title: Insights from human genetic studies into the pathways involved in osteoarthritis.
abstract: Genetic studies have revealed that most loci associated with osteoarthritis (OA) show ethnic stratification, with limited overlap between Asian and European populations. Consequently, such studies have often focused on particular ethnic groups, with those performed in European cohorts yielding the most replicated associations. As for other common diseases, the OA susceptibility loci mapped to date account for only a fraction of disease heritability. Nevertheless, analysis of these loci could identify biological pathways related to OA pathogenesis. Such an approach is taken in this Review and provides valuable insights into OA aetiology. For example, several of the loci associated with OA contain genes encoding key regulators of skeletogenesis and endochondral ossification. Furthermore, direct and indirect regulation of gene transcription is highlighted as an important factor in this disease. Interestingly, genes encoding structural proteins of the cartilage extracellular matrix do not seem to be a repository for OA susceptibility. Therefore, susceptibility might operate at a regulatory rather than a structural level, which is a potentially promising finding, as the activities of regulators are amenable to therapeutic modulation. Greater clarity will emerge as more association signals are identified; nonetheless, patterns of aetiology are clearly discernible, from a molecular perspective, even with the relatively small number currently available.
authors: Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Louise N
authors: LN
authors: Reynard
authors: John
authors: J
authors: Loughlin
mesh_terms: D044466:Asian People / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D010003:Osteoarthritis / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D044465:White People / Q000235:genetics
references: Cell. 1997 May 30;89(5):773-9
references: 9182765
references: Ann Rheum Dis. 2013 Jun;72(6):935-41
references: 22956599
references: J Cell Biol. 2001 Apr 2;153(1):87-100
references: 11285276
references: Cell Biol Int. 2011 May;35(5):529-35
references: 21073445
references: J Cell Biol. 1999 May 17;145(4):783-94
references: 10330406
references: Hum Genet. 2012 Aug;131(8):1305-17
references: 22407027
references: Development. 2005 Sep;132(17):3989-4003
references: 16079159
references: Arthritis Res Ther. 2010;12(5):216
references: 20959023
references: Nat Genet. 2012 Apr 15;44(5):491-501
references: 22504420
references: Ann Hum Genet. 2008 Jul;72(Pt 4):510-8
references: 18373722
references: Proc Natl Acad Sci U S A. 2012 May 22;109(21):8218-23
references: 22566624
references: J Immunol. 2009 Jun 15;182(12):7937-45
references: 19494318
references: Hum Mutat. 2012 Jan;33(1):144-57
references: 21922596
references: Hum Mol Genet. 2008 Jun 15;17(12):1867-75
references: 18334578
references: Hum Mol Genet. 2007 Sep 15;16(18):2226-32
references: 17616513
references: Am J Hum Genet. 2001 Sep;69(3):481-92
references: 11462173
references: Nat Genet. 2008 Feb;40(2):198-203
references: 18193045
references: Arthritis Rheum. 2006 Aug;54(8):2462-70
references: 16868966
references: Nat Genet. 2012 Dec;44(12):1336-40
references: 23143596
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Mod Pathol. 2009 Nov;22(11):1499-506
references: 19648885
references: Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):191-6
references: 21173257
references: Am J Med Genet A. 2005 Nov 1;138(4):379-83
references: 16222676
references: Bone. 2008 Jul;43(1):126-134
references: 18468505
references: BMC Med Genet. 2010 Jun 14;11:96
references: 20546612
references: J Biomed Biotechnol. 2011;2011:864904
references: 21716671
references: Arthritis Rheum. 2008 Jan;58(1):109-18
references: 18163510
references: J Bone Miner Res. 2007 Dec;22(12):1988-95
references: 17708712
references: Arthritis Rheum. 2007 Jan;56(1):177-87
references: 17195220
references: Hum Mol Genet. 2008 May 15;17(10):1497-504
references: 18299287
references: PLoS Genet. 2013 Jun;9(6):e1003557
references: 23825960
references: Osteoarthritis Cartilage. 2012 May;20(5):339-349
references: 22281264
references: Dev Dyn. 1999 Apr;214(4):279-90
references: 10213384
references: Development. 2008 Jun;135(11):1947-56
references: 18434416
references: Osteoarthritis Cartilage. 2010 Sep;18(9):1144-9
references: 20633687
references: Am J Hum Genet. 2011 Sep 9;89(3):446-50
references: 21871595
references: Dev Biol. 2006 Apr 1;292(1):116-28
references: 16476422
references: Mol Biosyst. 2008 Sep;4(9):909-19
references: 18704229
references: Stem Cells Dev. 2013 Jul 1;22(13):1968-76
references: 23388029
references: J Cell Biol. 2001 Apr 2;153(1):35-46
references: 11285272
references: J Orthop Surg Res. 2010 Apr 26;5:28
references: 20420676
references: J Biochem. 2000 Nov;128(5):763-70
references: 11056388
references: Curr Opin Rheumatol. 2008 Sep;20(5):553-9
