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Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA419649PRJNA419645PRJNA419647PRJNA419648

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE107297 | GEO | 2018/04/10

REPOSITORIES: GEO

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Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [HsMmMicroarray]

Project description:Similar temporal expression kinetics of transcription factors in human and mouse osteoclast differentiation evaluated by microarray We used the identical differentiation conditions to evaluate gene expression kinetics of mouse and human osteoclast differentiation by microarray

2018-04-10 | GSE107295 | GEO

Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [ChIP-seq]

Project description:Genome-wide association studies (GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating publicly available lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast- and osteoclast (OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor (TF) network was revealed. Further we conducted functional genomic analysis PU.1 and MITF genome wide binding with corresponding gene expression analysis which revealed a TF network essential for OC differentiation. Several of these TFs were regulated by cooperative binding of PU.1 with BRD4 to form superenhancers. Further, PU.1 is essential for conformational changes in the superenhancer region of Nfatc1. In summary, our study demonstrates that utilizing GWASs with genome-wide binding studies as a filter helps to decipher lineage-specific pathways contributing to complex disease states.

2018-04-10 | GSE107294 | GEO

Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [MoEx-1_0-st array]

Project description:Eavluation of temporal expression kinetics during mouse osteoclast differentiation evaluated by microarray. We overlayed gene expression data with correspoding DNA binding data from MITF and PU.1 ChIP-seq to evaluate gene regulatory networks in osteoclasts.

2018-04-10 | GSE107296 | GEO

Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts

Project description:Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts

| PRJNA419645 | ENA

Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [HsMmMicroarray]

Project description:Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [HsMmMicroarray]

| PRJNA419647 | ENA

Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [ChIP-seq]

Project description:Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [ChIP-seq]

| PRJNA419648 | ENA

Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [MoEx-1_0-st array]

Project description:Bone density loci identified by genome-wide association studies segregate a lineage-specific PU.1-dependent gene regulatory network in osteoclasts [MoEx-1_0-st array]

| PRJNA419649 | ENA

Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies.

Project description:Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.

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Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response.

Project description:Non-high-density lipoprotein cholesterol(NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2 %; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10 %). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D' = 1, r (2) = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.

| S-EPMC4112746 | biostudies-literature

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density.

Project description:Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

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