Liu F, Elefante S, van Duijn C M, Aulchenko Y S
Department of Epidemiology & Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
Ann Hum Genet. 2006 Nov;70(Pt 6):965-70. doi: 10.1111/j.1469-1809.2006.00279.x.
Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data.
在纯合性定位分析过程中，远系近亲通婚圈常常不为人知或被忽视。这可能会潜在地导致假阳性连锁结果的发生率增加。我们发现，未能考虑远系通婚圈可能会严重低估近亲程度，尤其是对于来自基因隔离人群的个体而言；在6名阿尔茨海默病（AD）患者中，远系通婚圈平均占近亲繁殖的57.7%。理论评估表明，在两点连锁分析中，忽略占近亲繁殖18% - 75%的远系通婚圈会大幅提高假阳性结论的频率，高达数百倍。在对这6名AD患者进行的多点连锁分析中，全染色体范围5%的“经验性”显著性对应着11.1%的真阳性错误率。我们表明，将多个通婚圈转换为一个涵盖所有近亲繁殖情况的假设通婚圈，可能是避免假阳性结果的一个便捷解决方案。当无法获取扩展的系谱数据时，仍可基于基因组数据构建假设通婚圈。
