%0 Journal Article %J PLoS One %D 2014 %T Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. %A Escott-Price, Valentina %A Bellenguez, Céline %A Wang, Li-San %A Choi, Seung-Hoan %A Harold, Denise %A Jones, Lesley %A Holmans, Peter %A Gerrish, Amy %A Vedernikov, Alexey %A Richards, Alexander %A DeStefano, Anita L %A Lambert, Jean-Charles %A Ibrahim-Verbaas, Carla A %A Naj, Adam C %A Sims, Rebecca %A Jun, Gyungah %A Bis, Joshua C %A Beecham, Gary W %A Grenier-Boley, Benjamin %A Russo, Giancarlo %A Thornton-Wells, Tricia A %A Denning, Nicola %A Smith, Albert V %A Chouraki, Vincent %A Thomas, Charlene %A Ikram, M Arfan %A Zelenika, Diana %A Vardarajan, Badri N %A Kamatani, Yoichiro %A Lin, Chiao-Feng %A Schmidt, Helena %A Kunkle, Brian %A Dunstan, Melanie L %A Vronskaya, Maria %A Johnson, Andrew D %A Ruiz, Agustin %A Bihoreau, Marie-Thérèse %A Reitz, Christiane %A Pasquier, Florence %A Hollingworth, Paul %A Hanon, Olivier %A Fitzpatrick, Annette L %A Buxbaum, Joseph D %A Campion, Dominique %A Crane, Paul K %A Baldwin, Clinton %A Becker, Tim %A Gudnason, Vilmundur %A Cruchaga, Carlos %A Craig, David %A Amin, Najaf %A Berr, Claudine %A Lopez, Oscar L %A De Jager, Philip L %A Deramecourt, Vincent %A Johnston, Janet A %A Evans, Denis %A Lovestone, Simon %A Letenneur, Luc %A Hernandez, Isabel %A Rubinsztein, David C %A Eiriksdottir, Gudny %A Sleegers, Kristel %A Goate, Alison M %A Fiévet, Nathalie %A Huentelman, Matthew J %A Gill, Michael %A Brown, Kristelle %A Kamboh, M Ilyas %A Keller, Lina %A Barberger-Gateau, Pascale %A McGuinness, Bernadette %A Larson, Eric B %A Myers, Amanda J %A Dufouil, Carole %A Todd, Stephen %A Wallon, David %A Love, Seth %A Rogaeva, Ekaterina %A Gallacher, John %A George-Hyslop, Peter St %A Clarimon, Jordi %A Lleo, Alberto %A Bayer, Anthony %A Tsuang, Debby W %A Yu, Lei %A Tsolaki, Magda %A Bossù, Paola %A Spalletta, Gianfranco %A Proitsi, Petra %A Collinge, John %A Sorbi, Sandro %A Garcia, Florentino Sanchez %A Fox, Nick C %A Hardy, John %A Naranjo, Maria Candida Deniz %A Bosco, Paolo %A Clarke, Robert %A Brayne, Carol %A Galimberti, Daniela %A Scarpini, Elio %A Bonuccelli, Ubaldo %A Mancuso, Michelangelo %A Siciliano, Gabriele %A Moebus, Susanne %A Mecocci, Patrizia %A Zompo, Maria Del %A Maier, Wolfgang %A Hampel, Harald %A Pilotto, Alberto %A Frank-García, Ana %A Panza, Francesco %A Solfrizzi, Vincenzo %A Caffarra, Paolo %A Nacmias, Benedetta %A Perry, William %A Mayhaus, Manuel %A Lannfelt, Lars %A Hakonarson, Hakon %A Pichler, Sabrina %A Carrasquillo, Minerva M %A Ingelsson, Martin %A Beekly, Duane %A Alvarez, Victoria %A Zou, Fanggeng %A Valladares, Otto %A Younkin, Steven G %A Coto, Eliecer %A Hamilton-Nelson, Kara L %A Gu, Wei %A Razquin, Cristina %A Pastor, Pau %A Mateo, Ignacio %A Owen, Michael J %A Faber, Kelley M %A Jonsson, Palmi V %A Combarros, Onofre %A O'Donovan, Michael C %A Cantwell, Laura B %A Soininen, Hilkka %A Blacker, Deborah %A Mead, Simon %A Mosley, Thomas H %A Bennett, David A %A Harris, Tamara B %A Fratiglioni, Laura %A Holmes, Clive %A de