Genetic Dissection of Femoral and Tibial Microarchitecture

Abstract

Our understanding of the genetic control of bone strength has relied mainly on estimates of bone mineral density. Here we have mapped genetic factors that influence femoral and tibial microarchitecture using high‐resolution x‐ray computed tomography (8‐μm isotropic voxels) across a family of 61 BXD strains of mice, roughly 10 isogenic cases per strain and balanced by sex. We computed heritabilities for 25 cortical and trabecular traits. Males and females have well‐matched heritabilities, ranging from 0.25 to 0.75. We mapped 16 genetic loci most of which were detected only in females. There is also a bias in favor of loci that control cortical rather than trabecular bone. To evaluate candidate genes, we combined well‐established gene ontologies with bone transcriptome data to compute bone‐enrichment scores for all protein‐coding genes. We aligned candidates with those of human genome‐wide association studies. A subset of 50 strong candidates fell into three categories: (1) experimentally validated genes already known to modulate bone function (Adamts4, Ddr2, Darc, Adam12, Fkbp10, E2f6, Adam17, Grem2, Ifi204); (2) candidates without any experimentally validated function in bone (eg, Greb1, Ifi202b), but linked to skeletal phenotypes in human cohorts; and (3) candidates that have high bone‐enrichment scores, but for which there is not yet any functional link to bone biology or skeletal system disease (including Ifi202b, Ly9, Ifi205, Mgmt, F2rl1, Iqgap2). Our results highlight contrasting genetic architecture between sexes and among major bone compartments. The alignment of murine and human data facilitates function analysis and should prove of value for preclinical testing of molecular control of bone structure. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Genetic Association of rs1021188 and DNA Methylation Signatures of TNFSF11 in the Risk of Conductive Hearing Loss

“…Importantly, we identified that CpG sites within the TNFSF11 promoter coincide with transcription factor binding sites, including ZNF460, Spi1, EGR1, EGR2, EGR3, EGR4, TFDP1, E2F6, and Plagl1, which seem to play a critical role in transcriptional control of TNFSF11 . Some of the transcription factors predicted to bind to this CpG-region, such as E2F6, have been linked to modulating bone function ( 69 ). Whether these transcription factors target this region requests to be experimentally validated before their potential roles in transcriptional regulation of TNFSF11 are appraised.…”

Diet X Gene Interactions Control Femoral Bone Adaptation to Low Dietary Calcium

“…Many studies have used forward genetics approaches to identify loci controlling bone phenotypes ( 8 , 37 , 38 ) including a number of studies in the BXD RI lines. ( 11 , 13 , 39 , 40 , 41 , 42 , 43 ) However, only our research has examined how genetics interacts with dietary Ca intake to influence Ca and bone metabolism. ( 17 , 20 , 44 ) As such, there are several novel aspects of our work.…”

“…Several groups have previously used BXD mice to study the genetics controlling femur bone mass ( 8 , 13 ) or bone strength. ( 43 ) The largest of these studies was conducted by Lu and colleagues ( 13 ) who used 61 BXD RI lines in a mapping study to identify QTL for femoral and tibial μCT phenotypes in female and male mice aged 50 to 375 days. In contrast to our findings, Lu and colleagues ( 13 ) did not find any QTL in males.…”

“…( 43 ) The largest of these studies was conducted by Lu and colleagues ( 13 ) who used 61 BXD RI lines in a mapping study to identify QTL for femoral and tibial μCT phenotypes in female and male mice aged 50 to 375 days. In contrast to our findings, Lu and colleagues ( 13 ) did not find any QTL in males. We believe several factors make our study more reliable than the Lu and colleagues ( 13 ) study, including: (i) strict control of environmental conditions and diet, (ii) careful balancing of RI lines across mouse shipments, (iii) use of a body size correction ( 26 ) to account for size differences among the BXD lines, (iv) better line estimates due to more replicates within lines (mean 7.72 ± 0.78, median = 8 versus mean [males] 4.64 ± 2.67, median = 4), and (v) use of a very narrow harvest age window (mean = 85 days; range 81–91 days versus mean [males] = 96 days; range 50–375 days).…”

“…In addition, studies show that the genetic loci controlling Tb phenotypes are distinct from those that control BMD and BMC. ( 10 , 11 , 12 , 13 ) Collectively, these studies suggest there are unique genetic regulators for Tb microarchitecture that are hidden in the genetic analysis of BMD or are distinct from the genetic regulators controlling cortical bone phenotypes.…”