Top

Published in:

01-05-2005 | Review

Genetic Studies of Osteoporosis — A Rethink Required

Author: M. A. Brown

Published in: Calcified Tissue International | Issue 5/2005

Excerpt

It has been 10 years since the seminal paper by Morrison and colleagues reporting the association of alleles of the vitamin D receptor and bone density [1], a paper which arguably kick-started the study of osteoporosis genetics. Since that report there have been literally thousands of osteoporosis genetic studies published, and large numbers of genes have been reported to be associated with the condition [2]. Although some of these reported associations are undoubtedly true, this snow-storm of papers and abstracts has clouded the field to such a great extent that it is very difficult to be certain of the veracity of most genetic associations reported hereto. The field needs to take stock and reconsider the best way forward, taking into account the biology of skeletal development and technological and statistical advances in human genetics, before more effort and money is wasted on continuing a process in which the primary achievement could be said to be a massive paper mountain. I propose in this review that the primary reasons for the paucity of success in osteoporosis genetics has been:

the absence of a major gene effect on bone mineral density (BMD), the most commonly studied bone phenotype;
failure to consider issues such as genetic heterogeneity, gene–environment interaction, and gene–gene interaction;
small sample sizes and over-optimistic data interpretation; and
incomplete assessment of the genetic variation in candidate genes studied.

…

Morrison, NA, Qi, JC, Tokita, A, Kelly, PJ, Crofts, L, Nguyen, TV, Sambrook, PN, Eisman, JA 1994Prediction of bone density from vitamin D receptor allelesNature367284287PubMed

Liu, YZ, Liu, YJ, Recker, RR, Deng, HW 2003Molecular studies of identification of genes for osteoporosis: the 2002 updateJ Endocrinol177147196PubMed

Risch, N 1990Linkage strategies for genetically complex traitsI. Multilocus models. Am J Hum Genet46222228PubMed

Gueguen, R, Jouanny, P, Guillemin, F, Kuntz, C, Pourel, J, Siest, G 1995Segregation analysis and variance .components analysis of bone mineral density in healthy familiesJ Bone Miner Res1020172022PubMed

Duncan, EL, Cardon, LR, Sinsheimer, JS, Wass, JA, Brown, MA 2003Site and gender specificity of inheritance of bone mineral densityJ Bone Miner Res1815311538PubMed

Deng, HW, Livshits, G, Yakovenko, K, Xu, FH, Conway, T, Davies, KM, Deng, H, Recker, RR 2002Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral densityAnn Hum Genet666174PubMed

Livshits, G, Deng, HW, Nguyen, TV, Yakovenko, K, Recker, RR, Eisman, JA 2004Genetics of bone mineral density: evidence for a major pleiotropic effect from an intercontinental studyJ Bone Miner Res19914923PubMed

Cardon, LR, Garner, C, Bennett, ST, Mackay, IJ, Edwards, RM, Cornish, J, Hegde, M, Murray, MA, Reid, IR, Cundy, T 2000Evidence for a major gene for bone mineral density in idiopathic osteoporotic familiesJ Bone Miner Res1511321137PubMed

Ginsburg, E, Skaric-Juric, T, Kobyliansky, E, Karasik, D, Malkin, I, Rudan, P 2001Evidence on major gene control of cortical index in pedigree data from Middle Dalmatia, CroatiaAm J Hum Biol13398408PubMed

10.

Chitnavis, J, Sinsheimer, JS, Clipsham, K, Loughlin, J, Sykes, B, Burge, PD, Carr, AJ 1997Genetic influences in end-stage osteoarthritis risks of hip and knee replacement for idiopathic osteoarthritisJ Bone Joint Surg Br79660664PubMed

11.

Wordsworth, BP, Bell, JI 1992The immunogenetics of rheumatoid arthritisSpringer Semin Immunopathol145978PubMed

12.

Ferrari, SL, Deutsch, S, Choudhury, U, Chevalley, T, Bonjour, JP, Dermitzakis, ET, Rizzoli, R, Antonarakis, SE 2004Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whitesAm J Hum Genet74866875PubMedPubMedCentral

13.

Goring, HH, Terwilliger, JD, Blangero, J 2001Large upward bias in estimation of locus-specific effects from genomewide scansAm J Hum Genet6913571369PubMedPubMedCentral

14.

Terwilliger, JD, Weiss, KM 2003Confounding, ascertainment bias, and the blind quest for a genetic “fountain of youth”Ann Med35532544PubMed

15.

Olson, JM 1999A general conditional-logistic model for affected-relative-pair linkage studiesAm J Hum Genet6517601769PubMedPubMedCentral

16.

Holmans, P 2002Detecting gene-gene interactions using affected sib pair analysis with covariatesHum Hered5392102PubMed

17.

