TY - JOUR T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. JF - Nat Commun Y1 - 2015 A1 - Wessel, Jennifer A1 - Chu, Audrey Y A1 - Willems, Sara M A1 - Wang, Shuai A1 - Yaghootkar, Hanieh A1 - Brody, Jennifer A A1 - Dauriz, Marco A1 - Hivert, Marie-France A1 - Raghavan, Sridharan A1 - Lipovich, Leonard A1 - Hidalgo, Bertha A1 - Fox, Keolu A1 - Huffman, Jennifer E A1 - An, Ping A1 - Lu, Yingchang A1 - Rasmussen-Torvik, Laura J A1 - Grarup, Niels A1 - Ehm, Margaret G A1 - Li, Li A1 - Baldridge, Abigail S A1 - Stančáková, Alena A1 - Abrol, Ravinder A1 - Besse, Céline A1 - Boland, Anne A1 - Bork-Jensen, Jette A1 - Fornage, Myriam A1 - Freitag, Daniel F A1 - Garcia, Melissa E A1 - Guo, Xiuqing A1 - Hara, Kazuo A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Lange, Leslie A A1 - Layton, Jill C A1 - Li, Man A1 - Hua Zhao, Jing A1 - Meidtner, Karina A1 - Morrison, Alanna C A1 - Nalls, Mike A A1 - Peters, Marjolein J A1 - Sabater-Lleal, Maria A1 - Schurmann, Claudia A1 - Silveira, Angela A1 - Smith, Albert V A1 - Southam, Lorraine A1 - Stoiber, Marcus H A1 - Strawbridge, Rona J A1 - Taylor, Kent D A1 - Varga, Tibor V A1 - Allin, Kristine H A1 - Amin, Najaf A1 - Aponte, Jennifer L A1 - Aung, Tin A1 - Barbieri, Caterina A1 - Bihlmeyer, Nathan A A1 - Boehnke, Michael A1 - Bombieri, Cristina A1 - Bowden, Donald W A1 - Burns, Sean M A1 - Chen, Yuning A1 - Chen, Yii-DerI A1 - Cheng, Ching-Yu A1 - Correa, Adolfo A1 - Czajkowski, Jacek A1 - Dehghan, Abbas A1 - Ehret, Georg B A1 - Eiriksdottir, Gudny A1 - Escher, Stefan A A1 - Farmaki, Aliki-Eleni A1 - Frånberg, Mattias A1 - Gambaro, Giovanni A1 - Giulianini, Franco A1 - Goddard, William A A1 - Goel, Anuj A1 - Gottesman, Omri A1 - Grove, Megan L A1 - Gustafsson, Stefan A1 - Hai, Yang A1 - Hallmans, Göran A1 - Heo, Jiyoung A1 - Hoffmann, Per A1 - Ikram, Mohammad K A1 - Jensen, Richard A A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Karaleftheri, Maria A1 - Khor, Chiea C A1 - Kirkpatrick, Andrea A1 - Kraja, Aldi T A1 - Kuusisto, Johanna A1 - Lange, Ethan M A1 - Lee, I T A1 - Lee, Wen-Jane A1 - Leong, Aaron A1 - Liao, Jiemin A1 - Liu, Chunyu A1 - Liu, Yongmei A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Malerba, Giovanni A1 - Mamakou, Vasiliki A1 - Marouli, Eirini A1 - Maruthur, Nisa M A1 - Matchan, Angela A1 - McKean-Cowdin, Roberta A1 - McLeod, Olga A1 - Metcalf, Ginger A A1 - Mohlke, Karen L A1 - Muzny, Donna M A1 - Ntalla, Ioanna A1 - Palmer, Nicholette D A1 - Pasko, Dorota A1 - Peter, Andreas A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rice, Ken A1 - Sala, Cinzia F A1 - Sennblad, Bengt A1 - Serafetinidis, Ioannis A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Speliotes, Elizabeth K A1 - Stahl, Eli A A1 - Stirrups, Kathleen A1 - Tentolouris, Nikos A1 - Thanopoulou, Anastasia A1 - Torres, Mina A1 - Traglia, Michela A1 - Tsafantakis, Emmanouil A1 - Javad, Sundas A1 - Yanek, Lisa R A1 - Zengini, Eleni A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Brown, James B A1 - Cupples, L Adrienne A1 - Hansen, Torben A1 - Ingelsson, Erik A1 - Karter, Andrew J A1 - Lorenzo, Carlos A1 - Mathias, Rasika A A1 - Norris, Jill M A1 - Peloso, Gina M A1 - Sheu, Wayne H-H A1 - Toniolo, Daniela A1 - Vaidya, Dhananjay A1 - Varma, Rohit A1 - Wagenknecht, Lynne E A1 - Boeing, Heiner A1 - Bottinger, Erwin P A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Ferrannini, Ele A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Gibbs, Richard A A1 - Gudnason, Vilmundur A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Jansson, Jan-Håkan A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Padmanabhan, Sandosh A1 - Pankow, James S A1 - Polasek, Ozren A1 - Province, Michael A A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rudan, Igor A1 - Schulze, Matthias B A1 - Smith, Blair H A1 - Uitterlinden, André G A1 - Walker, Mark A1 - Watkins, Hugh A1 - Wong, Tien Y A1 - Zeggini, Eleftheria A1 - Laakso, Markku A1 - Borecki, Ingrid B A1 - Chasman, Daniel I A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Tai, E Shyong A1 - van Duijn, Cornelia M A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Boerwinkle, Eric A1 - Kao, W H Linda A1 - Florez, Jose C A1 - Loos, Ruth J F A1 - Wilson, James G A1 - Frayling, Timothy M A1 - Siscovick, David S A1 - Dupuis, Josée A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Scott, Robert A A1 - Goodarzi, Mark O KW - African Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Exome KW - Fasting KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glucagon-Like Peptide-1 Receptor KW - Glucose-6-Phosphatase KW - Humans KW - Insulin KW - Mutation Rate KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide AB -

