CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease

Deng-Feng Zhang; Jin Li; Huan Wu; Yue Cui; Rui Bi; He-Jiang Zhou; Hui-Zhen Wang; Chen Zhang; Dong Wang; Alzheimer's Disease Neuroimaging Initiative (ADNI); Qing-Peng Kong; Tao Li; Yiru Fang; Tianzi Jiang; Yong-Gang Yao

doi:10.1038/npp.2015.232

CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease

Neuropsychopharmacology. 2016 Mar;41(4):1034-45. doi: 10.1038/npp.2015.232. Epub 2015 Aug 5.

Authors

Deng-Feng Zhang^{1

2}, Jin Li³, Huan Wu^{2

4}, Yue Cui³, Rui Bi¹, He-Jiang Zhou¹, Hui-Zhen Wang¹, Chen Zhang⁵, Dong Wang¹; Alzheimer's Disease Neuroimaging Initiative (ADNI); Qing-Peng Kong⁴, Tao Li⁶, Yiru Fang⁵, Tianzi Jiang^{3

7

8

9}, Yong-Gang Yao^{1

2

7}

Collaborators

Alzheimer's Disease Neuroimaging Initiative (ADNI):
Michael W Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack Jr, William Jagust, John Q Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Andrew J Saykin, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Robert C Green, Tom Montine, Ronald Petersen, Paul Aisen, Ronald G Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B Balasubramanian, Jennifer Mason, Iris Sim, Laurel Beckett, Danielle Harvey, Michael Donohue, Clifford R Jack Jr, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCarli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, William Jagust, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C Morris, Nigel J Cairns, Erin Franklin, Lisa Taylor-Reinwald, Leslie M Shaw, John Q Trojanowki, Virginia Lee, Magdalena Korecka, Michal Figurski, Arthur W Toga, Karen Crawford, Scott Neu, Andrew J Saykin, Tatiana M Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Michael W Weiner, Lean Thal, Zaven Khachaturian, Leon Thal, Neil Buckholtz, Michael W Weiner, Peter J Snyder, William Potter, Steven Paul, Marilyn Albert, Richard Frank, Zaven Khachaturian, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L Heidebrink, Joanne L Lord, Ronald Petersen, Sara S Mason, Colleen S Albers, David Knopman, Kris Johnson, Rachelle S Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S Honig, Karen L Bell, Beau Ances, John C Morris, Maria Carroll, Mary L Creech, Erin Franklin, Mark A Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T Greig-Custo, Warren Barker, Marilyn Albert, Chiadi Onyike, Daniel D'Agostino 2nd, Stephanie Kielb, Martin Sadowski, Mohammed O Sheikh, Anaztasia Ulysse, Mrunalini Gaikwad, P Murali Doraiswamy, Jeffrey R Petrella, Salvador Borges-Neto, Terence Z Wong, Edward Coleman, Steven E Arnold, Jason H Karlawish, David A Wolk, Christopher M Clark, Charles D Smith, Greg 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, Steven G Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I Levey, James J Lah, Janet S Cellar, Jeffrey M Burns, Russell H Swerdlow, William M Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H S Silverman, Po H Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R Farlow, Ann Marie Hake, Brandy R Matthews, Jared R Brosch, Scott Herring, Christopher H van Dyck, Richard E Carson, Martha G MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A Sperling, Keith A Johnson, Gad Marshall, Jerome Yesavage, Joy L Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N Sabbagh, Christine M Belden, Sandra A Jacobson, Sherye A Sirrel, Neil Kowall, Ronald Killiany, Andrew E Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M Carlsson, Steven G Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W Scharre, Maria Kataki, Brendan Kelley, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Godfrey D Pearlson, Karen Blank, Karen Anderson, Laura A Flashman, Marc Seltzer, Mary L Hynes, Robert B Santulli, Kaycee M Sink, Leslie Gordineer, Jeff D Williamson, Pradeep Garg, Franklin Watkins, Brian R Ott, Geoffrey Tremont, Lori A Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J Rosen, Bruce L Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, John Rogers, Andrew Kertesz, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Michael W Weiner, Paul Aisen, Ronald Petersen, Robert C Green, Danielle Harvey, Clifford R Jack Jr, William Jagust, John C Morris, Andrew J Saykin, Leslie M Shaw, Arthur W Toga, John Q Trojanowki, Thomas Neylan, Jordan Grafman, Robert C Green, Tom Montine, Michael Weiner, Ronald Petersen, Paul Aisen, Ronald G Thomas, Michael Donohue, Devon Gessert, Tamie Sather, Melissa Davis, Rosemary Morrison, Gus Jiminez, Thomas Neylan, Jacqueline Hayes, Shannon Finley, Danielle Harvey, Michael Donohue, Clifford R Jack Jr, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matt Senjem, Kejal Kantarci, Chad Ward, William Jagust, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, Susan Landau, John C Morris, Nigel J Cairns, Erin Householder, Leslie M Shaw, John Q Trojanowki, Virginia Lee, Magdalena Korecka, Michal Figurski, Arthur W Toga, Karen Crawford, Scott Neu, Andrew J Saykin, Tatiana M Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Michael W Weiner, Karl Friedl, Lon S Schneider, Sonia Pawluczyk, Mauricio Becerra, James Brewer, Helen Vanderswag, Yaakov Stern, Lawrence S Honig, Karen L Bell, Debra Fleischman, Konstantinos Arfanakis, Raj C Shah, Ranjan Duara, Daniel Varon, Maria T Greig, P Murali Doraiswamy, Jeffrey R Petrella, Olga James, Anton P Porsteinsson, Bonnie Goldstein, Kimberly S Martin, Steven G Potkin, Adrian Preda, Dana Nguyen, Jacobo Mintzer, Dino Massoglia, Olga Brawman-Mintzer, Carl Sadowsky, Walter Martinez, Teresa Villena, William Jagust, Susan Landau, Howard Rosen, David Perry, Raymond Scott Turner, Kelly Behan, Brigid Reynolds, Reisa A Sperling, Keith A Johnson, Gad Marshall, Marwan N Sabbagh, Sandra A Jacobson, Sherye A Sirrel, Thomas O Obisesan, Saba Wolday, Joanne Allard, Sterling C Johnson, J Jay Fruehling, Sandra Harding, Elaine R Peskind, Eric C Petrie, Gail Li, Jerome A Yesavage, Joy L Taylor, Ansgar J Furst, Steven Chao, Norman Relkin, Gloria Chiang, Lisa Ravdin

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
² Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
³ Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
⁴ State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
⁵ Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Mental Health Center and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, China.
⁷ CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
⁸ Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
⁹ Queensland Brain Institute, University of Queensland, Brisbane, Australia.

Abstract

The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / genetics*
Alzheimer Disease / immunology*
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Asian People
Brain / pathology*
China
Complement Factor H / genetics
Complement Factor H / metabolism
Endophenotypes
Female
Genetic Predisposition to Disease*
Genetic Testing
Genotype
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
RNA, Messenger / metabolism
Risk Factors

Substances

CFH protein, human
RNA, Messenger
Complement Factor H

Abstract

Publication types

MeSH terms

Substances

Grants and funding