%0 Journal Article %J Transl Psychiatry %D 2021 %T Association of low-frequency and rare coding variants with information processing speed. %A Bressler, Jan %A Davies, Gail %A Smith, Albert V %A Saba, Yasaman %A Bis, Joshua C %A Jian, Xueqiu %A Hayward, Caroline %A Yanek, Lisa %A Smith, Jennifer A %A Mirza, Saira S %A Wang, Ruiqi %A Adams, Hieab H H %A Becker, Diane %A Eric Boerwinkle %A Campbell, Archie %A Cox, Simon R %A Eiriksdottir, Gudny %A Fawns-Ritchie, Chloe %A Gottesman, Rebecca F %A Grove, Megan L %A Guo, Xiuqing %A Hofer, Edith %A Kardia, Sharon L R %A Knol, Maria J %A Koini, Marisa %A Lopez, Oscar L %A Marioni, Riccardo E %A Nyquist, Paul %A Pattie, Alison %A Polasek, Ozren %A Porteous, David J %A Rudan, Igor %A Satizabal, Claudia L %A Schmidt, Helena %A Schmidt, Reinhold %A Sidney, Stephen %A Simino, Jeannette %A Smith, Blair H %A Turner, Stephen T %A van der Lee, Sven J %A Ware, Erin B %A Whitmer, Rachel A %A Yaffe, Kristine %A Yang, Qiong %A Zhao, Wei %A Gudnason, Vilmundur %A Launer, Lenore J %A Fitzpatrick, Annette L %A Psaty, Bruce M %A Fornage, Myriam %A Arfan Ikram, M %A van Duijn, Cornelia M %A Seshadri, Sudha %A Mosley, Thomas H %A Deary, Ian J %K Adult %K Aging %K Cognition %K Genome-Wide Association Study %K Geroscience %K Humans %K Polymorphism, Single Nucleotide %K Ubiquitin-Protein Ligases %X

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

%B Transl Psychiatry %V 11 %P 613 %8 2021 Dec 04 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864818?dopt=Abstract %R 10.1038/s41398-021-01736-6 %0 Journal Article %J Nat Commun %D 2021 %T Common variants in Alzheimer's disease and risk stratification by polygenic risk scores. %A de Rojas, Itziar %A Moreno-Grau, Sonia %A Tesi, Niccolo %A Grenier-Boley, Benjamin %A Andrade, Victor %A Jansen, Iris E %A Pedersen, Nancy L %A Stringa, Najada %A Zettergren, Anna %A Hernández, Isabel %A Montrreal, Laura %A Antúnez, Carmen %A Antonell, Anna %A Tankard, Rick M %A Bis, Joshua C %A Sims, Rebecca %A Bellenguez, Céline %A Quintela, Inés %A González-Perez, Antonio %A Calero, Miguel %A Franco-Macías, Emilio %A Macías, Juan %A Blesa, Rafael %A Cervera-Carles, Laura %A Menéndez-González, Manuel %A Frank-García, Ana %A Royo, Jose Luís %A Moreno, Fermin %A Huerto Vilas, Raquel %A Baquero, Miquel %A Diez-Fairen, Monica %A Lage, Carmen %A García-Madrona, Sebastián %A García-González, Pablo %A Alarcón-Martín, Emilio %A Valero, Sergi %A Sotolongo-Grau, Oscar %A Ullgren, Abbe %A Naj, Adam C %A Lemstra, Afina W %A Benaque, Alba %A Pérez-Cordón, Alba %A Benussi, Alberto %A Rábano, Alberto %A Padovani, Alessandro %A Squassina, Alessio %A de Mendonça, Alexandre %A Arias Pastor, Alfonso %A Kok, Almar A L %A Meggy, Alun %A Pastor, Ana Belén %A Espinosa, Ana %A Corma-Gómez, Anaïs %A Martín Montes, Angel %A Sanabria, Ángela %A DeStefano, Anita L %A Schneider, Anja %A Haapasalo, Annakaisa %A Kinhult Ståhlbom, Anne %A Tybjærg-Hansen, Anne %A Hartmann, Annette M %A Spottke, Annika %A Corbatón-Anchuelo, Arturo %A Rongve, Arvid %A Borroni, Barbara %A Arosio, Beatrice %A Nacmias, Benedetta %A Nordestgaard, Børge G %A Kunkle, Brian W %A Charbonnier, Camille %A Abdelnour, Carla %A Masullo, Carlo %A Martínez Rodríguez, Carmen %A Muñoz-Fernandez, Carmen %A Dufouil, Carole %A Graff, Caroline %A Ferreira, Catarina