scholarly journals Integrative genomics analysis of eQTL and GWAS summary data identifies PPP1CB as a novel bone mineral density risk genes

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Yu Zhai ◽  
Lu Yu ◽  
Yang Shao ◽  
Jianwei Wang
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Association Studies ◽  
Integrative Analysis ◽  
Genome Wide Association Studies ◽  
Integrative Genomics ◽  
Mineral Density ◽  
Risk Genes ◽  
Protein Protein Interaction ◽  
Eqtl Data

Abstract In recent years, multiple genome-wide association studies (GWAS) have identified numerous susceptibility variants and risk genes that demonstrate significant associations with bone mineral density (BMD). However, exploring how these genetic variants contribute risk to BMD remains a major challenge. We systematically integrated two independent expression quantitative trait loci (eQTL) data (N = 1890) and GWAS summary statistical data of BMD (N = 142,487) using Sherlock integrative analysis to reveal whether expression-associated variants confer risk to BMD. By using Sherlock integrative analysis and MAGMA gene-based analysis, we found there existed 36 promising genes, for example, PPP1CB, XBP1, and FDFT1, whose expression alterations may contribute susceptibility to BMD. Through a protein–protein interaction (PPI) network analysis, we further prioritized the PPP1CB as a hub gene that has interactions with predicted genes and BMD-associated genes. Two eSNPs of rs9309664 (PeQTL = 1.42 × 10−17 and PGWAS = 1.40 × 10−11) and rs7475 (PeQTL = 2.10 × 10−6 and PGWAS = 1.70 × 10−7) in PPP1CB were identified to be significantly associated with BMD risk. Consistently, differential gene expression analysis found that the PPP1CB gene showed significantly higher expression in low BMD samples than that in high BMD samples based on two independent expression datasets (P = 0.0026 and P = 0.043, respectively). Together, we provide a convergent line of evidence to support that the PPP1CB gene involves in the etiology of osteoporosis.

scholarly journals Replication of previous genome-wide association studies of bone mineral density in premenopausal American women

2010 ◽  
Vol 25 (8) ◽  
pp. 1821-1829 ◽  
Author(s):  
Shoji Ichikawa ◽  
Daniel L Koller ◽  
Leah R Padgett ◽  
Dongbing Lai ◽  
Siu L Hui ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
American Women ◽  
Genome Wide

scholarly journals Systems genetics analyses in Diversity Outbred mice inform human bone mineral density GWAS and identify Qsox1 as a novel determinant of bone strength

2020 ◽  
Author(s):  
Basel Al-Barghouthi ◽  
Larry D. Mesner ◽  
Gina M. Calabrese ◽  
Daniel Brooks ◽  
Steve M. Tommasini ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bone Mineral ◽  
Association Studies ◽  
Systems Genetics ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Diversity Outbred ◽  
Wide Range

ABSTRACTGenome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we used Diversity Outbred (DO) mice to directly address these limitations by performing the first systems genetics analysis of over 50 complex skeletal phenotypes. We applied a network approach to cortical bone RNA-seq data to discover 46 genes likely to be causal for human BMD GWAS associations, including the novel genes SERTAD4 and GLT8D2. We also performed GWAS in the DO for a wide-range of bone traits and identified Qsox1 as a novel gene influencing cortical bone accrual and bone strength. Our results provide a new perspective on the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

scholarly journals The Genetics of Bone Loss: Challenges and Prospects

2011 ◽  
Vol 96 (5) ◽  
pp. 1258-1268 ◽  
Author(s):  
Braxton D. Mitchell ◽  
Laura M. Yerges-Armstrong
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Association Studies ◽  
Evidence Synthesis ◽  
Susceptibility Genes ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Genome Wide

