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A cross-tissue transcriptome-wide association study identifies new susceptibility genes for frailty
Daoyi Lin1,2, Shuyan Wu1, Wangyu Li3
1Department of Anesthesiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China.
Frontiers in Genetics
|July 29, 2024
Summary
This study identified two novel genes, HTT and LRPPRC, associated with frailty risk using transcriptome-wide association studies (TWAS). HTT may increase frailty risk, while LRPPRC may offer protection, particularly in brain regions.
Area of Science:
- Genetics
- Gerontology
- Molecular Biology
Background:
- Genome-wide association studies (GWAS) have identified 14 loci for frailty index (FI) susceptibility, but causative genes and mechanisms remain unclear.
- Understanding the genetic basis of frailty is crucial for developing targeted interventions.
Purpose of the Study:
- To identify novel genes and biological pathways associated with frailty index (FI) susceptibility.
- To elucidate the genetic architecture and causal relationships underlying frailty.
Main Methods:
- Cross-tissue transcriptome-wide association study (TWAS) integrating GWAS and GTEx gene expression data.
- Validation using FUSION, FOCUS, and MAGMA; Mendelian randomization and co-localization analyses.
- Tissue and functional enrichment analyses, conditional/joint analyses, and fine mapping.
Main Results:
- Identified two novel susceptibility genes for FI: HTT (potentially increasing risk) and LRPPRC (potentially protective).
- Co-localization analysis revealed a shared SNP between LRPPRC and FI.
- Frailty-associated SNPs were enriched in brain regions; identified genetic regions 2p21 and 4q16.3.
- Enriched pathways include MHC complex, PD-1 signaling, cognition, and inflammatory response.
Conclusions:
- Uncovered two novel genes influencing FI risk through predicted expression levels.
- Provides new insights into the genetic underpinnings of frailty, particularly involving brain-related pathways.