B %A Chillotti, Caterina %A Reynolds, Chandra A %A Fenoglio, Chiara %A Van Broeckhoven, Christine %A Clark, Christopher %A Pisanu, Claudia %A Satizabal, Claudia L %A Holmes, Clive %A Buiza-Rueda, Dolores %A Aarsland, Dag %A Rujescu, Dan %A Alcolea, Daniel %A Galimberti, Daniela %A Wallon, David %A Seripa, Davide %A Grünblatt, Edna %A Dardiotis, Efthimios %A Düzel, Emrah %A Scarpini, Elio %A Conti, Elisa %A Rubino, Elisa %A Gelpi, Ellen %A Rodriguez-Rodriguez, Eloy %A Duron, Emmanuelle %A Eric Boerwinkle %A Ferri, Evelyn %A Tagliavini, Fabrizio %A Küçükali, Fahri %A Pasquier, Florence %A Sanchez-Garcia, Florentino %A Mangialasche, Francesca %A Jessen, Frank %A Nicolas, Gaël %A Selbæk, Geir %A Ortega, Gemma %A Chêne, Geneviève %A Hadjigeorgiou, Georgios %A Rossi, Giacomina %A Spalletta, Gianfranco %A Giaccone, Giorgio %A Grande, Giulia %A Binetti, Giuliano %A Papenberg, Goran %A Hampel, Harald %A Bailly, Henri %A Zetterberg, Henrik %A Soininen, Hilkka %A Karlsson, Ida K %A Alvarez, Ignacio %A Appollonio, Ildebrando %A Giegling, Ina %A Skoog, Ingmar %A Saltvedt, Ingvild %A Rainero, Innocenzo %A Rosas Allende, Irene %A Hort, Jakub %A Diehl-Schmid, Janine %A Van Dongen, Jasper %A Vidal, Jean-Sebastien %A Lehtisalo, Jenni %A Wiltfang, Jens %A Thomassen, Jesper Qvist %A Kornhuber, Johannes %A Haines, Jonathan L %A Vogelgsang, Jonathan %A Pineda, Juan A %A Fortea, Juan %A Popp, Julius %A Deckert, Jürgen %A Buerger, Katharina %A Morgan, Kevin %A Fließbach, Klaus %A Sleegers, Kristel %A Molina-Porcel, Laura %A Kilander, Lena %A Weinhold, Leonie %A Farrer, Lindsay A %A Wang, Li-San %A Kleineidam, Luca %A Farotti, Lucia %A Parnetti, Lucilla %A Tremolizzo, Lucio %A Hausner, Lucrezia %A Benussi, Luisa %A Froelich, Lutz %A Ikram, M Arfan %A Deniz-Naranjo, M Candida %A Tsolaki, Magda %A Rosende-Roca, Maitée %A Löwenmark, Malin %A Hulsman, Marc %A Spallazzi, Marco %A Pericak-Vance, Margaret A %A Esiri, Margaret %A Bernal Sánchez-Arjona, María %A Dalmasso, Maria Carolina %A Martínez-Larrad, María Teresa %A Arcaro, Marina %A Nöthen, Markus M %A Fernández-Fuertes, Marta %A Dichgans, Martin %A Ingelsson, Martin %A Herrmann, Martin J %A Scherer, Martin %A Vyhnalek, Martin %A Kosmidis, Mary H %A Yannakoulia, Mary %A Schmid, Matthias %A Ewers, Michael %A Heneka, Michael T %A Wagner, Michael %A Scamosci, Michela %A Kivipelto, Miia %A Hiltunen, Mikko %A Zulaica, Miren %A Alegret, Montserrat %A Fornage, Myriam %A Roberto, Natalia %A van Schoor, Natasja M %A Seidu, Nazib M %A Banaj, Nerisa %A Armstrong, Nicola J %A Scarmeas, Nikolaos %A Scherbaum, Norbert %A Goldhardt, Oliver %A Hanon, Oliver %A Peters, Oliver %A Skrobot, Olivia Anna %A Quenez, Olivier %A Lerch, Ondrej %A Bossù, Paola %A Caffarra, Paolo %A Dionigi Rossi, Paolo %A Sakka, Paraskevi %A Mecocci, Patrizia %A Hoffmann, Per %A Holmans, Peter A %A Fischer, Peter %A Riederer, Peter %A Yang, Qiong %A Marshall, Rachel %A Kalaria, Rajesh N %A Mayeux, Richard %A Vandenberghe, Rik %A Cecchetti, Roberta %A Ghidoni, Roberta %A Frikke-Schmidt, Ruth %A Sorbi, Sandro %A Hägg, Sara %A Engelborghs, Sebastiaan %A Helisalmi, Seppo %A Botne Sando, Sigrid %A Kern, Silke %A Archetti, Silvana %A Boschi, Silvia %A Fostinelli, Silvia %A Gil, Silvia %A Mendoza, Silvia %A Mead, Simon %A Ciccone, Simona %A Djurovic, Srdjan %A