scholarly journals Identification of New Genes and Loci Associated With Bone Mineral Density Based on Mendelian Randomization

2021 ◽  
Vol 12 ◽  
Author(s):  
Yijun Liu ◽  
Guang Jin ◽  
Xue Wang ◽  
Ying Dong ◽  
Fupeng Ding
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Rare Variants ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Osteoporotic Fractures ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Mineral Density ◽  
New Genes

Bone mineral density (BMD) is a complex and highly hereditary trait that can lead to osteoporotic fractures. It is estimated that BMD is mainly affected by genetic factors (about 85%). BMD has been reported to be associated with both common and rare variants, and numerous loci related to BMD have been identified by genome-wide association studies (GWAS). We systematically integrated expression quantitative trait loci (eQTL) data with GWAS summary statistical data. We mainly focused on the loci, which can affect gene expression, so Summary data-based Mendelian randomization (SMR) analysis was implemented to investigate new genes and loci associated with BMD. We identified 12,477 single-nucleotide polymorphisms (SNPs) regulating 564 genes, which are associated with BMD. The genetic mechanism we detected could make a contribution in the density of BMD in individuals and play an important role in understanding the pathophysiology of cataclasis.

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 Αποτίμηση γενετικών παραγόντων κινδύνου για διαταραχές των οστών

2020 ◽  
Author(s):  
Μαρία Χρήστου
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Association Studies ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Genome Wide

Σκοπός της διδακτορικής διατριβής ήταν η αποσαφήνιση της αιτιολογίας της οστεοπόρωσης, της συχνότερης διαταραχής των οστών, μέσω μελέτης της γενετικής πλειοτροπίας της νόσου.Στην προσπάθεια αποτίμησης των πλειοτροπικών γενετικών πολυμορφισμών που σχετίζονται με ελαττωμένη οστική πυκνότητα (Bone Mineral Density, BMD) και διάφορους φαινοτύπους πραγματοποιήθηκε ανασκόπηση της βιβλιογραφίας. Περιγράφηκαν τα πρόσφατα δεδομένα γενετικής πλειοτροπίας μεταξύ της BMD και της οστεοπόρωσης και 5 φαινοτύπων εντός του μυοσκελετικού συστήματος (κάταγμα, οστεοαρθρίτιδα, ρευματοειδής αρθρίτιδα, άλιπη σωματική μάζα, εκφύλιση μεσοσπονδύλιου δίσκου στην οσφυϊκή μοίρα της σπονδυλικής στήλης), καθώς επίσης των ακόλουθων 15 φαινοτύπων εκτός του μυοσκελετικού συστήματος: δείκτης μάζας σώματος, περιφέρεια μέσης, λόγος περιφέρειας μέσης-ισχίου, λιπώδης μάζα, %λίπος, στεφανιαία νόσος, σακχαρώδης διαβήτης τύπου 2, λιπίδια πλάσματος, ύψος, ηλικία εμμηναρχής, ηλικία κατά την εφηβεία γενικότερα, κατανάλωση αλκοόλ, ανδρογενής αλωπεκία, καρκίνος μαστού και εκφύλιση ωχράς κηλίδας σχετιζόμενη με την ηλικία.Στην προσπάθεια περαιτέρω διερεύνησης των ανωτέρω ενδείξεων παρουσίας πλειοτροπίας μεταξύ μυοσκελετικών και μη φαινοτύπων και της ελαττωμένης BMD, καθώς επίσης περαιτέρω κατανόησης της γενετικής αρχιτεκτονικής της BMD, αναζητήθηκαν πλειοτροπικές συσχετίσεις με φαινομενικά μη σχετιζόμενους, μη οστικούς φαινοτύπους. Ειδικότερα, στη φάση ανακάλυψης της οστικής πλειοτροπίας, πραγματοποιώντας ευρεία σάρωση του γονιδιώματος (genome-wide pleiotropy scan), ελέγχθηκαν πολυμορφισμοί του NHGRI-EBI Καταλόγου που σχετίζονται με διάφορους μη οστικούς φαινοτύπους σε προηγούμενες μελέτες ευρείας σάρωσης του γονιδιώματος (Genome Wide Association Studies, GWAS) για συσχέτιση με την BMD (αυχένα κεφαλής μηριαίου οστού, οσφυϊκή μοίρα σπονδυλικής στήλης) σε περισσότερα από 80.000 άτομα του μεγάλου διεθνούς συνασπισμού GEFOS. Στη συνέχεια, στη φάση επικύρωσης της οστικής πλειοτροπίας, οι 72 ισχυρότεροι πολυμορφισμοί από τη φάση ανακάλυψης ελέγχθηκαν για επικύρωση σε περισσότερα από 400.000 άτομα από τη μεγάλη μελέτη UK Biobank.Με αυτόν τον τρόπο εντοπίστηκαν 12 πλειοτροπικοί πολυμορφισμοί που σχετίζονται με την BMD (πτέρνας) και τους ακόλουθους 14 μη οστικούς φαινοτύπους σε επίπεδο p-value<5x10-8: ύψος, περιφέρεια μέσης, νόσος Parkinson, καρκίνος στομάχου μη καρδιακού τύπου, ανδρογενής αλωπεκία, αλλεργικές ασθένειες (άσθμα, πυρετός εκ χόρτου, έκζεμα), ατοπική δερματίτιδα, ατοπία γενικότερα, μαγνήσιο ορού, ηλεκτρολύτες ούρων, πρωτεΐνες ορού, δικτυοερυθροκύτταρα, κατανάλωση καφέ και εκπαιδευτικό επίπεδο. Οι 12 πλειοτροπικοί πολυμορφισμοί βρίσκονταν σε 11 γενετικούς τόπους, σε 8 χρωμοσώματα. Εννέα πολυμορφισμοί περιλαμβάνονταν στον NHGRI-EBI Κατάλογο, ενώ 3 πολυμορφισμοί ήταν γειτονικοί. Συμπερασματικά, η διδακτορική διατριβή ανέδειξε την παρουσία διάφορων φαινοτυπικών συσχετίσεων για την οστεοπόρωση μέσω μελέτης της γενετικής πλειοτροπίας. Αξιοσημείωτα οφέλη από τη διερεύνηση της γενετικής πλειοτροπίας της οστεοπόρωσης αποτελούν οι κλινικές συνέπειες ενσωμάτωσης των μοριακών ανακαλύψεων (υπεύθυνα γονίδια και μονοπάτια) στην αιτιολογία της νόσου. Στόχος είναι οι μελλοντικές προσπάθειες να επικεντρωθούν στην ανάπτυξη νέων φαρμάκων με πλειοτροπικές δράσεις, στην επαναστόχευση των ήδη υπάρχοντων φαρμάκων, καθώς επίσης στην εκτίμηση του κινδύνου ανάπτυξης της νόσου σε άτομα υψηλού κινδύνου.

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 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.

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