15 results on '"Basel M. Al-Barghouthi"'
Search Results
2. Evaluation of a scalable approach to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells
- Author
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Luke J Dillard, Will T Rosenow, Gina M Calabrese, Larry D Mesner, Basel M Al-Barghouthi, Abdullah Abood, Emily A Farber, Suna Onengut-Gumuscu, Steven M Tommasini, Mark A Horowitz, Clifford J Rosen, Lutian Yao, Ling Qin, and Charles R Farber
- Abstract
Genome-wide association studies (GWASs) have revolutionized our understanding of the genetics of complex diseases, such as osteoporosis; however, the challenge has been converting associations to causal genes. Studies have demonstrated the utility of transcriptomics data in linking disease-associated variants to genes; though for osteoporosis, few population transcriptomics datasets have been generated on bone or bone cells, and an even smaller number have profiled individual cell-types. To begin to evaluate approaches to address this challenge, we profiled the transcriptomes of bone marrow-derived stromal cells (BMSCs) cultured under osteogenic conditions, a popular model of osteoblast differentiation and activity, from five Diversity Outbred (DO) mice using single-cell RNA-seq (scRNA-seq). The goal of the study was to determine if BMSCs could serve as a model for the generation of cell-type specific transcriptomic profiles of mesenchymal lineage cells derived from large populations of mice to inform genetic studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte-like cells, and immune cells. Importantly, all cells were nearly identical from a transcriptomic perspective to cells isolated directly from bone. We also demonstrated the ability to multiplex single cells and subsequently assign cells to their “mouse-of-origin” using demultiplexing approaches based on genotypes inferred from coding SNPs. We employed scRNA-seq analytical tools to confirm the biological identity of profiled cell-types. SCENIC was used to reconstruct gene regulatory networks (GRNs) and we showed that identified cell-types show GRNs expected of osteogenic and pre-adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte-like cells, and MALPs captured a significant component of BMD heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA-seq can be used as a scalable and biologically informative model to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells in large mouse, and potentially human, populations.
- Published
- 2022
3. Identification of Known and Novel Long Noncoding RNAs Potentially Responsible for the Effects of Bone Mineral Density (BMD) Genomewide Association Study (GWAS) Loci
- Author
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Abdullah Abood, Larry Mesner, Will Rosenow, Basel M. Al‐Barghouthi, Nina Horowitz, Elise F. Morgan, Louis C. Gerstenfeld, and Charles R. Farber
- Subjects
Bone Density ,Endocrinology, Diabetes and Metabolism ,Humans ,Osteoporosis ,Orthopedics and Sports Medicine ,Genetic Predisposition to Disease ,RNA, Long Noncoding ,Polymorphism, Single Nucleotide ,Genome-Wide Association Study - Abstract
Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long noncoding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor single-nucleotide polymorphisms (SNPs) demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (false discovery rate [FDR] correction 0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability [RCP] 0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
- Published
- 2022
4. Author response for 'Identification of known and novel long non‐coding <scp>RNAs</scp> potentially responsible for the effects of <scp>BMD GWAS</scp> loci'
- Author
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null Abdullah Abood, null Larry Mesner, null Will Rosenow, null Basel M. Al‐Barghouthi, null Nina Horwitz, null Elise F. Morgan, null Louis C. Gerstenfeld, and null Charles R. Farber
- Published
- 2022
5. Intramembranous Bone Regeneration in Diversity Outbred Mice is Heritable
- Author
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Meghan M. Moran, Frank C. Ko, Larry D. Mesner, Gina M. Calabrese, Basel M. Al-Barghouthi, Charles R. Farber, and D. Rick Sumner
- Subjects
Collaborative Cross Mice ,Male ,History ,Histology ,Bone Regeneration ,Polymers and Plastics ,Physiology ,Endocrinology, Diabetes and Metabolism ,Bone and Bones ,Article ,Industrial and Manufacturing Engineering ,Mice ,Phenotype ,Bone Density ,Animals ,Humans ,Female ,Business and International Management ,Genome-Wide Association Study - Abstract
