Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis
Xiaopu Zhou(Hong Kong University of Science and Technology), Yu Chen(Chinese Academy of Sciences), Kin Y. Mok(Hong Kong University of Science and Technology), Qianhua Zhao(Fudan University), Keliang Chen(Fudan University), Yuewen Chen(Chinese Academy of Sciences), John Hardy(University College London), Yun Li(University of North Carolina at Chapel Hill), Amy K.Y. Fu(Hong Kong University of Science and Technology), Qihao Guo(Fudan University), Nancy Y. Ip(Hong Kong University of Science and Technology), for the Alzheimer’s Disease Neuroimaging Initiative, Andrew J. Saykin, Arthur W. Toga, Bret Borowski, Chad Ward, Charles DeCarli, Chet Mathis, Clifford R. Jack, Danielle Harvey, David M. Holtzman, David T. Jones, Devon Gessert, Eli Lilly, Eric M. Reiman, Erin Franklin, Franz Hefti, Greg Sorensen, Gustavo Jiménez, Howard Fillit, Jeff Gunter, Jennifer Salazar, John Hsiao, John C. Morris, John Q. Trojanowki, Karen Crawford Scott Neu, Kejal Kantarci, Kelley Faber, Kelly Harless, Kewei Chen(Fudan University), Kwangsik Nho, Laurel Beckett, Lean Thal, Leon J. Thal, Leslie M. Shaw, Lew Kuller, Li Shen, Lindsey Hergesheimer, Lisa Taylor‐Reinwald, Marek M. Mesulam, Magdalena Korecka, Marc Raichle, María C. Carrillo, Marilyn Albert, Matthew L. Senjem, Matt A. Bernstein, Michael Donohue, Michael W. Weiner, Michal Figurski, Neil Buckholtz, Nick C. Fox, Nigel J. Cairns, Norbert Schuff, Norm Foster, Paul Aisen, Paul M. Thompson, Peter Davies, Peter J. Snyder, Peter J. Snyder, Prashanthi Vemuri, Richard Frank, Robert A. Koeppe, Robert C. Green, Ronald Petersen, Sarah Walter, Steven M. Paul, Steven Potkin, Sungeun Kim, Tatiana M. Foroud, Tom Montine, Virginia Lee, William J. Jagust, William Z. Potter, Yuliana Cabrera, Zaven S. Khachaturian, Adam Fleisher, Aimee Pierce, Akiva Mintz, Alan J. Lerner, Alexander Norbash, Allan I. Levey, Allyson Rosen, Amanda Smith, Anaztasia Ulysse, Andrew E. Budson, Andrew Kertesz, Angela Oliver, Ann Marie Hake, Anna Burke, Antero Sarrael, Anton P. Porsteinsson, Ashley Lamb, Athena Lee, Balebail Ashok Raj, Barton Lane, Beatriz Yáñez‐Rivera, Beau M. Ances, Benita Mudge, Betty Lind, Bojana Stefanovic, Bonnie S. Goldstein, Borna Bonakdarpour, Brandy R. Matthews, Brian R. Ott, Brigid Reynolds, Bruce L. Miller, Bryan M. Spann, Carl Sadowsky, Charles Bernick, Charles D. Smith, Chiadi U. Onyike, Chris Heyn, Chris Hosein, Christi Leach, Christine M. Belden, Christopher H. van Dyck, Christopher M. Clark, Chuang‐Kuo Wu, Colleen S. Albers, Connie Brand, Courtney Bodge, Curtis Tatsuoka, Cynthia M. Carlsson, Dana Mathews, Daniel D’Agostino, Daniel Silverman, Daniel Marson, David A. Wolk, David Bachman, David W. Clark, David Geldmacher, David Hart, David S. Knopman, David C. Perry, David Winkfield, Del D. Miller, Diana Kerwin, Dick Drost, Donna M. Simpson, Donna Munic, Douglas W. Scharre, Robert Bartha, Dzintra Celmins, Earl A. Zimmerman, Edmond Teng, Edward Coleman, Edward Zamrini, Effie Mitsis, Elizabeth Finger, Elizabeth Oates, Elizabeth Sosa, Ellen Woo, Emily Rogalskı, Evan Fletcher, Francine Parfitt, Gaby Thai, Gad A. Marshall, Gary Conrad, Geoffrey Tremont, George Bartzokis, Ging‐Yuek Robin Hsiung, Gloria Chiang, Godfrey D. Pearlson, Gregory A. Jicha, Helen Vanderswag, Hillel Grossman, Horacio Capote, Howard Bergman, Howard Chertkow, Howard Feldman, Howard J. Rosen, Hristina Koleva, Hyungsub Shim, Irina Rachinsky, Jacobo