Ivanov Dobril K, Escott-Price Valentina, Ziehm Matthias, Magwire Michael M, Mackay Trudy F C, Partridge Linda, Thornton Janet M
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
J Gerontol A Biol Sci Med Sci. 2015 Dec;70(12):1470-8. doi: 10.1093/gerona/glv047. Epub 2015 Apr 28.
We used 197 Drosophila melanogaster Genetic Reference Panel (DGRP) lines to perform a genome-wide association analysis for virgin female lifespan, using 2M common single nucleotide polymorphisms (SNPs). We found considerable genetic variation in lifespan in the DGRP, with a broad-sense heritability of 0.413. There was little power to detect signals at a genome-wide level in single-SNP and gene-based analyses. Polygenic score analysis revealed that a small proportion of the variation in lifespan (4.7%) was explicable in terms of additive effects of common SNPs (≥2% minor allele frequency). However, several of the top associated genes are involved in the processes previously shown to impact ageing (eg, carbohydrate-related metabolism, regulation of cell death, proteolysis). Other top-ranked genes are of unknown function and provide promising candidates for experimental examination. Genes in the target of rapamycin pathway (TOR; Chrb, slif, mipp2, dredd, RpS9, dm) contributed to the significant enrichment of this pathway among the top-ranked 100 genes (p = 4.79×10(-06)). Gene Ontology analysis suggested that genes involved in carbohydrate metabolism are important for lifespan; including the InterPro term DUF227, which has been previously associated with lifespan determination. This analysis suggests that our understanding of the genetic basis of natural variation in lifespan from induced mutations is incomplete.
我们使用197个黑腹果蝇遗传参考品系（DGRP）进行了处女雌蝇寿命的全基因组关联分析，使用了约200万个常见单核苷酸多态性（SNP）。我们发现DGRP中寿命存在相当大的遗传变异，广义遗传力为0.413。在单SNP和基于基因的分析中，在全基因组水平检测信号的能力较弱。多基因评分分析表明，寿命变异的一小部分（约4.7%）可以用常见SNP（次要等位基因频率≥2%）的加性效应来解释。然而，一些顶级关联基因参与了先前显示会影响衰老的过程（例如，碳水化合物相关代谢、细胞死亡调控、蛋白水解）。其他排名靠前的基因功能未知，为实验研究提供了有前景的候选基因。雷帕霉素靶标通路（TOR；Chrb、slif、mipp2、dredd、RpS9、dm）中的基因导致该通路在排名前100的基因中显著富集（p = 4.79×10(-06)）。基因本体分析表明，参与碳水化合物代谢的基因对寿命很重要；包括先前与寿命决定相关的InterPro术语DUF227。该分析表明，我们通过诱导突变对寿命自然变异的遗传基础的理解是不完整的。
