Wilcox Marsha A, Wyszynski Diego F, Panhuysen Carolien I, Ma Qianli, Yip Agustin, Farrell John, Farrer Lindsay A
Genetics Program, Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 02118, USA.
BMC Genet. 2003 Dec 31;4 Suppl 1(Suppl 1):S15. doi: 10.1186/1471-2156-4-S1-S15.
The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits.
Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis.
We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 x 10(-6)) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23).
This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.
弗雷明汉心脏研究对医学进步贡献巨大。所研究的大多数表型为单变量性状（定量或定性）。本研究的目的是通过识别同质人群组并赋予定性和定量性状分数来推导多变量性状；评估推导性状的遗传力；并对其中一个可遗传性状进行定性和定量连锁分析。
使用多重对应分析（主成分分析的非参数类似方法）进行数据降维。采用两阶段聚类，即结合k均值聚类和凝聚层次聚类，根据数据降维得到的轴（因子）分数对个体进行聚类。使用二元逻辑回归计算聚类成员概率。使用SOLAR计算遗传力，其也用于定量性状分析。使用GENEHUNTER-PLUS进行定性性状分析。
我们发现了四个表型不同的组。最小组的成员具有遗传性（38%，p < 1×10⁻⁶），且具有与致动脉粥样硬化性血脂异常一致的特征。我们在11号和14号染色体（11q13、14q23、14q31）上发现定性和定量LOD分数均高于3。在6号染色体（6p21）和11号染色体（11q23）上有两个Kong & Cox LOD分数高于1.0。
这种方法可能有助于在连锁分析之前通过明确表型定义来识别复杂表型中的遗传异质性。我们的一些发现位于与致动脉粥样硬化性血脂异常及相关诊断要素相关的区域，有些可能是新发现，也可能是假阳性。
