TY - JOUR
T1 - Crosstalk of genetic variants, allele-specific DNA methylation, and environmental factors for complex disease risk
AU - Wang, Huishan
AU - Lou, Dan
AU - Wang, Zhibin
N1 - Funding Information:
The laboratory of ZW at Johns Hopkins was supported by U.S. National Institutes of Health (R01ES25761, U01ES026721 opportunity fund, and R21ES028351) and Johns Hopkins Catalyst Award. ZW also thanks Dr. Jian Yang at the University of Queensland for the critical reading of the manuscript, and sincerely apologizes to fellow investigators whose important contributions were not directly referenced due to space and reference limitations.
Publisher Copyright:
© 2007 - 2019 Frontiers Media S.A. All Rights Reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Allele-specific DNA methylation (ASM)
KW - Allele-specific binding of transcription factors (ABTFs)
KW - Allele-specific gene expression (ASE)
KW - Genetic variants
KW - Quantitative trait locus (QTL)
KW - Regional “autosomal chromosome inactivation (ACI)”
KW - SNP intensifier model
KW - Single nucleotide polymorphisms (SNPs)
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U2 - 10.3389/fgene.2018.00695
DO - 10.3389/fgene.2018.00695
M3 - Review article
C2 - 30687383
AN - SCOPUS:85064233713
VL - 10
JO - Frontiers in Genetics
JF - Frontiers in Genetics
SN - 1664-8021
IS - JAN
M1 - 695
ER -