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918 results on '"Amos, CI"'

1. Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

Author

Walsh, Kyle, Wiencke, John, Wrensch, Margaret, Walsh, KM, Amos, CI, Wenzlaff, AS, Gorlov, IP, Sison, JD, Wu, X, Spitz, MR, Hansen, HM, Lu, EY, and Wei, C

Abstract

Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic varia

Published
2012

2. Genetic analysis of lung cancer and the germline impact on somatic mutation burden

Author

Gabriel, AAG, Atkins, JR, Penha, RCC, Smith-Byrne, K, Gaborieau, V, Voegele, C, Abedi-Ardekani, B, Milojevic, M, Olaso, R, Meyer, V, Boland, A, Deleuze, JF, Zaridze, D, Mukeriya, A, Swiatkowska, B, Janout, V, Schejbalová, M, Mates, D, Stojšić, J, Ognjanovic, M, consortium, ILCCO, Witte, JS, Rashkin, SR, Kachuri, L, Hung, RJ, Kar, S, Brennan, P, Sertier, A-S, Ferrari, A, Viari, A, Johansson, M, Amos, CI, Foll, M, McKay, JD, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Oxford, Université Paris-Saclay, N.N. Blokhin Russian Cancer Research Center, Nofer Institute of Occupational Medicine (NIOM), Palacky University Olomouc, Charles University [Prague] (CU), National Institute of Public Health [Romania] (INSP), University Clinical Centre of Serbia, International Organisation for Cancer Prevention and Research, University of California [San Francisco] (UC San Francisco), University of California (UC), St Jude Children's Research Hospital, Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada, University of Bristol [Bristol], Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Lyon, Institut National de Recherche en Informatique et en Automatique (Inria), Baylor College of Medicine (BCM), and Baylor University

Subjects
Cancer Research, Germ Cells, Lung Neoplasms, Oncology, [SDV]Life Sciences [q-bio], Mutation, Humans, Genetic Predisposition to Disease, ICEP, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Background Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. Methods To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. Results The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P Conclusions This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.

Published
2022

3. Body size at different ages and risk of six cancers: a Mendelian randomization and prospective cohort study

Author

Mariosa, D, Smith-Byrne, K, Richardson, TG, Ferrari, P, Gunter, MJ, Papadimitriou, N, Murphy, N, Christakoudi, S, Tsilidis, KK, Riboli, E, Muller, D, Purdue, MP, Chanock, SJ, Hung, RJ, Amos, CI, O'Mara, TA, Amiano, P, Pasanisi, F, Rodriguez-Barranco, M, Krogh, V, Tjønneland, A, Halkjær, J, Perez-Cornago, A, Chirlaque, M-D, Skeie, G, Rylander, C, Borch, KB, Aune, D, Heath, AK, Ward, HA, Schulze, M, Bonet, C, Weiderpass, E, Smith, GD, Brennan, P, Johansson, M, Mariosa, Daniela, Smith-Byrne, Karl, Richardson, Tom G, Ferrari, Pietro, Gunter, Marc J, Papadimitriou, Niko, Murphy, Neil, Christakoudi, Sofia, Tsilidis, Konstantinos K, Riboli, Elio, Muller, David, Purdue, Mark P, Chanock, Stephen J, Hung, Rayjean J, Amos, Christopher I, O'Mara, Tracy A, Amiano, Pilar, Pasanisi, Fabrizio, Rodriguez-Barranco, Miguel, Krogh, Vittorio, Tjønneland, Anne, Halkjær, Jytte, Perez-Cornago, Aurora, Chirlaque, María-Dolore, Skeie, Guri, Rylander, Charlotta, Borch, Kristin Benjaminsen, Aune, Dagfinn, Heath, Alicia K, Ward, Heather A, Schulze, Matthia, Bonet, Catalina, Weiderpass, Elisabete, Smith, George Davey, Brennan, Paul, and Johansson, Mattias

Subjects
Adult, SUSCEPTIBILITY LOCI, Epidemiology, OVARIAN-CANCER, Body Mass Index, 1117 Public Health and Health Services, POOLED ANALYSIS, Cohort Studies, MASS INDEX, Neoplasms, Body Size, Humans, Obesity, Prospective Studies, Genetics & Heredity, LIFE-COURSE, 0604 Genetics, Science & Technology, IDENTIFICATION, ENDOMETRIAL CANCER, Mendelian Randomization Analysis, Oncology, ADIPOSITY, Mathematical & Computational Biology, Life Sciences & Biomedicine, ANTHROPOMETRIC FACTORS, Genome-Wide Association Study
Abstract

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for six obesity-related cancers, we performed univariable and multivariable analyses using i) Mendelian randomization (MR) analysis and ii) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger body size at age 10 was associated with higher risk of endometrial (ORMR=1.61, 95%CI = 1.23-2.11) and kidney cancer (ORMR=1.40, 95%CI = 1.09-1.80). These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life BMI was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.

Published
2022

4. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author

Chen, H, Majumdar, A, Wang, L, Kar, S, Brown, KM, Feng, H, Turman, C, Dennis, J, Easton, D, Michailidou, K, Simard, J, Breast Cancer Association Consortium (BCAC), Bishop, T, Cheng, IC, Huyghe, JR, Schmit, SL, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO, O'Mara, TA, Spurdle, AB, Endometrial Cancer Association Consortium (ECAC), Gharahkhani, P, Schumacher, J, Jankowski, J, Gockel, I, Esophageal Cancer GWAS Consortium, Bondy, ML, Houlston, RS, Jenkins, RB, Melin, B, Glioma International Case Control Consortium (GICC), Lesseur, C, Ness, AR, Diergaarde, B, Olshan, AF, Head-Neck Cancer GWAS Consortium, Amos, CI, Christiani, DC, Landi, MT, McKay, JD, International Lung Cancer Consortium (ILCCO), Brossard, M, Iles, MM, Law, MH, MacGregor, S, Melanoma GWAS Consortium, Beesley, J, Jones, MR, Tyrer, J, Winham, SJ, Ovarian Cancer Association Consortium (OCAC), Klein, AP, Petersen, G, Li, D, Wolpin, BM, Pancreatic Cancer Case-Control Consortium (PANC4), Pancreatic Cancer Cohort Consortium (PanScan), Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Brennan, P, Chanock, SJ, Gaborieau, V, Purdue, MP, Renal Cancer GWAS Consortium, Pharoah, P, Hung, RJ, Amundadottir, LT, Kraft, P, Pasaniuc, B, and Lindström, S

Abstract

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

Published
2021

5. Air Pollution, Residential Greenness and Metabolic Dysfunction during Early Pregnancy in the INfancia y Medio Ambiente (INMA) Cohort

Author

Rammah A, Whitworth KW, Amos CI, Estarlich M, Guxens M, Ibarluzea J, Iñiguez C, Subiza-Pérez M, Vrijheid M, and Symanski E

Subjects
lipids, GDM, residential greenness, PM2, gestational diabetes, NO2
Abstract

Despite extensive study, the role of air pollution in gestational diabetes remains unclear, and there is limited evidence of the beneficial impact of residential greenness on metabolic dysfunction during pregnancy. We used data from mothers in the Spanish INfancia y Medio Ambiente (INMA) Project from 2003-2008. We obtained spatiotemporally resolved estimates of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) exposures in early pregnancy and estimated residential greenness using satellite-based Normal Difference Vegetation Index (NDVI) within 100, 300 and 500 m buffers surrounding the mother's residence. We applied logistic regression models to evaluate associations between each of the three exposures of interest and (a) glucose intolerance and (b) abnormal lipid levels. We found limited evidence of associations between increases in PM2.5 and NO2 exposures and the metabolic outcomes. Though not statistically significant, high PM2.5 exposure (>= 25 mu g/m(3)) was associated with increased odds of glucose intolerance (OR = 1.16, 95% CI: 0.82, 1.63) and high cholesterol (OR = 1.14, 95% CI: 0.90, 1.44). High NO2 exposure (>= 39.8 mu g/m(3)) was inversely associated with odds of high triglycerides (OR = 0.70, 95% CI: 0.45, 1.08). Whereas NDVI was not associated with glucose intolerance, odds of high triglycerides were increased, although the results were highly imprecise. Results were unchanged when the air pollutant variables were included in the regression models. Given the equivocal findings in our study, additional investigations are needed to assess effects of air pollution and residential greenness on metabolic dysfunction during pregnancy.

Published
2021

7. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH

Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020

10. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

Duffy, David L, Zhu, Gu, Xin, Li, Sanna, Marianna, Iles, Mark M, Jacobs, Leonie C, Evans, David M, Yazar, Seyhan, Beesley, Jonathan, Law, Matthew H, Kraft, Peter, Visconti, Alessia, Taylor, John C, Lui, Fan, Wright, Margaret J, Henders, Anjali K, Bowdler, Lisa, Glass, Dan, Ikram, Arfan M, Uitterlinden, André G, Madden, Pamela A, Heath, Andrew C, Nelson, Elliot C, Green, Adele C, Chanock, Stephen, Barrett, Jennifer H, Brown, Matthew A, Hayward, Nicholas K, Macgregor, Stuart, Sturm, Richard A, Hewitt, Alex W, Kayser, Manfred, Hunter, David J, Newton Bishop, Julia A, Spector, Timothy D, Montgomery, Grant W, Mackey, David A, Smith, George Davey, Nijsten, Tamar E, Bishop, D Timothy, Bataille, Veronique, Falchi, Mario, Han, Jiali, Martin, Nicholas, G, Lee, Je, Brossard, M, Moses, Ek, Song, F, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Scarrà, Gb, Brown, Km, Dębniak, T, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Schulze, Hj, Dunning, Am, Demenais, F, Amos, Ci., Apollo - University of Cambridge Repository, Dermatology, Genetic Identification, Epidemiology, Internal Medicine, and Consortium, Melanoma Gwas

Subjects
0301 basic medicine, Skin Neoplasms, Medizin, General Physics and Astronomy, Genome-wide association study, Receptors, G-Protein-Coupled, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, lcsh:Science, skin and connective tissue diseases, Melanoma, Telomerase, Genetics, 0303 health sciences, Nevus, Pigmented, Stem Cell Factor, Multidisciplinary, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, Genetic Pleiotropy, Microphthalmia-associated transcription factor, 3. Good health, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, Interferon Regulatory Factors, Medical genetics, PPARGC1B, Dock8, medicine.medical_specialty, Science, Telomere-Binding Proteins, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Histone Deacetylases, White People, Group VI Phospholipases A2, 03 medical and health sciences, Genetic predisposition, Pigmented Nevus, medicine, Nevus, Humans, Genetic Predisposition to Disease, neoplasms, 030304 developmental biology, General Chemistry, medicine.disease, Repressor Proteins, MicroRNAs, 030104 developmental biology, Cutaneous melanoma, RNA, lcsh:Q, Carrier Proteins, IRF4, Genome-Wide Association Study
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 individuals. 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 example, 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.

Published
2018

11. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Author

Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Shi, Jianxin, Mai, Xu, 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., Lee, Je, Brossard, M, Martin, Ng, Moses, Ek, Song, F, Barrett, Jh, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Taylor, Jc, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Bianchi Scarrà, G, Dȩbniak, T, Duffy, Dl, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Montgomery, Gw, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Wu, W, Qureshi, Aa, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Hayward, Nk, Han, J, Schulze, Hj, Dunning, Am, Bishop, Jan, Demenais, F, Amos, Ci, Macgregor, S, Iles, Mm, Barnabas, Bb, Bouffard, Gg, Brooks, Sy, Coleman, H, Dekhtyar, L, Guan, X, Ho, Sl, Legaspi, R, Maduro, Ql, Masiello, Ca, Mcdowell, Jc, Montemayor, C, Mullikin, Jc, Park, M, Riebow, Nl, Schandler, K, Schmidt, B, Sison, C, Smith, R, Stantripop, S, Thomas, Jw, Thomas, Pj, Vemulapalli, M, and Young, Ac.

Subjects
0301 basic medicine, Hemeproteins, Linkage disequilibrium, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Biology, Quantitative trait locus, Melanocyte, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, Heme-Binding Proteins, 0302 clinical medicine, Genetics, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Genetic Predisposition to Disease, Melanoma, Genetics (clinical), Cells, Cultured, Genetic association, Research, medicine.disease, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Interferon Regulatory Factors, Melanocytes, Carrier Proteins
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 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.

