The genetic regulation of protein expression in cerebrospinal fluid


A proteogenomics study headed by researchers from Lund University has looked at the relationships between genetic variants and the levels of almost 400 proteins measured in cerebrospinal fluid (CSF) from over 1500 subjects. Examining genetic effects on protein levels (protein quantitative trait loci, or pQTLs) in relationship to disease phenotypes can provide vital insights into pathobiology and identify causally linked proteins that could represent new drug targets.


Protein measurements using Olink® Target 96 CVD II, Inflammation, Neurology and Neuro-Exploratory panels in combination with a GWAS analysis identified 176 pQTLs for 145 CSF proteins, most of which represented novel findings. Of these, 117 were cis-pQTLS (sequence variant located within or close to the gene encoding the affected protein) and 59 trans-pQTLs (sequence variant located far away from the gene encoding the affected protein). When the cis-pQTL data was analysed in the context of disease phenotype data and Mendelian Randomization (MR) was applied,  causal roles were suggested for several proteins in neurological diseases: ApoE, CD33, and GRN in Alzheimer’s disease, MMP-10 in preclinical Alzheimer’s disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, & ADAM15 in Parkinson’s disease. Examination of brain ventricle volume via MRI data available for some subjects in the study indicated that ventricle volume could be a confounder for some CSF pQTLs, likely due to protein dilution effects.

This study provided a wealth of information about gene variants related to the expression of proteins with relevance to neurological diseases. The findings findings point to pathways to be explored for novel therapies and provide important guidance for the design of future studies.



Hansson O, Kumar A, Janelidze S, et al. The genetic regulation of protein expression in cerebrospinal fluid. (2022) EMBO Molecular Medicine, DOI: 10.15252/emmm.202216359

The main novelties included the use of highly specific proximity extension assays in a large cohort, and the integration of brain volumetrics to account for confounding factors. New possible treatment targets for several neurological diseases were nominated

Hansson et al. (2022)

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