The genetic regulation of protein expression in cerebrospinal fluid. Issue 1 (12th December 2022)

• Record Type: Journal Article
• Authors: Hansson, Oskar; Kumar, Atul; Janelidze, Shorena; Stomrud, Erik; Insel, Philip S; Blennow, Kaj; Zetterberg, Henrik; Fauman, Eric; Hedman, Åsa K; Nagle, Michael W; Whelan, Christopher D; Baird, Denis; Mälarstig, Anders; Mattsson‐Carlgren, Niklas
• Is Part Of: EMBO molecular medicine. Volume 15:Issue 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-12
• Subjects: biomarkers -- cerebrospinal fluid -- genetic regulation -- Mendelian randomization -- pQTL; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202216359
• Languages: English
• ISSNs: 1757-4676

Abstract

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 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. Synopsis: The genetic regulation of cerebrospinal fluid (CSF) proteins can be explored to increase the understanding of brain disease mechanisms. This study explored protein quantitative trait loci (pQTLs) for 398 CSF proteins analyzed by highly specific protein extension assays in a large human population. 176 significant CSF pQTLs were identified, most of which were novel and had not been described previously for CSF proteins. When combining the results with external GWAS data sources in Mendelian randomization experiments, proteins were identified with potential causal roles in neurological diseases, including Alzheimer's disease, Parkinson's disease, and others. When combining the CSF pQTL results with brain magnetic resonance imaging (MRI), ventricle volume was identified as a possible confounder for some of the pQTLs. Abstract : The genetic regulation of cerebrospinal fluid (CSF) proteins can be explored to increase the understanding of brain disease mechanisms. This study explored protein quantitative trait loci (pQTLs) for 398 CSF proteins analyzed by highly specific protein extension assays in a large human population.