ORCID Profile
0000-0001-9147-6802
Current Organisation
University of Leeds
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Publisher: Elsevier BV
Date: 05-2019
Publisher: American Psychiatric Association Publishing
Date: 02-2012
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: MDPI AG
Date: 29-09-2021
Abstract: Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.
Publisher: Public Library of Science (PLoS)
Date: 26-06-2009
Publisher: Springer Science and Business Media LLC
Date: 31-07-2017
DOI: 10.1038/NG.3927
Abstract: Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ∼100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (-/GGGCCC r
Publisher: Springer Science and Business Media LLC
Date: 23-04-2021
DOI: 10.1186/S12889-021-10424-5
Abstract: In iduals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. In iduals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, in iduals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
Publisher: Elsevier BV
Date: 09-2010
Publisher: Oxford University Press (OUP)
Date: 30-06-2014
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.BIOPSYCH.2005.01.018
Abstract: Several studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control s le. Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar s le (726 Caucasian UK DSM-IV bipolar I patients 1407 ethnically matched controls). No significant differences were found in the distribution of the 3-locus haplotype in the full s le. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia s le. This finding was not significant after correction for multiple testing. Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset s le is small and the hypothesis requires testing in independent, adequately powered s les.
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2017
DOI: 10.1101/195354
Abstract: Despite recent therapeutic advances in the management of BRAF V600 -mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF / NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to kill BRAF / NRAS wild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combination in vivo using patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy in BRAF / NRAS wild type melanoma patients.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2013
Publisher: BMJ
Date: 15-02-2011
Publisher: Oxford University Press (OUP)
Date: 17-09-2011
DOI: 10.1093/HMG/DDR415
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
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: 30-03-2014
DOI: 10.1038/NG.2947
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
DOI: 10.1038/NATURE10630
Publisher: Elsevier BV
Date: 09-1997
DOI: 10.1038/KI.1997.373
Abstract: To determine the effect of the ACE gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney disease (ADPKD), 189 in iduals from 46 families with PKD1 were genotyped for each polymorphism. Of the 189 patients 52 (28%) reached ESRF at an average age of 48 +/- 1 year. In patients genotyped for the ACE gene insertion/deletion polymorphism the frequencies of the DD, ID and II genotypes were similar to those expected from Hardy Weinberg equilibrium. In patients with ESRF there was an excess of patients homozygous for the deletion allele (DD: 48% chi2 = 9.97 (1df) P = 0.002). Cumulative renal survival was significantly reduced among those with DD genotype compared to ID and II genotypes. The estimated mean renal survival (95% confidence intervals) were: DD, 52 years [48, 57] II, 59 years [54, 63] ID, 64 years [56, 72] chi2 = 6.13 (1df) P = 0.013, DD versus ID/II. The mean age of renal failure was significantly younger in the DD genotype compared to ID and II genotypes (DD, ID, and II: 44 +/- 2, 49 +/- 2 and 54 +/- 3 years, respectively P < 0.05 DD vs. ID, P < 0.05 DD vs. II). Ten of the eleven patients who reached ESRF before the age of 40 were homozygous for the deletion allele. The relative risk for ESRF below the age 40 for DD genotype was 17. For all ages there was an overall increased risk of 1.4 for ESRF with the DD genotype. There was no interaction between age of onset of ESRF and either the angiotensinogen M235T allele or angiotensin 1 receptor A1166C polymorphism. This study strongly suggests that PKD 1 patients homozygous for the deletion allele of the ACE gene are at increased risk of developing ESRF at a early age.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
Publisher: Springer Science and Business Media LLC
Date: 20-11-2014
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: 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: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Oxford University Press (OUP)
Date: 22-09-2020
DOI: 10.1111/BJD.18411
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1038/S41467-021-21207-2
Abstract: Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10 −5 ) and overall survival (HR = 1.61, p = 1.67 × 10 −4 ), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates ( p AUROC = 7.03 × 10 −4 ), or published prognostic signatures ( p AUROC 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p 2.2 × 10 −16 ), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
Publisher: Wiley
Date: 12-06-2008
DOI: 10.1002/IJC.23495
