<p>To better characterize the genetic architecture underlying Alzheimer’s disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than <i>APOE</i> was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of &gt;4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.</p>

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Consensus meta-analysis of genome-wide association studies for Alzheimer’s disease and related dementias

  • Céline Bellenguez,
  • Atahualpa Castillo Morales,
  • Najaf Amin,
  • Sven J. van der Lee,
  • Manon Muntaner,
  • Kayenat Parveen,
  • Fahri Küçükali,
  • Benjamin Grenier-Boley,
  • Sami Heikkinen,
  • Itziar de Rojas,
  • Maria Carolina Dalmasso,
  • Luca Kleineidam,
  • Oliver Peters,
  • Anja Schneider,
  • Martin Dichgans,
  • Dan Rujescu,
  • Norbert Scherbaum,
  • Jürgen Deckert,
  • Steffi Riedel-Heller,
  • Lucrezia Hausner,
  • Laura Molina-Porcel,
  • Emrah Düzel,
  • Timo Grimmer,
  • Jens Wiltfang,
  • Stefanie Heilmann-Heimbach,
  • Susanne Moebus,
  • Matthias Schmid,
  • Thomas Tegos,
  • Nikolaos Scarmeas,
  • Oriol Dols-Icardo,
  • Fermin Moreno,
  • Jordi Pérez-Tur,
  • María J. Bullido,
  • Pau Pastor,
  • Raquel Sánchez-Valle,
  • Victoria Álvarez,
  • Mercè Boada,
  • Pablo García-González,
  • Raquel Puerta,
  • Pablo Mir,
  • Luis M. Real,
  • Gerard Piñol-Ripoll,
  • Jose María García-Alberca,
  • Eloy Rodriguez-Rodriguez,
  • Hilkka Soininen,
  • Alexandre de Mendonça,
  • Shima Mehrabian,
  • Jakub Hort,
  • Martin Vyhnalek,
  • Nicolai Sandau,
  • Jiao Luo,
  • Jesper Qvist Thomassen,
  • Yolande A. L. Pijnenburg,
  • Wiesje van der Flier,
  • Harro Seelaar,
  • Inez Ramakers,
  • Janne Papma,
  • Marc Hulsman,
  • Gert-Jan Biessels,
  • Caroline Graff,
  • Hakan Thonberg,
  • Abbe Ullgren,
  • Goran Papenberg,
  • Vilmantas Giedraitis,
  • Malin Löwenmark,
  • Lena Kilander,
  • Julie Williams,
  • Peter Holmans,
  • Julie Le Borgne,
  • Sagnik Palmal,
  • Aude Nicolas,
  • Philippe Amouyel,
  • Anne Boland,
  • Jean-François Deleuze,
  • Gael Nicolas,
  • Carole Dufouil,
  • Florence Pasquier,
  • Olivier Hanon,
  • Stéphanie Debette,
  • Edna Grünblatt,
  • Julius Popp,
  • Daniela Galimberti,
  • Beatrice Arosio,
  • Patrizia Mecocci,
  • Vincenzo Solfrizzi,
  • Lucilla Parnetti,
  • Alessio Squassina,
  • Lucio Tremolizzo,
  • Barbara Borroni,
  • Michael Wagner,
  • Benedetta Nacmias,
  • Marco Spallazzi,
  • Davide Seripa,
  • Innocenzo Rainero,
  • Antonio Daniele,
  • Paola Bossù,
  • Carlo Masullo,
  • Giacomina Rossi,
  • Frank Jessen,
  • Henne Holstege,
  • Karen Mather,
  • M. Victoria Fernandez,
  • Patrick G. Kehoe,
  • Magda Tsolaki,
  • Cornelia van Duijn,
  • Ruth Frikke-Schmidt,
  • Roberta Ghidoni,
  • Pascual Sánchez-Juan,
  • Kristel Sleegers,
  • Martin Ingelsson,
  • Mikko Hiltunen,
  • Rebecca Sims,
  • Ole Andreassen,
  • Agustín Ruiz,
  • Alfredo Ramirez,