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract ER - TY - JOUR T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. JF - Nat Genet Y1 - 2017 A1 - Sims, Rebecca A1 - van der Lee, Sven J A1 - Naj, Adam C A1 - Bellenguez, Céline A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Kunkle, Brian W A1 - Boland, Anne A1 - Raybould, Rachel A1 - Bis, Joshua C A1 - Martin, Eden R A1 - Grenier-Boley, Benjamin A1 - Heilmann-Heimbach, Stefanie A1 - Chouraki, Vincent A1 - Kuzma, Amanda B A1 - Sleegers, Kristel A1 - Vronskaya, Maria A1 - Ruiz, Agustin A1 - Graham, Robert R A1 - Olaso, Robert A1 - Hoffmann, Per A1 - Grove, Megan L A1 - Vardarajan, Badri N A1 - Hiltunen, Mikko A1 - Nöthen, Markus M A1 - White, Charles C A1 - Hamilton-Nelson, Kara L A1 - Epelbaum, Jacques A1 - Maier, Wolfgang A1 - Choi, Seung-Hoan A1 - Beecham, Gary W A1 - Dulary, Cécile A1 - Herms, Stefan A1 - Smith, Albert V A1 - Funk, Cory C A1 - Derbois, Céline A1 - Forstner, Andreas J A1 - Ahmad, Shahzad A1 - Li, Hongdong A1 - Bacq, Delphine A1 - Harold, Denise A1 - Satizabal, Claudia L A1 - Valladares, Otto A1 - Squassina, Alessio A1 - Thomas, Rhodri A1 - Brody, Jennifer A A1 - Qu, Liming A1 - Sánchez-Juan, Pascual A1 - Morgan, Taniesha A1 - Wolters, Frank J A1 - Zhao, Yi A1 - Garcia, Florentino Sanchez A1 - Denning, Nicola A1 - Fornage, Myriam A1 - Malamon, John A1 - Naranjo, Maria Candida Deniz A1 - Majounie, Elisa A1 - Mosley, Thomas H A1 - Dombroski, Beth A1 - Wallon, David A1 - Lupton, Michelle K A1 - Dupuis, Josée A1 - Whitehead, Patrice A1 - Fratiglioni, Laura A1 - Medway, Christopher A1 - Jian, Xueqiu A1 - Mukherjee, Shubhabrata A1 - Keller, Lina A1 - Brown, Kristelle A1 - Lin, Honghuang A1 - Cantwell, Laura B A1 - Panza, Francesco A1 - McGuinness, Bernadette A1 - Moreno-Grau, Sonia A1 - Burgess, Jeremy D A1 - Solfrizzi, Vincenzo A1 - Proitsi, Petra A1 - Adams, Hieab H A1 - Allen, Mariet A1 - Seripa, Davide A1 - Pastor, Pau A1 - Cupples, L Adrienne A1 - Price, Nathan D A1 - Hannequin, Didier A1 - Frank-García, Ana A1 - Levy, Daniel A1 - Chakrabarty, Paramita A1 - Caffarra, Paolo A1 - Giegling, Ina A1 - Beiser, Alexa S A1 - Giedraitis, Vilmantas A1 - Hampel, Harald A1 - Garcia, Melissa E A1 - Wang, Xue A1 - Lannfelt, Lars A1 - Mecocci, Patrizia A1 - Eiriksdottir, Gudny A1 - Crane, Paul K A1 - Pasquier, Florence A1 - Boccardi, Virginia A1 - Henández, Isabel A1 - Barber, Robert C A1 - Scherer, Martin A1 - Tarraga, Lluis A1 - Adams, Perrie M A1 - Leber, Markus A1 - Chen, Yuning A1 - Albert, Marilyn S A1 - Riedel-Heller, Steffi A1 - Emilsson, Valur A1 - Beekly, Duane A1 - Braae, Anne A1 - Schmidt, Reinhold A1 - Blacker, Deborah A1 - Masullo, Carlo A1 - Schmidt, Helena A1 - Doody, Rachelle S A1 - Spalletta, Gianfranco A1 - Jr, W T Longstreth A1 - Fairchild, Thomas J A1 - Bossù, Paola A1 - Lopez, Oscar L A1 - Frosch, Matthew P A1 - Sacchinelli, Eleonora A1 - Ghetti, Bernardino A1 - Yang, Qiong A1 - Huebinger, Ryan M A1 - Jessen, Frank A1 - Li, Shuo A1 - Kamboh, M Ilyas A1 - Morris, John A1 - Sotolongo-Grau, Oscar A1 - Katz, Mindy J A1 - Corcoran, Chris A1 - Dunstan, Melanie A1 - Braddel, Amy A1 - Thomas, Charlene A1 - Meggy, Alun A1 - Marshall, Rachel A1 - Gerrish, Amy A1 - Chapman, Jade A1 - Aguilar, Miquel A1 - Taylor, Sarah A1 - Hill, Matt A1 - Fairén, Mònica Díez A1 - Hodges, Angela A1 - Vellas, Bruno A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Daniilidou, Makrina A1 - Uphill, James A1 - Patel, Yogen A1 - Hughes, Joseph T A1 - Lord, Jenny A1 - Turton, James A1 - Hartmann, Annette M A1 - Cecchetti, Roberta A1 - Fenoglio, Chiara A1 - Serpente, Maria A1 - Arcaro, Marina A1 - Caltagirone, Carlo A1 - Orfei, Maria Donata A1 - Ciaramella, Antonio A1 - Pichler, Sabrina A1 - Mayhaus, Manuel A1 - Gu, Wei A1 - Lleo, Alberto A1 - Fortea, Juan A1 - Blesa, Rafael A1 - Barber, Imelda S A1 - Brookes, Keeley A1 - Cupidi, Chiara A1 - Maletta, Raffaele Giovanni A1 - Carrell, David A1 - Sorbi, Sandro A1 - Moebus, Susanne A1 - Urbano, Maria A1 - Pilotto, Alberto A1 - Kornhuber, Johannes A1 - Bosco, Paolo A1 - Todd, Stephen A1 - Craig, David A1 - Johnston, Janet A1 - Gill, Michael A1 - Lawlor, Brian A1 - Lynch, Aoibhinn A1 - Fox, Nick C A1 - Hardy, John A1 - Albin, Roger L A1 - Apostolova, Liana G A1 - Arnold, Steven E A1 - Asthana, Sanjay A1 - Atwood, Craig S A1 - Baldwin, Clinton T A1 - Barnes, Lisa L A1 - Barral, Sandra A1 - Beach, Thomas G A1 - Becker, James T A1 - Bigio, Eileen H A1 - Bird, Thomas D A1 - Boeve, Bradley F A1 - Bowen, James D A1 - Boxer, Adam A1 - Burke, James R A1 - Burns, Jeffrey M A1 - Buxbaum, Joseph D A1 - Cairns, Nigel J A1 - Cao, Chuanhai A1 - Carlson, Chris S A1 - Carlsson, Cynthia M A1 - Carney, Regina M A1 - Carrasquillo, Minerva M A1 - Carroll, Steven L A1 - Diaz, Carolina Ceballos A1 - Chui, Helena C A1 - Clark, David G A1 - Cribbs, David H A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Dick, Malcolm A1 - Duara, Ranjan A1 - Evans, Denis A A1 - Faber, Kelley M A1 - Fallon, Kenneth B A1 - Fardo, David W A1 - Farlow, Martin R A1 - Ferris, Steven A1 - Foroud, Tatiana M A1 - Galasko, Douglas R A1 - Gearing, Marla A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Graff-Radford, Neill