%0 Journal Article %J Mol Psychiatry %D 2018 %T Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. %A Bis, Joshua C %A Jian, Xueqiu %A Kunkle, Brian W %A Chen, Yuning %A Hamilton-Nelson, Kara L %A Bush, William S %A Salerno, William J %A Lancour, Daniel %A Ma, Yiyi %A Renton, Alan E %A Marcora, Edoardo %A Farrell, John J %A Zhao, Yi %A Qu, Liming %A Ahmad, Shahzad %A Amin, Najaf %A Amouyel, Philippe %A Beecham, Gary W %A Below, Jennifer E %A Campion, Dominique %A Charbonnier, Camille %A Chung, Jaeyoon %A Crane, Paul K %A Cruchaga, Carlos %A Cupples, L Adrienne %A Dartigues, Jean-François %A Debette, Stephanie %A Deleuze, Jean-Francois %A Fulton, Lucinda %A Gabriel, Stacey B %A Genin, Emmanuelle %A Gibbs, Richard A %A Goate, Alison %A Grenier-Boley, Benjamin %A Gupta, Namrata %A Haines, Jonathan L %A Havulinna, Aki S %A Helisalmi, Seppo %A Hiltunen, Mikko %A Howrigan, Daniel P %A Ikram, M Arfan %A Kaprio, Jaakko %A Konrad, Jan %A Kuzma, Amanda %A Lander, Eric S %A Lathrop, Mark %A Lehtimäki, Terho %A Lin, Honghuang %A Mattila, Kari %A Mayeux, Richard %A Muzny, Donna M %A Nasser, Waleed %A Neale, Benjamin %A Nho, Kwangsik %A Nicolas, Gaël %A Patel, Devanshi %A Pericak-Vance, Margaret A %A Perola, Markus %A Psaty, Bruce M %A Quenez, Olivier %A Rajabli, Farid %A Redon, Richard %A Reitz, Christiane %A Remes, Anne M %A Salomaa, Veikko %A Sarnowski, Chloe %A Schmidt, Helena %A Schmidt, Michael %A Schmidt, Reinhold %A Soininen, Hilkka %A Thornton, Timothy A %A Tosto, Giuseppe %A Tzourio, Christophe %A van der Lee, Sven J %A van Duijn, Cornelia M %A Vardarajan, Badri %A Wang, Weixin %A Wijsman, Ellen %A Wilson, Richard K %A Witten, Daniela %A Worley, Kim C %A Zhang, Xiaoling %A Bellenguez, Céline %A Lambert, Jean-Charles %A Kurki, Mitja I %A Palotie, Aarno %A Daly, Mark %A Boerwinkle, Eric %A Lunetta, Kathryn L %A DeStefano, Anita L %A Dupuis, Josée %A Martin, Eden R %A Schellenberg, Gerard D %A Seshadri, Sudha %A Naj, Adam C %A Fornage, Myriam %A Farrer, Lindsay A %X

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

%B Mol Psychiatry %8 2018 Aug 14 %G eng %R 10.1038/s41380-018-0112-7 %0 Journal Article %J Ann Clin Transl Neurol %D 2018 %T Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease. %A Vardarajan, Badri N %A Barral, Sandra %A Jaworski, James %A Beecham, Gary W %A Blue, Elizabeth %A Tosto, Giuseppe %A Reyes-Dumeyer, Dolly %A Medrano, Martin %A Lantigua, Rafael %A Naj, Adam %A Thornton, Timothy %A DeStefano, Anita %A Martin, Eden %A Wang, Li-San %A Brown, Lisa %A Bush, William %A van Duijn, Cornelia %A Goate, Allison %A Farrer, Lindsay %A Haines, Jonathan L %A Boerwinkle, Eric %A Schellenberg, Gerard %A Wijsman, Ellen %A Pericak-Vance, Margaret A %A Mayeux, Richard %A Wang, Li-San %X

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).

Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

%B Ann Clin Transl Neurol %V 5 %P 406-417 %8 2018 Apr %G eng %N 4 %R 10.1002/acn3.537 %0 Journal Article %J Ann Clin Transl Neurol %D 2018 %T Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. %A Raghavan, Neha S %A Brickman, Adam M %A Andrews, Howard %A Manly, Jennifer J %A Schupf, Nicole %A Lantigua, Rafael %A Wolock, Charles J %A Kamalakaran, Sitharthan %A Petrovski, Slave %A Tosto, Giuseppe %A Vardarajan, Badri N %A Goldstein, David B %A Mayeux, Richard %X

Objective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 × 10; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.

