ArticlePLoS genetics2015
Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 2 of them syntheses that pooled it.
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Who cites it
119 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder.Translational psychiatry · 2022Pooled it
- A case-control study on the SNP309T → G and 40-bp Del1518 of the MDM2 gene and a systematic review for MDM2 polymorphisms in the patients with breast cancer.Journal of clinical laboratory analysis · 2020Pooled it
- Verification of the Chromosome Region 9q21 Association with Pelvic Organ Prolapse Using RegulomeDB Annotations.BioMed research international · 2015Trial
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- Genetic variants in m6A regulator genes confer susceptibility and progression of HCC in a Northern Chinese population.Discover oncology · 2025Article
- Connecting intermediate phenotypes to disease using multi-omics in heart failure.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2025Article
- Connecting intermediate phenotypes to disease using multi-omics in heart failure.medRxiv : the preprint server for health sciences · 2024Article
- Expression of Truncated Products at the 5'-Terminal Region of RIPK2 and Evolutive Aspects that Support Their Biological Importance.Genome biology and evolution · 2024Article
- History of tuberculosis disease is associated with genetic regulatory variation in Peruvians.PLoS genetics · 2024Article
- Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis.medRxiv : the preprint server for health sciences · 2024Article
- Former smoking associated with epigenetic modifications in human granulosa cells among women undergoing assisted reproduction.Scientific reports · 2024Article
- Identification of region-specific gene isoforms in the human brain using long-read transcriptome sequencing.Science advances · 2024Article
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- Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant.Cell genomics · 2023Article
- Distinct genome-wide DNA methylation and gene expression signatures in classical monocytes from African American patients with systemic sclerosis.Clinical epigenetics · 2023Article
59 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.
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