title: Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines.
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.
authors.affiliation: Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.|Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA.|Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA.|Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Brian Thomas
authors.initials: BT
authors.lastname: Joyce
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, USA.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Kibbe
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA.|The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
authors.forename: Lifang
authors.initials: L
authors.lastname: Hou
authors.affiliation: 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.|The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. wei.zhang1@northwestern.edu.|Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. wei.zhang1@northwestern.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D044383:Black People / Q000235:genetics; D002460:Cell Line; D002874:Chromosome Mapping; D003596:Cytosine / Q000378:metabolism*; D057890:Epigenomics; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D015894:Genome, Human; D060148:HapMap Project; D006801:Humans; D018895:Microsatellite Repeats; D009549:Nigeria; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014589:Utah; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D003596:Cytosine