Citations 16
Protective variant for hippocampal atrophy identified by whole exome sequencing
Kim, Sungeun , Risacher, Shannon L. , Shen, Li , Corneveaux, Jason J., Swaminathan, Shanker , Lin, Hai , Inlow, Mark , Siniard, Ashley L., Reiman, Rebecca, Aisen, Paul, Petersen, Ronald , Jack, Clifford R. , Weiner, Michael W. , Baldwin, Clinton T., Lunetta, Kathryn L. , Farrer, Lindsay A. , Furney, Simon J. , Lovestone, Simon , Simmons, Andrew , Mecocci, Patrizia , Vellas, Bruno , Tsolaki, Magda , Kłoszewska, Iwona, McDonald, Brenna C. , Farlow, Martin R. , Study, for the Indiana Memory and Aging, Huentelman, Matthew J. , Saykin, Andrew J. , Initiative, for the Alzheimer's Disease Neuroimaging, Nho, Kwangsik T. , Ramanan, Vijay K. , Liu, Yunlong , Foroud, Tatiana , Green, Robert C. , Soininen, Hilkka S. , Ghetti, Bernardino , Study, for the Indiana Memory and Aging, Initiative, for the Alzheimer's Disease Neuroimaging, Jack, Clifford R , Saykin, Andrew J , Shen, Li , Tsolaki, Magda , Mecocci, Patrizia
Annals of Neurology | January 5, 2015 | Volume: 77 | Issue: 3 | Pages: 547-552
We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552
Rarity of the Alzheimer Disease–ProtectiveAPPA673T Variant in the United States
Wang, Li-San, Graham, Robert , Crane, Paul K. , Kunkle, Brian W. , Cruchaga, Carlos , Murcia, Josue D. Gonzalez , Cannon‐Albright, Lisa , Baldwin, Clinton T., Blennow, Kaj , Kukull, Walter A. , Faber, Kelley M., Schupf, Nicole , Norton, Maria C. , Tschanz, JoAnn T. , Munger, Ronald G. , Corcoran, Christopher, Lin, Chiao‐Feng , Dombroski, Beth A. , Cantwell, Laura B., Partch, Amanda, Håkonarson, Håkon , George‐Hyslop, Peter St , Goate, Alison , Foroud, Tatiana, Carney, Regina M., Larson, Eric B., Behrens, Timothy W. , Kauwe, John, Haines, Jonathan L. , Farrer, Lindsay A. , Pericak‐Vance, Margaret A. , Mayeux, Richard , Schellenberg, Gerard D., Albert, Marilyn S. , Albin, Roger L. , Apostolova, Liana G. , Arnold, Steven E. , Barber, Robert W., Barmada, M. Michael , Beach, Thomas G. , Beecham, Gary W. , Beekly, Duane, Bennett, David A. , Bigio, Eileen H. , Bird, Thomas D., Blacker, Deborah , Bowen, James D. , Boxer, Adam, Buxbaum, Joseph D. , Cairns, Nigel J. , Cao, Chuanhai , Carlson, Chris , Carroll, Steven L. , Chui, Helena C., Clark, David G., Cribbs, David H. , DeCarli, Charles , DeKosky, Steven T. , Demirci, F. Yesim , Dick, Malcolm, Duara, Ranjan , Ertekin‐Taner, Nilüfer , Fallon, Kenneth B., Farlow, Martin R. , Ferris, Steven H. , Frosch, Matthew P. , Gearing, Marla , Geschwind, Daniel H. , Gilbert, John R., Glass, Jonathan D. , Graff‐Radford, Neill R. , Growdon, John H., Hamilton, Ronald L. , Hamilton‐Nelson, Kara L., Harrell, Lindy E., Hulette, Christine M., Jicha, Gregory A. , Jin, Lee‐Way, Jun, Gyungah , Kamboh, M. Ilyas , Karydas, Anna, Koo, Edward H. , Kowall, Neil W. , Kramer, Joel H. , Kramer, Patricia, LaFerla, Frank M. , Leverenz, James B. , Lieberman, Andrew P. , Lunetta, Kathryn L. , Lyketsos, Constantine G. , Mack, Wendy J. , Marson, Daniel , Martin, Eden R. , Martiniuk, Frank , Mash, Deborah C. , Masliah, Eliezer , McCormick, Wayne C., McKee, Ann C. , Miller, Carol A., Miller, Joshua