Genetic Dissection of Femoral and Tibial Microarchitecture

JBMR Plus

Danny Arends¹  Cheryl Ackert‐Bicknell²  Olivia L Sabik³  Charles R Farber³  Jinsong Huang⁴  Fuyi Xu⁴  Robert W Williams⁴  Lu Lu⁴  Nicolae Valentin David⁵  Leigh Darryl Quarles⁶  Zhousheng Xiao⁶  Bing Zhang⁷  Jing Wang⁷  Weikuan Gu⁸ 

[1] Breeding Biology and Molecular Animal Breeding Humboldt University Berlin Germany;Center for Musculoskeletal Research University of Rochester Rochester NY USA;Center for Public Health Genomics University of Virginia Charlottesville VA USA;Department of Genetics, Genomics and Informatics University of Tennessee Health Science Center Memphis TN USA;Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL USA;Department of Medicine University of Tennessee Health Science Center Memphis TN USA;Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA;Department of Orthopaedic Surgery and Biomedical Engineering University of Tennessee Health Science Center Memphis TN USA;

关键词: ANIMAL MODEL;    CORTICAL BONE;    GENE ONTOLOGY;    GENOME‐WIDE ASSOCIATION STUDIES;    IGNOROME;    μCT;    QUANTITATIVE TRAIT LOCUS;    SEX DIFFERENCE;    SYSTEMS GENETICS;    TRABECULAR BONE;   

DOI  :  10.1002/jbm4.10241

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown