neuropsychiatric disorders.

Authors:  Brent L Fogel; Hane Lee; Samuel P Strom; Joshua L Deignan; Stanley F Nelson
Journal:  Ann N Y Acad Sci       Date:  2015-08-06       Impact factor: 5.691

9.  Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.

Authors:  Vincent Chouraki; Christiane Reitz; Fleur Maury; Joshua C Bis; Celine Bellenguez; Lei Yu; Johanna Jakobsdottir; Shubhabrata Mukherjee; Hieab H Adams; Seung Hoan Choi; Eric B Larson; Annette Fitzpatrick; Andre G Uitterlinden; Philip L de Jager; Albert Hofman; Vilmundur Gudnason; Badri Vardarajan; Carla Ibrahim-Verbaas; Sven J van der Lee; Oscar Lopez; Jean-François Dartigues; Claudine Berr; Philippe Amouyel; David A Bennett; Cornelia van Duijn; Anita L DeStefano; Lenore J Launer; M Arfan Ikram; Paul K Crane; Jean-Charles Lambert; Richard Mayeux; Sudha Seshadri
Journal:  J Alzheimers Dis       Date:  2016-06-18       Impact factor: 4.472

10.  Subcellular Changes in Bridging Integrator 1 Protein Expression in the Cerebral Cortex During the Progression of Alzheimer Disease Pathology.

Authors:  Stephanie L Adams; Kathy Tilton; James A Kozubek; Sudha Seshadri; Ivana Delalle
Journal:  J Neuropathol Exp Neurol       Date:  2016-06-26       Impact factor: 3.685

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