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Multivariate GWAS o...
Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
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Neumann, Alexander (author)
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Ohlei, Olena (author)
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Küçükali, Fahri (author)
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Bos, Isabelle J (author)
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Timsina, Jigyasha (author)
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Vos, Stephanie (author)
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Prokopenko, Dmitry (author)
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Tijms, Betty M (author)
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- Andreasson, Ulf, 1968 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Blennow, Kaj, 1958 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Vandenberghe, Rik (author)
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Scheltens, Philip (author)
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Teunissen, Charlotte E (author)
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Engelborghs, Sebastiaan (author)
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Frisoni, Giovanni B (author)
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Blin, Oliver (author)
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Richardson, Jill C (author)
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Bordet, Régis (author)
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Lleó, Alberto (author)
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Alcolea, Daniel (author)
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Popp, Julius (author)
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Marsh, Thomas W (author)
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Gorijala, Priyanka (author)
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Clark, Christopher (author)
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Peyratout, Gwendoline (author)
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Martinez-Lage, Pablo (author)
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Tainta, Mikel (author)
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Dobson, Richard J B (author)
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Legido-Quigley, Cristina (author)
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Van Broeckhoven, Christine (author)
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Tanzi, Rudolph E (author)
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Ten Kate, Mara (author)
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Lill, Christina M (author)
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Barkhof, Frederik (author)
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Cruchaga, Carlos (author)
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Lovestone, Simon (author)
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Streffer, Johannes (author)
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Visser, Pieter Jelle (author)
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Sleegers, Kristel (author)
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Bertram, Lars (author)
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: Genome medicine. - 1756-994X. ; 15:1
- Related links:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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 analysesof 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Humans
- Female
- Male
- Alzheimer Disease
- genetics
- pathology
- 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
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Neumann, Alexand ...
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Ohlei, Olena
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Küçükali, Fahri
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Bos, Isabelle J
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Timsina, Jigyash ...
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Vos, Stephanie
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show more...
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Prokopenko, Dmit ...
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Tijms, Betty M
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Andreasson, Ulf, ...
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Blennow, Kaj, 19 ...
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Vandenberghe, Ri ...
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Scheltens, Phili ...
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Teunissen, Charl ...
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Engelborghs, Seb ...
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Frisoni, Giovann ...
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Blin, Oliver
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Richardson, Jill ...
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Bordet, Régis
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Lleó, Alberto
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Alcolea, Daniel
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Popp, Julius
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Marsh, Thomas W
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Gorijala, Priyan ...
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Clark, Christoph ...
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Peyratout, Gwend ...
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Martinez-Lage, P ...
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Tainta, Mikel
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Dobson, Richard ...
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Legido-Quigley, ...
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Van Broeckhoven, ...
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Tanzi, Rudolph E
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Ten Kate, Mara
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Lill, Christina ...
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Barkhof, Frederi ...
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Cruchaga, Carlos
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Lovestone, Simon
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Streffer, Johann ...
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Zetterberg, Henr ...
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Visser, Pieter J ...
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Sleegers, Kriste ...
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Bertram, Lars
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Genome medicine
- By the university
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University of Gothenburg