Supplementary Material for: Could Inbred Cases Identified in GWAS Data Succeed in Detecting Rare Recessive Variants Where Affected Sib-Pairs Have Failed?

To detect fully penetrant rare recessive variants that could constitute Mendelian subentities of complex diseases, we propose a novel strategy, the HBD-GWAS strategy, which can be applied to genome-wide association study (GWAS) data. This strategy first involves the identification of inbred individuals among cases using the genome-wide SNP data and then focuses on these inbred affected individuals and searches for genomic regions of shared homozygosity by descent that could harbor rare recessive disease-causing variants. In this second step, analogous to homozygosity mapping, a heterogeneity lod-score, HFLOD, is computed to quantify the evidence of linkage provided by the data. In this paper, we evaluate this strategy theoretically under different scenarios and compare its performances with those of linkage analysis using affected sib-pair (ASP) data. If cases affected by these Mendelian subentities are not enriched in the sample of cases, the HBD-GWAS strategy has almost no power to detect them, unless they explain an important part of the disease prevalence. The HBD-GWAS strategy outperforms the ASP linkage strategy only in a very limited number of situations where there exists a strong allelic heterogeneity. When several rare recessive variants within the same gene are involved, the ASP design indeed often fails to detect the gene, whereas, by focusing on inbred individuals using the HBD-GWAS strategy, the gene might be detected provided very large samples of cases are available.

为了检测可作为复杂疾病孟德尔亚型的完全外显率罕见隐性变异，我们提出了一种可应用于全基因组关联研究（Genome-Wide Association Study, GWAS）数据的全新策略——HBD-GWAS策略。该策略首先利用全基因组单核苷酸多态性（Single Nucleotide Polymorphism, SNP）数据对病例队列中的近交个体进行识别，随后将分析聚焦于这些受累近交个体，搜寻可能携带罕见隐性致病变异的共享血缘同源纯合性基因组区域。在第二步中，该策略与纯合性定位分析类似，会计算异质性LOD评分（HFLOD）以量化数据所提供的连锁证据。本文从理论层面在多种场景下对该策略进行了评估，并将其性能与基于受累同胞对（Affected Sib-Pair, ASP）数据的连锁分析性能进行了对比。若病例队列中未富集携带这类孟德尔亚型的病例，则HBD-GWAS策略几乎无法检出这类变异，除非这类变异能够解释疾病患病率的重要组成部分。仅在存在较强等位基因异质性的极少数场景中，HBD-GWAS策略的性能才会优于ASP连锁分析策略。当同一基因内存在多个罕见隐性变异时，ASP研究设计往往无法检出该致病基因；而通过HBD-GWAS策略聚焦受累近交个体，只要拥有足够大的病例样本量，即可实现该基因的检出。