  • Jean-Charles Lambert,
  • Adam C. Naj,
  • Farid Rajabli,
  • Penelope Benchek,
  • Lincoln M. P. Shade,
  • Qi Qiao,
  • Nicholas Kushch,
  • Jin Sha,
  • Katrina Bazemore,
  • Congcong Zhu,
  • Wan-Ping Lee,
  • Jacob Haut,
  • Kara L. Hamilton-Nelson,
  • Nicholas R. Wheeler,
  • Yi Zhao,
  • John J. Farrell,
  • Michelle A. Grunin,
  • Yuk Yee Leung,
  • Pavel P. Kuksa,
  • Donghe Li,
  • Eder Lucio da Fonseca,
  • Jesse B. Mez,
  • Ellen L. Palmer,
  • Jagan Pillai,
  • Richard M. Sherva,
  • Yeunjoo E. Song,
  • Xiaoling Zhang,
  • Takeshi Ikeuchi,
  • Taha Iqbal,
  • Otto Valladares,
  • Dolly Reyes-Dumeyer,
  • Amanda B. Kuzma,
  • Erin Abner,
  • Larry D. Adams,
  • Alyssa Aguirre,
  • Marilyn S. Albert,
  • Roger L. Albin,
  • Mariet Allen,
  • Liana G. Apostolova,
  • Steven E. Arnold,
  • Sanjay Asthana,
  • Craig S. Atwood,
  • Sanford Auerbach,
  • Clinton T. Baldwin,
  • Robert C. Barber,
  • Lisa L. Barnes,
  • Sandra Barral,
  • Thomas G. Beach,
  • James T. Becker,
  • Gary W. Beecham,
  • Duane Beekly,
  • David A. Bennett,
  • John Bertelson,
  • Thomas D. Bird,
  • Deborah Blacker,
  • Bradley F. Boeve,
  • James D. Bowen,
  • Adam Boxer,
  • James Brewer,
  • Jeffrey M. Burns,
  • Joseph D. Buxbaum,
  • Nigel J. Cairns,
  • Laura B. Cantwell,
  • Chuanhai Cao,
  • Christopher S. Carlson,
  • Cynthia M. Carlsson,
  • Regina M. Carney,
  • Minerva M. Carrasquillo,
  • Marie-Francoise Chesselet,
  • Nathaniel A. Chin,
  • Helena C. Chui,
  • Jaeyoon Chung,
  • Steven A. Claas,
  • Suzanne Craft,
  • Paul K. Crane,
  • David H. Cribbs,
  • Elizabeth A. Crocco,
  • Carlos Cruchaga,
  • Michael L. Cuccaro,
  • Munro Cullum,
  • Eveleen Darby,
  • Barbara Davis,
  • Philip L. De Jager,
  • Charles DeCarli,
  • John DeToledo,
  • Malcolm Dick,
  • Dennis W. Dickson,
  • Beth A. Dombroski,
  • Rachelle S. Doody,
  • Ranjan Duara,
  • Logan C. Dumitrescu,
  • Nilüfer Ertekin-Taner,
  • Denis A. Evans,
  • Kelley M. Faber,
  • Thomas J. Fairchild,
  • Kenneth B. Fallon,
  • Martin R. Farlow,
  • Victoria Fernandez-Hernandez,
  • Robert P. Friedland,
  • Tatiana M. Foroud,
  • Matthew P. Frosch,
  • Brian Fulton-Howard,
  • Douglas R. Galasko,
  • Marla Gearing,
  • Daniel H. Geschwind,
  • Bernardino Ghetti,
  • John R. Gilbert,
  • Rodney C. P. Go,
  • Alison M. Goate,
  • Thomas J. Grabowski,
  • Neill R. Graff-Radford,
  • Nora E. Gray,
  • John H. Growdon,
  • Hakon Hakonarson,
  • James Hall,
  • Ronald L. Hamilton,
  • Oscar Harari,
  • John Hardy,
  • Elizabeth Head,
  • Victor W. Henderson,
  • Michelle Hernandez,
  • Timothy J. Hohman,
  • Lawrence S. Honig,
  • Ryan M. Huebinger,
  • Matthew J. Huentelman,
  • Bradley T. Hyman,
  • Linda S. Hynan,
  • Laura Ibanez,
  • Gail P. Jarvik,
  • Suman Jayadev,
  • Lee-Way Jin,
  • Kim Johnson,
  • Leigh Johnson,
  • M. Ilyas Kamboh,
  • Yuriko Katsumata,
  • Mindy J. Katz,
