Sequencing not required: Imputing rare variants into a cohort of 100,000 on aging

描述（由申请人提供）：罕见变异可能导致大量未表征的遗传风险，这些风险是许多疾病的基础。大型队列是必要的，有足够的权力来测试这些变异。然而，用下一代测序评估罕见变异仍然成本太高，时间太长，无法大规模使用。 我们提出了一个创新的项目，使用现有的和不断增长的全基因组和全外显子组序列数据将罕见变异归因于一个非常大的10万人队列，这些人已经在超过65万个单核苷酸多态性（SNP）进行了基因分型。众所周知，插补变异的能力取决于参考样本组中携带该变异的个体数量，但对于非常罕见的变异，插补的效果如何仍不清楚。通过结合所有可用的公共参考面板，我们的目标是将参考对象的数量增加10倍，超过1000个基因组计划通常使用的1,092个个体。我们将通过应用于端粒长度来测试我们方法的有效性，端粒长度已经在基因分型的相同10万个体中测量。端粒长度是反映细胞衰老的重要特征。众所周知，端粒长度会随着年龄的增长而下降，并已证明与心血管疾病及其危险因素、癌症、糖尿病和死亡率有关，但端粒长度的遗传性尚未得到充分解释。了解端粒长度背后的遗传因素将有助于更好地理解端粒生物学，并具有明显的健康意义。

DESCRIPTION (provided by applicant): Rare variants may be responsible for a significant amount of the uncharacterized genetic risk underlying many diseases. Large cohorts are necessary to have sufficient power to test such variants. However, assessing rare variants with next generation sequencing is still too cost and time prohibitive to be used on a very large scale. We propose an innovative project to impute rare variants using the existing and ever-growing amounts of whole-genome and whole-exome sequence data into an extremely large cohort of 100,000 individuals who have been genotyped at over 650,000 single nucleotide polymorphisms (SNPs). It is well known that the ability to impute a variant depends on the number of individuals carrying that variant in the reference panel, but it is still not clear how well imputation can wor for very rare variants. By combining all the available public reference panels we aim to increase the number of referent subjects 10-fold beyond the 1,092 individuals typically used from the 1000 Genomes Project. We will test the validity of our approach by application to telomere length, which has been measured in the same 100,000 individuals that were genotyped. Telomere length is an important characteristic reflecting cellular aging. It is known to decline with age, and has demonstrated associations with cardiovascular disease and its risk factors, cancer, diabetes, and mortality, but the heritability of telomere length has not been fully explained. Understanding the genetic factors underlying telomere length will lead to a better understanding of telomere biology, with obvious health implications.