ABCA7 frameshift deletion associated with Alzheimer disease in African Americans
2016; Wolters Kluwer; Volume: 2; Issue: 3 Linguagem: Inglês
10.1212/nxg.0000000000000079
ISSN2376-7839
AutoresHolly N. Cukier, Brian W. Kunkle, Badri N. Vardarajan, Sophie Rolati, Kara L. Hamilton‐Nelson, Martin Kohli, Patrice L. Whitehead, Beth A. Dombroski, Derek Van Booven, Rosalyn Lang, Derek M. Dykxhoorn, Lindsay A. Farrer, Michael L. Cuccaro, Jeffery M. Vance, John R. Gilbert, Gary W. Beecham, Eden R. Martin, Regina M. Carney, Richard Mayeux, Gerard D. Schellenberg, Goldie S. Byrd, Jonathan L. Haines, Margaret A. Pericak‐Vance, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig Atwood, Clinton T. Baldwin, M. Michael Barmada, Lisa L. Barnes, Sandra Barral, Thomas G. Beach, James T. Becker, Gary W. Beecham, Duane Beekly, David A. Bennett, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, Adam Boxer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Goldie S. Byrd, Guiqing Cai, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, David H. Cribbs, Elizabeth Crocco, Carlos Cruchaga, Philip L. De Jager, Charles DeCarli, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Ranjan Duara, Nilüfer Ertekin‐Taner, Denis A. Evans, Kelley Faber, M. Daniele Fallin, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Lindsay A. Farrer, Steven H. Ferris, Tatiana Foroud, Matthew P. Frosch, Douglas Galasko, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Rodney C.P. Go, Alison Goate, Neill R. Graff‐Radford, Robert C. Green, Patrick Griffith, John H. Growdon, Jonathan L. Haines, Hákon Hákonarson, Ronald L. Hamilton, Kara L. Hamilton‐Nelson, Vahram Haroutunian, Lindy E. Harrell, Lawrence S. Honig, Ryan Huebinger, Christine M. Hulette, Bradley T. Hyman, Gregory A. Jicha, Lee‐Way Jin, Gyungah Jun, M. Ilyas Kamboh, Anna Karydas, John S. K. Kauwe, Jeffrey Kaye, Ronald Kim, Neil W. Kowall, Joel H. Kramer, Walter A. Kukull, Brian W. Kunkle, Frank M. LaFerla, James J. Lah, Rosalyn Lang-Walker, Eric B. Larson, James B. Leverenz, Allan I. Levey, Li Ge, Andrew P. Lieberman, Mark W. Logue, Oscar L. López, Kathryn L. Lunetta, Constantine G. Lyketsos, Wendy J. Mack, Jennifer J. Manly, Daniel Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Richard Mayeux, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Jill R. Murrell, Adam C. Naj, Thomas O. Obisesan, John Olichney, V. Shane Pankratz, Joseph E. Parisi, Amanda Partch, Henry L. Paulson, Margaret A. Pericak‐Vance, William Perry, Elaine R. Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Towfique Raj, Murray A. Raskind, Eric M. Reiman, Barry Reisberg, Christiane Reitz, John M. Ringman, Erik D. Roberson, Howard J. Rosen, Roger N. Rosenberg, Mark A. Sager, Mary Sano, Andrew J. Saykin, Gerard D. Schellenberg, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Russell H. Swerdlow, Rudolph E. Tanzi, Tricia A. Thornton‐Wells, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Otto Valladares, Vivianna M. Van Deerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Li‐San Wang, Sandra Weıntraub, Kathleen A. Welsh‐Bohmer, Jennifer Williamson, Thomas S. Wingo, Sarah Wishnek, Randall L. Woltjer, Clinton B. Wright, Steven G. Younkin, Chang‐En Yu, Lei Yu,
Tópico(s)MicroRNA in disease regulation
ResumoObjective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A ( ABC1 ), member 7 ( ABCA7 ) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease ( p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance ( p = 1.414 × 10 −5 , OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.
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