W., Montine, Thomas J. , Morris, John C. , Murrell, Jill R. , Olichney, John , Parisi, Joseph E., Peskind, Elaine R. , Petersen, Ronald , Pierce, Aimee, Poon, Wayne W. , Raj, Ashok , Raskind, Murray A. , Reiman, Eric M. , Reisberg, Barry , Reitz, Christiane , Ringman, John M. , Rosen, Howard J., Rosenberg, Roger N., Sano, Mary , Saykin, Andrew J. , Schneider, Lon S. , Smith, Amanda , Sonnen, Joshua A. , Stern, Robert A. , Tanzi, Rudolph E. , Thornton‐Wells, Tricia A., Trojanowski, John Q. , Troncoso, Juan C. , Tsuang, Debby W. , Vinters, Harry V. , Vonsattel, Jean Paul, Weıntraub, Sandra , Wishnek, Sarah, Woltjer, Randall L. , Wright, Clinton B., Younkin, Steven G., Yu, Chang‐En , Yu, Lei , DeCarli, Charles , Wang, Li-San, Naj, Adam Christian , Cruchaga, Carlos , Zetterberg, Henrik , Rogaeva, Ekaterina A. , Valladares, Otto , Green, Robert C. , Barnes, Lisa L. , Becker, James T. , Boeve, Bradley F. , Burke, James R. , Chui, Helena C. , Crocco, Elizabeth , Dickson, Dennis W. , Duara, Ranjan , Galasko, Douglas , Ganguli, Mary , Ghetti, Bernardino , Hamilton‐Nelson, Kara L. , Head, Elizabeth , Honig, Lawrence S. , Hyman, Bradley T. , Jarvik, Gail P. , Kaye, Jeffrey , Kim, Ronald , Lah, James J. , Levey, Allan I. , Li, Ge , López, Oscar L. , McCurry, Susan M. , McDavid, Andrew , Mesulam, Marsel M. , Miller, Bruce L. , Perry, William , Potter, Huntington , Quinn, Joseph F. , Roberson, Erik D. , Schneider, Julie A. , Seeley, William W. , Spina, Salvatore , Deerlin, Vivianna M. Van , Eldik, Linda J. Van , Vardarajan, Badri Narayan , Welsh-Bohmer, Kathleen Anne , Williamson, Jennifer , Bennett, David A. , Hakonarson, Hakon , Saykin, Andrew J , Leverenz, James B , Cannon-Albright, Lisa A , Stern, Robert A , Morris, John C , Goate, Alison M , Jicha, Gregory A , Sonnen, Joshua
JAMA Neurology | December 22, 2014 | Volume: 72 | Issue: 2 | Pages: 209
Convergent genetic and expression data implicate immunity in Alzheimer's disease
Jones, Lesley , Lambert, Jean‐Charles , Choi, Seung‐Hoan, Harold, Denise , Vedernikov, Alexey , Escott‐Price, Valentina , Stone, Timothy, Richards, Alexander , Bellenguez, Céline , Sims, Rebecca , DeStefano, Anita L. , Bis, Joshua C. , Beecham, Gary W. , Grenier‐Boley, Benjamin , Russo, Giancarlo , Thornton‐Wells, Tricia A., Jones, Nicola, Smith, Albert V. , Thomas, Charlene , Zélénika, Diana, Kamatani, Yoichiro, Lin, Chiao‐Feng , Schmidt, Helena , Kunkle, Brian W. , Dunstan, Melanie , Ruiz, Agustı́n , Bihoreau, Marie‐Thérèse, Reitz, Christiane, Hollingworth, Paul, Hanon, Olivier , Fitzpatrick, Annette L., Buxbaum, Joseph D. , Campion, Dominique , Crane, Paul K. , Guðnason, Vilmundur , Cruchaga, Carlos , Craig, David W. , Amin, Najaf , Jager, Philip L. De , Deramecourt, Vincent , Johnston, Janet, Evans, Denis A., Lovestone, Simon , Letteneur, Luc, Kornhuber, Johanes, Tárraga, Lluís , Eiriksdottir, Gudny, Goate, Alison , Fiévet, Nathalie, Huentelman, Matthew J. , Gill, Michael , Emilsson, Valur , Brown, Kristelle, Kamboh, M. Ilyas , Keller, Lina, Barberger‐Gateau, Pascale, McGuinness, Bernadette , Larson, Eric B., Dufouil, Carole , Todd, Stephen , Wallon, David , Kehoe, Patrick