Karasik David, Zhou Yanhua, Cupples L Adrienne, Hannan Marian T, Kiel Douglas P, Demissie Serkalem
Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA.
J Bone Miner Res. 2009 Apr;24(4):710-8. doi: 10.1359/jbmr.081222.
The risk of osteoporotic fracture is a function of both applied muscle mass and bone tissue distribution. Leg lean mass (LLM) and femoral bone geometry are both known to have substantial genetic components. Therefore, we estimated shared heritability (h(2)) and performed linkage analysis to identify chromosomal regions governing both LLM and bone geometry. A genome-wide scan (using 636 microsatellite markers) for linkage analyses was performed on 1346 adults from 327 extended families of the Framingham study. DXA measures were LLM, femoral neck length, neck-shaft angle (NSA), subperiosteal width, cross-sectional area (CSA), and section modulus (Z) at the femoral narrow neck and shaft (S) regions. Variance component linkage analysis was performed on normalized residuals (adjusted for age, height, BMI, and estrogen status in women). The results indicated substantial h(2) for LLM (0.42 +/- 0.07) that was comparable to bone geometry traits. Phenotypic correlations between LLM and bone geometry phenotypes ranged from 0.033 with NSA (p > 0.05) to 0.251 with S_Z (p < 0.001); genetic correlations ranged from 0.087 (NSA, p > 0.05) to 0.454 (S_Z, p < 0.001). Univariate linkage analysis of covariate-adjusted LLM identified no chromosomal regions with LOD scores >or=2.0; however, bivariate analysis identified two loci with LOD scores >3.0, shared by LLM with S_CSA on chromosome 12p12.3-12p13.2, and with NSA, on 14q21.3-22.1. In conclusion, we identified chromosomal regions potentially linked to both LLM and femoral bone geometry. Identification and subsequent characterization of these shared loci may further elucidate the genetic contributions to both osteoporosis and sarcopenia.
骨质疏松性骨折的风险是所施加的肌肉质量和骨组织分布的函数。已知腿部去脂体重（LLM）和股骨骨几何形状都有很大的遗传成分。因此，我们估计了共同遗传力（h(2)）并进行连锁分析，以确定控制LLM和骨几何形状的染色体区域。对弗雷明汉研究中327个大家庭的1346名成年人进行了全基因组扫描（使用636个微卫星标记）以进行连锁分析。双能X线吸收法测量的指标为LLM、股骨颈长度、颈干角（NSA）、骨膜下宽度、横截面积（CSA）以及股骨窄颈和骨干（S）区域的截面模量（Z）。对标准化残差进行方差成分连锁分析（针对年龄、身高、体重指数和女性雌激素状态进行了调整）。结果表明LLM具有显著的h(2)（0.42±0.07），这与骨几何形状特征相当。LLM与骨几何形状表型之间的表型相关性范围从与NSA的0.033（p>0.05）到与S_Z的0.251（p<0.001）；遗传相关性范围从0.087（NSA，p>0.05）到0.454（S_Z，p<0.001）。对协变量调整后的LLM进行单变量连锁分析未发现LOD得分≥2.0的染色体区域；然而，双变量分析确定了两个LOD得分>3.0的位点，LLM与12号染色体p12.3 - 12p13.2上的S_CSA以及14号染色体q21.3 - 22.1上的NSA共享这些位点。总之，我们确定了可能与LLM和股骨骨几何形状都相关的染色体区域。对这些共享位点的识别及后续特征分析可能会进一步阐明对骨质疏松症和肌肉减少症的遗传贡献。
