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

Shengjun Hong; Valerija Dobricic; Olena Ohlei; Isabelle Bos; Stephanie J B Vos; Dmitry Prokopenko; Betty M Tijms; Ulf Andreasson; Kaj Blennow; Rik Vandenberghe; Silvy Gabel; Philip Scheltens; Charlotte E Teunissen; Sebastiaan Engelborghs; Giovanni Frisoni; Olivier Blin; Jill C Richardson; Regis Bordet; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alberto Lleó; Daniel Alcolea; Julius Popp; Christopher Clark; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Richard J B Dobson; Cristina Legido-Quigley; Kristel Sleegers; Christine Van Broeckhoven; Rudolph E Tanzi; Mara Ten Kate; Michael Wittig; Andre Franke; Christina M Lill; Frederik Barkhof; Simon Lovestone; Johannes Streffer; Henrik Zetterberg; Pieter Jelle Visser; Lars Bertram

doi:10.1002/alz.12330

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

Alzheimers Dement. 2021 Oct;17(10):1628-1640. doi: 10.1002/alz.12330. Epub 2021 May 14.

Authors

Shengjun Hong¹, Valerija Dobricic¹, Olena Ohlei¹, Isabelle Bos^{2

3}, Stephanie J B Vos^{2

3}, Dmitry Prokopenko⁴, Betty M Tijms³, Ulf Andreasson^{5

6}, Kaj Blennow^{5

6}, Rik Vandenberghe^{7

8}, Silvy Gabel⁷, Philip Scheltens³, Charlotte E Teunissen⁹, Sebastiaan Engelborghs^{10

11}, Giovanni Frisoni^{12

13}, Olivier Blin¹⁴, Jill C Richardson¹⁵, Regis Bordet¹⁶; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alberto Lleó¹⁷, Daniel Alcolea¹⁷, Julius Popp^{18

19}, Christopher Clark¹⁸, Gwendoline Peyratout¹⁹, Pablo Martinez-Lage²⁰, Mikel Tainta²⁰, Richard J B Dobson^{21

22

23

24

25}, Cristina Legido-Quigley²⁶, Kristel Sleegers^{27

28}, Christine Van Broeckhoven^{27

28}, Rudolph E Tanzi⁴, Mara Ten Kate^{29

30}, Michael Wittig³¹, Andre Franke³¹, Christina M Lill^{1

32}, Frederik Barkhof³³, Simon Lovestone³⁴, Johannes Streffer^{35

36}, Henrik Zetterberg^{5

6

37

38}, Pieter Jelle Visser^{2

3

39}, Lars Bertram^{1

40}

Affiliations

¹ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
² Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
³ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands.
⁴ Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁷ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
⁸ Neurology Service, University Hospital Leuven, Leuven, Belgium.
⁹ Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands.
¹⁰ Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹¹ Department of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universiteit Brussel (VUB), Brussels, Belgium.
¹² University of Geneva, Geneva, Switzerland.
¹³ IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹⁴ AIX Marseille University, INS, Ap-hm, Marseille, France.
¹⁵ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
¹⁶ Inserm, CHU Lille, University of Lille, Lille, France.
¹⁷ Memory Unit, Neurology Department. Hospital de Sant Pau, Barcelona and Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
¹⁸ Centre for Gerontopsychiatric Medicine, Department of Geriatric Psychiatry, University Hospital of Psychiatry Zurich, Zürich, Switzerland.
¹⁹ Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
²⁰ Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
²¹ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²² NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
²³ Health Data Research UK London, University College London, London, UK.
²⁴ Institute of Health Informatics, University College London, London, UK.
²⁵ The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.
²⁶ Steno Diabetes Center, Copenhagen, Denmark and Institute of Pharmaceutical Sciences, King's College London, London, UK.
²⁷ Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
²⁸ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
²⁹ Alzheimer Center and Department of Neurology, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, the Netherlands.
³⁰ Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, the Netherlands.
³¹ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
³² Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, United Kingdom.
³³ Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
³⁴ Department of Psychiatry, University of Oxford, Oxford, UK.
³⁵ Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
³⁶ Translational Medicine Neuroscience, UCB Biopharma SPRL, Braine l'Alleud, Belgium.
³⁷ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
³⁸ UK Dementia Research Institute at UCL, London, UK.
³⁹ Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Instutet, Stockholm, Sweden.
⁴⁰ Department of Psychology, University of Oslo, Oslo, Norway.

PMID: 33991015
DOI: 10.1002/alz.12330

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.

Keywords: Alzheimer's disease; biomarker; cerebrospinal fluid; chitinase-3-like protein 1; genome-wide association study; neurofilament light; neurogranin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Alzheimer Disease / genetics*
Biomarkers / cerebrospinal fluid*
Chitinase-3-Like Protein 1 / genetics
Female
Genome-Wide Association Study*
Humans
Male
Membrane Proteins / genetics*
Nerve Tissue Proteins / genetics*
Neurofilament Proteins / genetics
Neurogranin / cerebrospinal fluid

Substances

Biomarkers
CHI3L1 protein, human
Chitinase-3-Like Protein 1
Membrane Proteins
Nerve Tissue Proteins
Neurofilament Proteins
TMEM106B protein, human
neurofilament protein L
Neurogranin

Abstract

Publication types

MeSH terms

Substances

Grants and funding