CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer’s disease

Despite the identification of numerous genetic risk variants for Alzheimer's disease (AD), mechanisms through which these variants act remain unclear. Identifying specific proteins levels affected by genetic variation can provide valuable insights into the underlying biological pathways implicated in AD. To gain more insight into effects of genetic variation on AD-related processes, we conducted a genome-wide protein pQTL study using untargeted TMT mass spectrometry in cerebrospinal fluid (CSF) of 2,215 proteins across 487 individuals. Replication was assessed in the independent EMIF-AD MBD cohort of 242 individuals. We identified 399 independent CSF pQTL signals ( P Bonferroni < 2.26 × 10⁻11) associated with 222 proteins, 69% of which were novel. Findings included gene-protein links such as RPS23P10/HSPA6 with CSF FCGR2A, BIN2 with CSF GALNT6, APOE with CSF HS3ST1, and the HLA -region with CSF HLA-DPB1 and PLXDC2. We replicated 230 of 270 gene-protein associations. A proteome-wide association study identified genetically predicted CSF protein levels to be associated with AD, including SIRPA, PLXDC2, and GALNT6. Many AD pQTLs in CSF were enriched in neuroimmune activation, suggesting a genetic basis for neuroimmune dysregulation in AD. This study highlights how genetic variation shapes protein expression in the central nervous system, offering mechanistic insight into AD.

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Publication Details

Journal
Molecular Neurodegeneration Advances
Published
2026-09-17
DOI
https://doi.org/10.1186/s44477-026-00048-7
Primary Topic
Genetic Mapping and Diversity in Plants and Animals
Type
article
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article

CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer’s disease

Arya Yigit, Julius Popp, Valerija Dobričić, Betty M. Tijms et al.
Molecular Neurodegeneration Advances
Genetic Mapping and Diversity in Plants and Animals
article

CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer’s disease

Arya Yigit, Julius Popp, Valerija Dobričić, Betty M. Tijms, Wiesje M. van der Flier, P. J. Visser, Charlotte E. Teunissen, Roel A. Ophoff, Mikel Tainta, Stephanie J. B. Vos, Pablo Martinez-Lage, Rik Vandenberghe, Lianne M. Reus, Henne Holstege, Henrik Zetterberg, Anouk den Braber, Kaj Blennow, Argonde C. van Harten, Lars Bertram, Yvonne Freund-Levi, Sven J. van der Lee, Lutz Frölich, Chenyang Jiang, Natalia Vilor-Tejedor, Johan Gobom, Magda Tsolaki, Toni Boltz
article en

Abstract

Despite the identification of numerous genetic risk variants for Alzheimer's disease (AD), mechanisms through which these variants act remain unclear. Identifying specific proteins levels affected by genetic variation can provide valuable insights into the underlying biological pathways implicated in AD. To gain more insight into effects of genetic variation on AD-related processes, we conducted a genome-wide protein pQTL study using untargeted TMT mass spectrometry in cerebrospinal fluid (CSF) of 2,215 proteins across 487 individuals. Replication was assessed in the independent EMIF-AD MBD cohort of 242 individuals. We identified 399 independent CSF pQTL signals ( P Bonferroni < 2.26 × 10⁻11) associated with 222 proteins, 69% of which were novel. Findings included gene-protein links such as RPS23P10/HSPA6 with CSF FCGR2A, BIN2 with CSF GALNT6, APOE with CSF HS3ST1, and the HLA -region with CSF HLA-DPB1 and PLXDC2. We replicated 230 of 270 gene-protein associations. A proteome-wide association study identified genetically predicted CSF protein levels to be associated with AD, including SIRPA, PLXDC2, and GALNT6. Many AD pQTLs in CSF were enriched in neuroimmune activation, suggesting a genetic basis for neuroimmune dysregulation in AD. This study highlights how genetic variation shapes protein expression in the central nervous system, offering mechanistic insight into AD.

Molecular Neurodegeneration AdvancesVol. 2(1)
Broad Institute (US), Radboud University Nijmegen (NL), University of California, Los Angeles (US), Heidelberg University (DE), Örebro University (SE), AHEPA University Hospital (GR), Sahlgrenska University Hospital (SE), University Hospital Heidelberg (DE), Maastricht University (NL), Massachusetts General Hospital (US), Stockholm South General Hospital (SE), Örebro County Council (SE), University Hospital of Zurich (CH), Central Institute of Mental Health (DE), Pasqual Maragall Foundation (ES), Amsterdam Neuroscience (NL), UK Dementia Research Institute (GB), Södertälje Sjukhus (SE), Barcelonaβeta Brain Research Center (ES), Örebro University Hospital (SE), Alzheimer Nederland (NL), Centre for Genomic Regulation (ES), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), University College London (GB), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL), University of Lübeck (DE), University of Lausanne (CH), KU Leuven (BE)
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