G. , George‐Hyslop, Peter St , Lleὀ, Alberti, Bayer, Anthony, Tsuang, Debby W. , Yu, Lei, Tsolaki, Magda , Bossù, Paola , Spalletta, Gianfranco , Proitsi, Petra, Collinge, John, Sorbi, Sandro , Hardy, John , Naranjo, María Cándida Déniz, Razquín, Cristina , Bosco, Paola , Clarke, Robert , Brayne, Carol , Galimberti, Daniela , CFAS, MRC, Moebus, Susanne , Mecocci, Patrizia , Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald , Pilotto, Alberto, Bullido, María J. , Panza, Francesco , Caffarra, Paolo , Nacmias, Benedetta , Gilbert, John R., Mayhaus, Manuel, Jessen, Frank , Dichgans, Martin , Lannfelt, Lars , Håkonarson, Håkon , Pichler, Sabrina, Carrasquillo, Minerva M., Beekly, Duane, Alavarez, Victoria, Zou, Fanggeng, Younkin, Steven G., Hamilton‐Nelson, Kara L., Mateo, Ignacio, Faber, Kelley M., Jónsson, Pálmi V. , Combarros, Onofre, O‘Donovan, Michael , Cantwell, Laura B., Blacker, Deborah , Mead, Simon , Harris, Tamara B., Fratiglioni, Laura , Bruijn, Renée F.A.G. de, Passmore, Peter , Montine, Thomas J. , Bettens, Karolien, Rotter, Jerome I. , Brice, Alexis , Morgan, Kevin , Foroud, Tatiana, Kukull, Walter A. , Hannequin, Didier , Powell, John , Nalls, Michael A., Ritchie, Karen , Lunetta, Kathryn L. , Kauwe, John S.K., Boerwinkle, Eric , Riemenschneider, Matthias, Boada, Merçé , Hiltunen, Mikko , Martin, Eden R. , Pástor, Pau , Schmidt, Reinhold, Dartigues, Jean‐François, Mayeux, Richard , Tzourio, Christophe , Hofman, Albert , Nöthen, Markus M. , Graff, Caroline , Haines, Jonathan L. , Lathrop, Mark, Pericak‐Vance, Margaret A. , Launer, Lenore J. , Farrer, Lindsay A. , Duijn, Cornelia M. van , Broeckhoven, Christine Van , Ramı́rez, Alfredo , Schellenberg, Gerard D., Seshadri, Sudha , Amouyel, Philippe , Williams, Julie , Holmans, Peter , Bennett, David A. , Proitsi, Petroula , Ballantyne, Christie M. , Denning, Nicola , Wang, Weixin , Ibrahim‐Verbaas, Carla A. , Naj, Adam Christian , Gerrish, Amy , Jun, Gyungah , Chouraki, Vincent Antoine , Ikram, M. Arfan , Vardarajan, Badri Narayan , Kamatani, Yoichiro, Pasquier, Florence , Becker, Tim , Cruchaga, Carlos , Berr, Claudine , López, Oscar L. , Rubinsztein, David Chaim , Sleegers, Kristel , Myers, Amanda , Love, Seth , Rogaeva, Ekaterina A. , Gallacher, John , Clarimón, Jordi , Bayer, Anthony, Proitsi, Petra, Sánchez-García, Florentino , Fox, Nick C. , Mancuso, Michelangelo , CFAS, MRC, Carrasquillo, Minerva M. , Ingelsson, Martin , Valladares, Otto , Coto, Eliécer , Hamilton‐Nelson, Kara L. , Owen, Michael J. , Soininen, Hilkka S. , Mosley, Thomas H. , Bennett, David , Holmes, Clive , Riemenschneider, Matthias, Rujescu, Dan , Psaty, Bruce M. , Bennett, David A. , Dichgans, Martin , Ramirez, Alfredo , Hakonarson, Hakon , Nöthen, Markus M , Seshadri, Sudha , Hardy, John , Amouyel, Philippe , Tzourio, Christophe , van Duijn, Cornelia M , Smith, Albert V , Ballantyne, Christie M , Rotter, Jerome I , Moebus, Susanne , Ruiz, Agustín , Pastor, Pau , Boada, Merce , Tsolaki, Magda , Brice, Alexis , Goate, Alison M , Galimberti, Daniela , Escott-Price, Valentina , Mecocci, Patrizia , Nacmias, Benedetta , Graff, Caroline , Riemenschneider, Markus J.
