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bioRxiv2016

Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort

Gene expression changes with age have consequences for healthy aging and disease development. Here we investigate age-related changes in gene expression measured by RNA-seq in four tissues and the interplay between genotypes and age-related changes in expression. Using concurrently measured methylation array data from fat we also investigate the relationship between methylation, gene expression and age. We identified age-dependent changes in mean levels of gene expression in 5,631 genes and in splicing of 904 genes. Age related changes were widely shared across tissues, with up to 60% of age-related changes in expression and 47% on splicing in multi-exonic genes shared; amongst these we highlight effects on genes involved in diseases such as Alzheimer and cancer. We identified 137 genes with age-related changes in variance and 42 genes with age-dependent discordance between genetically identical individuals; implying the latter are driven by environmental effects. We also give four examples where genetic control of expression is affected by the aging process. Analysis of methylation observed a widespread and stronger effect of age on methylation than expression; however we did not find a strong relationship between age-related changes in both expression and methylation. In summary, we quantified aging affects in splicing, level and variance of gene expression, and show that these processes can be both environmentally and genetically influenced.

Genomics↗

bioRxiv2016

Quantifying the degree of sharing of genetic and non-genetic causes of gene expression variability across four tissues.

Gene expression can provide biological mechanisms which underlie genetic associations with complex traits and diseases, but often the most relevant tissue for the trait is inaccessible and a proxy is the only alternative. Here, we investigate shared and tissue specific patterns of variability in expression in multiple tissues, to quantify the degree of sharing of causes (genetic or non-genetic) of variability in gene expression among tissues. Using gene expression in ~800 female twins from the TwinsUK cohort in skin, fat, whole blood and lymphoblastoid cell lines (LCLs), we identified 9166 significant cis-eQTLs in fat, 9551 in LCLs, 8731 in skin and 5313 in blood (1% FDR). We observed up to 80% of cis-eQTLs are shared in pairs of tissues. In addition, the cis genetic correlation between tissues is > 90% for 35% of the genes, indicating for these genes a largely tissue-shared component of cis regulation. However, variance components show that cis genetic signals explain only a small fraction of the variation in expression, with from 67-87% of the variance explained by environmental factors, and 53% of the genetic effects occurring in trans. We observe a trans genetic correlation of 0 for all genes except a few which show correlation between fat and skin expression. The environmental effects are also observed to be entirely tissue specific, despite related tissues largely sharing exposures. These results demonstrate that patterns of gene expression are largely tissue specific, strongly supporting the need to study higher order regulatory interactions in the appropriate tissue context with large samples sizes and diversity of environmental contexts.

Genomics↗