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1. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

Author

Simon Lovestone, Lars Bertram, Pieter Jelle Visser, Dmitry Prokopenko, Isabelle Bos, Régis Bordet, Daniel Alcolea, Sebastiaan Engelborghs, Betty M. Tijms, Silvy Gabel, Charlotte E. Teunissen, Olivier Blin, Jill C. Richardson, Olena Ohlei, Henrik Zetterberg, Richard Dobson, Christina M. Lill, Christopher M. Clark, Giovanni B. Frisoni, Philip Scheltens, Rik Vandenberghe, Johannes Streffer, Valerija Dobricic, Alberto Lleó, Cristina Legido-Quigley, Andre Franke, Mara ten Kate, Gwendoline Peyratout, Christine Van Broeckhoven, Kaj Blennow, Julius Popp, Frederik Barkhof, Stephanie J.B. Vos, Mikel Tainta, Michael Wittig, Pablo Martinez-Lage, Ulf Andreasson, Shengjun Hong, Alzheimer's Disease Neuroimaging Initiative, Kristel Sleegers, Rudolph E. Tanzi, Neuroimaging Initiative, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Pathologic Biochemistry and Physiology, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Radiology and nuclear medicine

Subjects
0301 basic medicine, Male, Epidemiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 3&#8208, LOCI, Genome-wide association study, Disease, Bioinformatics, Alzheimer&apos, 0302 clinical medicine, Cerebrospinal fluid, Chitinase-3-like protein 1, like protein 1, Neurofilament Proteins, neurofilament light, Medicine, Nerve Tissue Proteins/genetics, Neurogranin, Biomarker discovery, wide association study, RISK, neurogranin, Health Policy, genome&#8208, Alzheimer's disease, ATLAS, Psychiatry and Mental health, chitinase&#8208, Chitinase-3-Like Protein 1/genetics, Biomarker (medicine), biomarker, Female, Life Sciences & Biomedicine, chitinase-3-like protein 1, PROTEINS, Clinical Neurology, BETA, Nerve Tissue Proteins, cerebrospinal fluid, s disease, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurofilament Proteins/genetics, Alzheimer Disease, Neurogranin/cerebrospinal fluid, Humans, Biomarkers/cerebrospinal fluid, Membrane Proteins/genetics, GENOME-WIDE ASSOCIATION, Genetic association, Aged, Alzheimer Disease/genetics, Science & Technology, business.industry, Membrane Proteins, Genetic architecture, 030104 developmental biology, Neurology (clinical), Human medicine, Neurosciences & Neurology, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study
Abstract

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. ispartof: ALZHEIMERS & DEMENTIA vol:17 issue:10 pages:1628-1640 ispartof: location:United States status: published

Published
2021
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2. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

Author

Hong, SJ, Dobricic, V, Ohlei, O, Bos, I, Vos, SJB, Prokopenko, D, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Gabel, S, Scheltens, P, Teunissen, CE, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Lleo, A, Alcolea, D, Popp, J, Clark, C, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, Tanzi, RE, ten Kate, M, Wittig, M, Franke, A, Lill, CM, Barkhof, F, Lovestone, S, Streffer, J, Zetterberg, H, Visser, PJ, Bertram, L, and Neuroimaging Initiative

Subjects
s disease, wide association study, chitinase&#8208, like protein 1, neurogranin, neurofilament light, 3&#8208, biomarker, genome&#8208, Alzheimer&apos, cerebrospinal fluid
Abstract

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.

Published
2021

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