Nemesure B B, He Q, Mendell N
Department of Preventive Medicine, State University of New York at Stony Brook 11794, USA.
Genet Epidemiol. 1995;12(6):653-8. doi: 10.1002/gepi.1370120622.
The REGD procedure of the S.A.G.E. [1994] system was used to determine the mode of inheritance of the rare disease given in Problem 1. The likelihood ratio test statistic indicated that we should reject the hypotheses of dominant and recessive inheritance at the 0.01 level, so codominant inheritance was assumed. The estimated penetrance values computed from the beta estimates given by the S.A.G.E. output were 1.0, 0.7, and 0.0 for the AA, AB, and BB genotypes respectively. A sample of three markers from each chromosome was used to determine which chromosome(s) gave evidence of having loci linked to the disease locus. The lod minus 0.83 support interval, which has been shown to provide the best approximation to 95% coverage among interval estimates [Nemesure et al., in press], was obtained for each of these markers. The criterion for rejecting the hypothesis of close linkage using the support interval methodology required that the left side of the lod minus 0.83 support interval about the maximum likelihood estimate, theta, includes only values greater than theta = 0.10. This criterion suggested that chromosomes 2, 3, and 6 did not contain the disease genes. Classical lod-score linkage analysis using the usual criteria of 3.0 for linkage and -2.0 for exclusion did not result in any regions being identified. On dropping the required lod score to 1.0, chromosomes 1, 3, and 6 gave results in favor of linkage with lod scores of 1.94 (theta = 0.19), 1.20 (theta = 0.24), and 1.30 (theta = 0.23), respectively. Association studies comparing unrelated cases to unrelated controls were done for all markers on all chromosomes. Two associations were observed which were significant at the 0.05 level after adjusting for the large number of multiple comparisons being made. The strongest association observed was between allele 7 of marker 23 on chromosome 5 and the disease (chi 2(1) = 52.20, OR = 4.7) and the second strongest was between allele 8 of marker 31 on chromosome 1 (chi 2(1) = 20.10, OR = 3.4).
使用S.A.G.E. [1994]系统的REGD程序来确定问题1中给出的罕见疾病的遗传模式。似然比检验统计量表明，我们应该在0.01水平上拒绝显性和隐性遗传的假设，因此假定为共显性遗传。根据S.A.G.E.输出给出的β估计值计算出的估计外显率值，AA、AB和BB基因型分别为1.0、0.7和0.0。从每条染色体中选取三个标记样本，以确定哪些染色体有证据表明存在与疾病位点连锁的基因座。对于这些标记中的每一个，都获得了lod减去0.83支持区间，已证明该区间在区间估计中能最好地近似95%的覆盖率[Nemesure等人，即将发表]。使用支持区间方法拒绝紧密连锁假设的标准要求，围绕最大似然估计值theta的lod减去0.83支持区间的左侧仅包含大于theta = 0.10的值。该标准表明，染色体2、3和6不包含疾病基因。使用通常的连锁标准3.0和排除标准-2.0进行经典的lod分数连锁分析，没有确定任何区域。当将所需的lod分数降至1.0时，染色体1、3和6给出了支持连锁的结果，lod分数分别为1.94（theta = 0.19）、1.20（theta = 0.24）和1.30（theta = 0.23）。对所有染色体上的所有标记进行了将无关病例与无关对照进行比较的关联研究。在对大量多重比较进行校正后，观察到两个在0.05水平上显著的关联。观察到的最强关联是5号染色体上标记23的等位基因7与疾病之间的关联（卡方(1)=52.20，OR = 4.7），第二强的关联是1号染色体上标记31的等位基因8与疾病之间的关联（卡方(1)=20.10，OR = 3.4）。
