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Mouse Genome-Wide Association and Systems Genetics Identify As a Regulator of Bone Mineral Density and Osteoclastogenesis


Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal, and femoral BMD revealed four significant associations (−log10P>5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12, and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism through which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cells of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits.


Vyšlo v časopise: Mouse Genome-Wide Association and Systems Genetics Identify As a Regulator of Bone Mineral Density and Osteoclastogenesis. PLoS Genet 7(4): e32767. doi:10.1371/journal.pgen.1002038
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002038

Souhrn

Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal, and femoral BMD revealed four significant associations (−log10P>5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12, and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism through which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cells of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits.


Zdroje

1. 2001 Osteoporosis prevention, diagnosis, and therapy. JAMA 785 795 2001/02/15 ed

2. JohnellOKanisJAOdenAJohanssonHDe LaetC 2005 Predictive value of BMD for hip and other fractures. J Bone Miner Res 20 1185 1194

3. RalstonSH 2007 Genetics of osteoporosis. Proc Nutr Soc 66 158 165

4. XiongQJiaoYHastyKACanaleSTStuartJM 2009 Quantitative trait loci, genes, and polymorphisms that regulate bone mineral density in mouse. Genomics 93 401 414

5. FlintJValdarWShifmanSMottR 2005 Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6 271 286

6. KleinRFAllardJAvnurZNikolchevaTRotsteinD 2004 Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303 229 232

7. NakanishiRShimizuMMoriMAkiyamaHOkudairaS 2006 Secreted frizzled-related protein 4 is a negative regulator of peak BMD in SAMP6 mice. J Bone Miner Res 21 1713 1721

8. EdderkaouiBBaylinkDJBeamerWGWergedalJEPorteR 2007 Identification of mouse Duffy antigen receptor for chemokines (Darc) as a BMD QTL gene. Genome Res 17 577 585

9. Ackert-BicknellCLKarasikDLiQSmithRVHsuYH 2010 Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map. J Bone Miner Res 25 1808 1820

10. LiuPWangYVikisHMaciagAWangD 2006 Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice. Nat Genet 38 888 895

11. ChengRLimJESamochaKESokoloffGAbneyM 2010 Genome-wide Association Studies and the Problem of Relatedness Among Advanced Intercross Lines and Other Highly Recombinant Populations. Genetics

12. ValdarWSolbergLCGauguierDBurnettSKlenermanP 2006 Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat Genet 38 879 887

13. FarberCRvan NasAGhazalpourAAtenJEDossS 2009 An integrative genetics approach to identify candidate genes regulating BMD: combining linkage, gene expression, and association. J Bone Miner Res 24 105 116

14. GhazalpourADossSKangHFarberCWenPZ 2008 High-resolution mapping of gene expression using association in an outbred mouse stock. PLoS Genet 4 e1000149 doi:10.1371/journal.pgen.1000149

15. BennettBJFarberCROrozcoLKangHMGhazalpourA 2010 A high-resolution association mapping panel for the dissection of complex traits in mice. Genome Res 20 281 290

16. SchadtEE 2009 Molecular networks as sensors and drivers of common human diseases. Nature 461 218 223

17. FarberCRLusisAJ 2009 Future of osteoporosis genetics: enhancing genome-wide association studies. J Bone Miner Res 24 1937 1942

18. ZhangBHorvathS 2005 A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4 Article17

19. GhazalpourADossSZhangBWangSPlaisierC 2006 Integrating genetic and network analysis to characterize genes related to mouse weight. PLoS Genet 2 e130 doi:10.1371/journal.pgen.0020130

20. HorvathSZhangBCarlsonMLuKVZhuS 2006 Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl Acad Sci U S A 103 17402 17407

21. OldhamMCKonopkaGIwamotoKLangfelderPKatoT 2008 Functional organization of the transcriptome in human brain. Nat Neurosci 11 1271 1282

22. WolfeCJKohaneISButteAJ 2005 Systematic survey reveals general applicability of “guilt-by-association” within gene coexpression networks. BMC Bioinformatics 6 227

23. KangHMZaitlenNAWadeCMKirbyAHeckermanD 2008 Efficient control of population structure in model organism association mapping. Genetics 178 1709 1723

24. BennettBJFarberCROrozcoLKangHMGhazalpourA A high-resolution association mapping panel for the dissection of complex traits in mice. Genome Res 20 281 290

25. RamenskyVBorkPSunyaevS 2002 Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30 3894 3900

26. SunyaevSRamenskyVKochILatheW3rdKondrashovAS 2001 Prediction of deleterious human alleles. Hum Mol Genet 10 591 597

27. SabatakosGSimsNAChenJAokiKKelzMB 2000 Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 6 985 990

28. SoysaNSAllesNWeihDLovasAMianAH 2009 The Pivotal Role of the Alternative NF-kappaB Pathway in Maintenance of Basal Bone Homeostasis and Osteoclastogenesis. J Bone Miner Res

