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ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and

Natalia Cullell1,2,3,4, Cristina Gallego-Fábrega1, Jara Cárcel-Márquez1,5

  • 1Stroke Pharmacogenomics and Genetics Group, Biomedical Research Institute Sant Pau, 08041 Barcelona, Spain.

International Journal of Molecular Sciences
|March 25, 2022
PubMed

Insights

This study reveals ICA1L protein levels in the brain are causally linked to small vessel strokes (SVS) and non-lobar intracerebral haemorrhages (ICH). These findings highlight cis-regulation of ICA1L as a key mechanism in cerebral small vessel disease outcomes.

Area of Science:

  • Neuroscience
  • Genetics
  • Proteomics

Background:

  • Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD).
  • Previous genetic studies identified loci associated with both SVS and ICH, but cis-regulation at the protein level remained unstudied.
  • Understanding protein-level regulation is crucial for elucidating SVD pathogenesis.

Purpose of the Study:

  • To investigate the common protein-level cis-regulatory mechanisms underlying SVS and ICH using a proteome-wide association study (PWAS).
  • To identify specific proteins whose expression is associated with both SVS and ICH.
  • To explore the causal relationship between protein expression and these SVD outcomes.

Main Methods:

  • Integrated genome-wide association study (GWAS) and brain proteomic data using FUSION for PWAS.
  • Utilized dorsolateral prefrontal cortex (dPFC) proteomes from ROS/MAP and summary statistics for SVS and ICH GWAS.
  • Employed co-localization (COLOC) and summary data-based Mendelian randomization (SMR) for validation and causality assessment.

Main Results:

  • Identified ICA1L as a protein significantly associated with both SVS and non-lobar ICH in discovery and validation PWAS.
  • High co-localization posterior probability supported shared genetic regulation for ICA1L.
  • SMR analysis confirmed a causal association between brain ICA1L protein expression and SVS/non-lobar ICH.

Conclusions:

  • The association of ICA1L with SVS and non-lobar ICH is mediated by cis-regulation of its protein levels in the brain.
  • ICA1L represents a potential therapeutic target for mitigating SVD-related stroke and hemorrhage.
  • This study provides novel insights into the molecular mechanisms of cerebral small vessel disease.

Keywords:
PWASgenome-wide association study (GWAS)intracerebral haemorrhageproteome-wide association studysmall vessel diseasesmall vessel stroke

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