Linking the genetic architecture of cytosine modifications with human complex traits

Zhang, Xu; Moen, Erika L.; Liu, Cong; Mu, Wenbo; Gamazon, Eric R.; Delaney, Shannon M.; Wing, Claudia; Godley, Lucy A.; Dolan, M. Eileen; Zhang, Wei

doi:10.1093/hmg/ddu313

Cited by 37 publications

(63 citation statements)

References 58 publications

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“…We found the association between SNPs and E-CpGs in the previous methylation quantitative trait locus studies. Zhang et al [63] identified the corresponding methylation quantitative trait locus of 5240 (7306) CpGs based on HapMap LCLs of EA (AA) population, and 390 (495) of which CpGs were also E-CpGs in our study, where 3 (9) of which E-CpGs were located on ADME genes (Supplementary Table 11).…”

Section: Discussionmentioning

confidence: 62%

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

Chu

Yang

2017

Epigenomics

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Aim: This is the first systematic study to examine the population differentiation effect of DNA methylation on the treatment response and drug absorption, distribution, metabolism and excretion in multiple tissue types and cancer types. Materials & methods: We analyzed the whole methylome and transcriptome data of primary tumor tissues of four cancer types (breast, colon, head & neck and uterine corpus) and lymphoblastoid cell lines for African and European ancestry populations. Results: Ethnicity-associated CpG sites exhibited similar methylation patterns in the two studied populations, but the patterns differed between tumor tissues and lymphoblastoid cell lines. Ethnicity-associated CpG sites may have triggered gene expression, influenced drug absorption, distribution, metabolism and excretion, and showed tumorspecific patterns of methylation and gene regulation. Conclusion: Ethnicity should be carefully accounted for in future pharmacoepigenetics research.

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Section: Discussionmentioning

confidence: 62%

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

Chu

Yang

2017

Epigenomics

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“…We then compared our mQTLs to those in two recent studies of YRI LCLs (Banovich et al 2014;Zhang et al 2014), which both used the largest commercially available DNA methylation array, the Illumina Infinium HumanMethylation450 BeadChip (Bibikova et al 2011). Comparing these studies to one another, we found 19.1%-45.7% overlap (depending on the direction of analysis; see Methods).…”

Section: Applying Our Pooling Approach To Empirical Datamentioning

confidence: 97%

“…In addition, DNA methylation has been linked to a wide range of diseases, including cancer, Alzheimer's disease, bipolar disorder, and type 2 diabetes (Baylin et al 1998;Baylin and Herman 2000;Gamazon et al 2012;Irier and Jin 2012; The Cancer Genome Atlas Network 2012; Dayeh et al 2013;Pease et al 2013;Ambrosone et al 2014;De Jager et al 2014;Lunnon et al 2014). Interestingly, CpGs whose methylation has been associated with gene expression and disease are found not only in promoter regions or gene bodies but also in other parts of the genome, such as enhancers and insulators, suggesting additional roles of DNA methylation in transcriptional regulation (You et al 2011;Jones 2012;Gutierrez-Arcelus et al 2013;Banovich et al 2014;Zhang et al 2014). Although many studies have investigated potential additional roles, general conclusions about the role of methylation outside of promoters and gene bodies are still lacking (Jones 2012).…”

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confidence: 99%

“…In addition to epigenetic variation, DNA methylation can also be associated with genetic variation (Gibbs et al 2010;Bell et al 2011Bell et al , 2012Bibikova et al 2011;Fraser et al 2012;Lam et al 2012;Drong et al 2013;Grundberg et al 2013;GutierrezArcelus et al 2013;Heyn et al 2013;Liu et al 2013;Moen et al 2013;Zhi et al 2013;Ambrosone et al 2014;Banovich et al 2014;De Jager et al 2014;Lunnon et al 2014;Shi et al 2014;Smith et al 2014;Wagner et al 2014;Zhang et al 2014). Associations with genetic variants such as SNPs are qualitatively different from epigenetic associations with disease or gene expression because the causality is clear: Mendelian randomization ensures that an individual's genotype is a random combination of parental alleles, and thus any associations must be due to the effects of genotype (in a study free of confounding factors) (Mokry et al 2014).…”

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confidence: 99%

“…Nearly all published human mQTL studies have relied upon commercially available microarrays that interrogate either approximately 28,000 CpGs or approximately 480,000 CpGs, corresponding to 0.1% and 1.7% of CpGs in the genome, respectively (Gibbs et al 2010;Bell et al 2011Bell et al , 2012Fraser et al 2012;Drong et al 2013;Grundberg et al 2013;Gutierrez-Arcelus et al 2013;Heyn et al 2013;Liu et al 2013;Moen et al 2013;Zhi et al 2013;Ambrosone et al 2014;Banovich et al 2014;Shi et al 2014;Smith et al 2014;Wagner et al 2014;Zhang et al 2014). Not surprisingly, the number of CpGs associated with mQTLs is generally greater in the studies using the larger arrays.…”

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confidence: 99%

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A pooling-based approach to mapping genetic variants associated with DNA methylation

et al. 2015

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DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.

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Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines

et al. 2015

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Inter-individual variation in cytosine modifications has been linked to complex traits in humans. Cytosine modification variation is partially controlled by single nucleotide polymorphisms (SNPs), known as modified cytosine quantitative trait loci (mQTL). However, little is known about the role of short tandem repeat polymorphisms (STRPs), a class of structural genetic variants, in regulating cytosine modifications. Utilizing the published data on the International HapMap Project lymphoblastoid cell lines (LCLs), we assessed the relationships between 721 STRPs and the modification levels of 283540 autosomal CpG sites. Our findings suggest that, in contrast to the predominant cis-acting mode for SNP-based mQTL, STRPs are associated with cytosine modification levels in both cis-acting (local) and trans-acting (distant) modes. In local scans within the +/− 1Mb windows of target CpGs, 21, 9, and 21 cis-acting STRP-based mQTL were detected in CEU (Caucasian residents from Utah, USA), YRI (Yoruba people from Ibadan, Nigeria), and combined samples, respectively. In contrast, 139420, 76817, and 121866 trans-acting STRP-based mQTL were identified in CEU, YRI, and combined samples, respectively. A substantial proportion of CpG sites detected with local STRP-based mQTL were not associated with SNP-based mQTL, suggesting that STRPs represent an independent class of mQTL. Functionally, genetic variants neighboring CpG-associated STRPs are enriched with genome-wide association study (GWAS) loci for a variety of complex traits and diseases, including cancers, based on the National Human Genome Research Institute (NHGRI) GWAS Catalog. Therefore, elucidating these STRP-based mQTL in addition to SNP-based mQTL can provide novel insights into the genetic architectures of complex traits.

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Linking the genetic architecture of cytosine modifications with human complex traits

Cited by 37 publications

References 58 publications

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

A pooling-based approach to mapping genetic variants associated with DNA methylation

Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines

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