%B Ann Clin Transl Neurol %V 5 %P 832-842 %8 2018 Jul %G eng %N 7 %R 10.1002/acn3.582 %0 Journal Article %J Nat Genet %D 2022 %T New insights into the genetic etiology of Alzheimer's disease and related dementias. %A Bellenguez, Céline %A Küçükali, Fahri %A Jansen, Iris E %A Kleineidam, Luca %A Moreno-Grau, Sonia %A Amin, Najaf %A Naj, Adam C %A Campos-Martin, Rafael %A Grenier-Boley, Benjamin %A Andrade, Victor %A Holmans, Peter A %A Boland, Anne %A Damotte, Vincent %A van der Lee, Sven J %A Costa, Marcos R %A Kuulasmaa, Teemu %A Yang, Qiong %A de Rojas, Itziar %A Bis, Joshua C %A Yaqub, Amber %A Prokic, Ivana %A Chapuis, Julien %A Ahmad, Shahzad %A Giedraitis, Vilmantas %A Aarsland, Dag %A Garcia-Gonzalez, Pablo %A Abdelnour, Carla %A Alarcón-Martín, Emilio %A Alcolea, Daniel %A Alegret, Montserrat %A Alvarez, Ignacio %A Alvarez, Victoria %A Armstrong, Nicola J %A Tsolaki, Anthoula %A Antunez, Carmen %A Appollonio, Ildebrando %A Arcaro, Marina %A Archetti, Silvana %A Pastor, Alfonso Arias %A Arosio, Beatrice %A Athanasiu, Lavinia %A Bailly, Henri %A Banaj, Nerisa %A Baquero, Miquel %A Barral, Sandra %A Beiser, Alexa %A Pastor, Ana Belén %A Below, Jennifer E %A Benchek, Penelope %A Benussi, Luisa %A Berr, Claudine %A Besse, Céline %A Bessi, Valentina %A Binetti, Giuliano %A Bizarro, Alessandra %A Blesa, Rafael %A Boada, Merce %A Boerwinkle, Eric %A Borroni, Barbara %A Boschi, Silvia %A Bossù, Paola %A Bråthen, Geir %A Bressler, Jan %A Bresner, Catherine %A Brodaty, Henry %A Brookes, Keeley J %A Brusco, Luis Ignacio %A Buiza-Rueda, Dolores %A Bûrger, Katharina %A Burholt, Vanessa %A Bush, William S %A Calero, Miguel %A Cantwell, Laura B %A Chene, Geneviève %A Chung, Jaeyoon %A Cuccaro, Michael L %A Carracedo, Angel %A Cecchetti, Roberta %A Cervera-Carles, Laura %A Charbonnier, Camille %A Chen, Hung-Hsin %A Chillotti, Caterina %A Ciccone, Simona %A Claassen, Jurgen A H R %A Clark, Christopher %A Conti, Elisa %A Corma-Gómez, Anaïs %A Costantini, Emanuele %A Custodero, Carlo %A Daian, Delphine %A Dalmasso, Maria Carolina %A Daniele, Antonio %A Dardiotis, Efthimios %A Dartigues, Jean-François %A de Deyn, Peter Paul %A de Paiva Lopes, Katia %A de Witte, Lot D %A Debette, Stephanie %A Deckert, Jürgen %A Del Ser, Teodoro %A Denning, Nicola %A DeStefano, Anita %A Dichgans, Martin %A Diehl-Schmid, Janine %A Diez-Fairen, Monica %A Rossi, Paolo Dionigi %A Djurovic, Srdjan %A Duron, Emmanuelle %A Düzel, Emrah %A Dufouil, Carole %A Eiriksdottir, Gudny %A Engelborghs, Sebastiaan %A Escott-Price, Valentina %A Espinosa, Ana %A Ewers, Michael %A Faber, Kelley M %A Fabrizio, Tagliavini %A Nielsen, Sune Fallgaard %A Fardo, David W %A Farotti, Lucia %A Fenoglio, Chiara %A Fernández-Fuertes, Marta %A Ferrari, Raffaele %A Ferreira, Catarina B %A Ferri, Evelyn %A Fin, Bertrand %A Fischer, Peter %A Fladby, Tormod %A Fließbach, Klaus %A Fongang, Bernard %A