Heilmann-Heimbach, Stefanie %A Riedel-Heller, Steffi %A Kuulasmaa, Teemu %A Del Ser, Teodoro %A Lebouvier, Thibaud %A Polak, Thomas %A Ngandu, Tiia %A Grimmer, Timo %A Bessi, Valentina %A Escott-Price, Valentina %A Giedraitis, Vilmantas %A Deramecourt, Vincent %A Maier, Wolfgang %A Jian, Xueqiu %A Pijnenburg, Yolande A L %A Kehoe, Patrick Gavin %A Garcia-Ribas, Guillermo %A Sánchez-Juan, Pascual %A Pastor, Pau %A Pérez-Tur, Jordi %A Piñol-Ripoll, Gerard %A Lopez de Munain, Adolfo %A García-Alberca, Jose María %A Bullido, María J %A Alvarez, Victoria %A Lleo, Alberto %A Real, Luis M %A Mir, Pablo %A Medina, Miguel %A Scheltens, Philip %A Holstege, Henne %A Marquié, Marta %A Sáez, María Eugenia %A Carracedo, Ángel %A Amouyel, Philippe %A Schellenberg, Gerard D %A Williams, Julie %A Seshadri, Sudha %A van Duijn, Cornelia M %A Mather, Karen A %A Sánchez-Valle, Raquel %A Serrano-Ríos, Manuel %A Orellana, Adelina %A Tarraga, Lluis %A Blennow, Kaj %A Huisman, Martijn %A Andreassen, Ole A %A Posthuma, Danielle %A Clarimon, Jordi %A Boada, Mercè %A van der Flier, Wiesje M %A Ramirez, Alfredo %A Lambert, Jean-Charles %A van der Lee, Sven J %A Ruiz, Agustin %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Apolipoproteins E %K Case-Control Studies %K Cohort Studies %K Datasets as Topic %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Humans %K Male %K Middle Aged %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %K Risk Assessment %K Risk Factors %X

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

%B Nat Commun %V 12 %P 3417 %8 2021 Jun 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34099642?dopt=Abstract %R 10.1038/s41467-021-22491-8 %0 Journal Article %J Nat Genet %D 2017 %T Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. %A Sims, Rebecca %A van der Lee, Sven J %A Naj, Adam C %A Bellenguez, Céline %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Kunkle, Brian W %A Boland, Anne %A Raybould, Rachel %A Bis, Joshua C %A Martin, Eden R %A Grenier-Boley, Benjamin %A Heilmann-Heimbach, Stefanie %A Chouraki, Vincent %A Kuzma, Amanda B %A Sleegers, Kristel %A Vronskaya, Maria %A Ruiz, Agustin %A Graham, Robert R %A Olaso, Robert %A Hoffmann, Per %A Grove, Megan L %A Vardarajan, Badri N %A Hiltunen, Mikko %A Nöthen, Markus M %A White, Charles C %A Hamilton-Nelson, Kara L %A Epelbaum, Jacques %A Maier, Wolfgang %A Choi, Seung-Hoan %A Beecham, Gary W %A Dulary, Cécile %A Herms, Stefan %A Smith, Albert V %A Funk, Cory C %A Derbois, Céline %A Forstner, Andreas J %A Ahmad, Shahzad %A Li, Hongdong %A Bacq, Delphine %A Harold, Denise %A Satizabal, Claudia L %A Valladares, Otto %A Squassina, Alessio %A Thomas, Rhodri %A Brody, Jennifer A %A Qu, Liming %A Sánchez-Juan, Pascual %A Morgan, Taniesha %A Wolters, Frank J %A Zhao, Yi %A Garcia, Florentino Sanchez %A Denning, Nicola %A Fornage, Myriam %A Malamon, John %A Naranjo, Maria Candida Deniz %A Majounie, Elisa %A Mosley, Thomas H %A Dombroski, Beth %A Wallon, David %A Lupton, Michelle K %A Dupuis, Josée %A Whitehead, Patrice %A Fratiglioni, Laura %A Medway, Christopher %A Jian, Xueqiu %A Mukherjee, Shubhabrata %A Keller, Lina %A Brown, Kristelle %A Lin, Honghuang %A Cantwell, Laura B %A Panza, Francesco %A McGuinness, Bernadette %A Moreno-Grau, Sonia %A Burgess, Jeremy D %A Solfrizzi, Vincenzo %A