Dataset Information

A Population Genomics Study Using a Disease-Targeted Cell model: Integration of cis-eQTLs Discovered in Human Primary Osteoblasts with GWAS of Bone Phenotypes

ABSTRACT:

The common genetic variants associated with complex traits typically lie in non-coding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus. The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

Reprinted from Grundberg E, Kwan T, Ge B et al., Genome Res Nov 2009, with permission from Genome Research, Cold Spring Harbor Press, PMID:19654370.

OTHER RELATED OMICS DATASETS IN: PRJNA75607PRJNA75605PRJNA108537E-GEOD-10311

PROVIDER: phs000225.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

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

Rivadeneira Fernando F Styrkársdottir Unnur U Estrada Karol K Halldórsson Bjarni V BV Hsu Yi-Hsiang YH Richards J Brent JB Zillikens M Carola MC Kavvoura Fotini K FK Amin Najaf N Aulchenko Yurii S YS Cupples L Adrienne LA Deloukas Panagiotis P Demissie Serkalem S Grundberg Elin E Hofman Albert A Kong Augustine A Karasik David D van Meurs Joyce B JB Oostra Ben B Pastinen Tomi T Pols Huibert A P HA Sigurdsson Gunnar G Soranzo Nicole N Thorleifsson Gudmar G Thorsteinsdottir Unnur U Williams Frances M K FM Wilson Scott G SG Zhou Yanhua Y Ralston Stuart H SH van Duijn Cornelia M CM Spector Timothy T Kiel Douglas P DP Stefansson Kari K Ioannidis John P A JP Uitterlinden André G AG

Nature genetics 20091004 11

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), 4q2 ...[more]

PMID: 19801982

Publication: 1/9

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Project description:Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent to which environmental perturbation influences such traits has not been studied to date. We carried out large-scale induction experiments using primary human bone cells derived from 113 unrelated donors of Swedish origin harvested under 18 different conditions (seven treatments, two vehicles, each assessed at two time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t=2h), dexamethasone (DEX) (t=24h), and PGE2 (t=24h). Using these treatments, we performed expression profiling for 18,144 RefSeq transcripts applying biological replicates of the complete study cohort (ntotal=782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs. We found that 93% of cis-eQTLs at 1% FDR were replicated in at least one additional treatment and in fact, on average only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment, though treatment-specific cis-regulatory effects were 2-6-fold more abundant among up-or downregulated genes. We further followed-up and validated the DEX-specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 and 250kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interaction between cellular environment and cis-variants are relatively rare (~1.5%), but that detection of such specific interactions can be achieved by combination of functional genomic tools. Total RNA from cultured trabecular bone cells obtained from ~100 unrelated Caucasian donors treated under multiple different conditions and timepoints. Each sample represented by two or three biological replicates. This dataset includes samples treated with bone morphogenetic protein 2 (BMP2) for 2 hours.

Dataset Information

A Population Genomics Study Using a Disease-Targeted Cell model: Integration of cis-eQTLs Discovered in Human Primary Osteoblasts with GWAS of Bone Phenotypes

Publications

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

Similar Datasets

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