  • John S. Kauwe,
  • Jeffrey A. Kaye,
  • C. Dirk Keene,
  • Aisha Khaleeq,
  • Masataka Kikuchi,
  • Janice Knebl,
  • Neil W. Kowall,
  • Joel H. Kramer,
  • Walter A. Kukull,
  • Frank M. LaFerla,
  • James J. Lah,
  • Eric B. Larson,
  • Alan Lerner,
  • James B. Leverenz,
  • Allan I. Levey,
  • Andrew P. Lieberman,
  • Richard B. Lipton,
  • Mark Logue,
  • Oscar L. Lopez,
  • Kathryn L. Lunetta,
  • Constantine G. Lyketsos,
  • Douglas Mains,
  • Daniel C. Marson,
  • Eden R. R. Martin,
  • Frank Martiniuk,
  • Deborah C. Mash,
  • Eliezer Masliah,
  • Paul Massman,
  • Arjun Masurkar,
  • Wayne C. McCormick,
  • Susan M. McCurry,
  • Ann C. McKee,
  • Marsel Mesulam,
  • Bruce L. Miller,
  • Carol A. Miller,
  • Joshua W. Miller,
  • Thomas J. Montine,
  • Edwin S. Monuki,
  • John C. Morris,
  • Shubhabrata Mukherjee,
  • Amanda J. Myers,
  • Trung Nguyen,
  • Thomas Obisesan,
  • Sid O’Bryant,
  • John M. Olichney,
  • Raymond Palmer,
  • Joseph E. Parisi,
  • Henry L. Paulson,
  • Valory Pavlik,
  • David Paydarfar,
  • Victoria Perez,
  • Elaine Peskind,
  • Ronald C. Petersen,
  • Helen Petrovitch,
  • Marsha Polk,
  • Wayne W. Poon,
  • Huntington Potter,
  • Liming Qu,
  • Mary Quiceno,
  • Joseph F. Quinn,
  • Ashok Raj,
  • Murray Raskind,
  • Eric M. Reiman,
  • Barry Reisberg,
  • Joan S. Reisch,
  • John M. Ringman,
  • Erik D. Roberson,
  • Monica Rodriguear,
  • Ekaterina Rogaeva,
  • Howard J. Rosen,
  • Roger N. Rosenberg,
  • Donald R. Royall,
  • Marwan Sabbagh,
  • A. Dessa Sadovnick,
  • Mark A. Sager,
  • Mary Sano,
  • Andrew J. Saykin,
  • Julie A. Schneider,
  • Lon S. Schneider,
  • William W. Seeley,
  • Susan H. Slifer,
  • Scott Small,
  • Amanda G. Smith,
  • Joshua A. Sonnen,
  • Peter St George-Hyslop,
  • Takiyah D. Starks,
  • Robert A. Stern,
  • Alan B. Stevens,
  • Stephen M. Strittmatter,
  • David Sultzer,
  • Russell H. Swerdlow,
  • Rudolph E. Tanzi,
  • Jeffrey L. Tilson,
  • Juan C. Troncoso,
  • Debby W. Tsuang,
  • Vivianna M. Van Deerlin,
  • Linda J. Van Eldik,
  • Jeffery M. Vance,
  • Badri N. Vardarajan,
  • Robert Vassar,
  • Harry V. Vinters,
  • Jean-Paul Vonsattel,
  • Sandra Weintraub,
  • Kathleen A. Welsh-Bohmer,
  • Patrice L. Whitehead,
  • Ellen M. Wijsman,
  • Kirk C. Wilhelmsen,
  • Benjamin Williams,
  • Jennifer Williamson,
  • Henrik Wilms,
  • Thomas S. Wingo,
  • Thomas Wisniewski,
  • Randall L. Woltjer,
  • Clinton B. Wright,
  • Chuang-Kuo Wu,
  • Steven G. Younkin,
  • Chang-En Yu,
  • Lei Yu,
  • Xiongwei Zhu,
  • Brian W. Kunkle,
  • William S. Bush,
  • Akinori Miyashita,
  • Giuseppe Tosto,
  • Gyungah R. Jun,
  • Christiane Reitz,
  • Goldie S. Byrd,
  • David W. Fardo,
  • Li-San Wang,
  • Lindsay A. Farrer,
  • Jonathan L. Haines,
  • Richard Mayeux,
  • Margaret A. Pericak-Vance,
  • Gerard D. Schellenberg,
  • Bernard Fongang,
  • Amber Yaqub,
