Browsing by Author "Iles, Mark M."

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    Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
    (Cold Spring Harbor Laboratory Press, 2018-11) Zhang, Tongwu; Choi, Jiyeon; Kovacs, Michael A.; Shi, Jianxin; Xu, Mai; Goldstein, Alisa M.; Trower, Adam J.; Bishop, D. Timothy; Iles, Mark M.; Duffy, David L.; MacGregor, Stuart; Amundadottir, Laufey T.; Law, Matthew H.; Loftus, Stacie K.; Pavan, William J.; Brown, Kevin M.; Epidemiology, School of Public Health
    Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4 Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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    Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure
    (Nature Publishing Group, 2018-05-08) Visconti, Alessia; Duffy, David L.; Liu, Fan; Zhu, Gu; Wu, Wenting; Chen, Yan; Hysi, Pirro G.; Zeng, Changqing; Sanna, Marianna; Iles, Mark M.; Kanetsky, Peter A.; Demenais, Florence; Hamer, Merel A.; Uitterlinden, Andre G.; Ikram, M. Arfan; Nijsten, Tamar; Martin, Nicholas G.; Kayser, Manfred; Spector, Tim D.; Han, Jiali; Bataille, Veronique; Falchi, Mario; Epidemiology, School of Public Health
    The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.
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    Identification of a melanoma susceptibility locus and somatic mutation in TET2
    (Oxford University Press, 2014-09) Song, Fengju; Amos, Christopher I.; Lee, Jeffrey E.; Lian, Christine G.; Fang, Shenying; Liu, Hongliang; MacGregor, Stuart; Iles, Mark M.; Law, Matthew H.; Lindeman, Neil I.; Montgomery, Grant W.; Duffy, David L.; Cust, Anne E.; Jenkins, Mark A.; Whiteman, David C.; Kefford, Richard F.; Giles, Graham G.; Armstrong, Bruce K.; Aitken, Joanne F.; Hopper, John L.; Brown, Kevin M.; Martin, Nicholas G.; Mann, Graham J.; Bishop, D. Timothy; Bishop, Julia A. Newton; Kraft, Peter; Qureshi, Abrar A.; Kanetsky, Peter A.; Hayward, Nicholas K.; Hunter, David J.; Wei, Qingyi; Han, Jiali; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10(-) (7). This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.