Cook, NR, Zee, RY, Ridker, PM 2004Tree and spline based association analysis of gene-gene interaction models for ischemic strokeStat Med2314391453PubMed

18.

Hahn, LW, Ritchie, MD, Moore, JH 2003Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactionsBioinformatics19376382PubMed

19.

Culverhouse, R, Klein, T, Shannon, W 2004Detecting epistatic interactions contributing to quantitative traitsGenet Epidemiol27141152PubMed

20.

Guo, SW 2000Gene-environment interactions and the affected-sib-pair designsHum Hered50271285PubMed

21.

Seeman, E, Hopper, JL 1997Genetic and environmental components of the population variance in bone densityOsteoporos Int7 S1016PubMed

22.

Baldock, P, Eisman, JA 2004Genetic determinants of bone massCurr Opin Rheumatol16450456PubMed

23.

Recker, RR, Deng, HW 2002Role of genetics in osteoporosisEndocrine175566PubMed

24.

Karasik, D, Cupples, LA, Hannan, MT, Kiel, DP 2004Genome screen for a combined bone phenotype using principal component analysis: the Framingham studyBone34547556PubMed

25.

Andrew, T, Anitoniades, L, Scurrah, KJ, Macgregor, AJ, Spector, TD (2005) “Risk of Wrist Fracture in women Is Heritable and Is Influenced by Genes That are Largely Independent of Those Influencing BMD.” J Bone Miner Res 20: 67-74PubMed

26.

Kannus, P, Palvanen, M, Kaprio, J, Parkkari, J, Koskenvuo, M 1999Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twinsBMJ31913341337PubMedPubMedCentral

27.

MacGregor, A, Snieder, H, Spector, TD 2000Genetic factors and osteoporotic fractures in elderly peopleTwin data support genetic contribution to risk of fracture. BMJ32016691670; author reply 1670–1661PubMed

28.

Deng, HW, Mahaney, MC, Williams, JT, Li, J, Conway, T, Davies, KM, Li, JL, Deng, H, Recker, RR 2002Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseasesGenet Epidemiol221225PubMed

29.

Deng, HW, Mahaney, MC, Williams, JT, Li, J, Conway, T, Davies, KM, Li, JL, Deng, H, Recker, RR (2002) “Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases.” Genet epidemiol 22: 12-25PubMed

30.

Keen, RW, Hart, DJ, Arden, NK, Doyle, DV, Spector, TD 1999Family history of appendicular fracture and risk of osteoporosis: a population-based studyOsteoporos Int10161166PubMed

31.

Seeman, E, Hopper, JL, Bach, LA, Cooper, ME, Parkinson, E, McKay, J, Jerums, G 1989Reduced bone mass in daughters of women with osteoporosisN Engl J Med320554558PubMed

32.

Seeman, E, Tsalamandris, C, Formica, C, Hopper, JL, McKay, J 1994Reduced femoral neck bone density in the daughters of women with hip fractures: the role of low peak bone density in the pathogenesis of osteoporosisJ Bone Miner Res9739743PubMed

33.

Gong, Y, Slee, RB, Fukai, N, Rawadi, G, Roman-Roman, S, Reginato, AM, Wang, H, Cundy, T, Glorieux, FH, Lev, D, Zacharin, M, Oexle, K, Marcelino, J, Suwairi, W, Heeger, S, Sabatakos, G, Apte, S, Adkins, WN, Allgrove, J, Arslan-Kirchner, M, Batch, JA, Beighton, P, Black, GC, Boles, RG, Boon, LM, Borrone, C, Brunner, HG, Carle, GF, Dallapiccola, B, Paepe, A, Floege, B, Halfhide, ML, Hall, B, Hennekam, RC, Hirose, T, Jans, A, Juppner, H, Kim, CA, Keppler-Noreuil, K, Kohlschuetter, A, LaCombe, D, Lambert, M, Lemyre, E, Letteboer, T, Peltonen, L, Ramesar, RS, Romanengo, M, Somer, H, Steichen-Gersdorf, E, Steinmann, B, Sullivan, B, Superti-Furga, A, Swoboda, W, Boogaard, MJ, Hul, W, Vikkula, M, Votruba, M, Zabel, B, Garcia, T, Baron, R, Olsen, BR, Warman, ML 2001LDL receptor-related protein 5 (LRP5) affects bone accrual and eye developmentCell107513523PubMed

34.