Proitsi, Petra %A Adams, Hieab H %A Allen, Mariet %A Seripa, Davide %A Pastor, Pau %A Cupples, L Adrienne %A Price, Nathan D %A Hannequin, Didier %A Frank-García, Ana %A Levy, Daniel %A Chakrabarty, Paramita %A Caffarra, Paolo %A Giegling, Ina %A Beiser, Alexa S %A Giedraitis, Vilmantas %A Hampel, Harald %A Garcia, Melissa E %A Wang, Xue %A Lannfelt, Lars %A Mecocci, Patrizia %A Eiriksdottir, Gudny %A Crane, Paul K %A Pasquier, Florence %A Boccardi, Virginia %A Henández, Isabel %A Barber, Robert C %A Scherer, Martin %A Tarraga, Lluis %A Adams, Perrie M %A Leber, Markus %A Chen, Yuning %A Albert, Marilyn S %A Riedel-Heller, Steffi %A Emilsson, Valur %A Beekly, Duane %A Braae, Anne %A Schmidt, Reinhold %A Blacker, Deborah %A Masullo, Carlo %A Schmidt, Helena %A Doody, Rachelle S %A Spalletta, Gianfranco %A Longstreth, W T %A Fairchild, Thomas J %A Bossù, Paola %A Lopez, Oscar L %A Frosch, Matthew P %A Sacchinelli, Eleonora %A Ghetti, Bernardino %A Yang, Qiong %A Huebinger, Ryan M %A Jessen, Frank %A Li, Shuo %A Kamboh, M Ilyas %A Morris, John %A Sotolongo-Grau, Oscar %A Katz, Mindy J %A Corcoran, Chris %A Dunstan, Melanie %A Braddel, Amy %A Thomas, Charlene %A Meggy, Alun %A Marshall, Rachel %A Gerrish, Amy %A Chapman, Jade %A Aguilar, Miquel %A Taylor, Sarah %A Hill, Matt %A Fairén, Mònica Díez %A Hodges, Angela %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Daniilidou, Makrina %A Uphill, James %A Patel, Yogen %A Hughes, Joseph T %A Lord, Jenny %A Turton, James %A Hartmann, Annette M %A Cecchetti, Roberta %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Caltagirone, Carlo %A Orfei, Maria Donata %A Ciaramella, Antonio %A Pichler, Sabrina %A Mayhaus, Manuel %A Gu, Wei %A Lleo, Alberto %A Fortea, Juan %A Blesa, Rafael %A Barber, Imelda S %A Brookes, Keeley %A Cupidi, Chiara %A Maletta, Raffaele Giovanni %A Carrell, David %A Sorbi, Sandro %A Moebus, Susanne %A Urbano, Maria %A Pilotto, Alberto %A Kornhuber, Johannes %A Bosco, Paolo %A Todd, Stephen %A Craig, David %A Johnston, Janet %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Fox, Nick C %A Hardy, John %A Albin, Roger L %A Apostolova, Liana G %A Arnold, Steven E %A Asthana, Sanjay %A Atwood, Craig S %A Baldwin, Clinton T %A Barnes, Lisa L %A Barral, Sandra %A Beach, Thomas G %A Becker, James T %A Bigio, Eileen H %A Bird, Thomas D %A Boeve, Bradley F %A Bowen, James D %A Boxer, Adam %A Burke, James R %A Burns, Jeffrey M %A Buxbaum, Joseph D %A Cairns, Nigel J %A Cao, Chuanhai %A Carlson, Chris S %A Carlsson, Cynthia M %A Carney, Regina M %A Carrasquillo, Minerva M %A Carroll, Steven L %A Diaz, Carolina Ceballos %A Chui, Helena C %A Clark, David G %A Cribbs, David H %A Crocco, Elizabeth A %A DeCarli, Charles %A Dick, Malcolm %A Duara, Ranjan %A Evans, Denis A %A Faber, Kelley M %A Fallon, Kenneth B %A Fardo, David W %A Farlow, Martin R %A Ferris, Steven %A Foroud, Tatiana M %A Galasko, Douglas R %A Gearing, Marla %A Geschwind, Daniel H %A Gilbert, John R %A Graff-Radford, Neill R %A Green, Robert C %A Growdon, John H %A Hamilton, Ronald L %A Harrell, Lindy E %A Honig, Lawrence S %A Huentelman, Matthew J %A Hulette, Christine M %A Hyman, Bradley T %A Jarvik, Gail P %A Abner, Erin %A Jin, Lee-Way %A Jun, Gyungah %A Karydas, Anna %A Kaye, Jeffrey A %A Kim, Ronald %A Kowall, Neil W %A