Sex-specific genetic predictors of Alzheimer’s disease biomarkers
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Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
KeywordsAlzheimer disease Cerebrospinal fluid biomarkers Neuropathology Sex difference APOE Amyloid Tau
We thank all the participants and their families, as well as the many institutions and their staff that provided support for all studies involved in this collaboration. We thank the study participants and staff of the Rush Alzheimer’s Disease Center and of the Kaiser Permanente (formerly Group Health)/University of Washington Adult Changes in Thought study. We also thank the Alzheimer Disease Genetic Consortium (ADGC) for genotyping and providing data for the BIOCARD, UPENN, and MAYO cohorts.
ADNI Coinvestigators: Michael W. Weiner, M.D. (University of California San Francisco, ADNI Principal Investigator); Ron Petersen, Ph.D., M.D. (Mayo Clinic, Protocol principal investigator); Paul Aisen, M.D. (University of California San Diego, Clinical Core Director); Clifford Jack, M.D. (Mayo Clinic, MRI Core Director); William Jagust, M.D. (University of California Berkeley, PET Core Director); Leslie M. Shaw, Ph.D. (University of Pennsylvania, Biomarker Core Director); John Trojanowski, Ph.D. (University of Pennsylvania, Biomarker Core Director); Laurel Beckett, Ph.D. (University of California Davis, Biostatistics Core Director); Art Toga, Ph.D. (UCLA, LONI Principal Investigator); Andrew Saykin, Psy.D. (Indiana University Purdue University Indianapolis, Genetics Core Director); John C. Morris, M.D. (Washington University in St. Louis; Neuropathology Core Director); Tom Montine, Ph.D. (University of Washington, Resource Allocation Review Committee); Robert Green, M.D., MPH (Boston University, ADNI Data and Publications Committee).
ADGC Member List: Erin Abner, PhD. University of Kentucky, Perrie Adams, PhD. University of Texas Southwestern Medical Center, Marilyn Albert, PhD. Johns Hopkins University, Roger Albin, MD. University of Michigan, Liana Apostolova, MD. Indiana University, Steven Arnold, MD. University of Pennsylvania Perelman School of Medicine, Sanjay Asthana, MD. University of Wisconsin, Craig Atwood, PhD. University of Wisconsin, Clinton Baldwin, PhD. Boston University, Robert Barber, PhD. University of North Texas Health Science Center, Lisa Barnes, PhD. Rush University Medical Center, Sandra Barral, PhD. Columbia University, Thomas Beach, MD PhD. Banner Sun Health Research Institute, James Becker, PhD. University of Pittsburgh School of Medicine, Gary Beecham, PhD. University of Miami, Duane Beekly, BS. University of Washington, David Bennett, MD. Rush University Medical Center, Eileen Bigio, MD. Northwestern University Feinberg School of Medicine, Thomas Bird, MD. University of Washington, Deborah Blacker, MD. Harvard School of Public Health, Bradley Boeve, MD. Mayo Clinic, James Bowen, MD. Swedish Medical Center, Adam Boxer, MD PhD. University of California San Francisco, James Burke, MD PhD. Duke University, Jeffrey Burns, MD MS. University of Kansas Medical Center, Joseph Buxbaum, PhD. Mount Sinai School of Medicine, Nigel Cairns, PhD FRCPath. Washington University, Laura Cantwell, MPH. University of Pennsylvania Perelman School of Medicine, Chuanhai Cao, PhD. University of South Florida, Chris Carlson, PhD. Fred Hutchinson Cancer Research Center, Cynthia Carlsson, MD. University of Wisconsin, Regina Carney, MD. University of Miami, Minerva Carrasquillo, PhD. Mayo Clinic, Helena Chui, MD. University of Southern California, Paul Crane, MD MPH. University of Washington, David Cribbs, PhD. University of California Irvine, Elizabeth Crocco, MD. University of Miami, Carlos Cruchaga, PhD. Washington University School of Medicine, Philip De Jager, MD PhD. Brigham and Women’s Hospital and Harvard