PVS

PVS quantifies the pleiotropy of genomic variants by measuring their phenomic associations to inform genome interpretation and disease-risk assessment from sequencing data.

Key Features:

• Semantic Reasoning: Employs semantic reasoning using the Human Phenotype Ontology (HPO) and Disease Ontology (DO) to assess phenotype relatedness.
• Semantic Similarity Methods: Evaluated 78 semantic similarity methods and integrated six robust metrics to define pleiotropy scores for single nucleotide polymorphisms (SNPs).
• Genotype–Phenotype Catalog Analysis: Computed PVS for 12,541 SNPs mapped to 382 unique HPO terms and 317 unique DO terms, including 10,021 SNPs linked to DO phenotypes and 8,569 SNPs linked to HPO terms.
• Validation with EHR-linked Genomes: Validated using the BioME electronic health record-linked genomic database comprising 11,210 individuals.
• Personalized Scores: Generates personalized pleiotropy scores for individuals with genomic data to support variant interpretation.
• VCF Integration: Provides a software framework to annotate Variant Call Format (VCF) files with PVS values.

Scientific Applications:

• Pleiotropic SNP Identification: Identification of SNPs with high pleiotropy to elucidate complex genetic influences across multiple phenotypes.
• Variant Prioritization: Prioritization of variants by degree of pleiotropy to guide follow-up genetic and functional studies.
• Pleiotropic Hub Discovery: Detection of pleiotropic hubs that may mediate novel phenotypes.
• Drug Development: Inform target discovery and drug development by revealing variants with broad phenotypic effects.
• Personalized Medicine: Support personalized medicine through individual-level pleiotropy reports integrated into genomic analyses.

Methodology:

Applies semantic reasoning over HPO and DO, tests 78 semantic similarity methods and integrates six metrics to compute PVS for SNPs mapped to HPO/DO terms, validates scores using the BioME EHR-linked genomic database (11,210 individuals), and annotates results into VCF files.