Bruijn, Renee F A G %A Passmore, Peter %A Montine, Thomas J %A Bettens, Karolien %A Rotter, Jerome I %A Brice, Alexis %A Morgan, Kevin %A Foroud, Tatiana M %A Kukull, Walter A %A Hannequin, Didier %A Powell, John F %A Nalls, Michael A %A Ritchie, Karen %A Lunetta, Kathryn L %A Kauwe, John S K %A Boerwinkle, Eric %A Riemenschneider, Matthias %A Boada, Merce %A Hiltunen, Mikko %A Martin, Eden R %A Schmidt, Reinhold %A Rujescu, Dan %A Dartigues, Jean-François %A Mayeux, Richard %A Tzourio, Christophe %A Hofman, Albert %A Nöthen, Markus M %A Graff, Caroline %A Psaty, Bruce M %A Haines, Jonathan L %A Lathrop, Mark %A Pericak-Vance, Margaret A %A Launer, Lenore J %A Van Broeckhoven, Christine %A Farrer, Lindsay A %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Seshadri, Sudha %A Schellenberg, Gerard D %A Amouyel, Philippe %A Williams, Julie %K Alzheimer Disease %K Carrier Proteins %K Case-Control Studies %K Genome-Wide Association Study %K Heat-Shock Proteins %K Humans %K Polymorphism, Single Nucleotide %K Receptors, Antigen, B-Cell %X

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

%B PLoS One %V 9 %P e94661 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract %R 10.1371/journal.pone.0094661 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Céline %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, André G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %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 Jr, W T Longstreth %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, Håkan %A Forsell, Charlotte %A Lilius, Lena %A Kinhult-Ståhlbom, 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, Merce %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-Francois %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 × 10-4) 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 × 10-8) 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 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 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 %R 10.1038/ng.3916 %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 Brain %D 2019 %T Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. %A Mishra, Aniket %A Chauhan, Ganesh %A Violleau, Marie-Helene %A Vojinovic, Dina %A Jian, Xueqiu %A Bis, Joshua C %A Li, Shuo %A Saba, Yasaman %A Grenier-Boley, Benjamin %A Yang, Qiong %A Bartz, Traci M %A Hofer, Edith %A Soumaré, Aïcha %A Peng, Fen %A Duperron, Marie-Gabrielle %A Foglio, Mario %A Mosley, Thomas H %A Schmidt, Reinhold %A Psaty, Bruce M %A Launer, Lenore J %A Boerwinkle, Eric %A Zhu, Yicheng %A Mazoyer, Bernard %A Lathrop, Mark %A Bellenguez, Céline %A van Duijn, Cornelia M %A Ikram, M Arfan %A Schmidt, Helena %A Longstreth, W T %A Fornage, Myriam %A Seshadri, Sudha %A Joutel, Anne %A Tzourio, Christophe %A Debette, Stephanie %X

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

