VTRNA2-1: Genetic Variation, Heritable Methylation and Disease Association.

Pierre-Antoine Dugué,Melissa C Southey,Helen Tsimiklis,James G Dowty,Tu Nguyen-Dumont,Kconfab Kconfab,Ee Ming Wong,John L Hopper,Roger L Milne,Jason A Steen,Jihoon Eric Joo,Derrick Theys,Fleur Hammet,Maryam Mahmoodi,Graham G Giles,Timothy Mckay,Chenglong Yu

doi:10.3390/ijms22052535

Abstract

VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 × 10−4); however, these explained little of the methylation variation (R2 < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: −0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.

Highlights

IntroductionMendelian-like inheritance of germline DNA methylation can be due to cis- or transacting genetic factors known as methylation Quantitative Trait Loci (mQTL) or epimutations (heritable change in gene activity that is not associated with a DNA mutation but rather with gain or loss of DNA methylation or other heritable modification of chromatin).Both can mimic germline pathogenic variants in their effect on gene function and disease association and discriminating between the two possibilities (mQTL or epimutation) in specific genomic regions and disease context is often challenging.We previously made a genome-wide assessment of heritable methylation using a family design [1]; probes were ranked by a methylation-heritability metric and 24 of the 1000 most heritable CpGs were identified to be associated with breast cancer risk in these families
Mendelian-like inheritance of germline DNA methylation can be due to cis- or transacting genetic factors known as methylation Quantitative Trait Loci or epimutations.Both can mimic germline pathogenic variants in their effect on gene function and disease association and discriminating between the two possibilities in specific genomic regions and disease context is often challenging.We previously made a genome-wide assessment of heritable methylation using a family design [1]; probes were ranked by a methylation-heritability metric and 24 of the 1000 most heritable CpGs were identified to be associated with breast cancer risk in these families
Our aims were three-fold: first, to sequence the VTRNA2-1 region to assess the presence of rare genetic variation at this locus; second, to conduct a genomewide assessment of Methylation quantitative trait loci (mQTL) and single nucleotide polymorphisms (SNP)-based methylation heritability in the VTRNA2-1 region; third, to assess whether any genetic variants associated with DNA methylation in this region contribute to the previously observed associations with breast cancer risk

Summary

Introduction

Mendelian-like inheritance of germline DNA methylation can be due to cis- or transacting genetic factors known as methylation Quantitative Trait Loci (mQTL) or epimutations (heritable change in gene activity that is not associated with a DNA mutation but rather with gain or loss of DNA methylation or other heritable modification of chromatin).Both can mimic germline pathogenic variants in their effect on gene function and disease association and discriminating between the two possibilities (mQTL or epimutation) in specific genomic regions and disease context is often challenging.We previously made a genome-wide assessment of heritable methylation using a family design [1]; probes were ranked by a methylation-heritability metric and 24 of the 1000 most heritable CpGs were identified to be associated with breast cancer risk in these families. Mendelian-like inheritance of germline DNA methylation can be due to cis- or transacting genetic factors known as methylation Quantitative Trait Loci (mQTL) or epimutations (heritable change in gene activity that is not associated with a DNA mutation but rather with gain or loss of DNA methylation or other heritable modification of chromatin). Both can mimic germline pathogenic variants in their effect on gene function and disease association and discriminating between the two possibilities (mQTL or epimutation) in specific genomic regions and disease context is often challenging. Evidence that DNA methylation can be transmitted from parent to offspring in the absence of a genetic explanation is scarce and controversial [2,3,4].

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