Alzheimer's & Dementia | December 20, 2014 | Volume: 11 | Issue: 6 | Pages: 658-671
AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease
Jun, Gyungah , Reitz, Christiane, Kunkle, Brian W. , Park, Yo Son, Beecham, Gary W. , Rajbhandary, Ruchita, Hamilton‐Nelson, Kara L., Wang, Li-San, Kauwe, John, Huentelman, Matthew J. , Bird, Thomas D., Baldwin, Clinton T., Jarvik, Gail P. , Crane, Paul K. , Barmada, M. Michael , Demirci, F. Yesim , Cruchaga, Carlos , Kramer, Patricia L., Ertekin‐Taner, Nilüfer , Hardy, John , Graff‐Radford, Neill R. , Larson, Eric B., George‐Hyslop, Peter St , Buxbaum, Joseph D. , Evans, Denis A., Lunetta, Kathryn L. , Kamboh, M. Ilyas , Saykin, Andrew J. , Reiman, Eric M. , Jager, Philip L. De , Morris, John C. , Montine, Thomas J. , Goate, Alison , Blacker, Deborah , Tsuang, Debby W. , Håkonarson, Håkon , Kukull, Walter A. , Foroud, Tatiana, Martin, Eden R. , Haines, Jonathan L. , Mayeux, Richard , Farrer, Lindsay A. , Schellenberg, Gerard D., Pericak‐Vance, Margaret A. , Albert, Marilyn S. , Albin, Roger L. , Apostolova, Liana G. , Arnold, Steven E. , Barber, Robert W., Beach, Thomas G. , Beekly, Duane, Bigio, Eileen H. , Bowen, James D. , Boxer, Adam, Cairns, Nigel J. , Cantwell, Laura B., Cao, Chuanhai , Carlson, Chris , Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L. , Chui, Helena C., Clark, David G., Corneveaux, Jason J., Cribbs, David H. , DeCarli, Charles , DeKosky, Steven T. , Dick, Malcolm, Duara, Ranjan , Faber, Kelley M., Fallon, Kenneth B., Farlow, Martin R. , Ferris, Steven H. , Frosch, Matthew P. , Gearing, Marla , Geschwind, Daniel H. , Gilbert, John R., Glass, Jonathan D. , Growdon, John H., Hamilton, Ronald L. , Harrell, Lindy E., Hulette, Christine M., Jicha, Gregory A. , Jin, Lee‐Way, Karydas, Anna, Koo, Edward H. , Kowall, Neil W. , Kramer, Joel H. , LaFerla, Frank M. , Leverenz, James B. , Li, Ge , Lieberman, Andrew P. , Lin, Chiao‐Feng , Lyketsos, Constantine G. , Mack, Wendy J. , Martiniuk, Frank , Mash, Deborah C. , Masliah, Eliezer , McCormick, Wayne C., McKee, Ann C. , Miller, Carol A., Miller, Joshua W., Murrell, Jill R. , Olichney, John , Parisi, Joseph E., Paulson, Henry L. , Peskind, Elaine R. , Petersen, Ronald , Pierce, Aimee, Poon, Wayne W. , Raj, Ashok , Raskind, Murray A. , Reisberg, Barry , Ringman, John M. , Rosen, Howard J., Rosenberg, Roger N., Sano, Mary , Schneider, Lon S. , Smith, Amanda , Sonnen, Joshua A. , Stern, Robert A. , Tanzi, Rudolph E. , Thornton‐Wells, Tricia A., Trojanowski, John Q. , Troncoso, Juan C. , Vinters, Harry V. , Vonsattel, Jean Paul, Weıntraub, Sandra , Wishnek, Sarah, Woltjer, Randall L. , Wright, Clinton B., Younkin, Steven G., Yu, Chang‐En , Yu, Lei, Bennett, David A. , DeCarli, Charles , Pankratz, Vernon S, Naj, Adam Christian , Perry, William , Hamilton‐Nelson, Kara L. , Wang, Li-San, Myers, Amanda , Boeve, Bradley F. , Rogaeva, Ekaterina A. , Cruchaga, Carlos , Kramer, P. L., Green, Robert C. , Schneider, Julie A. , Bennett, David , Barnes, Lisa L. , Becker, James T. , Burke, James R. , Carrasquillo, Minerva M. , Chui, Helena C. , Crocco, Elizabeth , Dickson, Dennis W. , Duara, Ranjan , Galasko, Douglas , Ganguli, Mary , Ghetti, Bernardino , Head, Elizabeth , Honig, Lawrence S. , Hyman, Bradley T. , Kaye, Jeffrey , Kim, Ronald , Lah, James J. , Levey, Allan I. , López, Oscar L. , McCurry, Susan M. , McDavid, Andrew , Mesulam, Marsel M. , Miller, Bruce L. , Pankratz, V. Shane , Potter, Huntington , Quinn, Joseph F. , Roberson, Erik D. , Seeley, William W. , Spina, Salvatore , Valladares, Otto , Deerlin, Vivianna M. Van , Eldik, Linda J. Van , Vardarajan, Badri Narayan , Welsh-Bohmer, Kathleen Anne , Williamson, Jennifer , Bennett, David A. , Hakonarson, Hakon , Saykin, Andrew J , Leverenz, James B , Jarvik, Gail P , Paulson, Henry L , Stern, Robert A , Hardy, John , Morris, John C , Goate, Alison M , Jicha, Gregory A , Sonnen, Joshua
JAMA Neurology | September 8, 2014 | Volume: 71 | Issue: 11 | Pages: 1394
Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans
Schu, Matthew , Farrell, John J. , Bennett, David A. , Buxbaum, Joseph D. , Byrd, Goldie S. , Ertekin‐Taner, Nilüfer , Evans, Denis A., Goate, Alison , Graff‐Radford, Neill R. , Kamboh, M. Ilyas , Kukull, Walter A. , Haines, Jonathan L. , Mayeux, Richard , Pericak‐Vance, Margaret A. , Schellenberg, Gerard D. , Baldwin, Clinton T., Fallin, M. Daniele , Farrer, Lindsay A. , Tsuang, Debby W. , Carroll, Steven L. , Logue, Mark W. , Vardarajan, Badri Narayan , Foroud, Tatiana , Manly, Jennifer J. , Lunetta, Kathryn L. , Bennett, David A. , Goate, Alison M
Alzheimer's & Dementia | August 26, 2014 | Volume: 10 | Issue: 6 | Pages: 609
AbstractBackgroundLess is known about the genetic basis of Alzheimer's disease (AD) in African Americans (AAs) than in non‐Hispanic whites.MethodsWhole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD‐related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1037 cases and 1869 controls from the Alzheimer Disease Genetics Consortium (ADGC).ResultsForty‐four single nucleotide polymorphisms (SNPs) from WES passed filtering criteria and were successfully genotyped. Nominally significant (P < .05) association to AD was observed with two African‐descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (P = .014) and rs149979685 (P = .037). These associations were replicated in the ADGC sample (rs144662445: P = .0022, odds ratio [OR] = 2.75; rs149979685: P = .0022, OR = 3.61).ConclusionsBecause AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism.
P1–063: Association of TREM2 variants with Alzheimer's disease in African‐Americans: For the Alzheimer's Disease Genetics Consortium (ADGC)
Reitz, Christiane , Larson, Eric B. , Graff‐Radford, Neill, Evans, Denis A., Jager, Philip L. De , Ertekin‐Taner, Nilüfer , Cantwell, Laura B., Fallin, Danielle, Hall, Kathleen, Byrd, Goldie S. , Haines, Jonathan L. , Pericak‐Vance, Margaret A. , Schellenberg, Gerard, Mayeux, Richard , Jun, Gyungah , Naj, Adam Christian , Vardarajan, Badri Narayan , Wang, Weixin , Graff‐Radford, Neill, Crane, Paul K. , Buxbaum, Joseph D. , Logue, Mark W. , Green, Robert C. , Manly, Jennifer J. , Lunetta, Kathryn L. , Kamboh, M. Ilyas , López, Oscar L. , Bennett, David A. , Goate, Alison , Kukull, Walter A. , Foroud, Tatiana , Farrer, Lindsay A.
Alzheimer's & Dementia | October 9, 2013 | Volume: 9 | Issue: 4S_Part_4 | Pages: No page available