Genome Medicine (Oct 2023)
Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning
- Alexander Neumann,
- Olena Ohlei,
- Fahri Küçükali,
- Isabelle J. Bos,
- Jigyasha Timsina,
- Stephanie Vos,
- Dmitry Prokopenko,
- Betty M. Tijms,
- Ulf Andreasson,
- Kaj Blennow,
- Rik Vandenberghe,
- Philip Scheltens,
- Charlotte E. Teunissen,
- Sebastiaan Engelborghs,
- Giovanni B. Frisoni,
- Oliver Blin,
- Jill C. Richardson,
- Régis Bordet,
- Alberto Lleó,
- Daniel Alcolea,
- Julius Popp,
- Thomas W. Marsh,
- Priyanka Gorijala,
- Christopher Clark,
- Gwendoline Peyratout,
- Pablo Martinez-Lage,
- Mikel Tainta,
- Richard J. B. Dobson,
- Cristina Legido-Quigley,
- Christine Van Broeckhoven,
- Rudolph E. Tanzi,
- Mara ten Kate,
- Christina M. Lill,
- Frederik Barkhof,
- Carlos Cruchaga,
- Simon Lovestone,
- Johannes Streffer,
- Henrik Zetterberg,
- Pieter Jelle Visser,
- Kristel Sleegers,
- Lars Bertram,
- EMIF-AD & ADNI study group
Affiliations
- Alexander Neumann
- Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB
- Olena Ohlei
- Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck
- Fahri Küçükali
- Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB
- Isabelle J. Bos
- Netherlands Institute for Health Services Research
- Jigyasha Timsina
- Department of Psychiatry, Washington University School of Medicine
- Stephanie Vos
- Alzheimer Centrum Limburg, Maastricht University
- Dmitry Prokopenko
- Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital
- Betty M. Tijms
- Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC
- Ulf Andreasson
- Department of Psychiatry and Neurochemistry, University of Gothenburg
- Kaj Blennow
- Department of Psychiatry and Neurochemistry, University of Gothenburg
- Rik Vandenberghe
- Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven
- Philip Scheltens
- Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC
- Charlotte E. Teunissen
- Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC
- Sebastiaan Engelborghs
- Department of Biomedical Sciences, University of Antwerp
- Giovanni B. Frisoni
- Memory Center, Department of Rehabilitation and Geriatrics, Geneva University and University Hospitals
- Oliver Blin
- Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital
- Jill C. Richardson
- Neurosciences Therapeutic Area, GlaxoSmithKline R&D
- Régis Bordet
- Neuroscience & Cognition, CHU de Lille, University of Lille
- Alberto Lleó
- Memory Unit, Neurology Department, Hospital de Sant Pau
- Daniel Alcolea
- Memory Unit, Neurology Department, Hospital de Sant Pau
- Julius Popp
- Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich
- Thomas W. Marsh
- Department of Psychiatry, Washington University School of Medicine
- Priyanka Gorijala
- Department of Psychiatry, Washington University School of Medicine
- Christopher Clark
- Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich
- Gwendoline Peyratout
- Department of Psychiatry, University Hospital of Lausanne
- Pablo Martinez-Lage
- Center for Research and Advanced Therapies, CITA—Alzheimer Foundation
- Mikel Tainta
- Center for Research and Advanced Therapies, CITA—Alzheimer Foundation
- Richard J. B. Dobson
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Cristina Legido-Quigley
- Steno Diabetes Center
- Christine Van Broeckhoven
- Department of Biomedical Sciences, University of Antwerp
- Rudolph E. Tanzi
- Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital
- Mara ten Kate
- Alzheimer Center and Department of Neurology, VU University Medical Center
- Christina M. Lill
- Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck
- Frederik Barkhof
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit
- Carlos Cruchaga
- Department of Psychiatry, Washington University School of Medicine
- Simon Lovestone
- Janssen Medical Ltd
- Johannes Streffer
- Department of Biomedical Sciences, University of Antwerp
- Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, University of Gothenburg
- Pieter Jelle Visser
- Department of Biomedical Sciences, University of Antwerp
- Kristel Sleegers
- Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB
- Lars Bertram
- Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck
- EMIF-AD & ADNI study group
- DOI
- https://doi.org/10.1186/s13073-023-01233-z
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 23
Abstract
Abstract 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.
Keywords
- Alzheimer’s disease
- Dementia
- Biomarkers
- Cerebrospinal fluid (CSF)
- Genome-wide association study (GWAS)
- Multivariate analysis
