A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

中文翻译：

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使用谱系评估罕见变体对2型糖尿病和相关性状的贡献。

评估稀有变体对复杂疾病的贡献的主要挑战是识别足够多的稀有等位基因拷贝，以进行有益的统计分析。为了研究罕见变异对2型糖尿病（T2D）和相关性状风险的贡献，我们对20个T2D患病率高的墨西哥裔美国人大家庭的1,034名成员进行了深入的全基因组分析。如果在这些家庭中，大多数情况下，罕见的具有较大疗效的变体占了糖尿病风险的大部分，则我们的实验有能力检测出关联。使用643个谱系成员的21,677个转录本上的基因表达数据，我们确定了影响大的稀有变异顺式的证据群体研究中无法检测到的-表达定量性状基因座，这验证了我们的方法。但是，我们没有发现与T2D有关的任何具有大效应的罕见变体，也没有发现空腹血糖和胰岛素的相关性状，这表明在此样本中，大影响的稀有变体仅占这些性状遗传风险的一小部分家庭。可靠地鉴定大效果稀有变体将需要更大的谱系样本或不同的研究设计，以进一步丰富此类变体。