PDF(Pubmed)
Abstract：
Identifying genetic susceptibility factors for complex disorders remains a challenging task. To analyze collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible, we have developed a weights-based pipeline to prioritize variants and genes. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 and 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.
摘要：
确定复杂疾病的遗传易感因素仍然是一项具有挑战性的任务。为了分析可能存在遗传异质性的小型和大型家系的集合，但是生物共性是合理的，我们开发了一个基于权重的管道来优先考虑变异和基因.基于权重的VAriant排名（WARP）管道使用5个权重对变体进行优先级排序：疾病发病率，一个家庭的案例数量，基因组分数在一个家庭的案例中共享，等位基因频率和变异有害性。Weights,除了群体等位基因频率权重，在0和1之间进行归一化。权重以乘法方式组合以产生家族特异性变体权重,然后在其中观察到变体的所有家族中对其进行平均以产生多家族权重。按降序排序多家族权重创建变体和基因的排名列表以供进一步研究。使用来自欧洲基因组-表型档案的家族性黑素瘤序列数据验证WARP。该管道在13个家族中的4个（31％）中确定了已知种系黑色素瘤基因POT1，MITF和BAP1的变异。对其他9个家族的分析确定了几个有趣的基因，其中一些可能在黑色素瘤中起作用。WARP提供了一种在小型和大型家系研究中鉴定疾病易感基因的方法。
