Integrative multi-omics analyses identify key genes and elucidate bidirectional regulatory mechanisms in thyroid...

Area of Science:

• Endocrinology and Genetics
• Multi-omics integration for disease mechanism discovery

Background:

• Hyperthyroidism and hypothyroidism are prevalent endocrine disorders with complex genetic and metabolic underpinnings.
• Existing genome-wide association studies (GWAS) have identified some risk genes but gaps remain in non-coding variant annotation and tissue-specific regulatory networks.

Purpose of the Study:

• To systematically identify genes associated with hyperthyroidism and hypothyroidism.
• To unravel the molecular mechanisms underlying these thyroid disorders through multi-omics integration.
• To explore potential therapeutic targets within identified gene networks.

Main Methods:

• Utilized data from the ThyroidOmics Consortium (1,840 hyperthyroidism cases, 3,340 hypothyroidism cases, 49,983 controls).
• Employed SMR-HEIDI, cross-tissue TWAS, mBAT-combo rare variant analysis, and PoPS for gene prioritization.
• Validated findings using GTEx colocalization, PheWAS, KEGG pathway enrichment, and PPI network analyses.

Main Results:

• Identified FAM227B, PDE8B, and PDE10A as key genes for hyperthyroidism, and PDE8B for hypothyroidism.
• Confirmed tissue-specific colocalization of these genes with thyroid dysfunction signals.
• Elucidated PDE8B's bidirectional role in thyroid hormone synthesis via cAMP signaling and nucleotide metabolism.

Conclusions:

• PDE8B is a central gene in thyroid dysfunction, with significant tissue-specific colocalization and roles in signaling pathways.
• Findings provide a basis for developing phosphodiesterase family-based precision therapies for thyroid disorders.
• Results highlight potential comorbidity associations and drug targets, though generalizability across ethnicities requires further verification.