There are over one million cases of failed bone repair in the U.S. annually, resulting in substantial patient morbidity and societal costs. Multiple candidate genes affecting bone traits such as bone mineral density have been identified in human subjects and animal models using genome-wide association studies (GWAS). This approach for understanding the genetic factors affecting bone repair is impractical in human subjects but could be performed in a model organism if there is sufficient variability and heritability in the bone regeneration response. Diversity Outbred (DO) mice, which have significant genetic diversity and have been used to examine multiple intact bone traits, would be an excellent possibility. Thus, we sought to evaluate the phenotypic distribution of bone regeneration, sex effects and heritability of intramembranous bone regeneration on day 7 following femoral marrow ablation in 47 12-week old DO mice (23 males, 24 females). Compared to a previous study using 4 inbred mouse strains, we found similar levels of variability in the amount of regenerated bone (coefficient of variation of 86 % v. 88 %) with approximately the same degree of heritability (0.42 v. 0.49). There was a trend toward more bone regeneration in males than females. The amount of regenerated bone was either weakly or not correlated with bone mass at intact sites, suggesting that the genetic factors responsible for bone regeneration and intact bone phenotypes are at least partially independent. In conclusion, we demonstrate that DO mice exhibit variation and heritability of intramembranous bone regeneration that will be suitable for future GWAS.
- Published
- 2022
6. Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci
- Author
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Louis C. Gerstenfeld, Nina Horwitz, Will T. Rosenow, Basel M. Al-Barghouthi, Larry D. Mesner, Charles R. Farber, Abdullah Abood, and Elise F. Morgan
- Subjects
musculoskeletal diseases ,Bone mineral ,Osteoporosis ,Allelic Imbalance ,Expression quantitative trait loci ,Bone cell ,medicine ,Single-nucleotide polymorphism ,Genome-wide association study ,Computational biology ,Biology ,medicine.disease ,Genetic association - Abstract
Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.
- Published
- 2021
7. Transcriptome-wide Association Study and eQTL colocalization identify potentially causal genes responsible for bone mineral density GWAS associations
- Author
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Jinho Heo, Will T. Rosenow, Virginia L. Ferguson, Kang-Ping Du, David L. Brautigan, Robert D. Maynard, Louis C. Gerstenfeld, Larry D. Mesner, Elise F. Morgan, Bhavya Senwar, Gina M. Calabrese, Charles R. Farber, Aaron Nakasone, Cheryl L. Ackert-Bicknell, and Basel M. Al-Barghouthi
- Subjects
musculoskeletal diseases ,Transcriptome ,Bone mineral ,symbols.namesake ,Bonferroni correction ,Expression quantitative trait loci ,symbols ,Colocalization ,Genome-wide association study ,Computational biology ,Biology ,Gene ,Genetic association - Abstract
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 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.
- Published
- 2021
8. Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength
- Author
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Charles R. Farber, Clifford J. Rosen, Larry D. Mesner, Daniel J. Brooks, Steven M. Tommasini, Emily Farber, Kevin Nguyen, Samuel Haddox, Basel M. Al-Barghouthi, Suna Onengut-Gumuscu, Daniel Pomp, Mark C. Horowitz, Gina M. Calabrese, and Mary L. Bouxsein
- Subjects
0301 basic medicine ,Collaborative Cross Mice ,Male ,Osteoporosis ,General Physics and Astronomy ,Datasets as Topic ,Genome-wide association study ,Genome-wide association studies ,Mice ,0302 clinical medicine ,Bone Density ,Osteogenesis ,Oxidoreductases Acting on Sulfur Group Donors ,Femur ,RNA-Seq ,Bone mineral ,Mice, Knockout ,education.field_of_study ,Multidisciplinary ,Cell Differentiation ,Genomics ,Fluoresceins ,medicine.anatomical_structure ,Female ,Single-Cell Analysis ,Science ,Population ,Computational biology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,education ,Genetic association ,Fluorescent Dyes ,Osteoblasts ,Glycosyltransferases ,Mesenchymal Stem Cells ,General Chemistry ,medicine.disease ,Human genetics ,Computational biology and bioinformatics ,030104 developmental biology ,Cortical bone ,human activities ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Genome-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 use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics., Osteoporosis GWAS faces two challenges, causal gene discovery and a lack of phenotypic diversity. Here, the authors use the Diversity Outbred mouse population to inform human GWAS using networks and map genetic loci for 55 bone traits, identifying new potential bone strength genes.
