Longevity GWAS Using the Drosophila Genetic Reference Panel - PubMed (original) (raw)

Longevity GWAS Using the Drosophila Genetic Reference Panel

Dobril K Ivanov et al. J Gerontol A Biol Sci Med Sci. 2015 Dec.

Abstract

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.

Keywords: Ageing; Gene ontology; Gene-based analysis; Insulin signaling pathway; Polygenic score analysis; Target of rapamycin.

© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America.

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Figures

Figure 1.

Figure 1.

Distribution of lifespan (197 lines). The black vertical line represents the mean lifespan (55.28 days).

Figure 2.

Figure 2.

Manhattan plot for single-SNP GWAS. Each point represents a SNP. The height of the SNP represents the strength of association with lifespan, expressed as −log10(p value). The red horizontal line represents the genome-wide Bonferroni significance threshold (p = 2.28×10−08).

Figure 3.

Figure 3.

Manhattan plot for gene-based GWAS. Each point represents a gene. The height of the gene represents the strength of association with lifespan, expressed as −log10(p value). The red horizontal line represents genome-wide Bonferroni significance threshold (p = 3.53×10−06).

Figure 4.

Figure 4.

Overview of the insulin/insulin-like growth factor signaling (IIS) and target of rapamycin pathway (TOR) pathways. Rectangles represent genes; diamonds: molecules; triangles: environmental factors; trapezoids: other than IIS or TOR pathways; octagons: transcription factors; arrow lines represent activation; red t-shaped lines represent inhibition; brown boxes starting with c_ represent complexes; yellow boxes represent putative genes part of the IIS (CG11523) or TOR (RpS9) pathways; genes circled in red represent genes found in the top-ranked genes in the gene-based analysis; black horizontal line represents a symbolic separation between the TOR and IIS pathways.

Figure 5.

Figure 5.

Polygenic score and lifespan. Each box represents the interquartile range (IQR) with the median as a black horizontal line; the whiskers represent values 1.5*IQR; outliers are represented as separate points. The continuous black horizontal line connects the means within each p value threshold.

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