Little, RD, Carulli, JP, Mastro, RG, Dupuis, J, Osborne, M, Folz, C, Manning, SP, Swain, PM, Zhao, SC, Eustace, B, Lappe, MM, Spitzer, L, Zweier, S, Braunschweiger, K, Benchekroun, Y, Hu, X, Adair, R, Chee, L, FitzGerald, MG, Tulig, C, Caruso, A, Tzellas, N, Bawa, A, Franklin, B, McGuire, S, Nogues, X, Gong, G, Allen, KM, Anisowicz, A, Morales, AJ, Lomedico, PT, Recker, SM, Eerdewegh, P, Recker, RR, Johnson, ML 2002A mutation in the LDL receptor- related protein 5 gene results in the autosomal dominant high-bone-mass traitAm J Hum Genet701119PubMed

35.

Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) “Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2.” PLoS Biol 1:E69PubMedPubMedCentral

36.

Grant, SF, Reid, DM, Blake, G, Herd, R, Fogelman, I, Ralston, SH 1996Reduced bone density and osteoporosis associated with a polymorphic Spl binding site in the collagen type I alpha 1 geneNat Genet14203205PubMed

37.

Koller, DL, Econs, MJ, Morin, PA, Christian, JC, Hui, SL, Parry, P, Curran, ME, Rodriguez, LA, Conneally, PM, Joslyn, G, Peacock, M, Johnston, CC, Foroud, T 2000Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosisJ Clin Endocrinol Metab8531163120PubMed

38.

Lander, E, Kruglyak, L 1995Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNat Genet11241247PubMed

39.

Ralston, SH, Galway, N, MacKay, N, Albagha, OME, Cardon, LR, Compston, JE, Cooper, C, Duncan, EL, Keen, RW, Langdahl, B, McLellan, A, O’Riordan, JLH, Pols, HA, Reid, DM, Uitterlinden, AG, Wass, JA, Bennett, ST 2005Loci for regulation of BMD in men and women: the FAMOS studyHum Mol Genet14943951PubMed

40.

Kruglyak, L 1997What is significant in whole-genome linkage disequilibrium studies?Am J Hum Genet61810812PubMedPubMedCentral

41.

Wang, WY, Cordell, HJ, Todd, JA 2003Association mapping of complex diseases in linked regions: estimation of genetic effects and feasibility of testing rare variantsGenet Epidemiol243643PubMed

42.

Begovich, AB, Carlton, VE, Honigberg, LA, Schrodi, SJ, Chokkalingam, AP, Alexander, HC, Ardlie, KG, Huang, Q, Smith, AM, Spoerke, JM, Conn, MT, Chang, M, Chang, SY, Saiki, RK, Catanese, JJ, Leong, DU, Garcia, VE, McAllister, LB, Jeffery, DA, Lee, AT, Batliwalla, F, Remmers, E, Criswell, LA, Seldin, MF, Kastner, DL, Amos, CI, Sninsky, JJ, Gregersen, PK 2004A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritisAm J Hum Genet75330337PubMedPubMedCentral

43.

Franchimont, D, Vermeire, S, El Housni, H, Pierik, M, Steen, K, Gustot, T, Quertinmont, E, Abramowicz, M, Gossum, A, Deviere, J, Rutgeerts, P 2004Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitisGut53987992PubMedPubMedCentral

44.

Huizinga, TW, Pisetsky, DS, Kimberly, RP 2004Associations, populations, and the truth: recommendations for genetic association studies in Arthritis & RheumatismArthritis Rheum5020662071PubMed

45.

Garcia-Giralt, N, Nogues, X, Enjuanes, A, Puig, J, Mellibovsky, L, Bay-Jensen, A, Carreras, R, Balcells, S, Diez-Perez, A, Grinberg, D 2002Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral densityJ Bone Miner Res17384393PubMed

Title: Genetic Studies of Osteoporosis — A Rethink Required
Author: M. A. Brown
Publication date: 01-05-2005
Publisher: Springer New York
Published in: Calcified Tissue International / Issue 5/2005
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-004-0179-9

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Excerpt

Please log in to get access to this content

Other articles of this Issue 5/2005

Quantification of Trabecular Bone Structure Using Magnetic Resonance Imaging at 3 Tesla—Calibration Studies Using Microcomputed Tomography as a Standard of Reference

Umbilical Cord Leptin Predicts Neonatal Bone Mass

CSF-1 Induces fos Gene Transcription and Activates the Transcription Factor Elk-1 in Mature Osteoclasts

Depressed Bone Mineralization Following High Dose TGF-β1 Application in an Orthopedic Implant Model

Localization of Matrix Metalloproteinases, (MMPs) Their Tissue Inhibitors, and Vascular Endothelial Growth Factor (VEGF) in Growth Plates of Children and Adolescents Indicates a Role for MMPs in Human Postnatal Growth and Skeletal Maturation

Towards Standardization of Dual X-ray Absorptiometry (DXA) at the Forearm

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials