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The genetic regulation of protein expression in cerebrospinal fluid

Hansson, Oskar LU orcid ; Kumar, Atul LU orcid ; Janelidze, Shorena LU ; Stomrud, Erik LU ; Insel, Philip S. LU ; Blennow, Kaj LU ; Zetterberg, Henrik LU ; Fauman, Eric ; Hedman, Åsa K. and Nagle, Michael W. , et al. (2023) In EMBO Molecular Medicine 15(1).
Abstract

Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10−10, 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN... (More)

Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10−10, 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomarkers, cerebrospinal fluid, genetic regulation, Mendelian randomization, pQTL
in
EMBO Molecular Medicine
volume
15
issue
1
article number
e16359
publisher
Wiley-Blackwell
external identifiers
  • pmid:36504281
  • scopus:85144027045
ISSN
1757-4676
DOI
10.15252/emmm.202216359
language
English
LU publication?
yes
id
69f8b86a-b6ed-4984-afa4-2d24b8224e35
date added to LUP
2023-01-26 16:21:24
date last changed
2023-09-25 09:07:40
@article{69f8b86a-b6ed-4984-afa4-2d24b8224e35,
  abstract     = {{<p>Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P &lt; 1.25 × 10<sup>−10</sup>, 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.</p>}},
  author       = {{Hansson, Oskar and Kumar, Atul and Janelidze, Shorena and Stomrud, Erik and Insel, Philip S. and Blennow, Kaj and Zetterberg, Henrik and Fauman, Eric and Hedman, Åsa K. and Nagle, Michael W. and Whelan, Christopher D. and Baird, Denis and Mälarstig, Anders and Mattsson-Carlgren, Niklas}},
  issn         = {{1757-4676}},
  keywords     = {{biomarkers; cerebrospinal fluid; genetic regulation; Mendelian randomization; pQTL}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{The genetic regulation of protein expression in cerebrospinal fluid}},
  url          = {{http://dx.doi.org/10.15252/emmm.202216359}},
  doi          = {{10.15252/emmm.202216359}},
  volume       = {{15}},
  year         = {{2023}},
}