Non-coding variability at the APOE locus contributes to the Alzheimer’s risk

Authors: Xiaopu Zhou, Yu Chen, Kin Y. Mok, Timothy Kwok, Vincent Mok, Qihao Guo, Fanny C.F. Ip, Yuewen Chen, Nandita Mullapudi, Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William J. Jagust, John Q. Trojanowski, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John C. Morris, Leslie M. Shaw, Zaven S. Khachaturian, Greg Sorensen, Lew Kuller, Marcus E. Raichle, Steven M. Paul, Peter J. Davies, Howard Fillit, Franz Hefti, David M. Holtzman, Marek M. Mesulam, William C. Potter, Peter J. Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matt A. Bernstein, Paul M. Thompson, Norbert Schuff, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Prashanthi Vemuri, David T. Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor‐Reinwald, Virginia M.‐Y. Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana Foroud, Steven G. Potkin, Li Shen, Kelley Faber, Sung Eun Kim, Kwangsik Nho, Leon J. Thal, Neil Buckholtz, Marylyn Albert, R.T. Frank, John Hsiao, Jeffrey Kaye, Joseph F. Quinn, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, James M. Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne Lord, Sara S. Mason, Colleen S. Albers, David S. Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva‐Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau M. Ances, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik D. Roberson, Hillel Grossman, Effie Mitsis, Leyla de Toledo‐Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Maria T. Greig, Peggy Roberts, Chiadi U. Onyike, Daniel D’Agostino, Stephanie Kielb, James E. Galvin, Brittany Cerbone, Christina A. Michel, Henry Rusinek, Mony J. de Leon, Lidia Glodzik, Susan De Santi, P. Murali Doraiswamy, Jeffrey R. Petrella, Terence Z. Wong, Steven E. Arnold, Jason Karlawish, David A. Wolk, Charles D. Smith, Gregory A. Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc-Adams-Ortiz, Kyle Womack, Dana Mathews, Mary Quiceno, Ramon Diaz‐Arrastia, Richard King, Myron Weiner, Kristen Martin-Cook, Michael D. Devous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S. Anderson, Russell H. Swerdlow, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel Silverman, Po H. Lu, George Bartzokis, Neill R. Graff‐Radford, Francine Parfitt, Tracy Kendall, Heather Johnson, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Scott Herring, Cynthia Hunt, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Ging‐Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly, Charles Bernick, Donna Munic, Andrew Kertesz, John Rogers, Dick Trost, Diana Kerwin, Kristine Lipowski, Chuang-Kuo Wu, Nancy E. Johnson, Carl Sadowsky, Walter Martínez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Meghan Frey, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil W. Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Joanne Allard, Alan J. Lerner, Paula Ogrocki, Leon Hudson, Evan Fletcher, Owen Carmichael, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T‐Y Lee, Robert Bartha, Sterling C. Johnson, Sanjay Asthana, Cynthia M. Carlsson, Adrian Preda, Dana Nguyen, Pierre N. Tariot, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Anahita Adeli, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Tamar J. Kitzmiller, Eben S. Schwartz, Kaycee M. Sink, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Laura L. Boles Ponto, Hyungsub Shim, Karen E. Smith, Norman Relkin, Gloria Chaing, Lisa Raudin, Amanda Smith, Kristin Fargher, Balebail Ashok Raj, Thomas C. Neylan, Jordan Grafman, Melissa Davis, Rosemary Morrison, Jacqueline Hayes, Shannon Finley, Karl E. Friedl, Debra Fleischman, Konstantinos Arfanakis, Olga James, Dino Massoglia, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Joy L. Taylor, Ansgar J. Furst, Paola Giusti‐Rodríguez, Patrick F. Sullivan, John Hardy, Amy K.Y. Fu, Yun Li, Nancy Y. Ip - Nature Communications 2019 cited by 125

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.