Abstract
Original language | English |
---|---|
Article number | 79 |
Pages (from-to) | 79 |
Journal | Genome Medicine |
Volume | 15 |
Issue number | 1 |
DOIs | |
Publication status | Published - Dec 2023 |
Keywords
- Alzheimer’s disease
- Biomarkers
- Cerebrospinal fluid (CSF)
- Dementia
- Genome-wide association study (GWAS)
- Mediation
- Multivariate analysis
- Principal component analysis
- Structural equation modeling
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In: Genome Medicine, Vol. 15, No. 1, 79, 12.2023, p. 79.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning
AU - Neumann, Alexander
AU - Ohlei, Olena
AU - Küçükali, Fahri
AU - Bos, Isabelle J.
AU - Timsina, Jigyasha
AU - Vos, Stephanie
AU - Prokopenko, Dmitry
AU - Tijms, Betty M.
AU - Andreasson, Ulf
AU - Blennow, Kaj
AU - Vandenberghe, Rik
AU - Scheltens, Philip
AU - Teunissen, Charlotte E.
AU - Engelborghs, Sebastiaan
AU - Frisoni, Giovanni B.
AU - Blin, Oliver
AU - Richardson, Jill C.
AU - Bordet, R. gis
AU - Lleó, Alberto
AU - Alcolea, Daniel
AU - Popp, Julius
AU - Marsh, Thomas W.
AU - Gorijala, Priyanka
AU - Clark, Christopher
AU - Peyratout, Gwendoline
AU - Martinez-Lage, Pablo
AU - Tainta, Mikel
AU - Dobson, Richard J. B.
AU - Legido-Quigley, Cristina
AU - van Broeckhoven, Christine
AU - Tanzi, Rudolph E.
AU - ten Kate, Mara
AU - Lill, Christina M.
AU - Barkhof, Frederik
AU - Cruchaga, Carlos
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Zetterberg, Henrik
AU - Visser, Pieter Jelle
AU - Sleegers, Kristel
AU - EMIF-AD & ADNI study group
AU - Bertram, Lars
N1 - Funding Information: The present study was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, EPAD grant no. 115736, and from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 666992. Resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007–2013) and EFPIA companies’ in-kind contribution. Research at VIB-UAntwerp was in part supported by the Research Foundation Flanders (FWO), and the University of Antwerp Research Fund, Belgium. AN was also supported by the European Union’s HorizonEurope Research and Innovation Programme (FAMILY; grant agreement No 101057529) and the European Research Council (TEMPO; grant agreement No 101039672). The DESCRIPA study was funded by the European Commission within the fifth framework program (QLRT-2001–2455). The EDAR study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11,020, #13,007, and #15,005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation-Alzheimer Research Switzerland (grant number 2017-PI01). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532), the European Research Council (#681,712 and #101,053,962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201,809–2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21–831,376-C, #ADSF-21–831,381-C and #ADSF-21–831,377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). FB is supported by the NIHR biomedical research center at UCLH. Further support came from the Lifebrain EU Horizon 2020 project (#732,592, to CML and LB), the Deutsche Forschungsgemeinschaft (#LI2654/2–1 and LI 2654/4–1 to CML and #BE2287/6–1 to LB), and the Cure Alzheimer’s Fund (to CML and LB). Lastly, we acknowledge support from the high-performance environment (“OmicsCluster”) at University of Lübeck where most of the GWAS-related analyses were performed. Funding Information: The results published here are in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.org ). Data generation was supported by the following NIH grants: P30AG10161, P30AG72975, R01AG15819, R01AG17917, R01AG036836, U01AG46152, U01AG61356, U01AG046139, P50 AG016574, R01 AG032990, U01AG046139, R01AG018023, U01AG006576, U01AG006786, R01AG025711, R01AG017216, R01AG003949, R01NS080820, U24NS072026, P30AG19610, U01AG046170, RF1AG057440, and U24AG061340, and the Cure PSP, Mayo and Michael J Fox foundations, Arizona Department of Health Services and the Arizona Biomedical Research Commission. Funding Information: FB is on the steering committee or iDMC member for Biogen, Merck, Roche, EISAI, and Prothena. consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics, has research agreements with Merck, Biogen, GE Healthcare, Roche, and is co-founder and shareholder of Queen Square Analytics