Transcriptome-wide association study identifies novel genes associated with bone mineral density and lean body mass in children

Abstract

Objective: To identify novel candidate genes whose expression is associated with bone mineral density (BMD) and body lean mass (LM) in children.

Methods: A tissue-specific transcriptome-wide association study (TWAS) was conducted utilizing a large-scale genome-wide association study (GWAS) dataset associated with BMD and LM and involving 10,414 participants. The measurement of BMD and LM phenotypes was made based on total-body dual-energy X-ray absorptiometry (TB-DXA) scans. TWAS was conducted by using FUSION software. Reference panels for muscle skeleton (MS), peripheral blood (NBL) and whole blood (YBL) were used for TWAS analysis. Functional enrichment and protein-protein interaction (PPI) analyses of the genes identified by TWAS were performed by using the online tool Metascape ( http://metascape.org ).

Results: For BMD, we identified 174 genes with P < 0.05, such as IKZF1 (P = 1.46 × 10^-9) and CHKB (P = 8.31 × 10^-7). For LM, we identified 208 genes with P < 0.05, such as COPS5 (P = 3.03 × 10^-12) and MRPS33 (P = 5.45 × 10^-10). Gene ontology (GO) enrichment analysis of the BMD-associated genes revealed 200 GO terms, such as protein catabolic process (Log P = -5.09) and steroid hormone-mediated signaling pathway (Log P = -3.13). GO enrichment analysis of the LM-associated genes detected 287 GO terms, such as the apoptotic signaling pathway (Log P = -8.08) and lipid storage (Log P = -3.55).

Conclusion: This study identified several candidate genes for BMD and LM in children, providing novel clues to the genetic mechanisms underlying the development of childhood BMD and LM.

Keywords: Body lean mass (LM); Bone mineral density (BMD); Expression-trait association; Genome-wide association study (GWAS); Transcriptome-wide association study (TWAS).