Medical School, Charles DeCarli, MD. University of California Davis, Malcolm Dick, PhD. University of California Irvine, Dennis Dickson, MD. Mayo Clinic, Rachelle Doody, MD PhD. Baylor College of Medicine, Ranjan Duara, MD. Mount Sinai Medical Center, Nilufer Ertekin-Taner, MD PhD. Mayo Clinic, Denis Evans, MD. Rush University Medical Center, Kelley Faber, MS. Indiana University, Thomas Fairchild, PhD. University of North Texas Health Science Center, Kenneth Fallon, MD. University of Alabama at Birmingham, David Fardo, PhD. University of Kentucky, Martin Farlow, MD. Indiana University, Lindsay Farrer, PhD. Boston University, Steven Ferris, PhD. New York University, Tatiana Foroud, PhD. Indiana University, Matthew Frosch, MD PhD. Massachusetts General Hospital, Douglas Galasko, MD. University of California San Diego, Marla Gearing, PhD. Emory University, Daniel Geschwind, MD PhD. University of California Los Angeles, Bernardino Ghetti, MD. Indiana University, John Gilbert, PhD. University of Miami, Alison Goate, D.Phil. Mount Sinai School of Medicine, Neill Graff-Radford, MD. Mayo Clinic, Robert Green, MD MPH. Brigham and Women’s Hospital and Harvard Medical School, John Growdon, MD. Massachusetts General Hospital/Harvard Medical School, Jonathan Haines, PhD. Case Western Reserve University, Hakon Hakonarson, MD PhD. Children’s Hospital of Philadelphia, Ronald Hamilton, MD. University of Pittsburgh, Kara Hamilton-Nelson, MPH. University of Miami, John Hardy, PhD. University College London, Lindy Harrell, MD PhD. University of Alabama at Birmingham, Lawrence Honig, MD PhD. Columbia University, Ryan Huebinger, PhD. University of Texas Southwestern Medical Center, Matthew Huentelman, PhD. Translational Genomics Research Institute, Christine Hulette, MD. Duke University, Bradley Hyman, MD PhD. Massachusetts General Hospital/Harvard Medical School, Gail Jarvik, MD PhD. University of Washington, Lee-Way Jin, MD PhD. University of California Davis, Gyungah Jun, PhD. Boston University, M. Ilyas Kamboh, PhD. University of Pittsburgh, Anna Karydas, BA. University of California San Francisco, Mindy Katz, MPH. Albert Einstein College of Medicine, John Kauwe, PhD. Brigham Young University, Jeffrey Kaye, MD. Oregon Health & Science University, C. Dirk Keene, MD PhD. University of Washington, Ronald Kim, MD. University of California Irvine, Neil Kowall, MD. Boston University, Joel Kramer, PsyD. University of California San Francisco, Walter Kukull, PhD. University of Washington, Brian Kunkle, PHD MPH. University of Miami, Amanda Kuzma, MS. University of Pennsylvania Perelman School of Medicine, Frank LaFerla, PhD. University of California Irvine, James Lah, MD PhD. Emory University, Eric Larson, MD MPH. University of Washington, James Leverenz, MD. Cleveland Clinic, Allan Levey, MD PhD. Emory University, Ge Li, MD PhD. VA Puget Sound Health Care System/GRECC, Andrew Lieberman, MD PhD. University of Michigan, Richard Lipton, MD. Albert Einstein College of Medicine, Oscar Lopez, MD. University of Pittsburgh Alzheimer’s Disease Research Center, Kathryn Lunetta, PhD. Boston University, Constantine Lyketsos, MD MHS. Johns Hopkins University, John Malamon, MSE. University of Pennsylvania Perelman School of Medicine, Daniel Marson, JD PhD. University of Alabama at Birmingham, Eden Martin, PhD. University of Miami, Frank Martiniuk, PhD. New York University, Deborah Mash, PhD. University of Miami, Eliezer Masliah, MD. University of California San Diego, Richard Mayeux, MD. Columbia University , Wayne McCormick, MD MPH. University of Washington, Susan McCurry, PhD. University of Washington, Andrew McDavid, BA. Fred Hutchinson Cancer Research Center, Stefan McDonough, PhD. Pfizer Worldwide Research and Development, Ann McKee, MD. Boston University, Marsel Mesulam, MD. Northwestern University