R A1 - Green, Robert C A1 - Growdon, John H A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Honig, Lawrence S A1 - Huentelman, Matthew J A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Jarvik, Gail P A1 - Abner, Erin A1 - Jin, Lee-Way A1 - Jun, Gyungah A1 - Karydas, Anna A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Kowall, Neil W A1 - Kramer, Joel H A1 - LaFerla, Frank M A1 - Lah, James J A1 - Leverenz, James B A1 - Levey, Allan I A1 - Li, Ge A1 - Lieberman, Andrew P A1 - Lunetta, Kathryn L A1 - Lyketsos, Constantine G A1 - Marson, Daniel C A1 - Martiniuk, Frank A1 - Mash, Deborah C A1 - Masliah, Eliezer A1 - McCormick, Wayne C A1 - McCurry, Susan M A1 - McDavid, Andrew N A1 - McKee, Ann C A1 - Mesulam, Marsel A1 - Miller, Bruce L A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Morris, John C A1 - Murrell, Jill R A1 - Myers, Amanda J A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Pankratz, Vernon S A1 - Parisi, Joseph E A1 - Paulson, Henry L A1 - Perry, William A1 - Peskind, Elaine A1 - Pierce, Aimee A1 - Poon, Wayne W A1 - Potter, Huntington A1 - Quinn, Joseph F A1 - Raj, Ashok A1 - Raskind, Murray A1 - Reisberg, Barry A1 - Reitz, Christiane A1 - Ringman, John M A1 - Roberson, Erik D A1 - Rogaeva, Ekaterina A1 - Rosen, Howard J A1 - Rosenberg, Roger N A1 - Sager, Mark A A1 - Saykin, Andrew J A1 - Schneider, Julie A A1 - Schneider, Lon S A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tanzi, Rudolph E A1 - Thornton-Wells, Tricia A A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Garzia, Fabienne A1 - Golamaully, Feroze A1 - Septier, Gislain A1 - Engelborghs, Sebastien A1 - Vandenberghe, Rik A1 - De Deyn, Peter P A1 - Fernadez, Carmen Muñoz A1 - Benito, Yoland Aladro A1 - Thonberg, Håkan A1 - Forsell, Charlotte A1 - Lilius, Lena A1 - Kinhult-Ståhlbom, Anne A1 - Kilander, Lena A1 - Brundin, RoseMarie A1 - Concari, Letizia A1 - Helisalmi, Seppo A1 - Koivisto, Anne Maria A1 - Haapasalo, Annakaisa A1 - Dermecourt, Vincent A1 - Fiévet, Nathalie A1 - Hanon, Olivier A1 - Dufouil, Carole A1 - Brice, Alexis A1 - Ritchie, Karen A1 - Dubois, Bruno A1 - Himali, Jayanadra J A1 - Keene, C Dirk A1 - Tschanz, JoAnn A1 - Fitzpatrick, Annette L A1 - Kukull, Walter A A1 - Norton, Maria A1 - Aspelund, Thor A1 - Larson, Eric B A1 - Munger, Ron A1 - Rotter, Jerome I A1 - Lipton, Richard B A1 - Bullido, María J A1 - Hofman, Albert A1 - Montine, Thomas J A1 - Coto, Eliecer A1 - Boerwinkle, Eric A1 - Petersen, Ronald C A1 - Alvarez, Victoria A1 - Rivadeneira, Fernando A1 - Reiman, Eric M A1 - Gallo, Maura A1 - O'Donnell, Christopher J A1 - Reisch, Joan S A1 - Bruni, Amalia Cecilia A1 - Royall, Donald R A1 - Dichgans, Martin A1 - Sano, Mary A1 - Galimberti, Daniela A1 - St George-Hyslop, Peter A1 - Scarpini, Elio A1 - Tsuang, Debby W A1 - Mancuso, Michelangelo A1 - Bonuccelli, Ubaldo A1 - Winslow, Ashley R A1 - Daniele, Antonio A1 - Wu, Chuang-Kuo A1 - Peters, Oliver A1 - Nacmias, Benedetta A1 - Riemenschneider, Matthias A1 - Heun, Reinhard A1 - Brayne, Carol A1 - Rubinsztein, David C A1 - Bras, Jose A1 - Guerreiro, Rita A1 - Al-Chalabi, Ammar A1 - Shaw, Christopher E A1 - Collinge, John A1 - Mann, David A1 - Tsolaki, Magda A1 - Clarimon, Jordi A1 - Sussams, Rebecca A1 - Lovestone, Simon A1 - O'Donovan, Michael C A1 - Owen, Michael J A1 - Behrens, Timothy W A1 - Mead, Simon A1 - Goate, Alison M A1 - Uitterlinden, André G A1 - Holmes, Clive A1 - Cruchaga, Carlos A1 - Ingelsson, Martin A1 - Bennett, David A A1 - Powell, John A1 - Golde, Todd E A1 - Graff, Caroline A1 - De Jager, Philip L A1 - Morgan, Kevin A1 - Ertekin-Taner, Nilufer A1 - Combarros, Onofre A1 - Psaty, Bruce M A1 - Passmore, Peter A1 - Younkin, Steven G A1 - Berr, Claudine A1 - Gudnason, Vilmundur A1 - Rujescu, Dan A1 - Dickson, Dennis W A1 - Dartigues, Jean-François A1 - DeStefano, Anita L A1 - Ortega-Cubero, Sara A1 - Hakonarson, Hakon A1 - Campion, Dominique A1 - Boada, Merce A1 - Kauwe, John Keoni A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - Ikram, M Arfan A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Tzourio, Christophe A1 - Launer, Lenore J A1 - Escott-Price, Valentina A1 - Mayeux, Richard A1 - Deleuze, Jean-Francois A1 - Amin, Najaf A1 - Holmans, Peter A A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Lambert, Jean-Charles A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Schellenberg, Gerard D KW - Adaptor Proteins, Signal Transducing KW - Alzheimer Disease KW - Amino Acid Sequence KW - Case-Control Studies KW - Exome KW - Gene Expression Profiling KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Immunity, Innate KW - Linkage Disequilibrium KW - Membrane Glycoproteins KW - Microglia KW - Odds Ratio KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Protein Interaction Maps KW - Receptors, Immunologic KW - Sequence Homology, Amino Acid AB -

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.

