Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

Abstract

45Recently, the "omnigenic" model of the genetic architecture of complex traits proposed two 46 general categories of causal genes, core and peripheral. Core genes are hypothesized to play a 47 direct role in regulating disease; thus, their identification has the potential to reveal critical 48 regulators and novel therapeutic targets. Here, we sought to identify genes with "core-like" 49 characteristics for bone mineral density (BMD), one of the most significant predictors of 50 osteoporotic fracture. This was accomplished by analyzing genome-wide association study 51 (GWAS) data through the lens of a cell-type and timepoint-specific gene co-expression network 52 for mineralizing osteoblasts. We identified a single co-expression network module that was 53 enriched for genes implicated by GWAS and partitioned BMD heritability, correlated with in vitro 54 osteoblast mineralization, and enriched for genes, which when mutated in humans or mice, led 55 to a skeletal phenotype. Further characterization of this module identified four novel genes 56 (B4GALNT3, CADM1, DOCK9, and GPR133) located within BMD GWAS loci with colocalizing 57 expression quantitative trait loci (eQTL) and altered BMD in mouse knockouts, suggesting they 58 are causal genetic drivers of BMD in humans. Our network-based approach identified a "core" 59 module for BMD and provides a resource for expanding our understanding of the genetics of 60 bone mass. 61 62 63 64 65 66 67 68 69 70 3

IRF4 suppresses osteogenic differentiation of BM-MSCs by transcriptionally activating miR-636/DOCK9 axis

“…identified DOCK9 as one of the core modules for bone mineral density through integrating a Co-expression Network and GWAS Data. 29 In the present study, DOCK9 overexpression promoted the osteogenic differentiation of BM-MSCs, suggesting that it might be involved in bone formation. More importantly, miR-636 depletion played an indispensable role in recovering the impairment of osteogenic differentiation induced by IRF4 overexpression in BM-MSCs.…”

RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

“…The transcriptomic profiles of sorted α and β cells in addition to islets provided new insight into cell-specific contributions to T2D pathogenesis. Co-expression network analysis and association with GWAS variants and physiological parameters, similar to a recent approach 48 , allowed us to prioritize processes with physiological relevance that were more likely to be disease-causing rather than disease-induced. For instance, both β01 (metabolism-enriched) and β06 (cilia-enriched) modules are associated with T2D GWAS variants, indicating that regulatory circuitry related to metabolism and cilia function may have causative roles in development of T2D.…”

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics

“…Visual assessment of colocalization was performed using the LocusCompareR R library (114). For adequately powered colocalization analyses, we considered a PP4 of >0.8 as being consistent with colocalization between the two traits, although lower thresholds have recently been proposed (115)(116)(117)(118).…”