Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

Humans Female Male Alzheimer Disease / genetics Genome-Wide Association Study tau Proteins / genetics Biomarkers Inflammation Apolipoproteins E / genetics Membrane Proteins / genetics Nerve Tissue Proteins / genetics Receptors, N-Methyl-D-Aspartate / genetics
Alzheimer’s disease Biomarkers Cerebrospinal fluid (CSF) Dementia Genome-wide association study (GWAS) Mediation Multivariate analysis Principal component analysis Structural equation modeling

Journal

Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844

Informations de publication

Date de publication:
04 10 2023
Historique:
received: 24 07 2023
accepted: 12 09 2023
medline: 6 10 2023
pubmed: 5 10 2023
entrez: 4 10 2023
Statut: epublish

Résumé

Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Sections du résumé

BACKGROUND
Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.
METHODS
We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.
RESULTS
Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.
CONCLUSIONS
These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Identifiants

DOI: 10.1186/s13073-023-01233-z PMID: 37794492 PMC: PMC10548686
pubmed: 37794492
doi: 10.1186/s13073-023-01233-z
pii: 10.1186/s13073-023-01233-z
pmc: PMC10548686
doi:

Substances chimiques

tau Proteins 0
Biomarkers 0
Apolipoproteins E 0
TMEM106B protein, human 0
Membrane Proteins 0
Nerve Tissue Proteins 0
GRIN2D protein, human 0
Receptors, N-Methyl-D-Aspartate 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

79

Subventions

Organisme : European Research Council
ID : 101039672
Pays : International
Organisme : Department of Health
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG044546
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG003991
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG053303
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG058501
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG058922
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072975
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG036836
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046152
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061356
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046139
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG016574
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG032990
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046139
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG018023
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG018023
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG006786
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG017216
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG039495
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS080820
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS072026
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG019610
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046170
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057440
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG061340
Pays : United States

Informations de copyright

© 2023. BioMed Central Ltd., part of Springer Nature.

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Auteurs

Alexander Neumann (A)

Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, Netherlands.

Olena Ohlei (O)

Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, Lübeck, 23562, Germany.

Fahri Küçükali (F)

Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

Isabelle J Bos (IJ)

Netherlands Institute for Health Services Research, Utrecht, Netherlands.

Jigyasha Timsina (J)

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.

Stephanie Vos (S)

Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.

Dmitry Prokopenko (D)

Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Betty M Tijms (BM)

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.

Ulf Andreasson (U)

Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

Kaj Blennow (K)

Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

Rik Vandenberghe (R)

Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
Neurology Service, University Hospital Leuven, Leuven, Belgium.

Philip Scheltens (P)

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.

Charlotte E Teunissen (CE)

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.

Sebastiaan Engelborghs (S)

Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Department of Neurology and Memory Clinic, Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Giovanni B Frisoni (GB)

Memory Center, Department of Rehabilitation and Geriatrics, Geneva University and University Hospitals, Geneva, Switzerland.

Oliver Blin (O)

Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France.

Jill C Richardson (JC)

Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.

Régis Bordet (R)

Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France.

Alberto Lleó (A)

Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

Daniel Alcolea (D)

Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

Julius Popp (J)

Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zurich, Switzerland.
Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Thomas W Marsh (TW)

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.
Division of Biology & Biomedical Sciences, Washington University in St. Louis, St Louis, MO, USA.

Priyanka Gorijala (P)

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.

Christopher Clark (C)

Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zurich, Switzerland.

Gwendoline Peyratout (G)

Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Pablo Martinez-Lage (P)

Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.

Mikel Tainta (M)

Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
Zumarraga Hospital, Osakidetza, Integrated Health Organization (OSI) Goierri-Urola Garia, Basque Country, Spain.

Richard J B Dobson (RJB)

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Boston, UK.
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.
Health Data Research UK London, University College London, London, UK.
Institute of Health Informatics, University College London, London, UK.
The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.

Cristina Legido-Quigley (C)

Steno Diabetes Center, Copenhagen, Denmark.
Institute of Pharmaceutical Science, King's College London, London, UK.

Christine Van Broeckhoven (C)

Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.

Rudolph E Tanzi (RE)

Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Mara Ten Kate (M)

Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands.
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.

Christina M Lill (CM)

Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, Lübeck, 23562, Germany.
Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, UK.

Frederik Barkhof (F)

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands.
Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK.

Carlos Cruchaga (C)

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.
Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.

Simon Lovestone (S)

Janssen Medical Ltd, Wycombe, UK.
Department of Psychiatry, University of Oxford, Oxford, UK.

Johannes Streffer (J)

Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
AC Immune SA, Lausanne, Switzerland.
Janssen R&D, LLC, Beerse, Belgium.

Henrik Zetterberg (H)

Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
UK Dementia Research Institute, University College London, London, UK.
Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.

Pieter Jelle Visser (PJ)

Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.
Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands.

Kristel Sleegers (K)

Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

Lars Bertram (L)

Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, Lübeck, 23562, Germany. lars.bertram@uni-luebeck.de.
Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway. lars.bertram@uni-luebeck.de.
ORCID: 0000-0002-0108-124X

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Protéines tau › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines E › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Multivariate GWAS of Alzheimer's disease CSF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs au glutamate › Récepteurs ionotropes du glutamate › Récepteurs du N-méthyl-D-aspartate › Multivariate GWAS of Alzheimer's disease CSF...