GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
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 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 J. 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
Abstract
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 eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, 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.