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Hum Genet. 2016 Feb;135(2):223-32. doi: 10.1007/s00439-015-1628-4. Epub 2015 Dec 30.

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

Zhang Z1,2, Zheng Y2,3, Zhang X4, Liu C5, Joyce BT2,6, Kibbe WA7, Hou L2,8, Zhang W9,10,11.

Author information

1
Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
2
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA.
3
Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
4
Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
5
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60612, USA.
6
Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, 60612, USA.
7
Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, USA.
8
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
9
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA. wei.zhang1@northwestern.edu.
10
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. wei.zhang1@northwestern.edu.
11
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. wei.zhang1@northwestern.edu.

Abstract

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 283,540 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 ±1 Mb 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 the combined samples, respectively. In contrast, 139,420, 76,817, and 121,866 trans-acting STRP-based mQTL were identified in CEU, YRI, and the 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.

PMID:
26714498
PMCID:
PMC4715638
DOI:
10.1007/s00439-015-1628-4
[Indexed for MEDLINE]
Free PMC Article

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