Nature Genetics largest DNA methylation QTL map to date

An important topic in the field of molecular biology is the causal association between individual genomic features, such as single nucleotide polymorphisms (SNPs ), and various levels of gene regulation and the mechanisms by which such associations affect phenotype
.

In other words, it is the unraveling of the genetic basis of molecular features such as epigenetic modifications and gene expression

Several studies, including GTEx, the largest human tissue transcriptome expression database to date, rely on QTL methods to reveal many tissue- or environment-specific gene signatures that have a significant impact on gene expression levels [2,3]
.

As the research community has gradually deepened its understanding of the complex gene regulation mechanisms contained in the general concept of gene expression, including pre-transcriptional epigenetic regulation, post-transcriptional RNA regulation, and translational regulation, and corresponding quantitative bioinformatics methods With the development of , diverse QTL analysis paradigms have been proposed, such as sQTL [4] for RNA splicing patterns and roQTL5 for RNA translation efficiency

Due to the superior properties of QTL analysis in terms of statistical power and biological significance, it is often applied to transcriptomic data of large normal or diseased tissues with genotyping or whole-exome/genome sequencing Data collection and combined analysis with data such as genome-wide association analysis studies (GWAS) to mine the association of certain genome genetic variants with developmental disorders or diseases at the gene expression level
.

Such integrated analysis of multiple data modalities can finally construct a complete logical chain from genetic variation to molecular regulatory perturbation to phenotypic differences

On January 3, 2022, scientists from Germany, Singapore, the United Kingdom and other countries jointly published a long article entitledGenetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function in the journal Nature Genetics .

Large-scale human DNA methylation QTL (meQTL) map and in-depth analysis of its association with various known DNA methylation cis- and trans-regulatory elements, as well as DNA methylation.
A phenotypic GWAS map was integrated to systematically reveal the control mechanisms of human genetic variation mediated by DNA methylation on various physiological or pathological traits .

In order to overcome the shortcomings of previous DNA methylation QTL studies, which are often limited to small population samples, lack of independent repeated cohort validation, and lack of diverse tissue cell types, this study collected and analyzed 3799 European populations and 3195 patients.

Blood samples from the South Asian population , the two sample sets were distinguished from the discovery set and the validation set, and a very strict meQTL significance threshold was set

Another highlight of the study in terms of data quality and analytical rigor is the analysis of different cell subsets (such as CD4/CD8 positive cells, neutrophils, monocytes, and adipocytes) in the same blood sample set.

MeQTL associations were isolated and individually quantified and cross-referenced with meQTL profiles derived from whole blood sample data

It is worth mentioning that an important dimension in QTL analysis is the consideration of the spatial relationship between genetic variation sites and molecular signature sites, because it can help researchers identify potential regulatory mechanisms between the two
.

Specifically, in this study, the authors refer to the pairing of meQTLs with a distance of less than 1Mb between them as cis meQTLs (cis meQTLs), and the meQTLs with distances greater than 1Mb but located on the same chromosome as long-distance cis meQTLs (long-distance cis meQTLs).
-range cis meQTL), and finally the meQTL located on different chromosomes is called trans meQTL (trans meQTL)

For example, the SNP site rs730775 was linked in trans to the methylation levels of up to 49 CpG sites
.

In order to explain the possible molecular regulation mechanism between the two, the researchers integrated and analyzed the public eQTL and GWAS data, and found that rs730775 is located in the first intron region of the gene NFKBIE, and is the eQTL site of NFKBIE

In conclusion, this study obtained abundant genomic and methylome information from large-scale, multi-population, and multi-cellular human whole blood samples.
Based on the classical QTL analysis paradigm, a number of potentially important DNA methylation regulatory effects were discovered.
Simultaneous analysis of the single nucleotide polymorphism loci with genomic functional region data and related physiological and pathological GWAS data obtained the association between meQTL factors and disease occurrence and the molecular mechanism leading to this association.
QTL studies provide an invaluable resource and new insights specific to the DNA methylation perspective for the entire genotype-phenotype causal association research collective represented
.