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Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects

View Article: PubMed Central - PubMed

ABSTRACT

Background: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such “heritable” CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian.

Methods: Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes.

Results: We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/−110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/−1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site.

Conclusions: Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P = 4.08 × 10−6), implying a regulatory effect of these trimodal CpG sites.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-016-0295-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


Correlation between the QMDiab study and the KORA population study. Each point represents the median of the methylation values for one of the 457,004 CpG sites assayed in the two cohorts
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Fig1: Correlation between the QMDiab study and the KORA population study. Each point represents the median of the methylation values for one of the 457,004 CpG sites assayed in the two cohorts

Mentions: There was strong overall correlation of the median of all methylation sites between the Qatari and KORA samples (R = 0.94). The correlation plot of the two datasets is shown in Fig. 1. Considering both the Qatari cohort and the larger cohort KORA together, and also allowing only 5% of the subjects to have methylation values outside of the three predetermined ranges, an overlap of 955 trimodal sites was found. Additional file 1: Figure S1 shows a regional plot of the physical locations of those trimodal sites with respect to all of the methylation sites measured by the 450 K array, showing no particular location bias and that trimodal sites are dispersed genome-wide. A histogram of each of these sites can be viewed in Additional file 2: File S1.Fig. 1


Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects
Correlation between the QMDiab study and the KORA population study. Each point represents the median of the methylation values for one of the 457,004 CpG sites assayed in the two cohorts
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5120560&req=5

Fig1: Correlation between the QMDiab study and the KORA population study. Each point represents the median of the methylation values for one of the 457,004 CpG sites assayed in the two cohorts
Mentions: There was strong overall correlation of the median of all methylation sites between the Qatari and KORA samples (R = 0.94). The correlation plot of the two datasets is shown in Fig. 1. Considering both the Qatari cohort and the larger cohort KORA together, and also allowing only 5% of the subjects to have methylation values outside of the three predetermined ranges, an overlap of 955 trimodal sites was found. Additional file 1: Figure S1 shows a regional plot of the physical locations of those trimodal sites with respect to all of the methylation sites measured by the 450 K array, showing no particular location bias and that trimodal sites are dispersed genome-wide. A histogram of each of these sites can be viewed in Additional file 2: File S1.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such “heritable” CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian.

Methods: Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes.

Results: We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/−110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/−1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site.

Conclusions: Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P = 4.08 × 10−6), implying a regulatory effect of these trimodal CpG sites.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-016-0295-1) contains supplementary material, which is available to authorized users.

No MeSH data available.