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

描述(由申请人提供)：罕见的变异可能是许多疾病潜在的大量未表征的遗传风险的原因。要有足够的力量来测试这种变种，需要有大量的队列。然而，用下一代测序来评估稀有变异仍然是成本和时间太高，不能大规模使用。 我们提出了一个创新的项目，利用现有的和不断增长的全基因组和全外显子组序列数据，将罕见的变异归因于一个极大的队列，该队列由100,000个个体组成，这些人在超过650,000个单核苷酸多态(SNPs)上进行了基因分型。众所周知，推测一种变异的能力取决于参照组中携带该变异的个体的数量，但目前仍不清楚对非常罕见的变异的推断效果如何。通过合并所有可用的公共参考小组，我们的目标是将参考对象的数量增加10倍，超过1000基因组计划通常使用的1092个个体。我们将通过应用端粒长度来测试我们方法的有效性，端粒长度已经在同样的100,000个进行了基因分型的人中进行了测量。端粒长度是反映细胞衰老的重要指标。已知端粒长度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完全解释。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.