Genetic Variation in TRPS1 May Regulate Hip Geometry As Well As Bone Mineral Density

Overview

Journal Bone

Specialties Endocrinology
Orthopedics

Date 2012 Feb 7

PMID 22306695

Citations 11

Authors

Cheryl L Ackert-Bicknell

Serkalem Demissie

Shirng-Wern Tsaih

Wesley G Beamer

L Adrienne Cupples

Beverly J Paigen

Yi-Hsiang Hsu

Douglas P Kiel

David Karasik

Affiliations

Soon will be listed here.

Abstract

Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the Chr 15 region spanning from 6 to 24cM. This region contains 131 annotated genes. Using block haplotyping, all other genes except Trps1 were eliminated as candidates for this QTL. We then examined associations of 208 SNPs within 10kb of TRPS1 with BMD and hip geometry, using human genome-wide association study (GWAS) data from the GEFOS consortium. After correction for multiple testing, six TRPS1 SNPs were significantly associated with femoral neck BMD (P=0.0015-0.0019; adjusted P=0.038-0.048). We also found that three SNPs were highly associated with femoral neck width in women (rs10505257, P=8.6×10(-5), adjusted P=2.15×10(-3); rs7002384, P=5.5×10(-4), adjusted P=01.38×10(-2)). In conclusion, we demonstrated that combining association studies in humans with murine models provides an efficient strategy to identify new candidate genes for bone phenotypes.

Citing Articles

Copy Number Variation and Osteoporosis.

Lovsin N Curr Osteoporos Rep. 2023; 21(2):167-172.

PMID: 36795294 PMC: 10105686. DOI: 10.1007/s11914-023-00773-y.

Mouse genome-wide association and systems genetics identifies Lhfp as a regulator of bone mass.

Mesner L, Calabrese G, Al-Barghouthi B, Gatti D, Sundberg J, Churchill G PLoS Genet. 2019; 15(5):e1008123.

PMID: 31042701 PMC: 6513102. DOI: 10.1371/journal.pgen.1008123.

Severe brachydactyly and short stature resulting from a novel pathogenic TRPS1 variant within the GATA DNA-binding domain.

Karaca A, Reyes M, Shumate L, Taskaldiran I, Omma T, Gulcelik N Bone. 2019; 123:153-158.

PMID: 30914275 PMC: 6506180. DOI: 10.1016/j.bone.2019.03.028.

Targeting the gut microbiome to treat the osteoarthritis of obesity.

Schott E, Farnsworth C, Grier A, Lillis J, Soniwala S, Dadourian G JCI Insight. 2018; 3(8).

PMID: 29669931 PMC: 5931133. DOI: 10.1172/jci.insight.95997.

Differential effects of altered patterns of movement and strain on joint cell behaviour and skeletal morphogenesis.

Brunt L, Skinner R, Roddy K, Araujo N, Rayfield E, Hammond C Osteoarthritis Cartilage. 2016; 24(11):1940-1950.

PMID: 27374878 PMC: 5081689. DOI: 10.1016/j.joca.2016.06.015.

References

Gai Z, Gui T, Muragaki Y . The function of TRPS1 in the development and differentiation of bone, kidney, and hair follicles. Histol Histopathol. 2011; 26(7):915-21. DOI: 10.14670/HH-26.915. View

Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson B, Hsu Y, Richards J . Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009; 41(11):1199-206. PMC: 2783489. DOI: 10.1038/ng.446. View

Ishimori N, Stylianou I, Korstanje R, Marion M, Li R, Donahue L . Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene. J Bone Miner Res. 2008; 23(9):1529-37. PMC: 2586053. DOI: 10.1359/jbmr.080414. View

Suemoto H, Muragaki Y, Nishioka K, Sato M, Ooshima A, Itoh S . Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. Dev Biol. 2007; 312(2):572-81. DOI: 10.1016/j.ydbio.2007.10.001. View

Marshall D, Johnell O, Wedel H . Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996; 312(7041):1254-9. PMC: 2351094. DOI: 10.1136/bmj.312.7041.1254. View

Petkov P, Ding Y, Cassell M, Zhang W, Wagner G, Sargent E . An efficient SNP system for mouse genome scanning and elucidating strain relationships. Genome Res. 2004; 14(9):1806-11. PMC: 515327. DOI: 10.1101/gr.2825804. View

Li Y, Willer C, Ding J, Scheet P, Abecasis G . MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010; 34(8):816-34. PMC: 3175618. DOI: 10.1002/gepi.20533. View

Yu H, Mohan S, Edderkaoui B, Masinde G, Davidson H, Wergedal J . Detecting novel bone density and bone size quantitative trait loci using a cross of MRL/MpJ and CAST/EiJ inbred mice. Calcif Tissue Int. 2007; 80(2):103-10. DOI: 10.1007/s00223-006-0187-z. View

Ackert-Bicknell C, Demissie S, Marin de Evsikova C, Hsu Y, DeMambro V, Karasik D . PPARG by dietary fat interaction influences bone mass in mice and humans. J Bone Miner Res. 2008; 23(9):1398-408. PMC: 2683155. DOI: 10.1359/jbmr.080419. View

10.

Roeder K, Bacanu S, Wasserman L, Devlin B . Using linkage genome scans to improve power of association in genome scans. Am J Hum Genet. 2006; 78(2):243-52. PMC: 1380233. DOI: 10.1086/500026. View

11.

Faulkner K, Wacker W, Barden H, Simonelli C, Burke P, Ragi S . Femur strength index predicts hip fracture independent of bone density and hip axis length. Osteoporos Int. 2006; 17(4):593-9. DOI: 10.1007/s00198-005-0019-4. View

12.

Ralston S, de Crombrugghe B . Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev. 2006; 20(18):2492-506. DOI: 10.1101/gad.1449506. View

13.

Li R, Lyons M, Wittenburg H, Paigen B, Churchill G . Combining data from multiple inbred line crosses improves the power and resolution of quantitative trait loci mapping. Genetics. 2005; 169(3):1699-709. PMC: 1449540. DOI: 10.1534/genetics.104.033993. View

14.

HOWARD G, Nguyen T, Harris M, Kelly P, Eisman J . Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study. J Bone Miner Res. 1998; 13(8):1318-27. DOI: 10.1359/jbmr.1998.13.8.1318. View

15.

Beamer W, Shultz K, Donahue L, Churchill G, Sen S, Wergedal J . Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J Bone Miner Res. 2001; 16(7):1195-206. DOI: 10.1359/jbmr.2001.16.7.1195. View

16.

Lander E, Botstein D . Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics. 1989; 121(1):185-99. PMC: 1203601. DOI: 10.1093/genetics/121.1.185. View

17.

Masinde G, Li X, Gu W, Wergedal J, Mohan S, Baylink D . Quantitative trait loci for bone density in mice: the genes determining total skeletal density and femur density show little overlap in F2 mice. Calcif Tissue Int. 2002; 71(5):421-8. DOI: 10.1007/s00223-001-1113-z. View

18.

Broman K, Wu H, Sen S, Churchill G . R/qtl: QTL mapping in experimental crosses. Bioinformatics. 2003; 19(7):889-90. DOI: 10.1093/bioinformatics/btg112. View

19.

Hsu Y, Zillikens M, Wilson S, Farber C, Demissie S, Soranzo N . An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits. PLoS Genet. 2010; 6(6):e1000977. PMC: 2883588. DOI: 10.1371/journal.pgen.1000977. View

20.

Gluer C, Hans D . How to use ultrasound for risk assessment: a need for defining strategies. Osteoporos Int. 1999; 9(3):193-5. DOI: 10.1007/s001980050135. View