A transcription-centric model of SNP-age interaction

Abstract

Complex age-associated phenotypes are caused, in part, by an interaction between an individual’s genotype and age. The mechanisms governing such interactions are however not entirely understood. Here, we provide a novel transcriptional mechanism-based framework–SNiPage, to investigate such interactions, whereby a transcription factor (TF) whose expression changes with age (age-associated TF), binds to a polymorphic regulatory element in an allele-dependent fashion, rendering the target gene’s expression dependent on both, the age and the genotype. Applying SNiPage to GTEx, we detected ~637 significant TF-SNP-Gene triplets on average across 25 tissues, where the TF binds to a regulatory SNP in the gene’s promoter or putative enhancer and potentially regulates its expression in an age- and allele-dependent fashion. The detected SNPs are enriched for epigenomic marks indicative of regulatory activity, exhibit allele-specific chromatin accessibility, and spatial proximity to their putative gene targets. Furthermore, the TF-SNP interaction-dependent target genes have established links to aging and to age-associated diseases. In six hypertension-implicated tissues, detected interactions significantly inform hypertension state of an individual. Lastly, the age-interacting SNPs exhibit a greater proximity to the reported phenotype/diseases-associated SNPs than eSNPs identified in an interaction-independent fashion. Overall, we present a novel mechanism-based model, and a novel framework SNiPage, to identify functionally relevant SNP-age interactions in transcriptional control and illustrate their potential utility in understanding complex age-associated phenotypes.

Can the epigenome contribute to risk stratification for cancer onset?

“…Differences in breast aging, in light of its epigenome, compared to the person's chronological age have been linked with heightened breast cancer risk ( 20 , 39 ). The epigenetic clock is based on DNA methylation at 353 CpG sites calculated by elastic net regression or 385 CpG sites giving an estimate of mitotic division ( 9 , 39 ). Intrinsic epigenetic age acceleration (i.e.…”

“…Moreover, the expression of TF changes with age hence, so does their binding to regulatory SNPs. Age-interacting SNPs have been analyzed via a novel SNiPAge concept to better understand age-associated phenotypes ( 9 ). In the breast, 536 interaction triplets (TF-SNP-gene) linked to aging were detected based on TFs that show reduction in expression with age.…”

“…SNPs associated with aging and their biological functions appear to include DNA methylation that is an essential modulator of tumorigenesis ( 9 ). However, the exact contribution of these SNPs to epigenetic aging remains to be understood.…”

“…The metabolism has been implicated in the development of cancers, including breast cancer and metabolic pathways are modulated by aging, notably via the relation TF-SNPs ( 9 ). High BMI is both the result and a source of metabolic imbalance leading to pro-inflammatory and oxidative conditions ( 21 ); it acts as a breast cancer risk inducer among postmenopausal women and a mediator of aggressive breast cancers among premenopausal women.…”

“…Women at high risk for breast cancer also included those with a 10-year risk at age 40 of at least 8%. Interestingly, the biggest contributors to this risk stratification model were PRS and mammographic density ( 7 ), both having relationships with the epigenome ( 8 , 9 ).…”