Transcriptome-wide association study and eQTL colocalization identify potentially causal genes responsible for human...

Area of Science:

• Genetics
• Genomics
• Bone Biology

Background:

• Genome-wide association studies (GWAS) have identified over 1100 genetic associations for bone mineral density (BMD).
• Identifying the specific causal genes underlying these GWAS associations remains a significant challenge in human genetics.
• Transcriptome-wide association studies (TWAS) and expression quantitative trait loci (eQTL) colocalization are emerging computational methods to pinpoint causal genes.

Purpose of the Study:

• To identify putatively causal genes for bone mineral density (BMD) using the largest BMD GWAS data available.
• To leverage transcriptome-wide association studies (TWAS) and eQTL colocalization with Genotype-Tissue Expression (GTEx) data.
• To investigate the functional role of novel candidate genes, specifically *PPP6R3*, in BMD regulation.

Main Methods:

• Utilized TWAS and eQTL colocalization analysis on extensive BMD GWAS data.
• Integrated transcriptomic data from the Genotype-Tissue Expression (GTEx) project.
• Performed functional validation of the candidate gene *PPP6R3* through gene deletion studies in mice.

Main Results:

• Identified 512 significant putatively causal genes for BMD using combined TWAS and eQTL colocalization.
• The identified gene set was enriched for known regulators of BMD and bone-related biological processes.
• Demonstrated that *Ppp6r3* gene deletion in mice leads to decreased BMD, supporting its role in BMD regulation.

Conclusions:

• Provides an updated resource of putatively causal genes for BMD.
• Confirms *PPP6R3* as a novel, putatively causal gene associated with BMD GWAS.
• Highlights the utility of integrated TWAS/eQTL colocalization approaches for dissecting the genetic architecture of complex traits like BMD.