VL - 49 IS - 9 ER - TY - JOUR T1 - Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. JF - Nat Genet Y1 - 2019 A1 - Kunkle, Brian W A1 - Grenier-Boley, Benjamin A1 - Sims, Rebecca A1 - Bis, Joshua C A1 - Damotte, Vincent A1 - Naj, Adam C A1 - Boland, Anne A1 - Vronskaya, Maria A1 - van der Lee, Sven J A1 - Amlie-Wolf, Alexandre A1 - Bellenguez, Céline A1 - Frizatti, Aura A1 - Chouraki, Vincent A1 - Martin, Eden R A1 - Sleegers, Kristel A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Hamilton-Nelson, Kara L A1 - Moreno-Grau, Sonia A1 - Olaso, Robert A1 - Raybould, Rachel A1 - Chen, Yuning A1 - Kuzma, Amanda B A1 - Hiltunen, Mikko A1 - Morgan, Taniesha A1 - Ahmad, Shahzad A1 - Vardarajan, Badri N A1 - Epelbaum, Jacques A1 - Hoffmann, Per A1 - Boada, Merce A1 - Beecham, Gary W A1 - Garnier, Jean-Guillaume A1 - Harold, Denise A1 - Fitzpatrick, Annette L A1 - Valladares, Otto A1 - Moutet, Marie-Laure A1 - Gerrish, Amy A1 - Smith, Albert V A1 - Qu, Liming A1 - Bacq, Delphine A1 - Denning, Nicola A1 - Jian, Xueqiu A1 - Zhao, Yi A1 - Del Zompo, Maria A1 - Fox, Nick C A1 - Choi, Seung-Hoan A1 - Mateo, Ignacio A1 - Hughes, Joseph T A1 - Adams, Hieab H A1 - Malamon, John A1 - Sanchez-Garcia, Florentino A1 - Patel, Yogen A1 - Brody, Jennifer A A1 - Dombroski, Beth A A1 - Naranjo, Maria Candida Deniz A1 - Daniilidou, Makrina A1 - Eiriksdottir, Gudny A1 - Mukherjee, Shubhabrata A1 - Wallon, David A1 - Uphill, James A1 - Aspelund, Thor A1 - Cantwell, Laura B A1 - Garzia, Fabienne A1 - Galimberti, Daniela A1 - Hofer, Edith A1 - Butkiewicz, Mariusz A1 - Fin, Bertrand A1 - Scarpini, Elio A1 - Sarnowski, Chloe A1 - Bush, Will S A1 - Meslage, Stéphane A1 - Kornhuber, Johannes A1 - White, Charles C A1 - Song, Yuenjoo A1 - Barber, Robert C A1 - Engelborghs, Sebastiaan A1 - Sordon, Sabrina A1 - Voijnovic, Dina A1 - Adams, Perrie M A1 - Vandenberghe, Rik A1 - Mayhaus, Manuel A1 - Cupples, L Adrienne A1 - Albert, Marilyn S A1 - De Deyn, Peter P A1 - Gu, Wei A1 - Himali, Jayanadra J A1 - Beekly, Duane A1 - Squassina, Alessio A1 - Hartmann, Annette M A1 - Orellana, Adelina A1 - Blacker, Deborah A1 - Rodriguez-Rodriguez, Eloy A1 - Lovestone, Simon A1 - Garcia, Melissa E A1 - Doody, Rachelle S A1 - Munoz-Fernadez, Carmen A1 - Sussams, Rebecca A1 - Lin, Honghuang A1 - Fairchild, Thomas J A1 - Benito, Yolanda A A1 - Holmes, Clive A1 - Karamujić-Čomić, Hata A1 - Frosch, Matthew P A1 - Thonberg, Håkan A1 - Maier, Wolfgang A1 - Roschupkin, Gena A1 - Ghetti, Bernardino A1 - Giedraitis, Vilmantas A1 - Kawalia, Amit A1 - Li, Shuo A1 - Huebinger, Ryan M A1 - Kilander, Lena A1 - Moebus, Susanne A1 - Hernandez, Isabel A1 - Kamboh, M Ilyas A1 - Brundin, RoseMarie A1 - Turton, James A1 - Yang, Qiong A1 - Katz, Mindy J A1 - Concari, Letizia A1 - Lord, Jenny A1 - Beiser, Alexa S A1 - Keene, C Dirk A1 - Helisalmi, Seppo A1 - Kloszewska, Iwona A1 - Kukull, Walter A A1 - Koivisto, Anne Maria A1 - Lynch, Aoibhinn A1 - Tarraga, Lluis A1 - Larson, Eric B A1 - Haapasalo, Annakaisa A1 - Lawlor, Brian A1 - Mosley, Thomas H A1 - Lipton, Richard B A1 - Solfrizzi, Vincenzo A1 - Gill, Michael A1 - Longstreth, W T A1 - Montine, Thomas J A1 - Frisardi, Vincenza A1 - Diez-Fairen, Monica A1 - Rivadeneira, Fernando A1 - Petersen, Ronald C A1 - Deramecourt, Vincent A1 - Alvarez, Ignacio A1 - Salani, Francesca A1 - Ciaramella, Antonio A1 - Boerwinkle, Eric A1 - Reiman, Eric M A1 - Fiévet, Nathalie A1 - Rotter, Jerome I A1 - Reisch, Joan S A1 - Hanon, Olivier A1 - Cupidi, Chiara A1 - Andre Uitterlinden, A G A1 - Royall, Donald R A1 - Dufouil, Carole A1 - Maletta, Raffaele Giovanni A1 - de Rojas, Itziar A1 - Sano, Mary A1 - Brice, Alexis A1 - Cecchetti, Roberta A1 - George-Hyslop, Peter St A1 - Ritchie, Karen A1 - Tsolaki, Magda A1 - Tsuang, Debby W A1 - Dubois, Bruno A1 - Craig, David A1 - Wu, Chuang-Kuo A1 - Soininen, Hilkka A1 - Avramidou, Despoina A1 - Albin, Roger L A1 - Fratiglioni, Laura A1 - Germanou, Antonia A1 - Apostolova, Liana G A1 - Keller, Lina A1 - Koutroumani, Maria A1 - Arnold, Steven E A1 - Panza, Francesco A1 - Gkatzima, Olymbia A1 - Asthana, Sanjay A1 - Hannequin, Didier A1 - Whitehead, Patrice