Mapping the serum proteome to neurological diseases using whole genome sequencing

Nat Commun. 2021 Dec 2;12(1):7042. doi: 10.1038/s41467-021-27387-1.

Abstract

Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / blood
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Biomarkers / blood
  • Cohort Studies
  • Gene Expression
  • Gene Ontology
  • Genetic Predisposition to Disease
  • Genome, Human
  • Humans
  • Membrane Glycoproteins / blood
  • Membrane Glycoproteins / genetics*
  • Mendelian Randomization Analysis
  • Molecular Sequence Annotation
  • Parkinson Disease / blood
  • Parkinson Disease / diagnosis
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Proteome / genetics
  • Proteome / metabolism
  • Quantitative Trait Loci
  • Scavenger Receptors, Class A / blood
  • Scavenger Receptors, Class A / genetics*
  • Schizophrenia / blood
  • Schizophrenia / diagnosis
  • Schizophrenia / genetics*
  • Schizophrenia / pathology
  • Sialic Acid Binding Ig-like Lectin 3 / blood
  • Sialic Acid Binding Ig-like Lectin 3 / genetics*
  • Whole Genome Sequencing

Substances

  • Biomarkers
  • CD33 protein, human
  • GPNMB protein, human
  • MSR1 protein, human
  • Membrane Glycoproteins
  • Proteome
  • Scavenger Receptors, Class A
  • Sialic Acid Binding Ig-like Lectin 3