ORCID Profile
0000-0002-2603-6509
Current Organisation
University of Leeds
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Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JID.2021.08.449
Abstract: Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for s le overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P < 0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41467-018-06649-5
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
DOI: 10.1038/S41467-018-08078-W
Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
Publisher: Wiley
Date: 27-03-2013
DOI: 10.1111/PCMR.12069
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2022
DOI: 10.1101/2022.03.07.22272003
Abstract: Although there are well-known prognostic factors for survival from cutaneous melanoma (CM) such as primary tumour thickness and stage of the tumour at diagnosis, the role of germline genetic factors in determining survival is not well understood. To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia (MIA 5,762 patients with melanoma 800 deaths from melanoma) and UK Biobank (UKB: 5,220 patients with melanoma 241 deaths from melanoma). The GWAS were adjusted for age, sex and the first ten genetic principal components, and combined in a fixed-effects inverse-variance-weighted meta-analysis. Significant (P ×10 −8 ) results were investigated in the Leeds Melanoma Cohort (LMC 1,947 patients with melanoma 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts, with replication in the LMC. Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.61-2.71, P=2.08×10 −8 ) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR=2.38, 95% CI=1.77—3.21, P=1.07×10 −8 ) on chromosome 7. While neither SNP replicated (P .05) in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets and requires confirmation in additional cohorts. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR=0.88, 95% CI=0.83—0.94, P=6.93×10 −5 I 2 =88%). The association with the PRS was not replicated (P 0.05) in LMC, but remained significantly associated with MSS in the meta-analysis of the discovery and replication results. We found two loci potentially associated with MSS, and evidence that increased germline genetic susceptibility to develop CM may be associated with improved MSS.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
Publisher: Wiley
Date: 05-03-2018
DOI: 10.1002/IJC.31334
Abstract: Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for ex le, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17
Publisher: Oxford University Press (OUP)
Date: 30-06-2014
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2018
Abstract: 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 % 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.
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NCOMMS10495
Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 in iduals. Twelve loci reached genome-wide significance ( P × 10 −8 ), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14 , IGF2BP1 , PLA2G6 , CRTC1 ) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1038/S41467-020-20368-W
Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2017
DOI: 10.1101/173112
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs at a genome-wide level of significance in KITLG , DOCK8 , and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A , CYP1B1 , PPARGC1B , HDAC4 , FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1 , reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.
Publisher: Cold Spring Harbor Laboratory
Date: 08-12-2017
DOI: 10.1101/231423
Abstract: Most expression quantitative trait loci (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 % 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 LD-pruning and 4,997 eGenes (FDR .05), which are higher numbers than in any GTEx tissue type with a similar s le size. Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissues, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were not observed to be eGenes in two types of GTEx skin tissues or TCGA melanoma s les. The melanocyte dataset also identified cell-type specific trans- eQTLs with a pigmentation-associated SNP for four genes, likely through its cis -regulation of IRF4 , encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as melanoma-associated variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for six known GWAS loci including unique genes identified by the melanocyte dataset. Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new 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.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Springer Science and Business Media LLC
Date: 10-12-2021
DOI: 10.1038/S41467-021-27394-2
Abstract: Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low recent effective population sizes (N e ), with some showing a decrease 15‒20 generations ago that has resulted in extensive identity-by-descent sharing and homozygosity, increasing the risk of recessive disorders. Our results from two orthogonal methods (one using machine learning and the other coalescent-based) suggest that the detailed reporting of parental relatedness for mothers in the cohort under-represents the true levels of consanguinity. These results demonstrate the impact of cultural practices on population structure and genomic ersity in Pakistanis, and have important implications for medical genetic studies.
Publisher: Oxford University Press (OUP)
Date: 27-07-2020
DOI: 10.1093/HMG/DDAA156
Abstract: Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of in idually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.
Publisher: Oxford University Press (OUP)
Date: 17-10-2020
DOI: 10.1093/HMG/DDAA222
Abstract: Germline genetic variants have been identified, which predispose in iduals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 in iduals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated in iduals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 in iduals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P & 5 × 10−8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.
Publisher: Oxford University Press (OUP)
Date: 17-09-2011
DOI: 10.1093/HMG/DDR415
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 04-2015
Publisher: Elsevier BV
Date: 07-2010
Publisher: Springer Science and Business Media LLC
Date: 05-09-2022
DOI: 10.1186/S12967-022-03613-2
Abstract: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA 5,762 patients with melanoma 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC 1,947 patients with melanoma 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5 I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90). We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mark Iles.