Feinberg School of Medicine, Bruce Miller, MD. University of California San Francisco, Carol Miller, MD. University of Southern California, Joshua Miller, PhD. University of California Davis, Thomas Montine, MD PhD. University of Washington, John Morris, MD. Washington University, Shubhabrata Mukherjee, PhD. University of Washington, Amanda Myers, PhD. University of Miami, Adam Naj, PhD. University of Pennsylvania Perelman School of Medicine, Sid O’Bryant, PhD. University of North Texas Health Science Center, John Olichney, MD. University of California Davis, Joseph Parisi, MD. Mayo Clinic, Henry Paulson, MDPhD. University of Michigan, Margaret Pericak-Vance, PhD. University of Miami, Elaine Peskind, MD. University of Washington School of Medicine, Ronald Petersen, MD PhD. Mayo Clinic, Aimee Pierce, MD. University of California Irvine, Wayne Poon, PhD. University of California Irvine, Huntington Potter, PhD. University of Colorado School of Medicine, Liming Qu, MS. University of Pennsylvania Perelman School of Medicine, Joseph Quinn, MD. Oregon Health & Science University, Ashok Raj, MD. University of South Florida, Murray Raskind, MD. University of Washington School of Medicine, Eric Reiman, MD. Translational Genomics Research Institute, Barry Reisberg, MD. New York University, Joan Reisch, PhD. University of Texas Southwestern Medical Center, Christiane Reitz, MD PhD. Columbia University, John Ringman, MD. University of Southern California, Erik Roberson, MD PhD. University of Alabama at Birmingham, Ekaterina Rogaeva, PhD. University of Toronto, Howard Rosen, MD. University of California San Francisco, Roger Rosenberg, MD. University of Texas Southwestern, Donald Royall, MD. South Texas Veterans Health Administration Geriatric Research Education & Clinical Center (GRECC), UT Health Science Center at San Antonio, Mark Sager, MD. University of Wisconsin, Mary Sano, PhD. Mount Sinai School of Medicine, Andrew Saykin, PsyD. Indiana University, Gerard Schellenberg, PhD. University of Pennsylvania Perelman School of Medicine, Julie Schneider, MD. Rush University Medical Center, Lon Schneider, MD. University of Southern California, William Seeley, MD. University of California San Francisco, Amanda Smith, MD. University of South Florida, Joshua Sonnen, MD. University of Washington, Salvatore Spina, MD. Indiana University, Peter St George-Hyslop, MD FRCP. University of Toronto, Robert Stern, PhD. Boston University, Russell Swerdlow, MD. University of Kansas Medical Center, Rudolph Tanzi, PhD. Massachusetts General Hospital/Harvard Medical School, John Trojanowski, MD PhD. University of Pennsylvania Perelman School of Medicine, Juan Troncoso, MD. Johns Hopkins University, Debby Tsuang, MD. VA Puget Sound Health Care System/GRECC, Otto Valladares, MS. University of Pennsylvania Perelman School of Medicine, Vivianna Van Deerlin, MD PhD. University of Pennsylvania Perelman School of Medicine, Linda Van Eldik, Phd. University of Kentucky, Badri Vardarajan, MS. Columbia University, Harry Vinters, MD. University of California Los Angeles, Jean Paul Vonsattel, MD. Columbia University, Li-San Wang, PhD. University of Pennsylvania Perelman School of Medicine, Sandra Weintraub, PhD. Northwestern University Feinberg School of Medicine, Kathleen Welsh-Bohmer, PhD. Duke University, Kirk Wilhelmsen, MD PhD. University of North Carolina Chapel Hill, Jennifer Williamson, MS. Columbia University, Thomas Wingo, MD. Emory University, Randall Woltjer, MD PhD. Oregon Health & Science University, Clinton Wright, MD MS. University of Miami, Chuang-Kuo Wu, MD PhD. Texas Tech University Health Science Center, Steven Younkin, MD PhD. Mayo Clinic, Chang-En Yu, PhD. University of Washington, Lei Yu, PhD. Rush University Medical Center, Yi Zhao, MS. University of Pennsylvania Perelman School of Medicine.
