Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts

• Type of Material: Article
• Authors: Benjamin H. Mullin, University of Western Australia; Jennifer Tickner, University of Western Australia; Kun Zhu, University of Western Australia; Jacob Kenny, University of Western Australia; Shelby Mullin, University of Western Australia; Suzanne J. Brown, University of Western Australia; Frank Dudbridge, University of Leicester; Nathan J. Pavlos, University of Western Australia; Edward Mocarski, Emory University; John P. Walsh, University of Western Australia; Jiake Xu, University of Western Australia; Scott G. Wilson, University of Western Australia
• Language: English
• Date: 2020-03-26
• Publisher: BMC Journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-020-01997-2
• Title of Journal or Parent Work: Genome Biology
• Volume: 21
• Issue: 1
• Start Page: 80
• End Page: 80
• Grant/Funding Information: This work was supported by the Australian National Health and Medical Research Council (project grants 1010494, 1048216, 1087407, 1107828, 1127156, 1163933), the Sir Charles Gairdner Osborne Park Health Care Group (SCGOPHCG) Research Advisory Committee (grant 2016-17/017) and the iVEC/Pawsey Supercomputing Centre (with funding from the Australian Government and the Government of Western Australia; project grants: Pawsey0260 (S.G.W.), Director2025 (S.G.W.)).; The salary of B.H.M. was supported by a Raine Medical Research Foundation Priming Grant.
• Keywords: Physical activity; Calcium intake; FBN2; Osteoporosis; SNP; Quantitative ultrasound; Genome-wide association; Bone mineral density; Science & Technology; Loci; Osteoclast; Determinants; Metaanalysis; Biotechnology & Applied Microbiology; Carboxypeptidase-E; Life Sciences & Biomedicine; eQTL; Fracture; RIPK3; BMD; RIP3; GWAS; Genetics & Heredity
• Research Categories: Engineering, Biomedical; Biology, Genetics; Health Sciences, Immunology; Biology, Microbiology

Abstract

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.