Koeleman B P, Dudbridge F, Cordell H J, Todd J A
Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY, UK.
Ann Hum Genet. 2000 May;64(Pt 3):207-13. doi: 10.1017/S0003480000008095.
Linkage and association studies in complex diseases are used to identify and fine map disease loci. The process of identifying the aetiological polymorphism, the molecular variant responsible for the linkage and association of the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically-linked polymorphic markers flanking the disease variant, and the possibility that more than one polymorphism in the most associated region is aetiological. It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed for detection of additional variants, such as the Haplotype Method, Marker Association Segregation Chi-squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to test for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the advantages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequilibrium on the CETDT.
复杂疾病的连锁和关联研究用于识别疾病位点并进行精细定位。确定病因多态性（即导致染色体区域与疾病发生连锁和关联的分子变异）的过程因疾病变异的低外显率、疾病变异两侧物理连锁的多态性标记之间的连锁不平衡以及最相关区域中可能不止一个多态性是病因性的而变得复杂。能够在包含一组基因的区域（如6号染色体p21上的主要组织相容性复合体（MHC）区域）检测其他疾病决定因素很重要。已经开发了一些方法来检测其他变异，如单倍型方法、标记关联分离卡方（MASC）方法和纯合亲本检验。在此，扩展传递/不平衡检验被用于在先前关联位点的条件下检验关联性。该检验被称为条件扩展TDT（CETDT）。我们讨论了CETDT与现有方法相比的优势，并使用模拟数据研究了多态性、遗传和连锁不平衡对CETDT的影响。
