An important aspect of disease gene mapping is replication, that is, a putative finding in one group of individuals is confirmed in another set of individuals. As it can happen by chance that individuals share an estimated disease position, we developed a statistical approach to determine the p‐value for multiple individuals or families to share a possibly small number of candidate susceptibility variants. Here, we focus on candidate variants for dominant traits that have been obtained by our previously developed heterozygosity analysis, and we are testing the sharing of candidate variants obtained for different individuals. Our approach allows for multiple pathogenic variants in a gene to contribute to disease, and for estimated disease variant positions to be imprecise. Statistically, the method developed here falls into the category of equivalence testing, where the classical null and alternative hypotheses of homogeneity and heterogeneity are reversed. The null hypothesis situation is created by permuting genomic locations of variants for one individual after another. We applied our methodology to the ALSPAC data set of 1,927 whole‐genome sequenced individuals, where some individuals carry a pathogenic variant for the BRCA1 gene, but no two individuals carry the same variant. Our shared genomic segment analysis found significant evidence for BRCA1 pathogenic variants within ±5 kb of a given DNA variant.

中文翻译：

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具有等效性测试的共享基因组片段分析。

疾病基因作图的一个重要方面是复制，即在一组个体中的推定发现在另一组个体中得到证实。由于个体共享估计的疾病位置可能偶然发生，我们开发了一种统计方法来确定p- 多个个人或家庭共享少数候选易感性变异的价值。在这里，我们专注于通过我们之前开发的杂合性分析获得的显性特征的候选变体，并且我们正在测试为不同个体获得的候选变体的共享。我们的方法允许基因中的多种致病变异导致疾病，并且估计的疾病变异位置不精确。从统计学上讲，这里开发的方法属于等价检验的范畴，其中同质性和异质性的经典无效假设和替代假设被颠倒了。零假设情况是通过一个接一个地排列变体的基因组位置来创建的。我们将我们的方法应用于 ALSPAC 数据集 1，927 个全基因组测序个体，其中一些个体携带 BRCA1 基因的致病变异，但没有两个个体携带相同的变异。我们共享的基因组片段分析发现了在给定 DNA 变体 ±5 kb 范围内 BRCA1 致病性变异的重要证据。