LTD; HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). AL is on the editorial board of Neurology and Brain Communications, has served at scientific advisory boards from Fujirebio-Europe, Nutricia, Roche-Genentech, Biogen, Grifols, and Roche Diagnostics, and has filed a patent application of synaptic markers in neurodegenerative diseases. D.A. participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). SL is currently an employee of Janssen Medical Ltd (UK), a co-founder of Akrivia Health Ltd (UK) and within the past 5 years has filed patents related to biomarkers unrelated to the current work and advised or given lectures for Merck, Optum Labs, and Eisai as well as having received grant funding from multiple companies as part of EU IMI programs and from Astra Zeneca. JP received consultation honoraria from Nestle Institute of Health Sciences, Ono Pharma, OM Pharma, and Fujirebio, unrelated to the submitted work. SE has served on scientific advisory boards for Biogen, Danone, icometrix, Novartis, Nutricia, and Roche and received unrestricted research grants from Janssen Pharmaceutica and ADx Neurosciences (paid to institution). JR was an employee at GSK and currently an employee at the MSD London Discovery Centre, U.K. CC has received research support from: GSK and EISAI. CC is a member of the advisory board of Vivid Genomics and Circular Genomics and owns stocks. The remaining authors declare that they have no competing interests. Funding Information: We thank the participants of the EMIF-AD study and their families, as well as all people, who contributed data and sample collection and/or logistics across the different study centers. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. The data available in the AD Knowledge Portal would not be possible without the participation of research volunteers and the contribution of data by collaborating researchers. We thank the participants of the Religious Order Study and Memory and Aging projects for the generous donation, the Sun Health Research Institute Brain and Body Donation Program, the Mayo Clinic Brain Bank, and the Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue Repository. Data and analysis contributing investigators include Nilüfer Ertekin-Taner, Steven Younkin (Mayo Clinic, Jacksonville, FL), Todd Golde (University of Florida), Nathan Price (Institute for Systems Biology), David Bennett, Christopher Gaiteri (Rush University), Philip De Jager (Columbia University), Bin Zhang, Eric Schadt, Michelle Ehrlich, Vahram Haroutunian, Sam Gandy (Icahn School of Medicine at Mount Sinai), Koichi Iijima (National Center for Geriatrics and Gerontology, Japan), Scott Noggle (New York Stem Cell Foundation), and Lara Mangravite (Sage Bionetworks). Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Funding Information: The genotyping for the Knight-ADRC cohort was supported by grants from the National Institutes of Health (R01AG044546 (CC), P01AG003991(CC, JCM), RF1AG053303 (CC), RF1AG058501 (CC), U01AG058922 (CC), the Chan Zuckerberg Initiative (CZI), the Michael J. Fox Foundation (CC), the Department of Defense (LI- W81XWH2010849), the Alzheimer’s Association Zenith Fellows Award (ZEN-22–848,604, awarded to CC), and an Anonymous foundation. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/ ) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Funding Information: 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 & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & 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 ( 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. Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
AB - BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
KW - Alzheimer’s disease
KW - Biomarkers
KW - Cerebrospinal fluid (CSF)
KW - Dementia
KW - Genome-wide association study (GWAS)
KW - Mediation
KW - Multivariate analysis
KW - Principal component analysis
KW - Structural equation modeling
UR - http://www.scopus.com/inward/record.url?scp=85173180888&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13073-023-01233-z
DO - https://doi.org/10.1186/s13073-023-01233-z
M3 - Article
C2 - 37794492
SN - 1756-994X
VL - 15
SP - 79
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 79
ER -