Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts
| Autor: | Edward S. Mocarski, Jacob Kenny, Benjamin H. Mullin, Jennifer Tickner, Scott Wilson, Suzanne J. Brown, Jiake Xu, Nathan J. Pavlos, Kun Zhu, Shelby Mullin, Frank Dudbridge, John P. Walsh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
lcsh:QH426-470 Quantitative Trait Loci Osteoclasts SNP 030209 endocrinology & metabolism Genome-wide association study Computational biology Biology RIPK3 eQTL 03 medical and health sciences symbols.namesake 0302 clinical medicine Osteoclast Bone Density Risk Factors BMD medicine Animals Humans GWAS Femur RIP3 FBN2 Gene lcsh:QH301-705.5 030304 developmental biology Mice Knockout 0303 health sciences Research Human genetics lcsh:Genetics medicine.anatomical_structure Fracture lcsh:Biology (General) Receptor-Interacting Protein Serine-Threonine Kinases Expression quantitative trait loci Multiple comparisons problem Mendelian inheritance symbols Osteoporosis Female Genome-Wide Association Study |
| Zdroj: | Genome Biology, Vol 21, Iss 1, Pp 1-13 (2020) Genome Biology |
| ISSN: | 1474-7596 |
| Popis: | Background Osteoporosis is a complex disease with a strong genetic contribution. A recently published genome-wide association study (GWAS) for estimated bone mineral density (eBMD) identified 1103 independent genome-wide significant association signals. Most of these variants are non-coding, suggesting that regulatory effects may drive many of the associations. To identify genes with a role in osteoporosis, we integrate the eBMD GWAS association results with those from our previous osteoclast expression quantitative trait locus (eQTL) dataset. Results We identify sixty-nine significant cis-eQTL effects for eBMD GWAS variants after correction for multiple testing. We detect co-localisation of eBMD GWAS and osteoclast eQTL association signals for 21 of the 69 loci, implicating a number of genes including CCR5, ZBTB38, CPE, GNA12, RIPK3, IQGAP1 and FLCN. Summary-data-based Mendelian Randomisation analysis of the eBMD GWAS and osteoclast eQTL datasets identifies significant associations for 53 genes, with TULP4 presenting as a strong candidate for pleiotropic effects on eBMD and gene expression in osteoclasts. By performing analysis using the GARFIELD software, we demonstrate significant enrichment of osteoporosis risk variants among high-confidence osteoclast eQTL across multiple GWAS P value thresholds. Mice lacking one of the genes of interest, the apoptosis/necroptosis gene RIPK3, show disturbed bone micro-architecture and increased osteoclast number, highlighting a new biological pathway relevant to osteoporosis. Conclusion We utilise a unique osteoclast eQTL dataset to identify a number of potential effector genes for osteoporosis risk variants, which will help focus functional studies in this area. |
| Databáze: | OpenAIRE |
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