29. SchillingAFSchinkeTMunchCGebauerMNiemeierA 2005 Increased bone formation in mice lacking apolipoprotein E. J Bone Miner Res 20 274 282

30. DucyPZhangRGeoffroyVRidallALKarsentyG 1997 Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89 747 754

31. BaskindHANaLMaQPatelMPGeenenDL 2009 Functional conservation of asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene asx. PLoS ONE 4 e4750 doi:10.1371/journal.pone.0004750

32. ZhouPKitauraHTeitelbaumSLKrystalGRossFP 2006 SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. J Immunol 177 8777 8784

33. KanekoHArakawaTManoHKanedaTOgasawaraA 2000 Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone 27 479 486

34. LeeJKimKKimJHJinHMChoiHK 2006 Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation. Blood 107 2686 2693

35. MaoDEppleHUthgenanntBNovackDVFaccioR 2006 PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest 116 2869 2879

36. Sotillo RodriguezJEManskyKCJensenEDCarlsonAESchwarzT 2009 Enhanced osteoclastogenesis causes osteopenia in twisted gastrulation-deficient mice through increased BMP signaling. J Bone Miner Res 24 1917 1926

37. SchuettengruberBChourroutDVervoortMLeblancBCavalliG 2007 Genome regulation by polycomb and trithorax proteins. Cell 128 735 745

38. MartinezAMCavalliG 2006 The role of polycomb group proteins in cell cycle regulation during development. Cell Cycle 5 1189 1197

39. AraiSMiyazakiT 2005 Impaired maturation of myeloid progenitors in mice lacking novel Polycomb group protein MBT-1. Embo J 24 1863 1873

40. ZhangHWDingJJinJLGuoJLiuJN 2010 Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice. J Bone Miner Res 25 640 652

41. GildeaJJLopezRShearnA 2000 A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2. Genetics 156 645 663

42. FisherCLRandazzoFHumphriesRKBrockHW 2006 Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family. Gene 369 109 118

43. KatohMKatohM 2003 Identification and characterization of ASXL2 gene in silico. Int J Oncol 23 845 850

44. KatohMKatohM 2004 Identification and characterization of ASXL3 gene in silico. Int J Oncol 24 1617 1622

45. CarbucciaNMuratiATrouplinVBrecquevilleMAdelaideJ 2009 Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23 2183 2186

46. KawaguchiHManabeNMiyauraCChikudaHNakamuraK 1999 Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104 229 237

47. KennerLHoebertzABeilTKeonNKarrethF 2004 Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol 164 613 623

48. KawamuraNKugimiyaFOshimaYOhbaSIkedaT 2007 Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE 2 e1058 doi:10.1371/journal.pone.0001058

49. ZhaoHItoYChappelJAndrewsNWTeitelbaumSL 2008 Synaptotagmin VII regulates bone remodeling by modulating osteoclast and osteoblast secretion. Dev Cell 14 914 925

50. PetkovPMGraberJHChurchillGADiPetrilloKKingBL 2005 Evidence of a large-scale functional organization of mammalian chromosomes. PLoS Genet 1 e33 doi:10.1371/journal.pgen.0010033

51. GrundbergEKwanTGeBLamKCKokaV 2009 Population genomics in a disease targeted primary cell model. Genome Res 19 1942 1952

52. LinSMDuPHuberWKibbeWA 2008 Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36 e11

53. DuPKibbeWALinSM 2008 lumi: a pipeline for processing Illumina microarray. Bioinformatics 24 1547 1548

54. JohnsonWELiCRabinovicA 2007 Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8 118 127

55. YuJPressoirGBriggsWHVroh BiIYamasakiM 2006 A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nat Genet 38 203 208

56. ZhaoKAranzanaMJKimSListerCShindoC 2007 An Arabidopsis example of association mapping in structured samples. PLoS Genet 3 e4 doi:10.1371/journal.pgen.0030004

57. ChenLPageGPMehtaTFengRCuiX 2009 Single nucleotide polymorphisms affect both cis- and trans-eQTLs. Genomics 93 501 508

58. AlbertsRTerpstraPLiYBreitlingRNapJP 2007 Sequence polymorphisms cause many false cis eQTLs. PLoS ONE 2 e622 doi:10.1371/journal.pone.0000622

59. LangfelderPHorvathS 2008 WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9 559

60. FarberCR 2010 Identification of a gene module associated with BMD through the integration of network analysis and genome-wide association data. J Bone Miner Res 25 2359 2367

61. LangfelderPZhangBHorvathS 2008 Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics 24 719 720

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Genetika Reprodukčná medicína

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PLOS Genetics


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