- Published
- 2021
9. Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells
- Author
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Charles R. Farber, Katrina L Clines, Henry H Moon, Emily Farber, Gregory A. Clines, Richard J. Auchus, Patrick O’Day, and Basel M. Al-Barghouthi
- Subjects
0301 basic medicine ,Male ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Androstenediol ,Dehydroepiandrosterone ,030209 endocrinology & metabolism ,urologic and male genital diseases ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,LNCaP ,Medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,Testosterone ,Osteoblasts ,business.industry ,Bone metastasis ,Prostatic Neoplasms ,Androgen ,medicine.disease ,Androgen receptor ,030104 developmental biology ,chemistry ,Receptors, Androgen ,Cancer research ,Androgens ,business - Abstract
Bone metastasis is a complication of prostate cancer in up to 90% of men afflicted with advanced disease. Therapies that reduce androgen exposure remain at the forefront of treatment. However, most prostate cancers transition to a state whereby reducing testicular androgen action becomes ineffective. A common mechanism of this transition is intratumoral production of testosterone (T) using the adrenal androgen precursor dehydroepiandrosterone (DHEA) through enzymatic conversion by 3β- and 17β-hydroxysteroid dehydrogenases (3βHSD and 17βHSD). Given the ability of prostate cancer to form blastic metastases in bone, we hypothesized that osteoblasts might be a source of androgen synthesis. RNA expression analyses of murine osteoblasts and human bone confirmed that at least one 3βHSD and 17βHSD enzyme isoform was expressed, suggesting that osteoblasts are capable of generating androgens from adrenal DHEA. Murine osteoblasts were treated with 100 nM and 1 μM DHEA or vehicle control. Conditioned media from these osteoblasts were assayed for intermediate and active androgens by liquid chromatography-tandem mass spectrometry. As DHEA was consumed, the androgen intermediates androstenediol and androstenedione were generated and subsequently converted to T. Conditioned media of DHEA-treated osteoblasts increased androgen receptor (AR) signaling, prostate-specific antigen (PSA) production, and cell numbers of the androgen-sensitive prostate cancer cell lines C4-2B and LNCaP. DHEA did not induce AR signaling in osteoblasts despite AR expression in this cell type. We describe an unreported function of osteoblasts as a source of T that is especially relevant during androgen-responsive metastatic prostate cancer invasion into bone. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
- Published
- 2021
10. Author response for 'Osteoblasts Generate Testosterone from DHEA and Activate Androgen Signaling in Prostate Cancer Cells'
- Author
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null Henry H. Moon, null Katrina L. Clines, null Patrick J. O'Day, null Basel M. Al‐Barghouthi, null Emily A. Farber, null Charles R. Farber, null Richard J. Auchus, and null Gregory A. Clines
- Published
- 2021
11. Dissecting the Genetics of Osteoporosis using Systems Approaches
- Author
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Basel M. Al-Barghouthi and Charles R. Farber
- Subjects
Genotype ,Bone function ,Quantitative Trait Loci ,Osteoporosis ,Genome-wide association study ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,Article ,Fractures, Bone ,03 medical and health sciences ,0302 clinical medicine ,Bone Density ,Risk Factors ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Systems genetics ,030304 developmental biology ,Genetic association ,Bone mineral ,0303 health sciences ,Systems Biology ,Systems approaches ,medicine.disease ,Phenotype ,Increased risk ,030217 neurology & neurosurgery - Abstract
Osteoporosis is a condition characterized by low bone mineral density (BMD) and an increased risk of fracture. Traits contributing to osteoporotic fracture are highly heritable, indicating that a comprehensive understanding of bone requires a thorough understanding of the genetic basis of bone traits. Towards this goal, genome-wide association studies (GWASs) have identified over 500 loci associated with bone traits. However, few of the responsible genes have been identified, and little is known of how these genes work together to influence systems-level bone function. In this review, we describe how systems genetics approaches can be used to fill these knowledge gaps.
