Skip to main content
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jul;65(1):167–174. doi: 10.1086/302465

Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage.

K Chapman 1, Z Mustafa 1, C Irven 1, A J Carr 1, K Clipsham 1, A Smith 1, J Chitnavis 1, J S Sinsheimer 1, V A Bloomfield 1, M McCartney 1, O Cox 1, L R Cardon 1, B Sykes 1, J Loughlin 1
PMCID: PMC1378087  PMID: 10364529

Abstract

We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P</=.05 were then taken through to the second stage, with an additional 184 families. This second stage confirmed evidence of linkage for markers on chromosome 11q. Additional markers from this region were then typed to create a denser map. We obtained a maximum single-point LOD score, at D11S901, of 2.40 (P=.0004) and a maximum multipoint-LOD score of 3.15, between markers D11S1358 and D11S35. A subset of 196 of the 481 families, comprising affected female sibling pairs, generated a corrected LOD score of 2.54 (P=.0003) for marker D11S901, with evidence for linkage extending 12 cM proximal to this marker. When we stratified for affected male sibling pairs there was no evidence of linkage to chromosome 11. Our data suggest that a female-specific susceptibility gene for idiopathic osteoarthritis is located on chromosome 11q.

Full Text

The Full Text of this article is available as a PDF (225.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aerssens J., Dequeker J., Peeters J., Breemans S., Boonen S. Lack of association between osteoarthritis of the hip and gene polymorphisms of VDR, COL1A1, and COL2A1 in postmenopausal women. Arthritis Rheum. 1998 Nov;41(11):1946–1950. doi: 10.1002/1529-0131(199811)41:11<1946::AID-ART8>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  2. Chitnavis J., Sinsheimer J. S., Clipsham K., Loughlin J., Sykes B., Burge P. D., Carr A. J. Genetic influences in end-stage osteoarthritis. Sibling risks of hip and knee replacement for idiopathic osteoarthritis. J Bone Joint Surg Br. 1997 Jul;79(4):660–664. doi: 10.1302/0301-620x.79b4.7437. [DOI] [PubMed] [Google Scholar]
  3. Choi J. Y., Li W. L., Kouri R. E., Yu J., Kao F. T., Ruano G. Assignment of the acute phase response factor (APRF) gene to 17q21 by microdissection clone sequencing and fluorescence in situ hybridization of a P1 clone. Genomics. 1996 Oct 15;37(2):264–265. doi: 10.1006/geno.1996.0556. [DOI] [PubMed] [Google Scholar]
  4. Cooper C., McAlindon T., Snow S., Vines K., Young P., Kirwan J., Dieppe P. Mechanical and constitutional risk factors for symptomatic knee osteoarthritis: differences between medial tibiofemoral and patellofemoral disease. J Rheumatol. 1994 Feb;21(2):307–313. [PubMed] [Google Scholar]
  5. Creamer P., Hochberg M. C. Osteoarthritis. Lancet. 1997 Aug 16;350(9076):503–508. doi: 10.1016/S0140-6736(97)07226-7. [DOI] [PubMed] [Google Scholar]
  6. Deloukas P., Schuler G. D., Gyapay G., Beasley E. M., Soderlund C., Rodriguez-Tomé P., Hui L., Matise T. C., McKusick K. B., Beckmann J. S. A physical map of 30,000 human genes. Science. 1998 Oct 23;282(5389):744–746. doi: 10.1126/science.282.5389.744. [DOI] [PubMed] [Google Scholar]
  7. Dequeker J., Mokassa L., Aerssens J., Boonen S. Bone density and local growth factors in generalized osteoarthritis. Microsc Res Tech. 1997 May 15;37(4):358–371. doi: 10.1002/(SICI)1097-0029(19970515)37:4<358::AID-JEMT10>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  8. Felson D. T., Couropmitree N. N., Chaisson C. E., Hannan M. T., Zhang Y., McAlindon T. E., LaValley M., Levy D., Myers R. H. Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study. Arthritis Rheum. 1998 Jun;41(6):1064–1071. doi: 10.1002/1529-0131(199806)41:6<1064::AID-ART13>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  9. Gong Y., Vikkula M., Boon L., Liu J., Beighton P., Ramesar R., Peltonen L., Somer H., Hirose T., Dallapiccola B. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996 Jul;59(1):146–151. [PMC free article] [PubMed] [Google Scholar]
  10. Göring H. H., Ott J. Relationship estimation in affected sib pair analysis of late-onset diseases. Eur J Hum Genet. 1997 Mar-Apr;5(2):69–77. [PubMed] [Google Scholar]
  11. Hager J., Dina C., Francke S., Dubois S., Houari M., Vatin V., Vaillant E., Lorentz N., Basdevant A., Clement K. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet. 1998 Nov;20(3):304–308. doi: 10.1038/3123. [DOI] [PubMed] [Google Scholar]
