GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
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发表日期:
2024年10月8日
- Lincoln M. P. Shade,
- Yuriko Katsumata,
- Erin L. Abner,
- Khine Zin Aung,
- Steven A. Claas,
- Qi Qiao,
- Bernardo Aguzzoli Heberle,
- J. Anthony Brandon,
- Madeline L. Page,
- Timothy J. Hohman,
- Shubhabrata Mukherjee,
- Richard P. Mayeux,
- Lindsay A. Farrer,
- Gerard D. Schellenberg,
- Jonathan L. Haines,
- Walter A. Kukull,
- Kwangsik Nho,
- Andrew J. Saykin,
- David A. Bennett,
- Julie A. Schneider,
- Sarah Biber,
- Marilyn Albert,
- Sanjay Asthana,
- David Bennett,
- James Brewer,
- Helena Chui,
- Suzanne Craft,
- Charles DeCarli,
- Todd Golde,
- Thomas Grabowski,
- Victor Henderson,
- Bradley Hyman,
- Jeffrey Kaye,
- Neil Kowall,
- Frank LaFerla,
- Allan Levey,
- Oscar Lopez,
- Bruce Miller,
- John Morris,
- Henry Paulson,
- Ronald Petersen,
- Eric Reiman,
- Roger Rosenberg,
- Mary Sano,
- Andrew Saykin,
- Scott Small,
- Stephen Strittmatter,
- Russell Swerdlow,
- John Trojanowski,
- Linda Van Eldik,
- Robert Vassar,
- Thomas Wisniewski,
- Kari A. Stephens,
- Kwun C. G. Chan,
- Heather O’Connell,
- Kathryn Gauthreaux,
- Charles Mock,
- Yen-Chi Chen,
- Stacy Oswald,
- Zack Miller,
- Dean K. Shibata,
- Kyle Ormsby,
- Jessica Culhane,
- Sarah Yasuda,
- James D. Bowen,
- Paul K. Crane,
- Gail P. Jarvik,
- C. Dirk Keene,
- Eric B. Larson,
- Wayne C. McCormick,
- Susan M. McCurry,
- Shubhabrata Mukherjee,
- Neil W. Kowall,
- Ann C. McKee,
- Robert A. Stern,
- Lawrence S. Honig,
- Jean Paul Vonsattel,
- Jennifer Williamson,
- Scott Small,
- James R. Burke,
- Christine M. Hulette,
- Kathleen A. Welsh-Bohmer,
- Marla Gearing,
- James J. Lah,
- Allan I. Levey,
- Thomas S. Wingo,
- Liana G. Apostolova,
- Martin R. Farlow,
- Bernardino Ghetti,
- Andrew J. Saykin,
- Salvatore Spina,
- Marilyn S. Albert,
- Constantine G. Lyketsos,
- Juan C. Troncoso,
- Matthew P. Frosch,
- Robert C. Green,
- John H. Growdon,
- Bradley T. Hyman,
- Rudolph E. Tanzi,
- Huntington Potter,
- Dennis W. Dickson,
- Nilufer Ertekin-Taner,
- Neill R. Graff-Radford,
- Joseph E. Parisi,
- Ronald C. Petersen,
- Ranjan Duara,
- Joseph D. Buxbaum,
- Alison M. Goate,
- Mary Sano,
- Arjun V. Masurkar,
- Thomas Wisniewski,
- Eileen H. Bigio,
- Marsel Mesulam,
- Sandra Weintraub,
- Robert Vassar,
- Jeffrey A. Kaye,
- Joseph F. Quinn,
- Randall L. Woltjer,
- Lisa L. Barnes,
- David A. Bennett,
- Julie A. Schneider,
- Lei Yu,
- Victor Henderson,
- Kenneth B. Fallon,
- Lindy E. Harrell,
- Daniel C. Marson,
- Erik D. Roberson,
- Charles DeCarli,
- Lee-Way Jin,
- John M. Olichney,
- Ronald Kim,
- Frank M. LaFerla,
- Edwin Monuki,
- Elizabeth Head,
- David Sultzer,
- Daniel H. Geschwind,
- Harry V. Vinters,
- Marie-Francoise Chesselet,
- Douglas R. Galasko,
- James B. Brewer,
- Adam Boxer,
- Anna Karydas,