%B Brain %8 2019 Mar 11 %G eng %R 10.1093/brain/awz024 %0 Journal Article %J Nat Genet %D 2019 %T Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. %A Kunkle, Brian W %A Grenier-Boley, Benjamin %A Sims, Rebecca %A Bis, Joshua C %A Damotte, Vincent %A Naj, Adam C %A Boland, Anne %A Vronskaya, Maria %A van der Lee, Sven J %A Amlie-Wolf, Alexandre %A Bellenguez, Céline %A Frizatti, Aura %A Chouraki, Vincent %A Martin, Eden R %A Sleegers, Kristel %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Hamilton-Nelson, Kara L %A Moreno-Grau, Sonia %A Olaso, Robert %A Raybould, Rachel %A Chen, Yuning %A Kuzma, Amanda B %A Hiltunen, Mikko %A Morgan, Taniesha %A Ahmad, Shahzad %A Vardarajan, Badri N %A Epelbaum, Jacques %A Hoffmann, Per %A Boada, Merce %A Beecham, Gary W %A Garnier, Jean-Guillaume %A Harold, Denise %A Fitzpatrick, Annette L %A Valladares, Otto %A Moutet, Marie-Laure %A Gerrish, Amy %A Smith, Albert V %A Qu, Liming %A Bacq, Delphine %A Denning, Nicola %A Jian, Xueqiu %A Zhao, Yi %A Del Zompo, Maria %A Fox, Nick C %A Choi, Seung-Hoan %A Mateo, Ignacio %A Hughes, Joseph T %A Adams, Hieab H %A Malamon, John %A Sanchez-Garcia, Florentino %A Patel, Yogen %A Brody, Jennifer A %A Dombroski, Beth A %A Naranjo, Maria Candida Deniz %A Daniilidou, Makrina %A Eiriksdottir, Gudny %A Mukherjee, Shubhabrata %A Wallon, David %A Uphill, James %A Aspelund, Thor %A Cantwell, Laura B %A Garzia, Fabienne %A Galimberti, Daniela %A Hofer, Edith %A Butkiewicz, Mariusz %A Fin, Bertrand %A Scarpini, Elio %A Sarnowski, Chloe %A Bush, Will S %A Meslage, Stéphane %A Kornhuber, Johannes %A White, Charles C %A Song, Yuenjoo %A Barber, Robert C %A Engelborghs, Sebastiaan %A Sordon, Sabrina %A Voijnovic, Dina %A Adams, Perrie M %A Vandenberghe, Rik %A Mayhaus, Manuel %A Cupples, L Adrienne %A Albert, Marilyn S %A De Deyn, Peter P %A Gu, Wei %A Himali, Jayanadra J %A Beekly, Duane %A Squassina, Alessio %A Hartmann, Annette M %A Orellana, Adelina %A Blacker, Deborah %A Rodriguez-Rodriguez, Eloy %A Lovestone, Simon %A Garcia, Melissa E %A Doody, Rachelle S %A Munoz-Fernadez, Carmen %A Sussams, Rebecca %A Lin, Honghuang %A Fairchild, Thomas J %A Benito, Yolanda A %A Holmes, Clive %A Karamujić-Čomić, Hata %A Frosch, Matthew P %A Thonberg, Håkan %A Maier, Wolfgang %A Roschupkin, Gena %A Ghetti, Bernardino %A Giedraitis, Vilmantas %A Kawalia, Amit %A Li, Shuo %A Huebinger, Ryan M %A Kilander, Lena %A Moebus, Susanne %A Hernandez, Isabel %A Kamboh, M Ilyas %A Brundin, RoseMarie %A Turton, James %A Yang, Qiong %A Katz, Mindy J %A Concari, Letizia %A Lord, Jenny %A Beiser, Alexa S %A Keene, C Dirk %A Helisalmi, Seppo %A Kloszewska, Iwona %A Kukull, Walter A %A Koivisto, Anne Maria %A Lynch, Aoibhinn %A Tarraga, Lluis %A Larson, Eric B %A Haapasalo, Annakaisa %A Lawlor, Brian %A Mosley, Thomas H %A Lipton, Richard B %A Solfrizzi, Vincenzo %A Gill, Michael %A Longstreth, W T %A Montine, Thomas J %A Frisardi, Vincenza %A Diez-Fairen, Monica %A Rivadeneira, Fernando %A Petersen, Ronald C %A Deramecourt, Vincent %A Alvarez, Ignacio %A Salani, Francesca %A Ciaramella, Antonio %A Boerwinkle, Eric %A Reiman, Eric M %A Fiévet, Nathalie %A Rotter, Jerome I %A Reisch, Joan S %A Hanon, Olivier %A Cupidi, Chiara %A Andre Uitterlinden, A