- Published
- 2019
12. Complex DNA structures trigger copy number variation across the Plasmodium falciparum genome
- Author
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Karol Szlachta, Maureen A. Carey, Jennifer L. Guler, Adam C Huckaby, Yuh-Hwa Wang, Claire S Granum, and Basel M. Al-Barghouthi
- Subjects
DNA Copy Number Variations ,Sequence analysis ,Plasmodium falciparum ,Genome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,Humans ,Copy-number variation ,Malaria, Falciparum ,030304 developmental biology ,Sequence (medicine) ,Repetitive Sequences, Nucleic Acid ,Whole genome sequencing ,0303 health sciences ,biology ,Breakpoint ,Computational Biology ,DNA ,Genomics ,Sequence Analysis, DNA ,biology.organism_classification ,3. Good health ,chemistry ,Nucleic Acid Conformation ,Genome, Protozoan ,030217 neurology & neurosurgery - Abstract
Antimalarial resistance is a major obstacle in the eradication of the human malaria parasite, Plasmodium falciparum. Genome amplifications, a type of DNA copy number variation (CNV), facilitate overexpression of drug targets and contribute to parasite survival. Long monomeric A/T tracks are found at the breakpoints of many Plasmodium resistance-conferring CNVs. We hypothesize that other proximal sequence features, such as DNA hairpins, act with A/T tracks to trigger CNV formation. By adapting a sequence analysis pipeline to investigate previously reported CNVs, we identified breakpoints in 35 parasite clones with near single base-pair resolution. Using parental genome sequence, we predicted the formation of stable hairpins within close proximity to all future breakpoint locations. Especially stable hairpins were predicted to form near five shared breakpoints, establishing that the initiating event could have occurred at these sites. Further in-depth analyses defined characteristics of these ‘trigger sites’ across the genome and detected signatures of error-prone repair pathways at the breakpoints. We propose that these two genomic signals form the initial lesion (hairpins) and facilitate microhomology-mediated repair (A/T tracks) that lead to CNV formation across this highly repetitive genome. Targeting these repair pathways in P. falciparum may be used to block adaptation to antimalarial drugs.
- Published
- 2018
13. Author response for 'Osteoblasts Generate Testosterone from DHEA and Activate Androgen Signaling in Prostate Cancer Cells'
- Author
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Charles R. Farber, Basel M. Al-Barghouthi, Richard J. Auchus, Gregory A. Clines, Patrick O’Day, Emily Farber, Henry H Moon, and Katrina L. Clines
- Subjects
medicine.medical_specialty ,Prostate cancer ,Endocrinology ,business.industry ,medicine.drug_class ,Internal medicine ,Medicine ,business ,Androgen ,medicine.disease ,Testosterone - Published
- 2021
14. Systems genetics analyses in Diversity Outbred mice inform human bone mineral density GWAS and identify Qsox1 as a novel determinant of bone strength
- Author
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Emily Farber, Daniel Pomp, Basel M. Al-Barghouthi, Daniel J. Brooks, Steven M. Tommasini, Gina M. Calabrese, Suna Onengut-Gumuscu, Mary L. Bouxsein, Samuel Haddox, Larry D. Mesner, Mark C. Horowitz, Kevin Nguyen, Charles R. Farber, and Clifford J. Rosen
- Subjects
Bone mineral ,medicine.anatomical_structure ,Osteoporosis ,medicine ,Cortical bone ,Genome-wide association study ,Computational biology ,Biology ,medicine.disease ,Gene ,Phenotype ,Human genetics ,Genetic association - Abstract
Genome-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 55 complex skeletal phenotypes. We applied a network approach to cortical bone RNA-seq data to discover 72 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.
