Mapping disease genes: family-based association studies.
Mapping disease genes: family-based association studies.
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发表时间：
1995-08
影响因子：
9.8
通讯作者：
G. Thomson
中科院分区：
文献类型：
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作者：
G. Thomson
随着人类基因组图谱的快速发展，包括高度多态性和紧密连锁的标记，标记与疾病相关性的研究越来越多地与疾病基因图谱相关。在关联研究中使用核心家庭数据最初是为了避免患者和随机确定的对照之间可能的种族不匹配。未传递给患病儿童或从未传递给患病同胞对的父母标记等位基因形成所谓的AFBAC（受影响的基于家庭的对照）群体。在本文中，AFBAC方法的理论基础证明了任何单基因座疾病模型和任何核心家庭为基础的确定计划。在随机交配群体中，当存在与疾病相关的标记时，当标记和疾病基因之间的重组分数（θ）足够小以至于可以取为零（θ = 0）时，AFBAC群体提供了总体群体（对照）标记等位基因的无偏估计。在人群分层的情况下，只有亚群中存在的标志物关联才能通过基于家族的分析检测到。然而，更重要的是，当θ不等于0时，仅对于与疾病基因连锁的标记基因（θ < 1/2），才能观察到传递的亲本（患者）标记等位基因频率与未传递或从未传递的亲本标记等位基因频率（意味着标记与疾病相关）之间的差异。因此，在群体水平上，由群体分层、迁移或混合引起的非连锁标记基因座与疾病的关联被消除。这验证了使用家庭为基础的关联测试作为映射疾病基因的适当策略。
With recent rapid advances in mapping of the human genome, including highly polymorphic and closely linked markers, studies of marker associations with disease are increasingly relevant for mapping disease genes. The use of nuclear-family data in association studies was initially developed to avoid possible ethnic mismatching between patients and randomly ascertained controls. The parental marker alleles not transmitted to an affected child or never transmitted to an affected sib pair form the so-called AFBAC (affected family-based controls) population. In this paper, the theoretical foundation of the AFBAC method is proved for any single-locus model of disease and for any nuclear family-based ascertainment scheme. In a random-mating population, when there is a marker association with disease, the AFBAC population provides an unbiased estimate of the overall population (control) marker alleles when the recombination fraction (theta) between the marker and disease genes is sufficiently small that it can be taken as zero (theta = 0). With population stratification, only marker associations present in the subpopulations will be detected with family-based analyses. Of more importance, however, is the fact that, when theta not equal to 0, differences between transmitted parental (patient) marker allele frequencies and non- or never-transmitted parental marker allele frequencies (implying a marker association with disease) can only be observed for marker genes linked to a disease gene (theta < 1/2). Thus, associations of unlinked marker loci with disease at the population level, caused by population stratification, migration, or admixture, are eliminated. This validates the use of family-based association tests as an appropriate strategy for mapping disease genes.