Robinson W P, Barbosa J, Rich S S, Thomson G
Department of Integrative Biology, University of California, Berkeley 94720.
Genet Epidemiol. 1993;10(5):273-88. doi: 10.1002/gepi.1370100502.
For complex genetic diseases involving incomplete penetrance, genetic heterogeneity, and multiple disease genes, it is often difficult to determine the molecular variant(s) responsible for the disease pathogenesis. Linkage and association studies may help identify genetic regions and molecular variants suspected of being directly responsible for disease predisposition or protection, but, especially for complex diseases, they are less useful for determining when a predisposing molecular variant has been identified. In this paper, we expand upon the simple concept that if a genetic factor predisposing to disease has been fully identified, then a parent homozygous for this factor should transmit either of his/her copies at random to any affected children. Closely linked markers are used to determine identity by descent values in affected sib pairs from a parent homozygous for a putative disease predisposing factor. The expected deviation of haplotype sharing from 50%, when not all haplotypes carrying this factor are in fact equally predisposing, has been algebraically determined for a single locus general disease model. Equations to determine expected sharing for multiple disease alleles or multiple disease locus models have been formulated. The recessive case is in practice limiting and therefore can be used to estimate the maximum proportion of putative susceptibility haplotypes which are in fact predisposing to disease when the mode of inheritance of a disease is unknown. This method has been applied to 27 DR3/DR3 parents and 50 DR4/DR4 parents who have at least 2 children affected with insulin dependent diabetes mellitus (IDDM). The transmission of both DR3 and DR4 haplotypes is statistically different from 50% (P < 0.05 and P < 0.001, respectively). An upper estimate for the proportion of DR3 haplotypes associated with a high IDDM susceptibility is 49%, and for DR4 haplotypes 38%. Our results show that the joint presence of non-Asp at DQ beta position 57 and Arg at DQ alpha position 52, which has been proposed as a strong IDDM predisposing factor, is insufficient to explain the HLA component of IDDM predisposition.
对于涉及不完全外显率、遗传异质性和多个疾病基因的复杂遗传疾病，通常很难确定导致疾病发病机制的分子变异。连锁和关联研究可能有助于识别疑似直接导致疾病易感性或保护性的遗传区域和分子变异，但特别是对于复杂疾病，它们在确定何时已识别出易感性分子变异方面用处较小。在本文中，我们扩展了一个简单的概念，即如果已完全识别出导致疾病的遗传因素，那么对于该因素纯合的亲本应将其两个拷贝中的任意一个随机传递给任何患病子女。紧密连锁的标记用于确定来自假定疾病易感因素纯合亲本的患病同胞对中按系谱遗传的值的一致性。对于单基因座一般疾病模型，当并非所有携带该因素的单倍型实际上都具有同等易感性时，已通过代数方法确定了单倍型共享与50%的预期偏差。已经制定了用于确定多个疾病等位基因或多个疾病基因座模型的预期共享的方程。隐性情况在实际中具有局限性，因此当疾病的遗传模式未知时，可用于估计实际上易患疾病的假定易感单倍型的最大比例。该方法已应用于27对DR3/DR3亲本和50对DR4/DR4亲本，这些亲本至少有2个患有胰岛素依赖型糖尿病（IDDM）的子女。DR3和DR4单倍型的传递在统计学上均不同于50%（分别为P < 0.05和P < 0.001）。与高IDDM易感性相关的DR3单倍型比例的上限估计为49%，DR4单倍型为38%。我们的结果表明，已被提出作为强烈IDDM易感因素的DQβ位置57处非天冬氨酸和DQα位置52处精氨酸的共同存在，不足以解释IDDM易感性的HLA成分。
