Fbmd3^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Fbmd3^DBA/2J
• Name: femoral bone mineral density 3, females only; DBA/2J
• MGI ID: MGI:5827513
• QTL: Fbmd3 Location: Chr7:7050288-142367832 bp Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:229654

Osteoporosis is a disease characterized by low bone mass primarily due to microarchitectural changes in trabecular bone. Bone mineral density (BMD) is the major genetic determinant for osteoporosis.

The authors sought to identify genetic factors that regulate BMD in mice. They used the well-defined BXD recombinant inbred (RI) strain derived from progeny of the C57BL/6J (B6) and DBA/2J (D2) progenitor strains (male and female mice, approx. 4 per sex (n=370); 46 strains at 3 months-of-age). At the time of writing, all of the BXD strains had been genotyped at high density (625,000 SNPs).

The authors sought to identify gender-specific QTL for BMD based on separate analysis of both tibia and femur samples. Bone property measurements were conducted using the PIXImus dual-energy X-ray absorptiometer (DXA) (GE Lunar PIXImus, GE Healthcare, WI). There was an excellent correlation of BMD values between both bone types.

QTL mapping was conducted using publically available software on GeneNetwork (http://www.genenetwork.org/webqtl/main.py). The authors entered the BMD as determined by Piximus analysis of both femurs and tibia. For mapping, 2,000 permutation tests were conducted to determine statistical significance. The threshold was computed by evaluating the distribution of highest LRS scores generated by a set of 2,000 random permutations of strain means.

The authors established that there was a QTL for BMD in males on chromosome 15 that has an impact larger than QTL on all other chromosomes. For QTL of tibiae BMD of male mice, the QTL on Chr 15 reached a significant level with an LRS of more than 18 (LOD =~ 3.9; article Figure 1B). We have named this QTL Tbmd1 (tibial bone mineral density 1, males only). It is located between 38 - 52 Mb. A suggestive QTL for femur BMD in males was found in the same genomic location. DBA/2J alleles at the Tbmd1 locus reduced BMD on average by approximately 5%. B6 genotype had a positive impact on BMD for males, while the D2 genotype had a negative impact.

The authors report 73 genes/transcripts within the Tbmd1 region. By searching these transcripts with PGMapper, they found one important candidate gene: zinc finger transcription factor for trichorhinophalangeal syndrome type I protein (Trps1; MGI:1927616). SNP analysis identified a nonsynonymous SNP (rs32398060) in Trps1 that co-segregated with bone mineral density. Analysis of association between rs32398060 and BMD in a human population confirmed its significance.

For QTL of femoral BMD of female mice, permutation tests indicated the suggestive LRS = 10.58, significant LRS =17.73, and highly significant LRS = 20.82. Significant QTL were detected on five chromosomes: 2, 6, 7, 12, and 14. The genomic positions and LRS scores assigned to these QTL were inferred by MGD curators from Figure 1C in the associated manuscript:

QTL Fbmd1 (femoral bone mineral density 1, females only) maps to chromosome 2 from 25-45 Mb with an approximate LRS score of 12.5 (approx. LOD = 2.71).

QTL Fbmd2 (femoral bone mineral density 2, females only) maps to chromosome 6 from 75-115 Mb with an approximate LRS score of 12.0 (approx. LOD = 2.6).

QTL Fbmd3 (femoral bone mineral density 3, females only) maps to chromosome 7 from 150 Mb - chr end with an approximate LRS score of 10.5 (approx. LOD = 2.28).

QTL Fbmd4 (femoral bone mineral density 4, females only) maps to chromosome 12 from 10-25 Mb with an approximate LRS score of 14.8 (approx. LOD = 3.21).

QTL Fbmd5 (femoral bone mineral density 5, females only) maps to chromosome 14 from 100-130 Mb with an approximate LRS score of 12.0 (approx. LOD = 2.6).

References

• Original: J:229654 Wang L, et al., Trps1 differentially modulates the bone mineral density between male and female mice and its polymorphism associates with BMD differently between women and men. PLoS One. 2014;9(1):e84485
• All: 1 reference(s)