Shields D C, Ratanachaiyavong S, McGregor A M, Collins A, Morton N E
Department of Child Health, University of Southampton, Princess Anne Hospital.
Am J Hum Genet. 1994 Sep;55(3):540-54.
Combined segregation and linkage analysis is a powerful technique for modeling linkage to diseases whose etiology is more complex than the effect of a well-described single genetic locus and for investigating the influence of single genes on various aspects of the disease phenotype. Graves disease is familial and is associated with human leukocyte antigen (HLA) allele DR3. Probands with Graves disease, as well as close relatives, have raised levels of thyroid autoantibodies. This phenotypic information additional to affection status may be considered by the computer program COMDS for combined segregation and linkage analysis, when normals are classified into diathesis classes of increasing thyroid autoantibody titer. The ordinal model considers the cumulative odds of lying in successive classes, and a single additional parameter is introduced for each gene modeled. Distributional assumptions are avoided by providing estimates of the population frequencies of each class. Evidence for linkage was increased by considering the thyroid autoantibody diathesis and by testing two-locus models. The analysis revealed evidence for linkage to HLA-DR when the strong coupling of the linked locus to allele DR3 was considered (lod score of 6.6). Linkage analysis of the residual variation revealed no evidence of linkage to Gm, but a suggestion of linkage to Km.
联合分离分析和连锁分析是一种强大的技术，可用于对病因比单个明确的基因位点效应更复杂的疾病进行连锁建模，以及研究单个基因对疾病表型各个方面的影响。格雷夫斯病具有家族性，且与人类白细胞抗原（HLA）等位基因DR3相关。格雷夫斯病患者及其近亲的甲状腺自身抗体水平升高。当将正常人分类为甲状腺自身抗体滴度递增的素质类别时，计算机程序COMDS可在联合分离分析和连锁分析中考虑这种除患病状态之外的表型信息。有序模型考虑了处于连续类别中的累积概率，并且为每个建模基因引入了一个额外的参数。通过提供每个类别的群体频率估计值，避免了分布假设。通过考虑甲状腺自身抗体素质并测试两位点模型，连锁证据得到了增强。当考虑连锁位点与等位基因DR3的强耦合时（对数优势分数为6.6），分析揭示了与HLA-DR连锁的证据。对残余变异的连锁分析未发现与Gm连锁的证据，但有与Km连锁的迹象。
