Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
Hong, Shengjun (University of Lübeck)
Prokopenko, Dmitry (Massachusetts General Hospital (Boston))
Dobricic, Valerija (University of Lübeck)
Kilpert, Fabian (University of Lübeck)
Bos, Isabelle (Vrije Universiteit Amsterdam)
Vos, Stephanie J.B. (Maastricht University)
Tijms, Betty M (Vrije Universiteit Amsterdam)
Andreasson, Ulf (Sahlgrenska University Hospital (Suècia))
Blennow, Kaj (Sahlgrenska University Hospital (Suècia))
Vandenberghe, Rik (University Hospitals Leuven (Bèlgica))
Cleynen, Isabelle (KU Leuven)
Gabel, Silvy (KU Leuven)
Schaeverbeke, Jolien (KU Leuven)
Scheltens, Philip (Vrije Universiteit Amsterdam)
Teunissen, Charlotte E. (Vrije Universiteit)
Niemantsverdriet, Ellis (University of Antwerp)
Engelborghs, Sebastiaan (UZ Brussel and Vrije Universiteit Brussel (VUB))
Frisoni, Giovanni B. (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Blin, Olivier (Aix-Marseille Université)
Richardson, Jill C. (GlaxoSmithKline R&D)
Bordet, Régis (University of Lille)
Molinuevo, José Luis (Hospital Clínic i Provincial de Barcelona)
Rami Gonzalez, Lorena (Hospital Clínic i Provincial de Barcelona)
Kettunen, Petronella (University of Oxford)
Wallin, Anders (University of Gothenburg)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Sala, Isabel (Institut d'Investigació Biomèdica Sant Pau)
Popp, Julius (Lausanne University Hospital)
Peyratout, Gwendoline (Lausanne University Hospital)
Martinez-Lage, Pablo (Fundación CITA-Alzhéimer Fundazioa (San Sebastián, País Basc))
Tainta, Mikel (Fundación CITA-Alzhéimer Fundazioa (San Sebastián, País Basc))
Dobson, Richard J.B. (University College London)
Legido-Quigley, Cristina (King's College London)
Sleegers, Kristel (University of Antwerp)
Van Broeckhoven, Christine (University of Antwerp)
ten Kate, Mara (Amsterdam Neuroscience)
Barkhof, Frederik (University College London)
Zetterberg, Henrik (UK Dementia Research Institute)
Lovestone, Simon (University of Oxford)
Streffer, Johannes (UCB Biopharma SPRL)
Wittig, Michael (Christian-Albrechts-University of Kiel)
Franke, Andre (Christian-Albrechts-University of Kiel)
Tanzi, Rudolph E. (Massachusetts General Hospital (Boston))
Visser, Pieter Jelle (Vrije Universiteit Amsterdam)
Bertram, Lars (University of Oslo)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	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 (Aβ) 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 Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 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-Aβ 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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Molecular neuroscience ; Personalized medicine
Publicado en:	Translational psychiatry, Vol. 10 Núm. 1 (december 2020) , p. 403, ISSN 2158-3188

DOI: 10.1038/s41398-020-01074-z
PMID: 33223526

12 p, 1.3 MB

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