Zhang Zhi-Xin, Lei Shu-Feng, Deng Fei-Yan, Zhang Feng, Liu Yong-Jun, Recker Robert R, Papasian Christopher J, Deng Hong-Wen
Key Laboratory of Biomedical Information Engineering, Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an Shaanxi 710049, PR China.
Maturitas. 2009 Jan 20;62(1):16-20. doi: 10.1016/j.maturitas.2008.10.001. Epub 2008 Nov 18.
Osteoporosis is an age-related systemic skeletal disease, characterized by low bone mineral density (BMD). Low BMD is closely associated with late age at menarche (AAM). Our previous bivariate genome-wide linkage analyses (GWLAs) between BMD and AAM identified two shared genomic regions in 2584 Caucasian females including both pre- and post-menopausal females. However, menopause often causes dramatic bone loss in post-menopausal females; this may introduce some confounding effects on the bivariate GWLA for BMD and AAM. To address the effect of menopause on the identification of genetic factors shared by BMD and AAM, we segregated the previously studied population of 2584 females into two separate subgroups consisting of 1462 pre-menopause subjects and 1122 post-menopausal subjects, and performed further bivariate GWLAs. The BMD was measured by Hologic Dual-energy X-ray (DXA) scanners (Hologic Inc., Bedford, MA, USA). Based on the genome-wide thresholds corrected for multiple testing, we found more significant genomic regions in the pre-menopausal group than in total group (including pre- and post-menopausal women), e.g., we found 4, 1, and 2 shared by spine BMD and AAM, femoral neck (FNK) BMD and AAM and ultra distal (UD) BMD and AAM, respectively. We did not found any significant linkage signals in the post-menopausal group. Importantly, the linkage signals at all significant regions were much stronger in pre-menopausal group than in the other groups: post-menopausal females and total females. For example, the linkage LOD score for FNK BMD and AAM is as high as 4.88 in pre-menopausal females, but only 0.24 and 0.31 in post-menopausal and total females, respectively. These results suggest that menopause introduces some noise signals into GWLAs when estimating the shared genetic factors by BMD and AAM. Therefore, it is very important to classify female subjects properly according to their menopause stage when performing such studies.
骨质疏松症是一种与年龄相关的全身性骨骼疾病，其特征是骨矿物质密度（BMD）低。低骨矿物质密度与初潮年龄（AAM）晚密切相关。我们之前对骨矿物质密度和初潮年龄进行的双变量全基因组连锁分析（GWLA）在2584名白种女性（包括绝经前和绝经后女性）中确定了两个共享基因组区域。然而，绝经通常会导致绝经后女性出现显著的骨质流失；这可能会对骨矿物质密度和初潮年龄的双变量GWLA产生一些混杂影响。为了研究绝经对骨矿物质密度和初潮年龄共享遗传因素识别的影响，我们将之前研究的2584名女性人群分为两个独立的亚组，分别由1462名绝经前受试者和1122名绝经后受试者组成，并进行了进一步的双变量GWLA。骨矿物质密度通过Hologic双能X射线（DXA）扫描仪（美国马萨诸塞州贝德福德的Hologic公司）测量。基于针对多重检验校正的全基因组阈值，我们发现绝经前组比总组（包括绝经前和绝经后女性）有更多显著的基因组区域，例如，我们分别发现脊柱骨矿物质密度和初潮年龄、股骨颈（FNK）骨矿物质密度和初潮年龄以及超远端（UD）骨矿物质密度和初潮年龄共享的区域有4个、1个和2个。我们在绝经后组中未发现任何显著的连锁信号。重要的是，所有显著区域的连锁信号在绝经前组中比在其他组（绝经后女性和总女性）中要强得多。例如，绝经前女性中股骨颈骨矿物质密度和初潮年龄的连锁LOD分数高达4.88，但在绝经后女性和总女性中分别仅为0.24和0.31。这些结果表明，在通过骨矿物质密度和初潮年龄估计共享遗传因素时，绝经会给GWLA引入一些噪声信号。因此，在进行此类研究时，根据女性受试者的绝经阶段进行正确分类非常重要。