Context: A strong genetic influence on bone mineral density has been long established, and modern genotyping technologies have generated a flurry of new discoveries about the genetic determinants of bone mineral density (BMD) measured at a single time point. However, much less is known about the genetics of age-related bone loss. Identifying bone loss-related genes may provide new routes for therapeutic intervention and osteoporosis prevention. Evidence Acquisition: A review of published peer-reviewed literature on the genetics of bone loss was performed. Relevant studies were summarized, most of which were drawn from the period 1990–2010. Evidence Synthesis: Although bone loss is a challenging phenotype, available evidence supports a substantial genetic contribution. Some of the genes identified from recent genome-wide association studies of cross-sectional BMD are attractive candidate genes for bone loss, most notably genes in the nuclear factor κB and estrogen endocrine pathways. New insights into the biology of skeletal development and regulation of bone turnover have inspired new hypotheses about genetic regulation of bone loss and may provide new directions for identifying genes associated with bone loss. Conclusions: Although recent genome-wide association and candidate gene studies have begun to identify genes that influence BMD, efforts to identify susceptibility genes specific for bone loss have proceeded more slowly. Nevertheless, clues are beginning to emerge on where to look, and as population studies accumulate, there is hope that important bone loss susceptibility genes will soon be identified.

scholarly journals Transcriptome-wide Association Study and eQTL colocalization identify potentially causal genes responsible for bone mineral density GWAS associations

2021 ◽  
Author(s):  
Basel M Al-Barghouthi ◽  
Will T Rosenow ◽  
Kang-Ping Du ◽  
Jinho Heo ◽  
Robert Maynard ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Complex Traits ◽  
Association Studies ◽  
Tissue Expression ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Mineral Density ◽  
Genome Wide ◽  
Causal Genes

Genome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant (Bonferroni <= 0.05) using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.

scholarly journals Genome-Wide Association Study of Estradiol Levels, and the Causal Effect of Estradiol on Bone Mineral Density

2021 ◽  
Author(s):  
Daniel Schmitz ◽  
Weronica E Ek ◽  
Elin Berggren ◽  
Julia Höglund ◽  
Torgny Karlsson ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Causal Effect ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Skeletal Health ◽  
Genome Wide ◽  
Estradiol Levels

Context. Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. Objective. Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). Design. We performed GWAS for estradiol in males (N = 147,690) and females (N = 163,985) from UK Biobank (UKB). Estradiol was analyzed as a binary phenotype; above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. Results. We identified 14 independent loci associated (P<5x10-8) with estradiol levels in males, of which one (CYP3A7) was genome-wide and seven nominally (P<0.05) significant in females. In addition, one female specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS. For example, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7 which encode enzymes likely to be involved in estradiol elimination. The allele that tags the O blood group, at the ABO locus, was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P=1.58x10-11) and females (P=7.48x10-6). Conclusion. Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.

scholarly journals Genome-scale Capture C promoter interaction analysis implicates novel effector genes at GWAS loci for bone mineral density

2018 ◽  
Author(s):  
Alessandra Chesi ◽  
Yadav Wagley ◽  
Matthew E. Johnson ◽  
Elisabetta Manduchi ◽  
Chun Su ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Association Studies ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Gene Promoters ◽  
Mineral Density ◽  
Effector Genes ◽  
Genome Wide ◽  
Genome Scale

ASBTRACTOsteoporosis is a devastating disease with an essential genetic component. Genome wide association studies (GWAS) have discovered genetic variants robustly associated with bone mineral density (BMD), however they only report genomic signals and not necessarily the precise localization of culprit effector genes. Therefore, we sought to carry out physical and direct ‘variant to gene mapping’ in a relevant primary human cell type. We developed ‘SPATIaL-seq’ (genome-Scale, Promoter-focused Analysis of chromaTIn Looping), a massively parallel, high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our SPATIaL-seq and ATAC-seq data from human mesenchymal progenitor cell -derived osteoblasts, we observed consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~30% of the 110 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at ‘CPED1-WNT16’ and EPDR1 at ‘STARD3NL’, had pronounced inhibitory effects on osteoblastogenesis. Our approach therefore aids target discovery in osteoporosis and can be applied to other common genetic diseases.

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