Abstract: The aim of this study was to compare trends in prognostic factors and survival from cutaneous melanoma between 1993 and 2003 in 2 populations with dramatically different underlying incidence rates [Yorkshire, UK, and New South Wales (NSW), Australia] and to look at whether the greater investment in melanoma prevention and early detection in Australia has resulted in any relative differences in survival. Patients diagnosed with invasive melanoma between 1993 and 2003 in Yorkshire (n = 4,170) and NSW (n = 30,520) were identified from cancer registry databases and prognostic information (age, sex, socioeconomic background, tumour site and Breslow thickness) was extracted. Age-standardised incidence rates, 5-year relative survival and relative excess risk of death were calculated. Between 1993-1995 and 2001-2003, the incidence of melanoma increased in both areas. These increases were mainly seen in tumours with thickness <or=1 mm. Five-year relative survival was 86.9% (95% CI 85.2-88.5) in Yorkshire and 88.6% (95% CI 88.1-89.1) in NSW. Compared with that in NSW, survival in Yorkshire was lower for males and for those living in the most deprived areas. Despite the increase in good prognosis of thin tumours, there was no significant change in survival over the time period in either area. After adjustment for differences in prognostic factors, the relative excess risk of death in Yorkshire compared to that in NSW reduced from 1.36 (95% CI 1.20-1.53) to 1.11 (95% CI 0.99-1.23). Differences in tumour thickness appeared to be the most important factor.
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1086/377140
Abstract: Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82 recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
Publisher: Wiley
Date: 31-05-2013
DOI: 10.1002/AJMG.B.32169
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 03-2015
Publisher: Springer Science and Business Media LLC
Date: 05-07-2009
DOI: 10.1038/NG.410
Publisher: Oxford University Press (OUP)
Date: 18-02-2021
DOI: 10.1111/BJD.19705
Abstract: Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops. We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk. We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case-control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA s les. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls. When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P-heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites. We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.
Publisher: Wiley
Date: 10-03-2005
DOI: 10.1002/GCC.20177
Abstract: Germ-line mutations of the tumor-suppressor gene CDKN2A predispose in iduals to melanoma in families worldwide. However, coding mutations of CDKN2A have not been detected in a significant proportion of those affected. The identification of a disease-associated intronic mutation of CDKN2A in UK families, which has proved to be the most common CDKN2A mutation as yet identified in this population, has highlighted the possibility that additional causal mutations may lie within the intronic sequence of the gene. In this article, we describe the comprehensive screening of 109 English and 26 Australian melanoma pedigrees for intronic mutations of CDKN2A. In total, 24 sequence variants were identified across the two introns of the gene. We show evidence that two of the CDKN2A intronic variants (IVS1 + 1104 C > A and IVS1 - 1104 C > G) predispose to melanoma. IVS1 + 1104 was shown to result in the aberrant splicing of both p16(INK4a) and p14(ARF) mRNA. Overall, however, the proportion of English melanoma families with these variants is small.
Publisher: MDPI AG
Date: 28-07-2020
Abstract: Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of KDM6A, ATRX, KDM5C, and DDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2011
Abstract: Prognosis in patients with sentinel node (SN) –positive melanoma correlates with several characteristics of the metastases in the SN such as size and site. These factors reflect biologic behavior and may separate out patients who may or may not need additional locoregional and/or systemic therapy. Between 1993 and 2008, 1,080 patients (509 women and 571 men) were diagnosed with tumor burden in the SN in nine European Organisation for Research and Treatment of Cancer (EORTC) melanoma group centers. In total, 1,009 patients (93%) underwent completion lymph node dissection (CLND). Median Breslow thickness was 3.00 mm. The median follow-up time was 37 months. Tumor load and tumor site were reclassified in all nodes by the Rotterdam criteria for size and in 88% by the Dewar criteria for topography. Patients with submicrometastases ( 0.1 mm in diameter) were shown to have an estimated 5-year overall survival rate of 91% and a low nonsentinel node (NSN) positivity rate of 9%. This is comparable to the rate in SN-negative patients. The strongest predictive parameter for NSN positivity and prognostic parameter for survival was the Rotterdam-Dewar Combined (RDC) criteria. Patients with submicrometastases that were present in the subcapsular area only, had an NSN positivity rate of 2% and an estimated 5- and 10-year melanoma-specific survival (MSS) of 95%. Patients with metastases 0.1 mm, especially when present in the subcapsular area only, may be overtreated by a routine CLND and have an MSS that is indistinguishable from that of SN-negative patients. Thus the RDC criteria provide a rational basis for decision making in the absence of conclusions provided by randomized controlled trials.
