Related Experiment Video

Updated: Jul 4, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Genetic evidence prioritizes circulating proteins for heart failure beyond shared BMI-related genetic liability

Chen-Yang Su1, Tianyuan Lu1,2,3,4,5

  • 1Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.

Medrxiv : the Preprint Server for Health Sciences
|July 3, 2026
PubMed

Insights

Researchers identified nine circulating proteins linked to heart failure (HF) independent of body mass index (BMI) genetic links. This study advances understanding of HF pathways and nominates new protein targets for therapeutic exploration.

Area of Science:

  • Genetics and Genomics
  • Cardiovascular Diseases
  • Proteomics

Background:

  • Heart failure (HF) and body mass index (BMI) share significant genetic factors, potentially biasing genetic discoveries towards adiposity pathways.
  • Identifying HF-associated proteins independent of shared genetic components with BMI is crucial for comprehensive target discovery.

Purpose of the Study:

  • To identify circulating proteins associated with HF beyond the genetic overlap with BMI.
  • To leverage advanced genetic and proteomic analyses to uncover novel HF mechanisms and therapeutic targets.

Main Methods:

  • Applied GWAS-by-subtraction to separate HF genetic susceptibility into BMI-related and BMI-subtracted components.
  • Utilized proteome-wide Mendelian randomization and colocalization across four cohorts to prioritize protein-HF associations.
  • Integrated tissue-specific eQTL colocalization and cardiac transcriptomic data for further validation and druggability assessment.

Main Results:

  • The BMI-subtracted HF components showed reduced genetic correlation with BMI while retaining significant HF loci.
  • Nine circulating proteins were prioritized through Mendelian randomization and colocalization analyses across 19,930 tests.
  • Specific proteins like CELSR2 and CSF3 demonstrated significant associations with HF risk, with CELSR2 and TMEM106B colocalizing in cardiac tissue.

Conclusions:

  • Identified nine novel circulating proteins associated with HF, independent of shared genetic liability with BMI.
  • These findings expand the spectrum of genetically supported HF pathways and nominate candidate proteins for future research.
  • The study highlights the importance of accounting for shared genetic factors like BMI in human genetics-guided HF target discovery.
Abstract

Keywords:
GeneticsHeart FailureMendelian RandomizationObesityProteomics

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