Mintzer, Jaimie Ziolkowski, James B. Brewer, James J. Lah, Jamika Singleton-Garvin, Janet S. Cellar, Jared R. Brosch, Jared Tinklenberg, Jason Karlawish, Javier Villanueva‐Meyer, Jeffrey Kaye, Jeffrey M. Burns, Jeffrey R. Petrella, Jerome A. Yesavage, Joanne Allard, Joanne Lord, Joel Hetelle, John Brockington, John C. Morris, John Olichney, John Rogers, Joseph F. Quinn, Joseph S. Kass, Joy L. Taylor, Judith L. Heidebrink, Karen Anderson, Karen Blank, Karen Ekstam Smith, Karen L. Bell, Kathleen Johnson, Kathleen Tingus, Kathryn DeMarco, Kaycee M. Sink, Keith A. Johnson, Kelly M. Makino, Kenneth Spicer, Ki Won Nam, Kim Martin, Kim Poki-Walker, Kris Johnson, Kristin Fargher, Kristine Lipowski, Kyle Womack, Laura A. Flashman, Lawrence S. Honig, Liana G. Apostolova, Liberty Teodoro, Lisa C. Silbert, Lisa Ravdin, Lon S. Schneider, Lori A. Daiello, M. Saleem Ismail, Marc Seltzer, Marek-Marsel Mesulam, Maria Carroll, Maria Kataki, Maria T. Greig‐Custo, Marissa Natelson Love, Mark A. Mintun, Martin R. Farlow, Martin Sadowski, Mary L. Creech, Mary L. Hynes, Mary Quiceno, MaryAnn Oakley, Mauricio Becerra, Megan Witbracht, Melanie Keltz, Melissa Lamar, Mia Yang, Michael Borrie, Michael Lin, Michele Assaly, Michelle Rainka, Mimi Dang, Mohammed O. Sheikh, Mrunalini Gaikwad, Munir Chowdhury, Nadira Trncic, Nancy Johnson, Nancy Kowalksi, Nathaniel Pacini, Neil W. Kowall, Neill R. Graff‐Radford, Norman Relkin, Ntekim E. Oyonumo, Nunzio Pomara, Olga James, Olu Ogunlana, Oscar L. López, Owen Carmichael, P. Murali Doraiswamy, Parianne Fatica, Patricia Lynn Johnson, Patricia Samuels, Paul Malloy, Paula Ogrocki, Pauline Maillard, Peter Hardy, Pierre N. Tariot, Po H. Lu, Pradeep Varma, Rachelle S. Doody, Raina Carter, Raj C. Shah, Randall Griffith, Randy Yeh, Ranjan Duara, Rawan Tarawneh, Raymond Scott Turner, Raymundo Hernando, Reisa A. Sperling, Richard E. Carson, Riham El Khouli, Robert B. Santulli, Ronald Killiany, Rosemarie Rodriguez, Russell H. Swerdlow, Salvador Borges‐Neto, Sandra E. Black, Sandra Weıntraub, Sanjay Asthana, Sanjeev Vaishnavi, Sara Dolen, Sara S. Mason, Sarah Kremen, Scott Herring, Sherye A. Sirrel, Smita Kittur, Sonia Pawluczyk, Stacy Schneider, Stephanie Kielb, Stephanie Reeder, Stephen Correia, Stephen Pasternack, Stephen Pasternak, Stephen Salloway, Sterling C. Johnson, Steven Chao, Steven E. Arnold, Susan K. Schultz, Susan Rountree, T‐Y Lee, Terence Z. Wong, Teresa Villena, Thomas O. Obisesan, Valory Pavlik, Vernice Bates, Vesna Sossi, Victoria Shibley, William M. Brooks, William Pavlosky, Yaakov Stern, A. Cobbold Simon, Ashok Dongre, Bob Dean, Brad Navia, Dan Spellman, David Lee, David Shera, Eric Siemers, Eve H. Pickering, Frank Swenson, Fred Immerman, George G. Nomikos, Holly Soares, Hong Wan, Jeff Seeburger, Jeff Waring, John Q. Trojanowski, Judy Siuciak, Kevin Duffin, Les Shaw, Li-San Wang, Madhav Thambisetty, Marc K. Walton, Mary J. Savage, Mats Ferm, Max Kühn, Neil Buckholtz, Panos Zagouras, Patricia E. Cole, Ron Hendrickson, Sharon X. Xie, Sophie Allauzen, Walter J. Koroshetz, William Z. Potter
Cited by 103Open Access
Abstract
Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10 −14 ), two common variants, GCH1 (rs72713460, P = 4.36 × 10 −5 ) and KCNJ15 (rs928771, P = 3.60 × 10 −6 ), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE , GCH1 , and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
Related Papers
No related papers found
Powered by citation graph analysis