- Joel H. Kramer,
- Bruce L. Miller,
- Howard J. Rosen,
- William W. Seeley,
- Jeffrey M. Burns,
- Russell H. Swerdlow,
- Erin Abner,
- David W. Fardo,
- Linda J. Van Eldik,
- Roger L. Albin,
- Andrew P. Lieberman,
- Henry L. Paulson,
- Steven E. Arnold,
- John Q. Trojanowski,
- Vivianna M. Van Deerlin,
- Ronald L. Hamilton,
- M. Ilyas Kamboh,
- Oscar L. Lopez,
- James T. Becker,
- Chuanhai Cao,
- Ashok Raj,
- Amanda G. Smith,
- Helena C. Chui,
- Carol A. Miller,
- John M. Ringman,
- Lon S. Schneider,
- Thomas D. Bird,
- Joshua A. Sonnen,
- Chang-En Yu,
- Elaine Peskind,
- Murray Raskind,
- Ge Li,
- Debby W. Tsuang,
- Craig S. Atwood,
- Cynthia M. Carlsson,
- Mark A. Sager,
- Nathaniel A. Chin,
- Suzanne Craft,
- Nigel J. Cairns,
- John C. Morris,
- Carlos Cruchaga,
- Stephen Strittmatter,
- Eric M. Reiman,
- Thomas G. Beach,
- Matthew J. Huentelman,
- John Hardy,
- Amanda J. Myers,
- John S. K. Kauwe,
- Hakon Hakonarson,
- Deborah Blacker,
- Thomas J. Montine,
- Clinton T. Baldwin,
- Lindsay A. Farrer,
- Gyungah Jun,
- Kathryn L. Lunetta,
- William S. Bush,
- Jonathan L. Haines,
- Alan J. Lerner,
- Xiongwei Zhou,
- Sandra Barral,
- Christiane Reitz,
- Badri N. Vardarajan,
- Richard Mayeux,
- Gary W. Beecham,
- Regina M. Carney,
- Michael L. Cuccaro,
- John R. Gilbert,
- Kara L. Hamilton-Nelson,
- Brian W. Kunkle,
- Eden R. Martin,
- Margaret A. Pericak-Vance,
- Jeffery M. Vance,
- Laura B. Cantwell,
- Amanda P. Kuzma,
- John Malamon,
- Adam C. Naj,
- Liming Qu,
- Gerard D. Schellenberg,
- Otto Valladares,
- Li-San Wang,
- Yi Zhao,
- James B. Leverenz,
- Philip L. De Jager,
- Denis A. Evans,
- Mindy J. Katz,
- Richard B. Lipton,
- Bradley F. Boeve,
- Mariet Allen,
- Minerva M. Carrasquillo,
- Steven G. Younkin,
- Kelley M. Faber,
- Tatiana M. Foroud,
- Valory Pavlik,
- Paul Massman,
- Eveleen Darby,
- Monica Rodriguear,
- Aisha Khaleeq,
- Donald R. Royall,
- Alan Stevens,
- Marcia Ory,
- John C. DeToledo,
- Henrick Wilms,
- Kim Johnson,
- Victoria Perez,
- Michelle Hernandez,
- Kirk C. Wilhelmsen,
- Jeffrey Tilson,
- Scott Chasse,
- Robert C. Barber,
- Thomas J. Fairchild,
- Sid E. O’Bryant,
- Janice Knebl,
- James R. Hall,
- Leigh Johnson,
- Douglas Mains,
- Lisa Alvarez,
- Adriana Gamboa,
- David Paydarfar,
- John Bertelson,
- Martin Woon,
- Gayle Ayres,
- Alyssa Aguirre,
- Raymond Palmer,
- Marsha Polk,
- Perrie M. Adams,
- Ryan M. Huebinger,
- Joan S. Reisch,
- Roger N. Rosenberg,
- Munro Cullum,
- Benjamin Williams,
- Mary Quiceno,
- Linda Hynan,
- Janet Smith,
- Barb Davis,
- Trung Nguyen,
- Ekaterina Rogaeva,
- Peter St George-Hyslop,
- Mark T. W. Ebbert,
- Peter T. Nelson,
- David W. Fardo
摘要
Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified seven independent significantly associated loci, of which three were new (COL4A1, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.