Prediction of osteoporosis candidate genes by computational disease-gene identification strategy

Abstract

Osteoporosis is a complex disease with a strong genetic component. To date, more than 20 genome-wide linkage scans across multiple populations have been launched to hunt for osteoporosis susceptibility genes. Some significant or suggestive chromosomal regions of linkage to bone mineral density have been identified and replicated in genome-wide linkage screens. However, identification of key candidate genes within these confirmed regions is challenging. We used five freely available bioinformatics tools (Prioritizer, GeneSeeker, PROSPECTR and SUSPECTS, Disease Gene Prediction, and Endeavor) to analyze the 13 well-replicated osteoporosis susceptibility loci: 1p36, 1q21-25, 2p22-24, 3p14-25, 4q25-34, 6p21, 7p14-21, 11q14-25, 12q23-24, 13q14-34, 20p12, 2q24-32, and 5q12-21. Pathways and regulatory network analyses were performed using the Ingenuity Pathways Analysis (IPA) software. We identified a subset of most likely candidate osteoporosis susceptibility genes that are largely involved in transforming growth factor (TGF)-b signaling, granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, axonal guidance signaling, peroxisome proliferator-activated receptor (PPAR) signaling, and Wnt/b-catenin signaling pathway. Six nonoverlapping networks were generated by IPA 5.0 from 88 out of the 91 candidate genes. The list of most likely candidate genes and the associated pathway identified will assist researchers in prioritizing candidate disease genes for further empirical analysis and understanding the pathogenesis of osteoporosis.

Peroxisome proliferator-activated receptor gamma polymorphism is related to peak bone mass: the JPOS study

“…The relative impact of PPARγ genotypes on osteopenia or osteoporosis, defined collectively as a T-score below −1 [23], was assessed via binominal logistic regression. In our longitudinal analysis, participants were divided into four groups according to their menstrual status at baseline and follow-up: (1) participants who were classified as premenopausal at baseline and still menstrual at follow-up, (2) participants who were classified as premenopausal at baseline but were classified as postmenopausal at followup, (3) participants with fewer than 10 YSM at baseline, and (4) participants with at least 10 YSM at baseline.…”

“…Recently, Huang et al [2] investigated 13 osteoporosis susceptibility loci by computational bioinformatics tools and identified five candidate genes, including peroxisome proliferator-activated receptors (PPARs). PPARs comprise a superfamily of nuclear receptor proteins that function as ligand-dependent transcription factors.…”

Outcome of array CGH analysis for 255 subjects with intellectual disability and search for candidate genes using bioinformatics

“…These methods are based on single or multiple data sources (see examples in Table 1). To minimize the bias from diVerent single prioritization web tools, which also rely on diVerent statistical methods, a combination of multiple web tools tends to be used for disease gene prediction (Elbers et al 2007;Huang et al 2008;Liu et al 2008;Teber et al 2009; Thornblad et al 2007;TiYn et al 2006TiYn et al , 2008. Similarly, single gene prioritization web tools, which combine a large number of datasets, have been established.…”

Matrilin-3 Inhibits Chondrocyte Hypertrophy as a Bone Morphogenetic Protein-2 Antagonist

“…We have previously shown that Matn3 knock-out (KO) mice exhibit premature chondrocyte hypertrophy during embryonic development, increased bone mineral density in adulthood, and accelerated joint degeneration during aging (14). These data suggest that MATN3 is an important regulator of chondrocyte proliferation, differentiation, and bone mineralization in the cartilage ECM (35). Elucidating the currently unknown underlying mechanism by which MATN3 modulates cartilage homeostasis and development (as well as bone development) has important implications for better understanding the pathophysiology of OA and other MATN3-associated diseases.…”