  12. Heaney C., Shalev H., Elbedour K., Carmi R., Staack J. B., Sheffield V. C., Beier D. R. Human autosomal recessive osteopetrosis maps to 11q13, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation. Hum Mol Genet. 1998 Sep;7(9):1407–1410. doi: 10.1093/hmg/7.9.1407. [DOI] [PubMed] [Google Scholar]
  13. Hirsch R., Lethbridge-Cejku M., Hanson R., Scott W. W., Jr, Reichle R., Plato C. C., Tobin J. D., Hochberg M. C. Familial aggregation of osteoarthritis: data from the Baltimore Longitudinal Study on Aging. Arthritis Rheum. 1998 Jul;41(7):1227–1232. doi: 10.1002/1529-0131(199807)41:7<1227::AID-ART13>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  14. Holmans P., Craddock N. Efficient strategies for genome scanning using maximum-likelihood affected-sib-pair analysis. Am J Hum Genet. 1997 Mar;60(3):657–666. [PMC free article] [PubMed] [Google Scholar]
  15. Horton W. A. Evolution of the bone dysplasia family. Am J Med Genet. 1996 May 3;63(1):4–6. doi: 10.1002/(SICI)1096-8628(19960503)63:1<4::AID-AJMG3>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  16. Johnson M. L., Gong G., Kimberling W., Reckér S. M., Kimmel D. B., Recker R. B. Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13) Am J Hum Genet. 1997 Jun;60(6):1326–1332. doi: 10.1086/515470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kaprio J., Kujala U. M., Peltonen L., Koskenvuo M. Genetic liability to osteoarthritis may be greater in women than men. BMJ. 1996 Jul 27;313(7051):232–232. doi: 10.1136/bmj.313.7051.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Koller D. L., Rodriguez L. A., Christian J. C., Slemenda C. W., Econs M. J., Hui S. L., Morin P., Conneally P. M., Joslyn G., Curran M. E. Linkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12-13. J Bone Miner Res. 1998 Dec;13(12):1903–1908. doi: 10.1359/jbmr.1998.13.12.1903. [DOI] [PubMed] [Google Scholar]
  19. Lane N. E., Nevitt M. C. Osteoarthritis and bone mass. J Rheumatol. 1994 Aug;21(8):1393–1396. [PubMed] [Google Scholar]
  20. Lindberg H. Prevalence of primary coxarthrosis in siblings of patients with primary coxarthrosis. Clin Orthop Relat Res. 1986 Feb;(203):273–275. [PubMed] [Google Scholar]
  21. Loughlin J., Irven C., Fergusson C., Sykes B. Sibling pair analysis shows no linkage of generalized osteoarthritis to the loci encoding type II collagen, cartilage link protein or cartilage matrix protein. Br J Rheumatol. 1994 Dec;33(12):1103–1106. doi: 10.1093/rheumatology/33.12.1103. [DOI] [PubMed] [Google Scholar]
  22. Mansell J. P., Bailey A. J. Abnormal cancellous bone collagen metabolism in osteoarthritis. J Clin Invest. 1998 Apr 15;101(8):1596–1603. doi: 10.1172/JCI867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Matrisian L. M. The matrix-degrading metalloproteinases. Bioessays. 1992 Jul;14(7):455–463. doi: 10.1002/bies.950140705. [DOI] [PubMed] [Google Scholar]
  24. O'Connell J. R., Weeks D. E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998 Jul;63(1):259–266. doi: 10.1086/301904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Reed P. W., Davies J. L., Copeman J. B., Bennett S. T., Palmer S. M., Pritchard L. E., Gough S. C., Kawaguchi Y., Cordell H. J., Balfour K. M. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nat Genet. 1994 Jul;7(3):390–395. doi: 10.1038/ng0794-390. [DOI] [PubMed] [Google Scholar]
  26. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222–228. [PMC free article] [PubMed] [Google Scholar]
  27. Spector T. D., Cicuttini F., Baker J., Loughlin J., Hart D. Genetic influences on osteoarthritis in women: a twin study. BMJ. 1996 Apr 13;312(7036):940–943. doi: 10.1136/bmj.312.7036.940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Uitterlinden A. G., Burger H., Huang Q., Odding E., Duijn C. M., Hofman A., Birkenhäger J. C., van Leeuwen J. P., Pols H. A. Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee. J Clin Invest. 1997 Jul 15;100(2):259–263. doi: 10.1172/JCI119530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vikkula M., Palotie A., Ritvaniemi P., Ott J., Ala-Kokko L., Sievers U., Aho K., Peltonen L. Early-onset osteoarthritis linked to the type II procollagen gene. Detailed clinical phenotype and further analyses of the gene. Arthritis Rheum. 1993 Mar;36(3):401–409. doi: 10.1002/art.1780360317. [DOI] [PubMed] [Google Scholar]
  30. Wright G. D., Hughes A. E., Regan M., Doherty M. Association of two loci on chromosome 2q with nodal osteoarthritis. Ann Rheum Dis. 1996 May;55(5):317–319. doi: 10.1136/ard.55.5.317. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES