Enhanced Identification of Novel Potential Variants for Appendicular Lean Mass by Leveraging Pleiotropy With Bone Mineral Density

Abstract

Strong relationships have been found between appendicular lean mass (ALM) and bone mineral density (BMD). It may be due to a shared genetic basis, termed pleiotropy. By leveraging the pleiotropy with BMD, the aim of this study was to detect more potential genetic variants for ALM. Using the conditional false discovery rate (cFDR) methodology, a combined analysis of the summary statistics of two large independent genome wide association studies (GWAS) of ALM (n = 73,420) and BMD (n = 10,414) was conducted. Strong pleiotropic enrichment and 26 novel potential pleiotropic SNPs were found for ALM and BMD. We identified 156 SNPs for ALM (cFDR <0.05), of which 74 were replicates of previous GWASs and 82 were novel SNPs potentially-associated with ALM. Eleven genes annotated by 31 novel SNPs (13 pleiotropic and 18 ALM specific) were partially validated in a gene expression assay. Functional enrichment analysis indicated that genes corresponding to the novel potential SNPs were enriched in GO terms and/or KEGG pathways that played important roles in muscle development and/or BMD metabolism (adjP <0.05). In protein–protein interaction analysis, rich interactions were demonstrated among the proteins produced by the corresponding genes. In conclusion, the present study, as in other recent studies we have conducted, demonstrated superior efficiency and reliability of the cFDR methodology for enhanced detection of trait-associated genetic variants. Our findings shed novel insight into the genetic variability of ALM in addition to the shared genetic basis underlying ALM and BMD.

A Pathologically Friendly Strategy for Determining the Organ‐specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom‐seq and Imaging Mass Cytometry

“…[ 47 ] The memory subset had increased ascorbate metabolic activity. [ 48 ] Collectively, these findings further confirmed the distinct architectures of the immune microenvironment and the diverse phenotypic states of immune cells across different sites of LUAD at high resolution.…”

wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome

“…These satellite-like cells contribute to skeletal muscle repair in adult zebrafish and this process requires Pax7, similar to the mouse (Berberoglu et al, 2017). Previous studies have shown there are at least two populations of pax7+ cells, defined by expression of pax7a and pax7b, that contribute to muscle repair (Pipalia et al, 2016). In our scRNA-seq analyses, wnt16 was expressed in both pax7a+ and pax7b+ positive cells, suggesting that wnt16+ cells do not overlap with a specific pax7+ population.…”

“…This is considered a “hazardous duet” (Crepaldi and Maggi, 2005), since sarcopenia increases susceptibility for falls, amplifying the risk of fracture in fragile osteoporotic bone. Genome-wide association studies (GWAS) that have identified genetic variants with dual effects on bone- and muscle-related traits (Karasik and Kiel, 2008; Medina-Gomez et al, 2017; Peng et al, 2021; Trajanoska et al, 2019), indicating that bone and muscle mass have a shared genetic component. Pleiotropy may arise through variants having direct biological effects on each trait, or through an effect on one trait which affects the other.…”

wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome

“…This is considered a "hazardous duet" [4], since sarcopenia increases susceptibility for falls, amplifying the risk of fracture in fragile osteoporotic bone. Genome-wide association studies (GWAS) have identified genetic variants with dual effects on bone-and muscle-related traits [5][6][7][8], indicating that bone and muscle mass have a shared genetic component. Pleiotropy may arise through variants having direct biological effects on each trait, or, through an effect on one trait which affects the other.…”