TY - JOUR
T1 - TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
AU - Alzheimer's Disease Neuroimaging Initiative (ADNI)
AU - Hong, Shengjun
AU - Dobricic, Valerija
AU - Ohlei, Olena
AU - Bos, Isabelle
AU - Vos, Stephanie J.B.
AU - Prokopenko, Dmitry
AU - Tijms, Betty M.
AU - Andreasson, Ulf
AU - Blennow, Kaj
AU - Vandenberghe, Rik
AU - Gabel, Silvy
AU - Scheltens, Philip
AU - Teunissen, Charlotte E.
AU - Engelborghs, Sebastiaan
AU - Frisoni, Giovanni
AU - Blin, Olivier
AU - Richardson, Jill C.
AU - Bordet, Regis
AU - Lleó, Alberto
AU - Alcolea, Daniel
AU - Popp, Julius
AU - Clark, Christopher
AU - Peyratout, Gwendoline
AU - Martinez-Lage, Pablo
AU - Tainta, Mikel
AU - Dobson, Richard J.B.
AU - Legido-Quigley, Cristina
AU - Sleegers, Kristel
AU - Van Broeckhoven, Christine
AU - Tanzi, Rudolph E.
AU - ten Kate, Mara
AU - Wittig, Michael
AU - Franke, Andre
AU - Lill, Christina M.
AU - Barkhof, Frederik
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Zetterberg, Henrik
AU - Visser, Pieter Jelle
AU - Bertram, Lars
N1 - Funding Information:
The present study was conducted as part of the EMIF‐AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement No. 115372, the 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. Parts of this study were made possible through support from the German Research Foundation (DFG grant FOR2488: Main support by subproject “INF‐GDAC” BE2287/7‐1 to LB) and the Cure Alzheimer's Fund (to LB and RET). RV acknowledges support by the Stichting Alzheimer Onderzoek (#13007, #11020, #2017‐032) and the Flemish Government (VIND IWT 135043). KB is supported by the Swedish Research Council (#2017‐00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB‐201809‐2016615); the Swedish Alzheimer Foundation (#AF‐742881), Hjärnfonden, Sweden (#FO2017‐0243); the Swedish state under the agreement between the Swedish government and the County Councils; the ALF‐agreement (#ALFGBG‐715986); and European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712), and Swedish State Support for Clinical Research (#ALFGBG‐720931). SJBV received funding from the Innovative Medicines Initiative 2 Joint Undertaking under ROADMAP grant agreement No. 116020 and from ZonMw during the conduct of this study. No conflict of interest exists. Research at VIB‐UAntwerp was in part supported by the University of Antwerp Research Fund. The authors acknowledge the assistance of Ellen De Roeck, Naomi De Roeck, and Hanne Struyfs (UAntwerp) with data collection. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179) to JP.
Funding Information:
We thank Mrs. Tanja Wesse and Mrs. Sanaz Sedghpour Sabet at the Institute of Clinical Molecular Biology, Christian‐Albrechts‐University of Kiel, Kiel, Germany for technical assistance with the GSA genotyping. We thank Dr. Fabian Kilpert for his assistance with the QC and genotype imputations. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of Lübeck.
Funding Information:
For ADNI: Data was used for this project of which collection and sharing 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.
Funding Information:
The present study was conducted as part of the EMIF-AD MBD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement No. 115372, the 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. Parts of this study were made possible through support from the German Research Foundation (DFG grant FOR2488: Main support by subproject ?INF-GDAC? BE2287/7-1 to LB) and the Cure Alzheimer's Fund (to LB and RET). RV acknowledges support by the Stichting Alzheimer Onderzoek (#13007, #11020, #2017-032) and the Flemish Government (VIND IWT 135043). KB is supported by the Swedish Research Council (#2017-00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); the Swedish Alzheimer Foundation (#AF-742881), Hj?rnfonden, Sweden (#FO2017-0243); the Swedish state under the agreement between the Swedish government and the County Councils; the ALF-agreement (#ALFGBG-715986); and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), and Swedish State Support for Clinical Research (#ALFGBG-720931). SJBV received funding from the Innovative Medicines Initiative 2 Joint Undertaking under ROADMAP grant agreement No. 116020 and from ZonMw during the conduct of this study. No conflict of interest exists. Research at VIB-UAntwerp was in part supported by the University of Antwerp Research Fund. The authors acknowledge the assistance of Ellen De Roeck, Naomi De Roeck, and Hanne Struyfs (UAntwerp) with data collection. The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179) to JP. We thank Mrs. Tanja Wesse and Mrs. Sanaz Sedghpour Sabet at the Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany for technical assistance with the GSA genotyping. We thank Dr. Fabian Kilpert for his assistance with the QC and genotype imputations. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of L?beck. For ADNI: Data was used for this project of which collection and sharing 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:
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association
PY - 2021/10
Y1 - 2021/10
N2 - Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
AB - Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
KW - Alzheimer's disease
KW - biomarker
KW - cerebrospinal fluid
KW - chitinase-3-like protein 1
KW - genome-wide association study
KW - neurofilament light
KW - neurogranin
UR - http://www.scopus.com/inward/record.url?scp=85105851942&partnerID=8YFLogxK
U2 - 10.1002/alz.12330
DO - 10.1002/alz.12330
M3 - Article
AN - SCOPUS:85105851942
SN - 1552-5260
VL - 17
SP - 1628
EP - 1640
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 10
ER -
