MacLean C J, Sham P C, Kendler K S
Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Am J Hum Genet. 1993 Aug;53(2):353-66.
Many investigators who have been searching for linkage to complex diseases have by now accumulated a drawer full of negative results. If disease is actually caused by genes at several loci, these data might contain multiple-locus system (MLS) information that the investigator does not realize. Trying to obtain this information formally, through the MLS likelihood, leads to severe computational and statistical difficulties. Therefore, we propose a scheme of inference based on single-locus (SL) statistics, considered jointly. By simulation, we find that the MLS lod score is closely approximated by the sum of SL lod scores. However, we also find that for moderately large systems, say three of four loci, both MLS and SL lod scores are likely to be inconclusive. Nonetheless, MLS can often be detected through the correlation of individual pedigree SL lod scores. Significant correlation is itself evidence of an MLS, because, in the absence of linkage, false-positive lod scores are necessarily random. Under epistasis SL lod scores tend to be positively correlated among pedigrees, while under independent action SL lod scores from high-density samples tend to be negatively correlated.
许多一直在寻找复杂疾病连锁关系的研究人员，到目前为止已经积累了满满一抽屉的阴性结果。如果疾病实际上是由多个位点的基因引起的，那么这些数据可能包含研究人员尚未意识到的多位点系统（MLS）信息。试图通过MLS似然性正式获取这些信息，会导致严重的计算和统计困难。因此，我们提出了一种基于单一位点（SL）统计量联合考虑的推断方案。通过模拟，我们发现MLS连锁对数得分与SL连锁对数得分之和非常接近。然而，我们也发现，对于适度大的系统，比如四个位点中的三个，MLS和SL连锁对数得分都可能没有定论。尽管如此，MLS通常可以通过各个家系的SL连锁对数得分的相关性来检测。显著的相关性本身就是MLS的证据，因为在没有连锁的情况下，假阳性连锁对数得分必然是随机的。在基因上位作用下，家系间的SL连锁对数得分往往呈正相关，而在独立作用下，来自高密度样本的SL连锁对数得分往往呈负相关。