A1 - Atwood, Craig S A1 - Caffarra, Paolo A1 - Hampel, Harald A1 - Quintela, Inés A1 - Carracedo, Angel A1 - Lannfelt, Lars A1 - Rubinsztein, David C A1 - Barnes, Lisa L A1 - Pasquier, Florence A1 - Frölich, Lutz A1 - Barral, Sandra A1 - McGuinness, Bernadette A1 - Beach, Thomas G A1 - Johnston, Janet A A1 - Becker, James T A1 - Passmore, Peter A1 - Bigio, Eileen H A1 - Schott, Jonathan M A1 - Bird, Thomas D A1 - Warren, Jason D A1 - Boeve, Bradley F A1 - Lupton, Michelle K A1 - Bowen, James D A1 - Proitsi, Petra A1 - Boxer, Adam A1 - Powell, John F A1 - Burke, James R A1 - Kauwe, John S K A1 - Burns, Jeffrey M A1 - Mancuso, Michelangelo A1 - Buxbaum, Joseph D A1 - Bonuccelli, Ubaldo A1 - Cairns, Nigel J A1 - McQuillin, Andrew A1 - Cao, Chuanhai A1 - Livingston, Gill A1 - Carlson, Chris S A1 - Bass, Nicholas J A1 - Carlsson, Cynthia M A1 - Hardy, John A1 - Carney, Regina M A1 - Bras, Jose A1 - Carrasquillo, Minerva M A1 - Guerreiro, Rita A1 - Allen, Mariet A1 - Chui, Helena C A1 - Fisher, Elizabeth A1 - Masullo, Carlo A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Bisceglio, Gina A1 - Dick, Malcolm A1 - Ma, Li A1 - Duara, Ranjan A1 - Graff-Radford, Neill R A1 - Evans, Denis A A1 - Hodges, Angela A1 - Faber, Kelley M A1 - Scherer, Martin A1 - Fallon, Kenneth B A1 - Riemenschneider, Matthias A1 - Fardo, David W A1 - Heun, Reinhard A1 - Farlow, Martin R A1 - Kölsch, Heike A1 - Ferris, Steven A1 - Leber, Markus A1 - Foroud, Tatiana M A1 - Heuser, Isabella A1 - Galasko, Douglas R A1 - Giegling, Ina A1 - Gearing, Marla A1 - Hüll, Michael A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Morris, John A1 - Green, Robert C A1 - Mayo, Kevin A1 - Growdon, John H A1 - Feulner, Thomas A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Drichel, Dmitriy A1 - Honig, Lawrence S A1 - Cushion, Thomas D A1 - Huentelman, Matthew J A1 - Hollingworth, Paul A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Marshall, Rachel A1 - Jarvik, Gail P A1 - Meggy, Alun A1 - Abner, Erin A1 - Menzies, Georgina E A1 - Jin, Lee-Way A1 - Leonenko, Ganna A1 - Real, Luis M A1 - Jun, Gyungah R A1 - Baldwin, Clinton T A1 - Grozeva, Detelina A1 - Karydas, Anna A1 - Russo, Giancarlo A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Jessen, Frank A1 - Kowall, Neil W A1 - Vellas, Bruno A1 - Kramer, Joel H A1 - Vardy, Emma A1 - LaFerla, Frank M A1 - Jöckel, Karl-Heinz A1 - Lah, James J A1 - Dichgans, Martin A1 - Leverenz, James B A1 - Mann, David A1 - Levey, Allan I A1 - Pickering-Brown, Stuart A1 - Lieberman, Andrew P A1 - Klopp, Norman A1 - Lunetta, Kathryn L A1 - Wichmann, H-Erich A1 - Lyketsos, Constantine G A1 - Morgan, Kevin A1 - Marson, Daniel C A1 - Brown, Kristelle A1 - Martiniuk, Frank A1 - Medway, Christopher A1 - Mash, Deborah C A1 - Nöthen, Markus M A1 - Masliah, Eliezer A1 - Hooper, Nigel M A1 - McCormick, Wayne C A1 - Daniele, Antonio A1 - McCurry, Susan M A1 - Bayer, Anthony A1 - McDavid, Andrew N A1 - Gallacher, John A1 - McKee, Ann C A1 - van den Bussche, Hendrik A1 - Mesulam, Marsel A1 - Brayne, Carol A1 - Miller, Bruce L A1 - Riedel-Heller, Steffi A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Al-Chalabi, Ammar A1 - Morris, John C A1 - Shaw, Christopher E A1 - Myers, Amanda J A1 - Wiltfang, Jens A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Alvarez, Victoria A1 - Parisi, Joseph E A1 - Singleton, Andrew B A1 - Paulson, Henry L A1 - Collinge, John A1 - Perry, William R A1 - Mead, Simon A1 - Peskind, Elaine A1 - Cribbs, David H A1 - Rossor, Martin A1 - Pierce, Aimee A1 - Ryan, Natalie S A1 - Poon, Wayne W A1 - Nacmias, Benedetta A1 - Potter, Huntington A1 - Sorbi, Sandro A1 - Quinn, Joseph F A1 - Sacchinelli, Eleonora A1 - Raj, Ashok A1 - Spalletta, Gianfranco A1 - Raskind, Murray A1 - Caltagirone, Carlo A1 - Bossù, Paola A1 - Orfei, Maria Donata A1 - Reisberg, Barry A1 - Clarke, Robert A1 - Reitz, Christiane A1 - Smith, A David A1 - Ringman, John M A1 - Warden, Donald A1 - Roberson, Erik D A1 - Wilcock, Gordon A1 - Rogaeva, Ekaterina A1 - Bruni, Amalia Cecilia A1 - Rosen, Howard J A1 - Gallo, Maura A1 - Rosenberg, Roger N A1 - Ben-Shlomo, Yoav A1 - Sager, Mark A A1 - Mecocci, Patrizia A1 - Saykin, Andrew J A1 - Pastor, Pau A1 - Cuccaro, Michael L A1 - Vance, Jeffery M A1 - Schneider, Julie A A1 - Schneider, Lori S A1 - Slifer, Susan A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tang, Mitchell A1 - Tanzi, Rudolph E A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Saba, Yasaman A1 - Pilotto, Alberto A1 - Bullido, María J A1 - Peters, Oliver A1 - Crane, Paul K A1 - Bennett, David A1 - Bosco, Paola A1 - Coto, Eliecer A1 - Boccardi, Virginia A1 - De Jager, Phil L A1 - Lleo, Alberto A1 - Warner, Nick A1 - Lopez, Oscar L A1 - Ingelsson, Martin A1 - Deloukas, Panagiotis A1 - Cruchaga, Carlos A1 - Graff, Caroline A1 - Gwilliam, Rhian A1 - Fornage, Myriam A1 - Goate, Alison M A1 - Sánchez-Juan, Pascual A1 - Kehoe, Patrick G A1 - Amin, Najaf A1 - Ertekin-Taner, Nilifur A1 - Berr, Claudine A1 - Debette, Stephanie A1 - Love, Seth A1 - Launer, Lenore J A1 - Younkin, Steven G A1 - Dartigues, Jean-François A1 - Corcoran, Chris A1 - Ikram, M Arfan A1 - Dickson, Dennis W A1 - Nicolas, Gaël A1 - Campion, Dominique A1 - Tschanz, JoAnn A1 - Schmidt, Helena A1 - Hakonarson, Hakon A1 - Clarimon, Jordi A1 - Munger, Ron A1 - Schmidt, Reinhold A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - C O'Donovan, Michael A1 - DeStefano, Anita L A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Deleuze, Jean-Francois A1 - Owen, Michael J A1 - Gudnason, Vilmundur A1 - Mayeux, Richard A1 - Escott-Price, Valentina A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Ruiz, Agustin A1 - van Duijn, Cornelia M A1 - Holmans, Peter A A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Amouyel, Phillippe A1 - Schellenberg, Gerard D A1 - Lambert, Jean-Charles A1 - Pericak-Vance, Margaret A AB -

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.

VL - 51 IS - 3 ER - TY - JOUR T1 - Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. JF - Circulation Y1 - 2022 A1 - Thibord, Florian A1 - Klarin, Derek A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Levin, Michael G A1 - Chasman, Daniel I A1 - Goode, Ellen L A1 - Hveem, Kristian A1 - Teder-Laving, Maris A1 - Martinez-Perez, Angel A1 - Aïssi, Dylan A1 - Daian-Bacq, Delphine A1 - Ito, Kaoru A1 - Natarajan, Pradeep A1 - Lutsey, Pamela L A1 - Nadkarni, Girish N A1 - de Vries, Paul S A1 - Cuellar-Partida, Gabriel A1 - Wolford, Brooke N A1 - Pattee, Jack W A1 - Kooperberg, Charles A1 - Braekkan, Sigrid K A1 - Li-Gao, Ruifang A1 - Saut, Noémie A1 - Sept, Corriene A1 - Germain, Marine A1 - Judy, Renae L A1 - Wiggins, Kerri L A1 - Ko, Darae A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Giulianini, Franco A1 - de Andrade, Mariza A1 - Nøst, Therese H A1 - Boland, Anne A1 - Empana, Jean-Philippe A1 - Koyama, Satoshi A1 - Gilliland, Thomas A1 - Do, Ron A1 - Huffman, Jennifer E A1 - Wang, Xin A1 - Zhou, Wei A1 - Manuel Soria, Jose A1 - Carlos Souto, Juan A1 - Pankratz, Nathan A1 - Haessler, Jeffery A1 - Hindberg, Kristian A1 - Rosendaal, Frits R A1 - Turman, Constance A1 - Olaso, Robert A1 - Kember, Rachel L A1 - Bartz, Traci M A1 - Lynch, Julie A A1 - Heckbert, Susan R A1 - Armasu, Sebastian M A1 - Brumpton, Ben A1 - Smadja, David M A1 - Jouven, Xavier A1 - Komuro, Issei A1 - Clapham, Katharine R A1 - Loos, Ruth J F A1 - Willer, Cristen J A1 - Sabater-Lleal, Maria A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Morelli, Vania M A1 - Ridker, Paul M A1 - Vlieg, Astrid van Hylckama A1 - Deleuze, Jean-Francois A1 - Kraft, Peter A1 - Rader, Daniel J A1 - Min Lee, Kyung A1 - Psaty, Bruce M A1 - Heidi Skogholt, Anne A1 - Emmerich, Joseph A1 - Suchon, Pierre A1 - Rich, Stephen S A1 - Vy, Ha My T A1 - Tang, Weihong A1 - Jackson, Rebecca D A1 - Hansen, John-Bjarne A1 - Morange, Pierre-Emmanuel A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Damrauer, Scott M A1 - Johnson, Andrew D A1 - Smith, Nicholas L KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Thrombosis KW - Venous Thromboembolism AB -

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

