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.
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Acknowledgments
This work was partially supported by grants from the National Institutes of Health: R21HG006367 (to WZ), R21CA187869 (to WZ and LH), and The Robert H. Lurie Comprehensive Cancer Center-Developmental Funds P30CA060553 (to WZ).
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L. Hou and W. Zhang contributed equally to this work as senior authors.
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Supplementary material 1 Fig. 1 Pearson’s correlation coefficients (ρ) of STRPs and cytosine modifications in local scans between CEU and YRI samples. Scatter plot for Pearson’s correlations (ρ) of STRP length and M-values of local CpGs within ± 1 Mb windows of STRPs for CEU and YRI. (PNG 269 kb)
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Supplementary material 2 Fig. 2 QQ-plots of the observed p -values for trans -acting STRP-based mQTL. P-values are binned and displayed as hexagons. Different grey scales of each hexagon represent different counts of p-values. A total of > 200 million observed p-values from the whole-genome scan are shown. (a) CEU; (b) YRI. (PNG 204 kb)
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Supplementary material 3 Fig. 3 Enrichment of GWAS loci among cis -acting STRP-based mQTL. The null distributions of the numbers of SNPs overlapped with GWAS loci are displayed as histograms. The asterisk marks the true number of SNPs overlapped with GWAS loci within different windows: (a) ± 100 Kb; (b) ± 500 Kb; and (c) ± 1 Mb of cis-acting STRP-based mQTL (p-value < 10−3). (PNG 97 kb)
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Zhang, Z., Zheng, Y., Zhang, X. et al. Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines. Hum Genet 135, 223–232 (2016). https://doi.org/10.1007/s00439-015-1628-4
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DOI: https://doi.org/10.1007/s00439-015-1628-4