Kramer, Joel H %A LaFerla, Frank M %A Lah, James J %A Leverenz, James B %A Levey, Allan I %A Li, Ge %A Lieberman, Andrew P %A Lunetta, Kathryn L %A Lyketsos, Constantine G %A Marson, Daniel C %A Martiniuk, Frank %A Mash, Deborah C %A Masliah, Eliezer %A McCormick, Wayne C %A McCurry, Susan M %A McDavid, Andrew N %A McKee, Ann C %A Mesulam, Marsel %A Miller, Bruce L %A Miller, Carol A %A Miller, Joshua W %A Morris, John C %A Murrell, Jill R %A Myers, Amanda J %A O'Bryant, Sid %A Olichney, John M %A Pankratz, Vernon S %A Parisi, Joseph E %A Paulson, Henry L %A Perry, William %A Peskind, Elaine %A Pierce, Aimee %A Poon, Wayne W %A Potter, Huntington %A Quinn, Joseph F %A Raj, Ashok %A Raskind, Murray %A Reisberg, Barry %A Reitz, Christiane %A Ringman, John M %A Roberson, Erik D %A Rogaeva, Ekaterina %A Rosen, Howard J %A Rosenberg, Roger N %A Sager, Mark A %A Saykin, Andrew J %A Schneider, Julie A %A Schneider, Lon S %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tanzi, Rudolph E %A Thornton-Wells, Tricia A %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Garzia, Fabienne %A Golamaully, Feroze %A Septier, Gislain %A Engelborghs, Sebastien %A Vandenberghe, Rik %A De Deyn, Peter P %A Fernadez, Carmen Muñoz %A Benito, Yoland Aladro %A Thonberg, Hakan %A Forsell, Charlotte %A Lilius, Lena %A Kinhult-Stählbom, Anne %A Kilander, Lena %A Brundin, RoseMarie %A Concari, Letizia %A Helisalmi, Seppo %A Koivisto, Anne Maria %A Haapasalo, Annakaisa %A Dermecourt, Vincent %A Fiévet, Nathalie %A Hanon, Olivier %A Dufouil, Carole %A Brice, Alexis %A Ritchie, Karen %A Dubois, Bruno %A Himali, Jayanadra J %A Keene, C Dirk %A Tschanz, JoAnn %A Fitzpatrick, Annette L %A Kukull, Walter A %A Norton, Maria %A Aspelund, Thor %A Larson, Eric B %A Munger, Ron %A Rotter, Jerome I %A Lipton, Richard B %A Bullido, María J %A Hofman, Albert %A Montine, Thomas J %A Coto, Eliecer %A Boerwinkle, Eric %A Petersen, Ronald C %A Alvarez, Victoria %A Rivadeneira, Fernando %A Reiman, Eric M %A Gallo, Maura %A O'Donnell, Christopher J %A Reisch, Joan S %A Bruni, Amalia Cecilia %A Royall, Donald R %A Dichgans, Martin %A Sano, Mary %A Galimberti, Daniela %A St George-Hyslop, Peter %A Scarpini, Elio %A Tsuang, Debby W %A Mancuso, Michelangelo %A Bonuccelli, Ubaldo %A Winslow, Ashley R %A Daniele, Antonio %A Wu, Chuang-Kuo %A Peters, Oliver %A Nacmias, Benedetta %A Riemenschneider, Matthias %A Heun, Reinhard %A Brayne, Carol %A Rubinsztein, David C %A Bras, Jose %A Guerreiro, Rita %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Collinge, John %A Mann, David %A Tsolaki, Magda %A Clarimon, Jordi %A Sussams, Rebecca %A Lovestone, Simon %A O'Donovan, Michael C %A Owen, Michael J %A Behrens, Timothy W %A Mead, Simon %A Goate, Alison M %A Uitterlinden, André G %A Holmes, Clive %A Cruchaga, Carlos %A Ingelsson, Martin %A Bennett, David A %A Powell, John %A Golde, Todd E %A Graff, Caroline %A De Jager, Philip L %A Morgan, Kevin %A Ertekin-Taner, Nilufer %A Combarros, Onofre %A Psaty, Bruce M %A Passmore, Peter %A Younkin, Steven G %A Berr, Claudine %A Gudnason, Vilmundur %A Rujescu, Dan %A Dickson, Dennis W %A Dartigues, Jean-François %A DeStefano, Anita L %A Ortega-Cubero, Sara %A Hakonarson, Hakon %A Campion, Dominique %A Boada, Mercè %A Kauwe, John Keoni %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A