VL - 146 IS - 16 ER - TY - JOUR T1 - New insights into the genetic etiology of Alzheimer's disease and related dementias. JF - Nat Genet Y1 - 2022 A1 - Bellenguez, Céline A1 - Küçükali, Fahri A1 - Jansen, Iris E A1 - Kleineidam, Luca A1 - Moreno-Grau, Sonia A1 - Amin, Najaf A1 - Naj, Adam C A1 - Campos-Martin, Rafael A1 - Grenier-Boley, Benjamin A1 - Andrade, Victor A1 - Holmans, Peter A A1 - Boland, Anne A1 - Damotte, Vincent A1 - van der Lee, Sven J A1 - Costa, Marcos R A1 - Kuulasmaa, Teemu A1 - Yang, Qiong A1 - de Rojas, Itziar A1 - Bis, Joshua C A1 - Yaqub, Amber A1 - Prokic, Ivana A1 - Chapuis, Julien A1 - Ahmad, Shahzad A1 - Giedraitis, Vilmantas A1 - Aarsland, Dag A1 - Garcia-Gonzalez, Pablo A1 - Abdelnour, Carla A1 - Alarcón-Martín, Emilio A1 - Alcolea, Daniel A1 - Alegret, Montserrat A1 - Alvarez, Ignacio A1 - Alvarez, Victoria A1 - Armstrong, Nicola J A1 - Tsolaki, Anthoula A1 - Antunez, Carmen A1 - Appollonio, Ildebrando A1 - Arcaro, Marina A1 - Archetti, Silvana A1 - Pastor, Alfonso Arias A1 - Arosio, Beatrice A1 - Athanasiu, Lavinia A1 - Bailly, Henri A1 - Banaj, Nerisa A1 - Baquero, Miquel A1 - Barral, Sandra A1 - Beiser, Alexa A1 - Pastor, Ana Belén A1 - Below, Jennifer E A1 - Benchek, Penelope A1 - Benussi, Luisa A1 - Berr, Claudine A1 - Besse, Céline A1 - Bessi, Valentina A1 - Binetti, Giuliano A1 - Bizarro, Alessandra A1 - Blesa, Rafael A1 - Boada, Merce A1 - Boerwinkle, Eric A1 - Borroni, Barbara A1 - Boschi, Silvia A1 - Bossù, Paola A1 - Bråthen, Geir A1 - Bressler, Jan A1 - Bresner, Catherine A1 - Brodaty, Henry A1 - Brookes, Keeley J A1 - Brusco, Luis Ignacio A1 - Buiza-Rueda, Dolores A1 - Bûrger, Katharina A1 - Burholt, Vanessa A1 - Bush, William S A1 - Calero, Miguel A1 - Cantwell, Laura B A1 - Chene, Geneviève A1 - Chung, Jaeyoon A1 - Cuccaro, Michael L A1 - Carracedo, Angel A1 - Cecchetti, Roberta A1 - Cervera-Carles, Laura A1 - Charbonnier, Camille A1 - Chen, Hung-Hsin A1 - Chillotti, Caterina A1 - Ciccone, Simona A1 - Claassen, Jurgen A H R A1 - Clark, Christopher A1 - Conti, Elisa A1 - Corma-Gómez, Anaïs A1 - Costantini, Emanuele A1 - Custodero, Carlo A1 - Daian, Delphine A1 - Dalmasso, Maria Carolina A1 - Daniele, Antonio A1 - Dardiotis, Efthimios A1 - Dartigues, Jean-François A1 - de Deyn, Peter Paul A1 - de Paiva Lopes, Katia A1 - de Witte, Lot D A1 - Debette, Stephanie A1 - Deckert, Jürgen A1 - Del Ser, Teodoro A1 - Denning, Nicola A1 - DeStefano, Anita A1 - Dichgans, Martin A1 - Diehl-Schmid, Janine A1 - Diez-Fairen, Monica A1 - Rossi, Paolo Dionigi A1 - Djurovic, Srdjan A1 - Duron, Emmanuelle A1 - Düzel, Emrah A1 - Dufouil, Carole A1 - Eiriksdottir, Gudny A1 - Engelborghs, Sebastiaan A1 - Escott-Price, Valentina A1 - Espinosa, Ana A1 - Ewers, Michael A1 - Faber, Kelley M A1 - Fabrizio, Tagliavini A1 - Nielsen, Sune Fallgaard A1 - Fardo, David W A1 - Farotti, Lucia A1 - Fenoglio, Chiara A1 - Fernández-Fuertes, Marta A1 - Ferrari, Raffaele A1 - Ferreira, Catarina B A1 - Ferri, Evelyn A1 - Fin, Bertrand A1 - Fischer, Peter A1 - Fladby, Tormod A1 - Fließbach, Klaus A1 - Fongang, Bernard A1 - Fornage, Myriam A1 - Fortea, Juan A1 - Foroud, Tatiana M A1 - Fostinelli, Silvia A1 - Fox, Nick C A1 - Franco-Macías, Emlio A1 - Bullido, María J A1 - Frank-García, Ana A1 - Froelich, Lutz A1 - Fulton-Howard, Brian A1 - Galimberti, Daniela A1 - García-Alberca, Jose Maria A1 - Garcia-Gonzalez, Pablo A1 - Garcia-Madrona, Sebastian A1 - Garcia-Ribas, Guillermo A1 - Ghidoni, Roberta A1 - Giegling, Ina A1 - Giorgio, Giaccone A1 - Goate, Alison M A1 - Goldhardt, Oliver A1 - Gomez-Fonseca, Duber A1 - González-Perez, Antonio A1 - Graff, Caroline A1 - Grande, Giulia A1 - Green, Emma A1 - Grimmer, Timo A1 - Grünblatt, Edna A1 - Grunin, Michelle A1 - Gudnason, Vilmundur A1 - Guetta-Baranes, Tamar A1 - Haapasalo, Annakaisa A1 - Hadjigeorgiou, Georgios A1 - Haines, Jonathan L A1 - Hamilton-Nelson, Kara L A1 - Hampel, Harald A1 - Hanon, Olivier A1 - Hardy, John A1 - Hartmann, Annette M A1 - Hausner, Lucrezia A1 - Harwood, Janet A1 - Heilmann-Heimbach, Stefanie A1 - Helisalmi, Seppo A1 - Heneka, Michael T A1 - Hernandez, Isabel A1 - Herrmann, Martin J A1 - Hoffmann, Per A1 - Holmes, Clive A1 - 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Masullo, Carlo A1 - Mayeux, Richard A1 - Mead, Simon A1 - Mecocci, Patrizia A1 - Medina, Miguel A1 - Meggy, Alun A1 - Mehrabian, Shima A1 - Mendoza, Silvia A1 - Menéndez-González, Manuel A1 - Mir, Pablo A1 - Moebus, Susanne A1 - Mol, Merel A1 - Molina-Porcel, Laura A1 - Montrreal, Laura A1 - Morelli, Laura A1 - Moreno, Fermin A1 - Morgan, Kevin A1 - Mosley, Thomas A1 - Nöthen, Markus M A1 - Muchnik, Carolina A1 - Mukherjee, Shubhabrata A1 - Nacmias, Benedetta A1 - Ngandu, Tiia A1 - Nicolas, Gaël A1 - Nordestgaard, Børge G A1 - Olaso, Robert A1 - Orellana, Adelina A1 - Orsini, Michela A1 - Ortega, Gemma A1 - Padovani, Alessandro A1 - Paolo, Caffarra A1 - Papenberg, Goran A1 - Parnetti, Lucilla A1 - Pasquier, Florence A1 - Pastor, Pau A1 - Peloso, Gina A1 - Pérez-Cordón, Alba A1 - Pérez-Tur, Jordi A1 - Pericard, Pierre A1 - Peters, Oliver A1 - Pijnenburg, Yolande A L A1 - Pineda, Juan A A1 - Piñol-Ripoll, Gerard A1 - Pisanu, Claudia A1 - Polak, Thomas A1 - Popp, Julius A1 - Posthuma, Danielle A1 - Priller, Josef A1 - Puerta, Raquel A1 - Quenez, Olivier A1 - Quintela, Inés A1 - Thomassen, Jesper Qvist A1 - Rábano, Alberto A1 - Rainero, Innocenzo A1 - Rajabli, Farid A1 - Ramakers, Inez A1 - Real, Luis M A1 - Reinders, Marcel J T A1 - Reitz, Christiane A1 - Reyes-Dumeyer, Dolly A1 - Ridge, Perry A1 - Riedel-Heller, Steffi A1 - Riederer, Peter A1 - Roberto, Natalia A1 - Rodriguez-Rodriguez, Eloy A1 - Rongve, Arvid A1 - Allende, Irene Rosas A1 - Rosende-Roca, Maitée A1 - Royo, Jose Luis A1 - Rubino, Elisa A1 - Rujescu, Dan A1 - Sáez, María Eugenia A1 - Sakka, Paraskevi A1 - Saltvedt, Ingvild A1 - Sanabria, Ángela A1 - Sánchez-Arjona, María Bernal A1 - Sanchez-Garcia, Florentino A1 - Juan, Pascual Sánchez A1 - Sánchez-Valle, Raquel A1 - Sando, Sigrid B A1 - Sarnowski, Chloe A1 - Satizabal, Claudia L A1 - Scamosci, Michela A1 - Scarmeas, Nikolaos A1 - Scarpini, Elio A1 - Scheltens, Philip A1 - Scherbaum, Norbert A1 - Scherer, Martin A1 - Schmid, Matthias A1 - Schneider, Anja A1 - Schott, Jonathan M A1 - Selbæk, Geir A1 - Seripa, Davide A1 - Serrano, Manuel A1 - Sha, Jin A1 - Shadrin, Alexey A A1 - Skrobot, Olivia A1 - Slifer, Susan A1 - Snijders, Gijsje J L A1 - Soininen, Hilkka A1 - Solfrizzi, Vincenzo A1 - Solomon, Alina A1 - Song, Yeunjoo A1 - Sorbi, Sandro A1 - Sotolongo-Grau, Oscar A1 - Spalletta, Gianfranco A1 - Spottke, Annika A1 - Squassina, Alessio A1 - Stordal, Eystein A1 - Tartan, Juan Pablo A1 - Tarraga, Lluis A1 - Tesí, Niccolo A1 - Thalamuthu, Anbupalam A1 - Thomas, Tegos A1 - Tosto, Giuseppe A1 - Traykov, Latchezar A1 - Tremolizzo, Lucio A1 - Tybjærg-Hansen, Anne A1 - Uitterlinden, Andre A1 - Ullgren, Abbe A1 - Ulstein, Ingun A1 - Valero, Sergi A1 - Valladares, Otto A1 - Broeckhoven, Christine Van A1 - Vance, Jeffery A1 - Vardarajan, Badri N A1 - van der Lugt, Aad A1 - Dongen, Jasper Van A1 - van Rooij, Jeroen A1 - van Swieten, John A1 - Vandenberghe, Rik A1 - Verhey, Frans A1 - Vidal, Jean-Sébastien A1 - Vogelgsang, Jonathan A1 - Vyhnalek, Martin A1 - Wagner, Michael A1 - Wallon, David A1 - Wang, Li-San A1 - Wang, Ruiqi A1 - Weinhold, Leonie A1 - Wiltfang, Jens A1 - Windle, Gill A1 - Woods, Bob A1 - Yannakoulia, Mary A1 - Zare, Habil A1 - Zhao, Yi A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Zulaica, Miren A1 - Farrer, Lindsay A A1 - Psaty, Bruce M A1 - Ghanbari, Mohsen A1 - Raj, Towfique A1 - Sachdev, Perminder A1 - Mather, Karen A1 - Jessen, Frank A1 - Ikram, M Arfan A1 - de Mendonça, Alexandre A1 - Hort, Jakub A1 - Tsolaki, Magda A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - Williams, Julie A1 - Frikke-Schmidt, Ruth A1 - Clarimon, Jordi A1 - Deleuze, Jean-Francois A1 - Rossi, Giacomina A1 - Seshadri, Sudha A1 - Andreassen, Ole A A1 - Ingelsson, Martin A1 - Hiltunen, Mikko A1 - Sleegers, Kristel A1 - Schellenberg, Gerard D A1 - van Duijn, Cornelia M A1 - Sims, Rebecca A1 - van der Flier, Wiesje M A1 - Ruiz, Agustin A1 - Ramirez, Alfredo A1 - Lambert, Jean-Charles KW - Alzheimer Disease KW - Cognitive Dysfunction KW - Genome-Wide Association Study KW - Humans KW - tau Proteins AB -

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.

VL - 54 IS - 4 ER -