Analysis of the Genetic Variation and Age Interplay on Gene Expression Using RNA-seq Data from Multiple Tissues. A. Vi˝uela1, M. N. Davies1, A. Buil2,3,4, A. A. Brown5, H. F. Zheng6, J. B. Richards1,6, K. S. Small1, R. Durbin5, E. T. Dermitzakis2,3,4, T. D. Spector1 1) Dep. of Twin Research & Genetic Epidemiology, Kings College London, London, United Kingdom; 2) Dep. Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; 3) Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland; 4) Swiss Institute of Bioinformatics, Switzerland; 5) Wellcome Trust Sanger Institute, Hinxton, United Kingdom; 6) Dep. of Medicine, Human Genetics, Epidemiology and Biostatistics McGill University, Canada.
Global gene expression becomes noisier with age, but it is not clear whether this is due to changes in the genetic architecture of regulation (gene-environment interactions, GxE) or to environmental/stochastic factors. In particular, tissue specificity of age-related sources of variation in expression is largely unknown. We analysed RNA-seq data from adipose, skin, whole blood, and lymphoblastoid cell lines (LCLs) samples from ~800 female adult twins from the TwinsUK cohort (39-85 years old). Using this data, we first identified genes with an age-related component in expression. By looking at discordance and heritability we then investigated whether these changes were due to GxE or environmental factors. Finally, we investigated genetic variants whose effect changes with age (GxA). Analysing multiple tissues allows us to contrast the rate and nature of the ageing process in different tissues and environments. Analysis of gene expression identified 1172 (adipose), 3748 (skin), 458 (blood), and 22 (LCLs) genes whose expression was associated with age (FDR < 0.05). Of those, 398 genes were associated in two tissues; with 2 genes (PDE4D and SCL9A9) significantly associated in skin, adipose and blood. This suggests tissue specificity for the ageing process and for genetic regulation. We are currently investigating differential splicing events with age, another aspect of gene expression that may become deregulated with age. Changes in transcriptional noise with age (variance in gene expression) were identified in 16 genes in adipose (e.g: BCL6 or PRL1) and 61 in skin (e.g: MUC1 or SOD2). Of those, 14% (adipose) and 16% (skin) increased in variance with age. To understand the sources of variation we exploited the twin design by looking at changes in level of discordance in expression within MZ pairs. Within skin, 129 genes showed altered discordance in expression with age (BH corrected p-value < 0.05). Since MZ twins are genetically identical, discordance in expression points to environmental or GxA effects on expression. We are currently investigating changes in heritability to characterize the changing contributions of genotype and environment to variation in gene expression with age. Finally, we are performing a genome-wide scan of genetic variants with GxA interactions affecting expression (gxa-eQTLs) to identify relevant genes for aging. These interactions provide concrete examples of how genetic control of expression is modified over time.
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