  • Muralidharan Sargurupremraj,
  • Xueqiu Jian,
  • Aniket Mishra,
  • Joshua C. Bis,
  • Monica Gireud-Goss,
  • Jayandra Jung Himali,
  • Habil Zare,
  • Vilmundur Guðnason,
  • Lenore Launer,
  • Jan Bressler,
  • Hans J. Grabe,
  • M. Arfan Ikram,
  • Bruce M. Psaty,
  • W. T. Longstreth,
  • Sigurdur Sigurdsson,
  • Mohsen Ghanbari,
  • Franck J. Wolters,
  • Eric Boerwinkle,
  • Alexa S. Beiser,
  • Chloe Sarnowski,
  • Thomas H. Mosley,
  • Oscar L. Lopez,
  • Cornelia van Duijn,
  • Claudia Satizabal,
  • M. Kamran Ikram,
  • Yang Qiong,
  • Myriam Fornage,
  • Sudha Seshadri,
  • Rebecca Mahoney,
  • Nicola Denning,
  • Alun Meggy,
  • Rachel Marshall,
  • Danielle LeRoux,
  • Catherine Bresner,
  • Valentina Escott-Price,
  • Kevin Morgan,
  • Keeley Brookes,
  • Tamar Guetta-Baranes,
  • Clive Holmes,
  • Gill Windle,
  • Vanessa Burholt,
  • Emma Green,
  • Catherine Macleod,
  • Bob Woods,
  • Simon Mead,
  • Jonathan M. Schott,
  • Nick Fox,
  • Seth Love,
  • Clàudia Olivé,
  • Laura Montrreal,
  • M. Victoria Fernández,
  • Marta Marquié,
  • Amanda Cano,
  • Sergi Valero,
  • Oscar Sotolongo-Grau,
  • Alba Pérez-Cordón,
  • Ana Espinosa,
  • Ángela Sanabria,
  • Gemma Ortega,
  • Maitée Rosende-Roca,
  • Montserrat Alegret,
  • Lluís Tárraga,
  • María Eugenia Sáez,
  • Inés Quintela,
  • Ángel Carracedo,
  • Luis M. Real,
  • Juan Macías,
  • Anaïs Corma-Gómez,
  • Juan A. Pineda,
  • Silvia Mendoza,
  • Jose Luis Royo,
  • Guillermo Garcia-Ribas,
  • Sebastián García-Madrona,
  • Emilio Franco-Macías,
  • Dolores Buiza-Rueda,
  • María Bernal Sánchez-Arjona,
  • Raquel Huerto Vilas,
  • Alfonso Arias Pastor,
  • Mónica Diez-Fairen,
  • Ignacio Alvarez,
  • Carmen Lage,
  • Daniel Alcolea,
  • Juan Fortea,
  • Alberto Lleó,
  • Ana Frank-García,
  • Angel Martín Montes,
  • Anna Antonell,
  • Manuel Menéndez-González,
  • Adolfo Lopez de Munain,
  • Miguel Medina,
  • Miguel Calero,
  • Alberto Rábano,
  • Ana Belén Pastor,
  • Teodoro del Ser,
  • Florentino Sanchez-Garcia,
  • Carmen Muñoz-Fernandez,
  • M. Candida Deniz-Naranjo,
  • Danielle Posthuma,
  • Ole A. Andreassen,
  • Douglas P. Wightman,
  • Emil Uffelmann,
  • Hreinn Stefansson,
  • G. Bragi Walters,
  • Kari Stefansson,
  • Jon Snaedal,
  • Helga Eyjólfsdóttir,
  • Nancy L. Pedersen,
  • Chandra A. Reynolds,
  • Ida K. Karlsson,
  • Sara Hägg,
  • Anna Zettergren,
  • Ingmar Skoog,
  • Silke Kern,
  • Margda Waern,
  • Kaj Blennow,
  • Henrik Zetterberg,
  • Elisa Moreno,
  • Marta Riise Moksnes,
  • Kristian Hveem,
  • Bendik S. Winsvold,
  • Ben Brumpton,
  • Geir Selbæk,
  • Tormod Fladby,
  • Dag Aarsland,
  • Srdjan Djurovic,
  • Arvid Rongve,
  • Shahram Bahrami,
  • Alexey A. Shadrin,
  • Ingvild Saltvedt,
  • Geir Bråthen

摘要

To better characterize the genetic architecture underlying Alzheimer’s disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.