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2015
DOI: 10.1158/1055-9965.EPI-14-1062
Abstract: Background: We report the development of a cutaneous melanoma risk algorithm based upon seven factors hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public. Methods: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case–control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute in iduals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case–control study dataset. Results: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75 95% confidence interval (CI), 0.73–0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases. Conclusion: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset. Impact: This score may be a useful tool to inform members of the public about their melanoma risk. Cancer Epidemiol Biomarkers Prev 24(5) 817–24. ©2015 AACR.
Publisher: Wiley
Date: 07-06-2019
DOI: 10.1111/JDV.15680
Publisher: American Psychiatric Association Publishing
Date: 02-2012
Publisher: Springer Science and Business Media LLC
Date: 04-12-2011
DOI: 10.1038/NG.1013
Publisher: Wiley
Date: 26-11-2008
DOI: 10.1002/IJC.24011
Publisher: Wiley
Date: 19-10-2011
DOI: 10.1002/AJMG.B.31246
Abstract: The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria Human660W-Quadv1 Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3 Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 03-10-2015
Publisher: Elsevier BV
Date: 06-2018
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.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Oxford University Press (OUP)
Date: 13-12-2015
DOI: 10.1093/JNCI/DJU408
Publisher: Wiley
Date: 27-03-2013
DOI: 10.1111/PCMR.12069
Publisher: American Psychiatric Association Publishing
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 18-05-2008
DOI: 10.1038/NG.163
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 12-2016
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1046/J.0022-202X.2001.01415.X
Abstract: Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene-environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10-18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p = 0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p < 0.0001), and nevus densities were higher on sun-exposed sites (92 per m2) than sun-protected sites (58 per m2) (p < 0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95%CI 0.92-0.96) than in DZ pairs (0.61, 95%CI 0.49-0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi.
Publisher: BMJ
Date: 07-06-2017
DOI: 10.1136/JMEDGENET-2016-104402
Abstract: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood both environmental and genetic risk factors could contribute to their aetiology. We performed whole-exome sequencing (WES) in a familial aggregation of three in iduals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in Germline mutations in
Publisher: Elsevier BV
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 14-03-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Wiley
Date: 16-11-2010
DOI: 10.1002/IJC.25691
Publisher: Oxford University Press (OUP)
Date: 03-06-2017
DOI: 10.1093/JNCI/DJX083
Publisher: Oxford University Press (OUP)
Date: 12-2018
DOI: 10.1093/JNCI/DJY171
Publisher: Public Library of Science (PLoS)
Date: 12-05-2011
Publisher: Wiley
Date: 04-02-2022
Abstract: In addition to mutations, epigenetic alterations are important contributors to malignant transformation and tumor progression. The aim of this work was to identify epigenetic events in which promoter or gene body DNA methylation induces gene expression changes that drive melanocyte malignant transformation and metastasis. We previously developed a linear mouse model of melanoma progression consisting of spontaneously immortalized melanocytes, premalignant melanocytes, a nonmetastatic tumorigenic, and a metastatic cell line. Here, through the integrative analysis of methylome and transcriptome data, we identified the relationship between promoter and/or gene body DNA methylation alterations and gene expression in early, intermediate, and late stages of melanoma progression. We identified adenylate cyclase type 3 ( Adcy3 ) and inositol polyphosphate 4‐phosphatase type II ( Inpp4b ), which affect tumor growth and metastatic potential, respectively. Importantly, the gene expression and DNA methylation profiles found in this murine model of melanoma progression were correlated with available clinical data from large population‐based primary melanoma cohorts, revealing potential prognostic markers.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Julia Newton-Bishop.