Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk

Abstract

Over the past decades, genome-wide association studies (GWAS) have identified thousands of phenotype-associated DNA sequence variants for potential explanations of inter-individual phenotypic differences and disease susceptibility. However, it remains a challenge for translating the associations into causative mechanisms for complex diseases, partially due to the involved variants in the noncoding regions and the inconvenience of functional studies in human population samples. So far, accumulating evidence has suggested a complex crosstalk among genetic variants, allele-specific binding of transcription factors (ABTF), and allele-specific DNA methylation patterns (ASM), as well as environmental factors for disease risk. This review aims to summarize the current studies regarding the interactions of the aforementioned factors with a focus on epigenetic insights. We present two scenarios of single nucleotide polymorphisms (SNPs) in coding regions and non-coding regions for disease risk, via potentially impacting epigenetic patterns. While a SNP in a coding region may confer disease risk via altering protein functions, a SNP in non-coding region may cause diseases, via SNP-altering ABTF, ASM, and allele-specific gene expression (ASE). The allelic increases or decreases of gene expression are key for disease risk during development. Such ASE can be achieved via either a “SNP-introduced ABTF to ASM” or a “SNP-introduced ASM to ABTF.” Together with our additional in-depth review on insulator CTCF, we are convinced to propose a working model that the small effect of a SNP acts through altered ABTF and/or ASM, for ASE and eventual disease outcome (named as a “SNP intensifier” model). In summary, the significance of complex crosstalk among genetic factors, epigenetic patterns, and environmental factors requires further investigations for disease susceptibility.

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

“…This was shown to alter the abundance of coding variant containing transcripts and could serve to explain different penetrance in monogenic diseases (Castel et al 2018). Differential DNAm at GREs and changes in CTCF binding involved in chromatin structure establishment are discussed as the mechanisms by which variants in non-coding regions can influence allele preference (Wang et al 2019a).…”

Introns Control Stochasticity in Metazoan Gene Expression

“…A gene with low intrinsic noise would be expressed in a mostly balanced biallelic fashion (close to a 1:1 ratio of allele expression). This intrinsic noise is distinct from parental imprinting or X inactivation, and is reviewed from different perspectives here (12), here (13) and here (14,15). Intrinsic noise, stochastic autosomal allele expression bias and allele specific expression are often synonymous.…”

“…When intrinsic noise is low for a particular gene, the majority of cells within a tissue will present as biallelic. This intrinsic noise is distinct from parental imprinting or X inactivation, and is reviewed from different perspectives here 12 , here 13 and here 14,15 . These different groups refer to this phenomenon, or aspects of it, as intrinsic noise 12 , stochastic autosomal allele expression bias 13 , allele specific expression 14,15 , or monoallelic expression [12][13][14][15] .…”

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

“…Collectively, the mouse genome or human genome contains more ASMs (including both sequence-dependent and switchable ASMs) than previously appreciated [15,48,50,55]. The newly revealed random, switchable ASMs remind us of features in X chromosome inactivation, leading to a proposed hypothesis of regional autosomal chromosome inactivation [76].…”