references: 18698177
references: J Endocrinol. 2011 Nov;211(2):109-21
references: 21642379
references: Arthritis Rheum. 2011 Mar;63(3):708-12
references: 21360499
references: FEBS Lett. 1996 Feb 12;380(1-2):17-20
references: 8603731
references: Nat Genet. 2011 Feb;43(2):121-6
references: 21217753
references: Rheumatology (Oxford). 2010 Nov;49(11):2090-7
references: 20360039
references: Lancet. 2012 Sep 1;380(9844):815-23
references: 22763110
references: Ann N Y Acad Sci. 2006 Apr;1068:1-13
references: 16831900
references: Nat Genet. 1997 Sep;17(1):18-9
references: 9288091
references: Arthritis Rheum. 2012 Oct;64(10):3302-12
references: 22576962
references: Nat Genet. 2008 May;40(5):584-91
references: 18391950
references: Nat Genet. 1996 Mar;12(3):315-7
references: 8589725
references: Ann Rheum Dis. 2011 May;70(5):864-7
references: 21177295
references: Br J Sports Med. 2010 Dec;44(16):1160-5
references: 19443461
references: Arthritis Rheum. 2008 Oct;58(10):3132-44
references: 18821706
references: Biochem Biophys Res Commun. 2005 Mar 18;328(3):658-65
references: 15694399
references: Bone. 2006 Feb;38(2):199-205
references: 16198163
references: Cell Tissue Res. 2010 Jan;339(1):189-95
references: 19649655
references: Osteoarthritis Cartilage. 2009 Mar;17(3):328-35
references: 18775662
references: Int J Biochem Cell Biol. 1997 Nov;29(11):1241-4
references: 9451821
references: Ann Rheum Dis. 2011 Jan;70(1):208-13
references: 20805298
references: Am J Hum Genet. 2000 Jul;67(1):59-66
references: 10839977
references: Prog Mol Biol Transl Sci. 2010;93:113-32
references: 20807643
references: Hum Mol Genet. 2008 May 1;17(9):1222-33
references: 18203755
references: Hum Mol Genet. 2012 Mar 1;21(5):1111-23
references: 22095691
references: Dev Biol. 2003 Feb 1;254(1):116-30
references: 12606286
references: Genes Dev. 2011 Jul 1;25(13):1345-58
references: 21724828
references: Osteoarthritis Cartilage. 2006 Jul;14(7):652-9
references: 16488162
references: Cell. 1999 Oct 15;99(2):143-53
references: 10535733
references: J Cell Sci. 2009 May 1;122(Pt 9):1382-9
references: 19351720
references: J Hum Genet. 2010 Jan;55(1):27-31
references: 19893584
references: Expert Rev Mol Med. 2013 Feb 18;15:e2
references: 23414786
references: Calcif Tissue Int. 2009 Jun;84(6):439-45
references: 19424741
references: Nat Genet. 1997 Sep;17(1):58-64
references: 9288098
references: Osteoarthritis Cartilage. 2012 Feb;20(2):162-71
references: 22209871
references: Oncol Res. 2005;15(7-8):373-83
references: 16491955
references: Osteoarthritis Cartilage. 2010 Apr;18(4):581-92
references: 20060954
references: Nature. 2010 Oct 14;467(7317):832-8
references: 20881960
references: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17192-7
references: 15563592
references: Arthritis Rheum. 2010 Feb;62(2):499-510
references: 20112360
references: Am J Hum Genet. 2010 Mar 12;86(3):434-9
references: 20170896
references: Development. 2009 May;136(10):1697-706
references: 19369399
references: Clin Orthop Relat Res. 2010 Dec;468(12):3333-41
references: 20721706
references: Adv Exp Med Biol. 2012;727:223-40
references: 22399351
references: Ann Rheum Dis. 2013 Jul;72(7):1264-5
references: 23505243
references: Mech Dev. 1999 Feb;80(2):159-70
references: 10072783
references: Chem Biol Drug Des. 2008 Dec;72(6):455-82
references: 19090915
references: Am J Hum Genet. 2006 Apr;78(4):708-12
references: 16532400
references: J Biol Chem. 2000 Mar 24;275(12):8695-702
references: 10722711
references: Science. 1996 Aug 2;273(5275):613-22
references: 8662546
references: Exp Cell Res. 2004 Sep 10;299(1):128-36
references: 15302580
references: Nat Genet. 2007 Apr;39(4):529-33
references: 17384641
references: Osteoarthritis Cartilage. 2012 Sep;20(9):1029-38
references: 22659600
references: Arthritis Rheum. 2012 Oct;64(10):3278-89
references: 22674505
references: Nat Genet. 2008 May;40(5):609-15
references: 18391951
references: J Cell Biol. 1999 Jan 11;144(1):161-73
references: 9885252
references: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7604-9
references: 20368437
references: Rev Endocr Metab Disord. 2006 Dec;7(4):265-71
references: 17200892
references: Osteoarthritis Cartilage. 2013 Mar;21(3):514-23
references: 23296253
references: Arthritis Rheum. 2010 Aug;62(8):2347-52
references: 20506137
references: J Cell Biol. 2004 Jul 5;166(1):85-95
references: 15226309
references: J Clin Endocrinol Metab. 2012 Sep;97(9):2947-56
references: 22745236
references: Osteoarthritis Cartilage. 2008 Jan;16(1):70-82
references: 17644010
references: Ann Rheum Dis. 2012 Jul;71(7):1254-8
references: 22492780
references: Arthritis Rheum. 2009 Jul;60(7):2055-64
references: 19565498
references: Calcif Tissue Int. 2007 Oct;81(4):327-32
references: 17878995
references: Science. 1996 Aug 2;273(5275):663-6
references: 8662561
references: Development. 2002 Apr;129(8):1913-24
references: 11934857
references: Mol Cell Biol. 2009 Nov;29(21):5751-62
references: 19704004