Ikram, M Arfan %A Jones, Lesley %A Haines, Jonathan L %A Tzourio, Christophe %A Launer, Lenore J %A Escott-Price, Valentina %A Mayeux, Richard %A Deleuze, Jean-François %A Amin, Najaf %A Holmans, Peter A %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Wang, Li-San %A Lambert, Jean-Charles %A Seshadri, Sudha %A Williams, Julie %A Schellenberg, Gerard D %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Amino Acid Sequence %K Case-Control Studies %K Exome %K Gene Expression Profiling %K Gene Frequency %K Genetic Predisposition to Disease %K Genotype %K Humans %K Immunity, Innate %K Linkage Disequilibrium %K Membrane Glycoproteins %K Microglia %K Odds Ratio %K Phospholipase C gamma %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K Receptors, Immunologic %K Sequence Homology, Amino Acid %X

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10, odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10, OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10, OR = 1.67, MAF = 0.0143, MAF = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

%B Nat Genet %V 49 %P 1373-1384 %8 2017 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/28714976?dopt=Abstract %R 10.1038/ng.3916 %0 Journal Article %J Hum Mol Genet %D 2015 %T Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. %A Dong, Chengliang %A Wei, Peng %A Jian, Xueqiu %A Gibbs, Richard %A Boerwinkle, Eric %A Wang, Kai %A Liu, Xiaoming %K Computational Biology %K Exome %K Genome, Human %K Humans %K Polymorphism, Single Nucleotide %K Software %X

Accurate deleteriousness prediction for nonsynonymous variants is crucial for distinguishing pathogenic mutations from background polymorphisms in whole exome sequencing (WES) studies. Although many deleteriousness prediction methods have been developed, their prediction results are sometimes inconsistent with each other and their relative merits are still unclear in practical applications. To address these issues, we comprehensively evaluated the predictive performance of 18 current deleteriousness-scoring methods, including 11 function prediction scores (PolyPhen-2, SIFT, MutationTaster, Mutation Assessor, FATHMM, LRT, PANTHER, PhD-SNP, SNAP, SNPs&GO and MutPred), 3 conservation scores (GERP++, SiPhy and PhyloP) and 4 ensemble scores (CADD, PON-P, KGGSeq and CONDEL). We found that FATHMM and KGGSeq had the highest discriminative power among independent scores and ensemble scores, respectively. Moreover, to ensure unbiased performance evaluation of these prediction scores, we manually collected three distinct testing datasets, on which no current prediction scores were tuned. In addition, we developed two new ensemble scores that integrate nine independent scores and allele frequency. Our scores achieved the highest discriminative power compared with all the deleteriousness prediction scores tested and showed low false-positive prediction rate for benign yet rare nonsynonymous variants, which demonstrated the value of combining information from multiple orthologous approaches. Finally, to facilitate variant prioritization in WES studies, we have pre-computed our ensemble scores for 87 347 044 possible variants in the whole-exome and made them publicly available through the ANNOVAR software and the dbNSFP database.

%B Hum Mol Genet %V 24 %P 2125-37 %8 2015 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/25552646?dopt=Abstract %R 10.1093/hmg/ddu733 %0 Journal Article %J Hum Mutat %D 2013 %T dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. %A Liu, Xiaoming %A Jian, Xueqiu %A Boerwinkle, Eric %K Computational Biology %K Databases, Nucleic Acid %K Exome %K Gene Frequency %K Genome, Human %K Humans %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Software %X

dbNSFP is a database developed for functional prediction and annotation of all potential non-synonymous single-nucleotide variants (nsSNVs) in the human genome. This database significantly facilitates the process of querying predictions and annotations from different databases/web-servers for large amounts of nsSNVs discovered in exome-sequencing studies. Here we report a recent major update of the database to version 2.0. We have rebuilt the SNV collection based on GENCODE 9 and currently the database includes 87,347,043 nsSNVs and 2,270,742 essential splice site SNVs (an 18% increase compared to dbNSFP v1.0). For each nsSNV dbNSFP v2.0 has added two prediction scores (MutationAssessor and FATHMM) and two conservation scores (GERP++ and SiPhy). The original five prediction and conservation scores in v1.0 (SIFT, Polyphen2, LRT, MutationTaster and PhyloP) have been updated. Rich functional annotations for SNVs and genes have also been added into the new version, including allele frequencies observed in the 1000 Genomes Project phase 1 data and the NHLBI Exome Sequencing Project, various gene IDs from different databases, functional descriptions of genes, gene expression and gene interaction information, among others. dbNSFP v2.0 is freely available for download at http://sites.google.com/site/jpopgen/dbNSFP.

%B Hum Mutat %V 34 %P E2393-402 %8 2013 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/23843252?dopt=Abstract %R 10.1002/humu.22376 %0 Journal Article %J Hum Mutat %D 2011 %T dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. %A Liu, Xiaoming %A Jian, Xueqiu %A Eric Boerwinkle %K Algorithms %K Computational Biology %K Databases, Nucleic Acid %K Genetic Association Studies %K Humans %K Internet %K Polymorphism, Single Nucleotide %K Software %X

With the advance of sequencing technologies, whole exome sequencing has increasingly been used to identify mutations that cause human diseases, especially rare Mendelian diseases. Among the analysis steps, functional prediction (of being deleterious) plays an important role in filtering or prioritizing nonsynonymous SNP (NS) for further analysis. Unfortunately, different prediction algorithms use different information and each has its own strength and weakness. It has been suggested that investigators should use predictions from multiple algorithms instead of relying on a single one. However, querying predictions from different databases/Web-servers for different algorithms is both tedious and time consuming, especially when dealing with a huge number of NSs identified by exome sequencing. To facilitate the process, we developed dbNSFP (database for nonsynonymous SNPs' functional predictions). It compiles prediction scores from four new and popular algorithms (SIFT, Polyphen2, LRT, and MutationTaster), along with a conservation score (PhyloP) and other related information, for every potential NS in the human genome (a total of 75,931,005). It is the first integrated database of functional predictions from multiple algorithms for the comprehensive collection of human NSs. dbNSFP is freely available for download at http://sites.google.com/site/jpopgen/dbNSFP.

%B Hum Mutat %V 32 %P 894-9 %8 2011 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/21520341?dopt=Abstract %R 10.1002/humu.21517