Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Area of Science:

• Genomics
• Precision Medicine
• Computational Biology

Background:

• Stratified medicine aims to personalize treatments using individual patient data.
• Genetics offers potential for patient stratification, but operationalizing complex genetic risk factors remains challenging.
• Current polygenic risk scores (PRS) have limited clinical utility and lack clear biological underpinnings.

Purpose of the Study:

• To develop a novel approach, CASTom-iGEx, for stratifying individuals based on genetic risk factor profiles.
• To overcome limitations of existing methods like PRS in clinical utility and biological foundation.
• To identify biologically meaningful and clinically actionable patient subgroups.

Main Methods:

• Developed the CASTom-iGEx (CAST-omics integrated Gene Expression) approach.
• Stratified individuals by analyzing the aggregated impact of genetic risk factors on tissue-specific gene expression.
• Applied the approach to coronary artery disease and schizophrenia patient cohorts.

Main Results:

• Identified diverse patient strata or biotypes within cohorts.
• These biotypes exhibit distinct endophenotype profiles and clinical parameters.
• Biotype groupings are fundamentally different from and superior to PRS-based groupings.
• Discovered biologically meaningful patient subgroups converging on distinct disease-relevant biological processes.

Conclusions:

• The CASTom-iGEx approach identifies distinct patient biotypes with potentially different pathomechanisms.
• This method offers a biologically grounded and clinically actionable alternative to PRS for patient stratification.
• The universally applicable CASTom-iGEx strategy holds potential for advancing personalized medicine paradigms.