TY - JOUR
T1 - Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
AU - Hong, Shengjun
AU - Prokopenko, Dmitry
AU - Dobricic, Valerija
AU - Kilpert, Fabian
AU - Bos, Isabelle
AU - Vos, Stephanie J. B.
AU - Tijms, Betty M.
AU - Andreasson, Ulf
AU - Blennow, Kaj
AU - Vandenberghe, Rik
AU - Cleynen, Isabelle
AU - Gabel, Silvy
AU - Schaeverbeke, Jolien
AU - Scheltens, Philip
AU - Teunissen, Charlotte E.
AU - Niemantsverdriet, Ellis
AU - Engelborghs, Sebastiaan
AU - Frisoni, Giovanni
AU - Blin, Olivier
AU - Richardson, Jill C.
AU - Bordet, Regis
AU - Molinuevo, Jose Luis
AU - Rami, Lorena
AU - Kettunen, Petronella
AU - Wallin, Anders
AU - Lleo, Alberto
AU - Sala, Isabel
AU - Popp, Julius
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 - ten Kate, Mara
AU - Barkhof, Frederik
AU - Zetterberg, Henrik
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Wittig, Michael
AU - Franke, Andre
AU - Tanzi, Rudolph E.
AU - Visser, Pieter Jelle
AU - Bertram, Lars
AU - Alzheimer's Disease Neuroimaging Initiative
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 n° 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). R.V. acknowledges the support by the Stichting Alzheimer Onderzoek (#13007, #11020, #2017-032) and the Flemish Government (VIND IWT 135043). H.Z. is a Wallenberg Academy Fellow supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712) and Swedish State Support for Clinical Research (#ALFGBG-720931). S. J.B.V. 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 research was supported by ALF clinical grants from Region Västra Götaland to A.W. and to P.K. We 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 J.P. 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. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of Lübeck. The computations in the ADNI cohort were run on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University. 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 NeuroImaging at the University of Southern California.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/22
Y1 - 2020/12/22
N2 - Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (A beta) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to A beta 42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A beta 38 and CSF-A beta 40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-A beta and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
AB - Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (A beta) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to A beta 42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A beta 38 and CSF-A beta 40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-A beta and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
KW - RISK VARIANTS
KW - SUSCEPTIBILITY LOCI
KW - TAU
U2 - 10.1038/s41398-020-01074-z
DO - 10.1038/s41398-020-01074-z
M3 - Article
C2 - 33223526
SN - 2158-3188
VL - 10
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 403
ER -