Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
Por:
Hong, SJ, Prokopenko, D, Dobricic, V, Kilpert, F, Bos, I, Vos, SJB, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Cleynen, I, Gabel, S, Schaeverbeke, J, Scheltens, P, Teunissen, CE, Niemantsverdriet, E, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Molinuevo, JL, Rami, L, Kettunen, P, Wallin, A, Lleo, A, Sala, I, Popp, J, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, ten Kate, M, Barkhof, F, Zetterberg, H, Lovestone, S, Streffer, J, Wittig, M, Franke, A, Tanzi, RE, Visser, PJ, Bertram, L, Alzheimers Dis Neuroimaging Initia
Publicada:
22 dic 2020
Ahead of Print:
22 nov 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 (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.
Filiaciones:
Hong, SJ:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Neurogenet & Cardiogenet Univ, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Prokopenko, D:
Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Unit, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Neurol, McCance Ctr Brain Hlth, Boston, MA 02114 USA
Dobricic, V:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Neurogenet & Cardiogenet Univ, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Kilpert, F:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Neurogenet & Cardiogenet Univ, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Bos, I:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands
Vos, SJB:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Tijms, BM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands
Andreasson, U:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Blennow, K:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Vandenberghe, R:
Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium
Univ Hosp Leuven, Neurol Serv, Leuven, Belgium
Cleynen, I:
Katholieke Univ Leuven, Dept Human Genet, Lab Complex Genet, Leuven, Belgium
Gabel, S:
Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium
Schaeverbeke, J:
Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium
Scheltens, P:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands
Teunissen, CE:
Vrije Univ, Amsterdam Univ Med Ctr, Dept Clin Chem, Neurochem Lab,Amsterdam Neurosci, Amsterdam, Netherlands
Niemantsverdriet, E:
Univ Antwerp, Inst Born Bunge, Dept Biomed Sci, Antwerp, Belgium
Engelborghs, S:
Univ Antwerp, Inst Born Bunge, Dept Biomed Sci, Antwerp, Belgium
UZ Brussel, Dept Neurol, Brussels, Belgium
UZ Brussel, Ctr Neurosci, Brussels, Belgium
Vrije Univ Brussel VUB, Brussels, Belgium
Frisoni, G:
Univ Geneva, Geneva, Switzerland
IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Brescia, Italy
Blin, O:
AIX Marseille Univ, AP HM, INS, Marseille, France
Richardson, JC:
GlaxoSmithKline R&D, Neurosci Therapeut Area, Stevenage, Herts, England
Bordet, R:
Univ Lille, CHU Lille, INSERM, Lille, France
Molinuevo, JL:
Hosp Clin & Univ, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Rami, L:
Hosp Clin & Univ, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Kettunen, P:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Univ Oxford, Dept Neuropathol, Nuffield Dept Clin Neurosci, Oxford, England
Wallin, A:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Lleo, A:
Hosp Santa Creu & Sant Pau, Neurol Dept, Memory Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Sala, I:
Hosp Santa Creu & Sant Pau, Neurol Dept, Memory Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Popp, J:
Geneva Univ Hosp, Dept Mental Hlth & Psychiat, Geriatr Psychiat, Geneva, Switzerland
Univ Hosp Lausanne, Dept Psychiat, Lausanne, Switzerland
Peyratout, G:
Univ Hosp Lausanne, Dept Psychiat, Lausanne, Switzerland
Martinez-Lage, P:
CITA Alzheimer Fdn, Ctr Res & Adv Therapies, Dept Neurol, San Sebastian, Spain
Tainta, M:
CITA Alzheimer Fdn, Ctr Res & Adv Therapies, Dept Neurol, San Sebastian, Spain
Dobson, RJB:
Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Biostat & Hlth Informat, London, England
Kings Coll London, NIHR Maudsley Biomed Res Ctr BRC, South London & Maudsley NHS Fdn Trust SLaM, NIHR BioResource Ctr Maudsley, London, England
Kings Coll London, Inst Psychiat Psychol & Neurosci IoPPN, London, England
UCL, Hlth Data Res UK London, 222 Euston Rd, London, England
UCL, Inst Hlth Informat, 222 Euston Rd, London, England
UCL, Univ Coll London Hosp Biomed Res Ctr, Natl Inst Hlth Res, 222 Euston Rd, London, England
Legido-Quigley, C:
Steno Diabet Ctr, Copenhagen, Denmark
Kings Coll London, Inst Pharmaceut Sci, London, England
Sleegers, K:
VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
Van Broeckhoven, C:
VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
ten Kate, M:
Amsterdam Univ Med Ctr, Alzheimer Ctr, Amsterdam Neurosci, Amsterdam, Netherlands
Amsterdam Univ Med Ctr, Dept Neurol, Amsterdam Neurosci, Amsterdam, Netherlands
Amsterdam Univ Med Ctr, Dept Radiol & Nucl Med, Amsterdam Neurosci, Amsterdam, Netherlands
Barkhof, F:
UCL, Inst Neurol, London, England
Zetterberg, H:
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
UCL Queen Sq Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England
UCL, UK Dementia Res Inst, London, England
Lovestone, S:
Univ Oxford, Dept Psychiat, Oxford, England
Streffer, J:
Univ Antwerp, Reference Ctr Biol Markers Dementia BIODEM, Inst Born Bunge, Antwerp, Belgium
UCB Biopharma SPRL, Translat Med Neurosci, Braine Lalleud, Belgium
Wittig, M:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Franke, A:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Tanzi, RE:
Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Unit, Boston, MA 02114 USA
Massachusetts Gen Hosp, Dept Neurol, McCance Ctr Brain Hlth, Boston, MA 02114 USA
Visser, PJ:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands
Bertram, L:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Neurogenet & Cardiogenet Univ, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Oslo, Dept Psychol, Oslo, Norway
Gold, Green Published
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