Fornage, Myriam %A Fortea, Juan %A Foroud, Tatiana M %A Fostinelli, Silvia %A Fox, Nick C %A Franco-Macías, Emlio %A Bullido, María J %A Frank-García, Ana %A Froelich, Lutz %A Fulton-Howard, Brian %A Galimberti, Daniela %A García-Alberca, Jose Maria %A Garcia-Gonzalez, Pablo %A Garcia-Madrona, Sebastian %A Garcia-Ribas, Guillermo %A Ghidoni, Roberta %A Giegling, Ina %A Giorgio, Giaccone %A Goate, Alison M %A Goldhardt, Oliver %A Gomez-Fonseca, Duber %A González-Perez, Antonio %A Graff, Caroline %A Grande, Giulia %A Green, Emma %A Grimmer, Timo %A Grünblatt, Edna %A Grunin, Michelle %A Gudnason, Vilmundur %A Guetta-Baranes, Tamar %A Haapasalo, Annakaisa %A Hadjigeorgiou, Georgios %A Haines, Jonathan L %A Hamilton-Nelson, Kara L %A Hampel, Harald %A Hanon, Olivier %A Hardy, John %A Hartmann, Annette M %A Hausner, Lucrezia %A Harwood, Janet %A Heilmann-Heimbach, Stefanie %A Helisalmi, Seppo %A Heneka, Michael T %A Hernandez, Isabel %A Herrmann, Martin J %A Hoffmann, Per %A Holmes, Clive %A Holstege, Henne %A Vilas, Raquel Huerto %A Hulsman, Marc %A Humphrey, Jack %A Biessels, Geert Jan %A Jian, Xueqiu %A Johansson, Charlotte %A Jun, Gyungah R %A Kastumata, Yuriko %A Kauwe, John %A Kehoe, Patrick G %A Kilander, Lena %A Ståhlbom, Anne Kinhult %A Kivipelto, Miia %A Koivisto, Anne %A Kornhuber, Johannes %A Kosmidis, Mary H %A Kukull, Walter A %A Kuksa, Pavel P %A Kunkle, Brian W %A Kuzma, Amanda B %A Lage, Carmen %A Laukka, Erika J %A Launer, Lenore %A Lauria, Alessandra %A Lee, Chien-Yueh %A Lehtisalo, Jenni %A Lerch, Ondrej %A Lleo, Alberto %A Longstreth, William %A Lopez, Oscar %A de Munain, Adolfo Lopez %A Love, Seth %A Löwemark, Malin %A Luckcuck, Lauren %A Lunetta, Kathryn L %A Ma, Yiyi %A Macías, Juan %A MacLeod, Catherine A %A Maier, Wolfgang %A Mangialasche, Francesca %A Spallazzi, Marco %A Marquié, Marta %A Marshall, Rachel %A Martin, Eden R %A Montes, Angel Martín %A Rodríguez, Carmen Martínez %A Masullo, Carlo %A Mayeux, Richard %A Mead, Simon %A Mecocci, Patrizia %A Medina, Miguel %A Meggy, Alun %A Mehrabian, Shima %A Mendoza, Silvia %A Menéndez-González, Manuel %A Mir, Pablo %A Moebus, Susanne %A Mol, Merel %A Molina-Porcel, Laura %A Montrreal, Laura %A Morelli, Laura %A Moreno, Fermin %A Morgan, Kevin %A Mosley, Thomas %A Nöthen, Markus M %A Muchnik, Carolina %A Mukherjee, Shubhabrata %A Nacmias, Benedetta %A Ngandu, Tiia %A Nicolas, Gaël %A Nordestgaard, Børge G %A Olaso, Robert %A Orellana, Adelina %A Orsini, Michela %A Ortega, Gemma %A Padovani, Alessandro %A Paolo, Caffarra %A Papenberg, Goran %A Parnetti, Lucilla %A Pasquier, Florence %A Pastor, Pau %A Peloso, Gina %A Pérez-Cordón, Alba %A Pérez-Tur, Jordi %A Pericard, Pierre %A Peters, Oliver %A Pijnenburg, Yolande A L %A Pineda, Juan A %A Piñol-Ripoll, Gerard %A Pisanu, Claudia %A Polak, Thomas %A Popp, Julius %A Posthuma, Danielle %A Priller, Josef %A Puerta, Raquel %A Quenez, Olivier %A Quintela, Inés %A Thomassen, Jesper Qvist %A Rábano, Alberto %A Rainero, Innocenzo %A Rajabli, Farid %A Ramakers, Inez %A Real, Luis M %A Reinders, Marcel J T %A Reitz, Christiane %A Reyes-Dumeyer, Dolly %A Ridge, Perry %A Riedel-Heller, Steffi %A Riederer, Peter %A Roberto, Natalia %A Rodriguez-Rodriguez, Eloy %A Rongve, Arvid %A Allende, Irene Rosas %A Rosende-Roca, Maitée %A Royo, Jose Luis %A Rubino, Elisa %A Rujescu, Dan %A Sáez, María Eugenia %A Sakka, Paraskevi %A Saltvedt, Ingvild %A Sanabria, Ángela %A Sánchez-Arjona, María Bernal %A Sanchez-Garcia, Florentino %A Juan, Pascual Sánchez %A Sánchez-Valle, Raquel %A Sando, Sigrid B %A Sarnowski, Chloe %A Satizabal, Claudia L %A Scamosci, Michela %A Scarmeas, Nikolaos %A Scarpini, Elio %A Scheltens, Philip %A Scherbaum, Norbert %A Scherer, Martin %A Schmid, Matthias %A Schneider, Anja %A Schott, Jonathan M %A Selbæk, Geir %A Seripa, Davide %A Serrano, Manuel %A Sha, Jin %A Shadrin, Alexey A %A Skrobot, Olivia %A Slifer, Susan %A Snijders, Gijsje J L %A Soininen, Hilkka %A Solfrizzi, Vincenzo %A Solomon, Alina %A Song, Yeunjoo %A Sorbi, Sandro %A Sotolongo-Grau, Oscar %A Spalletta, Gianfranco %A Spottke, Annika %A Squassina, Alessio %A Stordal, Eystein %A Tartan, Juan Pablo %A Tarraga, Lluis %A Tesí, Niccolo %A Thalamuthu, Anbupalam %A Thomas, Tegos %A Tosto, Giuseppe %A Traykov, Latchezar %A Tremolizzo, Lucio %A Tybjærg-Hansen, Anne %A Uitterlinden, Andre %A Ullgren, Abbe %A Ulstein, Ingun %A Valero, Sergi %A Valladares, Otto %A Broeckhoven, Christine Van %A Vance, Jeffery %A Vardarajan, Badri N %A van der Lugt, Aad %A Dongen, Jasper Van %A van Rooij, Jeroen %A van Swieten, John %A Vandenberghe, Rik %A Verhey, Frans %A Vidal, Jean-Sébastien %A Vogelgsang, Jonathan %A Vyhnalek, Martin %A Wagner, Michael %A Wallon, David %A Wang, Li-San %A Wang, Ruiqi %A Weinhold, Leonie %A Wiltfang, Jens %A Windle, Gill %A Woods, Bob %A Yannakoulia, Mary %A Zare, Habil %A Zhao, Yi %A Zhang, Xiaoling %A Zhu, Congcong %A Zulaica, Miren %A Farrer, Lindsay A %A Psaty, Bruce M %A Ghanbari, Mohsen %A Raj, Towfique %A Sachdev, Perminder %A Mather, Karen %A Jessen, Frank %A Ikram, M Arfan %A de Mendonça, Alexandre %A Hort, Jakub %A Tsolaki, Magda %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A Williams, Julie %A Frikke-Schmidt, Ruth %A Clarimon, Jordi %A Deleuze, Jean-Francois %A Rossi, Giacomina %A Seshadri, Sudha %A Andreassen, Ole A %A Ingelsson, Martin %A Hiltunen, Mikko %A Sleegers, Kristel %A Schellenberg, Gerard D %A van Duijn, Cornelia M %A Sims, Rebecca %A van der Flier, Wiesje M %A Ruiz, Agustin %A Ramirez, Alfredo %A Lambert, Jean-Charles %K Alzheimer Disease %K Cognitive Dysfunction %K Genome-Wide Association Study %K Humans %K tau Proteins %X

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

%B Nat Genet %V 54 %P 412-436 %8 2022 Apr %G eng %N 4 %R 10.1038/s41588-022-01024-z