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. 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

Zhou Zhang  1   2 , Yinan Zheng  2   3 , Xu Zhang  4 , Cong Liu  5 , Brian Thomas Joyce  2   6 , Warren A Kibbe  7 , Lifang Hou  2   8 , Wei Zhang  9   10   11
Affiliations

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

Zhou Zhang et al. Hum Genet. 2016 Feb.

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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Figures

Fig. 1
Fig. 1. Identification of STRP-based mQTL
For both local (+/− 1Mb windows) and whole-genome scans, linear models were used to identify STRP-based mQTL in CEU and YRI, separately: cytosine modification level ~ length of STRPs + gender + error. Cis- and trans-acting STRP-based mQTL were then compared with SNP-based mQTL. Enrichment analysis for GWAS loci was performed for cis-acting STRP-based mQTL. KEGG pathway enrichment analysis was carried out for master STRPs (associated with > 200 CpGs) for trans-acting STRP-based mQTL.
Fig. 2
Fig. 2. Cis-acting STRP-based mQTL are population-specific
(a) Venn diagram shows the number of STRP-based mQTL in CEU, YRI (p-value <10−3), and the previously detected SNP-based mQTL; (b) Venn diagram shows the number of STRP-based mQTL in CEU, YRI (adjusted p-value < 0.05, corresponding to nominal p-value < 4.0×10−5), and the previously detected SNP-based mQTL. (c) Population specificity of STR-based mQTL (p-value < 10−3; X- axis: r2 of YRI, Y axis: r2 of CEU); (d) Population specificity of STRP-based mQTL (adjusted p-value < 0.05, corresponding to nominal p-value < 4.0×10−5; X- axis: r2 of YRI, Y axis: r2 of CEU). SNP-based mQTL were identified using the SCAN database with a p-value < 10−4.
Fig. 3
Fig. 3. Chromosomal distributions of STRP-based mQTL
The heatmap shows chromosomal distributions of all STRP-based mQTL from the whole-genome scans in (a) CEU; and (b) YRI. Besides cis-acting relationships, STRP-based mQTL are predominantly trans-acting.
Fig. 4
Fig. 4. 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) +/− 100Kb; (b) +/− 500Kb; and (c) +/− 1Mb, of cis-acting STRP-based mQTL (adjusted p-value < 0.05).
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