Duncan Emma L, Cardon Lon R, Sinsheimer Janet S, Wass John A H, Brown Matthew A
Metabolic Bone Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom.
J Bone Miner Res. 2003 Aug;18(8):1531-8. doi: 10.1359/jbmr.2003.18.8.1531.
Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability.
Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis.
We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < -2.5, Z-score < -2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck.
Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3-19%, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61-67% and at the femoral neck was 44-67%. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < -2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck.
These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.
通过对147个先证者骨密度极低的家庭中的816名成员进行复杂分离分析，研究了骨骼部位和性别对骨密度的遗传控制差异。在男性与男性的比较中，脊柱骨密度的相关性更强；在女性与女性的比较中，髋部骨密度的相关性更强，这与骨密度遗传力的性别和部位特异性一致。
来自动物和人类研究的证据表明，骨矿物质密度（BMD）的遗传控制在不同的骨骼部位和性别之间可能存在差异。这个问题对骨质疏松症遗传研究的设计和解释具有重要意义。
我们研究了147个家庭中816名个体的遗传特征，这些个体是通过骨密度极低的先证者招募而来（T评分 < -2.5，Z评分 < -2.0）。使用谱系分析软件包进行复杂分离分析。通过双能X线吸收法（DXA）测量腰椎（L1-L4）和股骨颈的骨密度。
复杂分离分析排除了这些家庭中腰椎和股骨颈骨密度分离的纯单基因和环境模型。当将绝经状态作为协变量考虑时，纯多基因模型在腰椎被排除，但在股骨颈未被排除。具有残余多基因成分的孟德尔模型未被排除。这些模型与一种罕见的孟德尔基因型的存在一致，该基因型的患病率为3%-19%，导致这些家庭中髋部和脊柱的骨密度较高，并伴有额外的多基因效应。腰椎的总遗传力范围为61%-67%，股骨颈为44%-67%。在男性和女性亲属对之间观察到股骨颈和腰椎骨密度相关性的显著差异，男性与男性的比较中脊柱骨密度相关性比股骨颈更强，女性与女性的比较中股骨颈骨密度相关性比腰椎更大。当考虑绝经状态时，亲子相关性也是如此。先证者Z评分 < -2.0的同胞在腰椎的复发风险比为5.4，在股骨颈为5.9。
这些发现支持骨密度遗传的性别和部位特异性。在骨质疏松症遗传研究的设计和解释中应考虑这些结果。