G %A Royall, Donald R %A Dufouil, Carole %A Maletta, Raffaele Giovanni %A de Rojas, Itziar %A Sano, Mary %A Brice, Alexis %A Cecchetti, Roberta %A George-Hyslop, Peter St %A Ritchie, Karen %A Tsolaki, Magda %A Tsuang, Debby W %A Dubois, Bruno %A Craig, David %A Wu, Chuang-Kuo %A Soininen, Hilkka %A Avramidou, Despoina %A Albin, Roger L %A Fratiglioni, Laura %A Germanou, Antonia %A Apostolova, Liana G %A Keller, Lina %A Koutroumani, Maria %A Arnold, Steven E %A Panza, Francesco %A Gkatzima, Olymbia %A Asthana, Sanjay %A Hannequin, Didier %A Whitehead, Patrice %A Atwood, Craig S %A Caffarra, Paolo %A Hampel, Harald %A Quintela, Inés %A Carracedo, Angel %A Lannfelt, Lars %A Rubinsztein, David C %A Barnes, Lisa L %A Pasquier, Florence %A Frölich, Lutz %A Barral, Sandra %A McGuinness, Bernadette %A Beach, Thomas G %A Johnston, Janet A %A Becker, James T %A Passmore, Peter %A Bigio, Eileen H %A Schott, Jonathan M %A Bird, Thomas D %A Warren, Jason D %A Boeve, Bradley F %A Lupton, Michelle K %A Bowen, James D %A Proitsi, Petra %A Boxer, Adam %A Powell, John F %A Burke, James R %A Kauwe, John S K %A Burns, Jeffrey M %A Mancuso, Michelangelo %A Buxbaum, Joseph D %A Bonuccelli, Ubaldo %A Cairns, Nigel J %A McQuillin, Andrew %A Cao, Chuanhai %A Livingston, Gill %A Carlson, Chris S %A Bass, Nicholas J %A Carlsson, Cynthia M %A Hardy, John %A Carney, Regina M %A Bras, Jose %A Carrasquillo, Minerva M %A Guerreiro, Rita %A Allen, Mariet %A Chui, Helena C %A Fisher, Elizabeth %A Masullo, Carlo %A Crocco, Elizabeth A %A DeCarli, Charles %A Bisceglio, Gina %A Dick, Malcolm %A Ma, Li %A Duara, Ranjan %A Graff-Radford, Neill R %A Evans, Denis A %A Hodges, Angela %A Faber, Kelley M %A Scherer, Martin %A Fallon, Kenneth B %A Riemenschneider, Matthias %A Fardo, David W %A Heun, Reinhard %A Farlow, Martin R %A Kölsch, Heike %A Ferris, Steven %A Leber, Markus %A Foroud, Tatiana M %A Heuser, Isabella %A Galasko, Douglas R %A Giegling, Ina %A Gearing, Marla %A Hüll, Michael %A Geschwind, Daniel H %A Gilbert, John R %A Morris, John %A Green, Robert C %A Mayo, Kevin %A Growdon, John H %A Feulner, Thomas %A Hamilton, Ronald L %A Harrell, Lindy E %A Drichel, Dmitriy %A Honig, Lawrence S %A Cushion, Thomas D %A Huentelman, Matthew J %A Hollingworth, Paul %A Hulette, Christine M %A Hyman, Bradley T %A Marshall, Rachel %A Jarvik, Gail P %A Meggy, Alun %A Abner, Erin %A Menzies, Georgina E %A Jin, Lee-Way %A Leonenko, Ganna %A Real, Luis M %A Jun, Gyungah R %A Baldwin, Clinton T %A Grozeva, Detelina %A Karydas, Anna %A Russo, Giancarlo %A Kaye, Jeffrey A %A Kim, Ronald %A Jessen, Frank %A Kowall, Neil W %A Vellas, Bruno %A Kramer, Joel H %A Vardy, Emma %A LaFerla, Frank M %A Jöckel, Karl-Heinz %A Lah, James J %A Dichgans, Martin %A Leverenz, James B %A Mann, David %A Levey, Allan I %A Pickering-Brown, Stuart %A Lieberman, Andrew P %A Klopp, Norman %A Lunetta, Kathryn L %A Wichmann, H-Erich %A Lyketsos, Constantine G %A Morgan, Kevin %A Marson, Daniel C %A Brown, Kristelle %A Martiniuk, Frank %A Medway, Christopher %A Mash, Deborah C %A Nöthen, Markus M %A Masliah, Eliezer %A Hooper, Nigel M %A McCormick, Wayne C %A Daniele, Antonio %A McCurry, Susan M %A Bayer, Anthony %A McDavid, Andrew N %A Gallacher, John %A McKee, Ann C %A van den Bussche, Hendrik %A Mesulam, Marsel %A Brayne, Carol %A Miller, Bruce L %A Riedel-Heller, Steffi %A Miller, Carol A %A Miller, Joshua W %A Al-Chalabi, Ammar %A Morris, John C %A Shaw, Christopher E %A Myers, Amanda J %A Wiltfang, Jens %A O'Bryant, Sid %A Olichney, John M %A Alvarez, Victoria %A Parisi, Joseph E %A Singleton, Andrew B %A Paulson, Henry L %A Collinge, John %A Perry, William R %A Mead, Simon %A Peskind, Elaine %A Cribbs, David H %A Rossor, Martin %A Pierce, Aimee %A Ryan, Natalie S %A Poon, Wayne W %A Nacmias, Benedetta %A Potter, Huntington %A Sorbi, Sandro %A Quinn, Joseph F %A Sacchinelli, Eleonora %A Raj, Ashok %A Spalletta, Gianfranco %A Raskind, Murray %A Caltagirone, Carlo %A Bossù, Paola %A Orfei, Maria Donata %A Reisberg, Barry %A Clarke, Robert %A Reitz, Christiane %A Smith, A David %A Ringman, John M %A Warden, Donald %A Roberson, Erik D %A Wilcock, Gordon %A Rogaeva, Ekaterina %A Bruni, Amalia Cecilia %A Rosen, Howard J %A Gallo, Maura %A Rosenberg, Roger N %A Ben-Shlomo, Yoav %A Sager, Mark A %A Mecocci, Patrizia %A Saykin, Andrew J %A Pastor, Pau %A Cuccaro, Michael L %A Vance, Jeffery M %A Schneider, Julie A %A Schneider, Lori S %A Slifer, Susan %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tang, Mitchell %A Tanzi, Rudolph E %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 Saba, Yasaman %A Pilotto, Alberto %A Bullido, María J %A Peters, Oliver %A Crane, Paul K %A Bennett, David %A Bosco, Paola %A Coto, Eliecer %A Boccardi, Virginia %A De Jager, Phil L %A Lleo, Alberto %A Warner, Nick %A Lopez, Oscar L %A Ingelsson, Martin %A Deloukas, Panagiotis %A Cruchaga, Carlos %A Graff, Caroline %A Gwilliam, Rhian %A Fornage, Myriam %A Goate, Alison M %A Sánchez-Juan, Pascual %A Kehoe, Patrick G %A Amin, Najaf %A Ertekin-Taner, Nilifur %A Berr, Claudine %A Debette, Stephanie %A Love, Seth %A Launer, Lenore J %A Younkin, Steven G %A Dartigues, Jean-François %A Corcoran, Chris %A Ikram, M Arfan %A Dickson, Dennis W %A Nicolas, Gaël %A Campion, Dominique %A Tschanz, JoAnn %A Schmidt, Helena %A Hakonarson, Hakon %A Clarimon, Jordi %A Munger, Ron %A Schmidt, Reinhold %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A C O'Donovan, Michael %A DeStefano, Anita L %A Jones, Lesley %A Haines, Jonathan L %A Deleuze, Jean-Francois %A Owen, Michael J %A Gudnason, Vilmundur %A Mayeux, Richard %A Escott-Price, Valentina %A Psaty, Bruce M %A Ramirez, Alfredo %A Wang, Li-San %A Ruiz, Agustin %A van Duijn, Cornelia M %A Holmans, Peter A %A Seshadri, Sudha %A Williams, Julie %A Amouyel, Phillippe %A Schellenberg, Gerard D %A Lambert, Jean-Charles %A Pericak-Vance, Margaret A %X

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

%B Nat Genet %V 51 %P 414-430 %8 2019 Mar %G eng %N 3 %R 10.1038/s41588-019-0358-2 %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