- Published
- 2020
15. Mouse genome-wide association and systems genetics identifies Lhfp as a regulator of bone mass
- Author
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Gary A. Churchill, Larry D. Mesner, Gina M. Calabrese, Dana. A. Godfrey, John P. Sundberg, Daniel M. Gatti, Cheryl L. Ackert-Bicknell, Basel M. Al-Barghouthi, and Charles R. Farber
- Subjects
Male ,Cancer Research ,Bone density ,Oncogene Proteins, Fusion ,Tetraspanins ,Inbred Strains ,Gene Identification and Analysis ,Gene Expression ,Genome-wide association study ,Genetic Networks ,QH426-470 ,Mice ,0302 clinical medicine ,Inbred strain ,Bone Density ,Osteogenesis ,Animal Cells ,Medicine and Health Sciences ,Genetics (clinical) ,Connective Tissue Cells ,Bone mineral ,Genetics ,Mice, Knockout ,0303 health sciences ,Genome ,Chromosome Mapping ,Osteoblast ,Cell Differentiation ,Genomics ,Osteoblast Differentiation ,3. Good health ,medicine.anatomical_structure ,Experimental Organism Systems ,Connective Tissue ,Female ,Cellular Types ,Anatomy ,Network Analysis ,Research Article ,musculoskeletal diseases ,Computer and Information Sciences ,Quantitative Trait Loci ,Locus (genetics) ,Bone Marrow Cells ,Quantitative trait locus ,Biology ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,Bone and Bones ,03 medical and health sciences ,medicine ,Genome-Wide Association Studies ,Animals ,Humans ,Gene Regulation ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Osteoblasts ,Biology and Life Sciences ,Computational Biology ,Mesenchymal Stem Cells ,Human Genetics ,Cell Biology ,Genome Analysis ,Biological Tissue ,Genetic Loci ,Expression quantitative trait loci ,Animal Studies ,Osteoporosis ,Cortical bone ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Developmental Biology - Abstract
Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P = 3.1 x 10−12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two separate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts. Furthermore, its expression was regulated by a local expression QTL (eQTL), which overlapped the BMD association. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp-/-) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp-/- mice displayed increased osteogenic differentiation. Lhfp-/- mice also had elevated BMD due to increased cortical bone mass. Lastly, we identified SNPs in human LHFP that were associated (P = 1.2 x 10−5) with heel BMD. In conclusion, we used GWAS and systems genetics to identify Lhfp as a regulator of osteoblast activity and bone mass., Author summary Osteoporosis is a common, chronic disease characterized by low bone mineral density (BMD) that puts millions of Americans at high risk of fracture. Variation in BMD in the general population is, in large part, determined by genetic factors. To identify novel genes influencing BMD, we performed a genome-wide association study in a panel of inbred mouse strains. We identified a locus on Chromosome 3 strongly associated with BMD. Using a combination of systems genetics approaches, we connected the expression of the Lhfp gene with BMD-associated genetic variants and predicted it influenced BMD by altering the activity of bone-forming osteoblasts. Using mice deficient in Lhfp, we demonstrated that Lhfp negatively regulates bone formation and BMD. These data suggest that inhibiting Lhfp may represent a novel therapeutic strategy to increase BMD and decrease the risk of fracture.
- Published
- 2018
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