YD and LD contributed equally to this work: analyzed data, prepared figures and tables, and wrote the manuscript. LLB, MT, BK, KAG, WSB, LBC, SM, PLDJ, WK, MH, PKC, SMR, CDK, TJM, GDS, JLH, EBL, SCJ, MA, AM, ALJ, LKD, JM S, and NJC contributed to the interpretation of data and critical revision of the manuscript for important intellectual content. JLdA, MVF, and JB prepared genetic data: performed imputation, cleaning, and calculated principal components. Also contributed to critical revision of the manuscript for important intellectual content. JH, AMF, MR, RCP, LM, VMVD, VM-YL, LMS, JQT, ERP, GL, LKD, MJC, HZ, ADNI, ADGC, AMG, DAB, and JAS provided data, contributed to analysis and/or interpretation of data, and contributed to critical revision of the manuscript for important intellectual content. CC and TJH contributed equally to this work: conceived and planned the study, analyzed data, prepared the manuscript, and supervised the project. All authors reviewed and approved the final manuscript.
This research was supported in part by K01 AG049164, K12 HD043483, K24 AG046373, HHSN311201600276P, S10 OD023680, R01 AG034962, R01 HL111516, R01 NS100980, R01 AG056534, P30 AG10161, RF1 AG15819, R01 AG17917, R01 AG30146, R01 AG019085, R01 AG15819, R01 AG30146, R01 AG027161, R01 AG021155, R01 AG037639, U01 AG46152, U01 AG006781, U01 AG032984, U01 HG004610, U01 HG006375, U24 AG021886, U24 AG041689, R01 AG044546, P01 AG003991, RF1 AG053303, R01 AG035083, R01 NS085419, and the Alzheimer’s Association (NIRG-11-200110), further supported in part by the Intramural Research Program, NIA, NIH and the Vanderbilt Memory and Alzheimer’s Center. YD is supported by an NIMH training grant (T32MH014877). Support for PDJ was provided by R01 AG048015. SK received support from NIA R03 AG050856, Alzheimer’s Association, Michael J Fox Foundation, and ARUK Biomarkers Across Neurodegenerative Diseases (BAND). MR received support from the German Federal Ministry of Education and Research (BMBF) National Genome Research Network (NGFN) Grant No. 01GS08125 and through the Helmholtz Alliance for Mental Health in an Aging Society (HELMA) Grant No. Ha-15. HZ is a Wallenberg Academy Fellow and is further supported but the Swedish and European Research Councils and the UK Dementia Research Institute. KB holds the Torsten Söderberg professorship at the Royal Swedish Academy of Sciences. The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Grabowski, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD). Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Compliance with ethical standards
Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research and Development, LLC.; Johnson and Johnson Pharmaceutical Research and Development LLC.; Lumosity; Lundbeck; Merck and Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Conflict of interest
Dr. Larson reports royalties from UpToDate. Dr. Schneider reports personal fees from Avid Radiopharmaceuticals, personal fees from Navidea Biopharmaceuticals, outside the submitted work. Dr. Zetterberg has served at advisory boards of Eli Lilly, Roche Diagnostics and Pharmasum Therapeutics and is one of the founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Dr. Blennow has served at advisory boards of Alzheon, BioArctic, Eli Lilly, IBL International, Fujirebio, Merck, and Roche Diagnostics and is one of the founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.
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