Negligible impact of rare autoimmune-locus coding-region variants on missing heritability.
Negligible impact of rare autoimmune-locus coding-region variants on missing heritability.
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全基因组关联研究（GWAS）已经在数百个常见自身免疫性疾病的基因座上发现了中等效应大小的常见变异;然而，很大一部分遗传性仍然无法解释，罕见变异可能对此有贡献。为了发现罕见的变异并测试它们与表型的关联，大多数研究重新测序小的初始样本量，然后在更大的样本集中对发现的变异进行基因分型。这种方法无法分析整个样本集中存在的大部分罕见变异。在这里，我们同时进行基于扩增子测序的变异发现和基因分型的25个GWAS风险基因的编码外显子在41，911英国居民的白色欧洲血统，包括24，892名受试者与6个自身免疫性疾病表型和17，019对照，并显示在已知基因座的罕见编码区变异在常见的自身免疫性疾病易感性中的作用可以忽略不计。这些结果不支持罕见变异合成全基因组关联假设（其中未观察到的罕见因果变异导致在共同标签变异处检测到关联）。许多已知的自身免疫性疾病风险基因座含有多个独立相关的常见和低频变异，因此这些基因座上的基因比其他基因更有可能携带罕见的编码区变异。我们的数据表明，常见自身免疫性疾病的遗传性缺失可能不是由于等位基因谱中罕见的编码区变异部分，而是可能如其他人所提出的，可能是由于许多常见变异基因座的弱效应。
Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute,. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set,,. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect,,,.