Spielman R S, McGinnis R E, Ewens W J
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia 19104-6145.
Am J Hum Genet. 1993 Mar;52(3):506-16.
A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.
在胰岛素依赖型糖尿病（IDDM）与位于11号染色体上胰岛素基因附近的串联重复DNA区域（5'侧翼多态性[5'FP]）的“1类”等位基因之间，一直观察到群体关联。这一发现表明，胰岛素基因区域含有一个或多个导致IDDM易感性的基因。然而，几项试图通过检测患病同胞对中的共分离来显示与IDDM连锁关系的研究未能找到连锁的证据。作为识别复杂疾病基因的方法，关联研究和患病同胞对方法都有局限性。众所周知，即使在没有连锁的情况下，疾病与遗传标记之间的群体关联也可能是群体结构的假象。另一方面，对数量不多的患病同胞对进行连锁研究可能无法检测到连锁关系，特别是如果存在连锁异质性的话。当发现群体关联时，我们考虑一种检测与遗传标记连锁关系的替代方法。利用来自至少有一个患病孩子的家庭的数据，我们评估了相关标记等位基因从杂合子父母向患病后代的传递情况。几位研究人员已经使用了这种方法，但作为连锁检测方法的统计学特性尚未得到研究。在本文中，我们描述了这种“连锁不平衡传递检验”（传递/不平衡检验[TDT]）的统计学基础。然后，我们展示了该检验与基于患病同胞中同源单倍型或基因比例的共分离检验之间的关系。TDT为5'FP与IDDM易感性之间的连锁提供了有力证据。该分析得出的结论一般适用于疾病关联研究，在这类研究中，遗传标记通常与候选基因紧密连锁。当发现一种疾病与这样一个标记相关联时，即使单倍型共享检验未检测到连锁，TDT也可能检测到连锁。