Published
2018

12. Publisher correction: Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, JW, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Stolzenberg-Solomon, RS, Kraft, P, Wolpin, BM, Jansen, PWTC, Olson, S, McGlynn, KA, Kanetsky, PA, Chatterjee, N, Barrett, JH, Dunning, AM, Taylor, JC, Newton-Bishop, JA, Timothy Bishop, D, Andresson, T, Petersen, GM, Amos, CI, Iles, MM, Nathanson, KL, Teresa Landi, M, Vermeulen, M, Brown, KM, and Amundadottir, LT

Abstract

This corrects the article DOI: 10.1038/ncomms15034

Published
2018

13. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Author

Zuber, V, Bettella, F, Witoelar, A, Andreassen, OA, Mills, IG, Urbanucci, A, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Weischer, M, Travis, RC, Neal, D, Pharoah, P, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Chenevix-Trench, G, Humphreys, M, Hung, RJ, Han, Y, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Heinrich, J, Risch, A, Wu, X, Ye, Y, Christiani, DC, Amos, CI, Easton, DF, Michailidou, K, Bolla, MK, Wang, Q, Berchuck, A, Antoniou, A, McGuffog, L, Couch, F, Offit, K, Dennis, J, Dunning, AM, Lee, A, Dicks, E, Luccarini, C, Benitez, J, Gonzalez-Neira, A, Simard, J, Tessier, DC, Bacot, F, Vincent, D, LaBoissière, S, Zuber, Verena [0000-0001-9827-1877], Pharoah, Paul [0000-0001-8494-732X], Khaw, Kay-Tee [0000-0002-8802-2903], Easton, Douglas [0000-0003-2444-3247], Wang, Jean [0000-0002-9139-0627], Antoniou, Antonis [0000-0001-9223-3116], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Dicks, Ed [0000-0002-0617-0401], and Apollo - University of Cambridge Repository

Subjects
risk loci, schizophrenia, breast cancer risk, super-enhancer, genome-wide association studies, BRD4, chromatin, functional annotation, prostate cancer risk, SNPs
Abstract

$\textbf{Background:}$ Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. $\textbf{Results:}$ Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. $\textbf{Conclusions:}$ This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.

Published
2017
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14. Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Author

Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, TR, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, S, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, NC, Lund, E, Duell, EJ, Canzian, F, Severi, G, Overvad, K, Gunter, MJ, Tumino, R, Svenson, U, Van Rij, A, Baas, AF, Bown, MJ, Samani, NJ, Van t'Hof, FNG, Tromp, G, Jones, GT, Kuivaniemi, H, Elmore, JR, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, PM, Neale, RE, Olson, SH, Gallinger, S, Li, D, Petersen, GM, Risch, HA, Klein, AP, Han, J, Abnet, CC, Freedman, ND, Taylor, PR, Maris, JM, Aben, KK, Kiemeney, LA, Vermeulen, SH, Wiencke, JK, and Walsh, KM

Abstract

Copyright 2017 American Medical Association. All rights reserved. IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

15. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, Jw, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Solomon, Rs, Kraft, P, Wolpin, Bm, Jansen, Pwtc, Olson, S, Mcglynn, Ka, Kanetsky, Pa, Chatterjee, N, Barrett, Jh, Dunning, Am, Taylor, Jc, Newton Bishop, Ja, Bishop, Dt, Andresson, T, Petersen, Gm, Amos, Ci, Iles, Mm, Nathanson, Kl, Landi, Mt, Vermeulen, M, Brown, Km, Amundadottir, Lt, Canzian, F, Kooperberg, C, Arslan, Aa, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Jacobs, Ej, Kamineni, A, Van Den Eeden, S, Klein, Ap, Kolonel, Ln, Li, D, Olson, Sh, Risch, Ha, Sesso, Hd, Visvanathan, K, Zheng, W, Albanes, D, Austin, Ma, Boutron Ruault, Mc, Bueno de Mesquita, Hb, Cotterchio, M, Gaziano, Jm, Giovannucci, El, Goggins, M, Gross, M, Hassan, M, Helzlsouer, Kj, Holly, Ea, Hunter, Dj, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Krogh, V, Kurtz, Rc, Lacroix, A, Le Marchand, L, Mannisto, S, Patel, Av, Peeters, Phm, Riboli, E, Shu, Xo, Sund, M, Thornquist, M, Tjønneland, A, Tobias, Gs, Trichopoulos, D, Wactawski Wende, J, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, Sj, Stevens, V, Caporaso, Ne, Brennan, P, Mckay, J, Wu, X, Hung, Rj, Mclaughlin, Jr, Bickeboller, H, Risch, A, Wichmann, E, Houlston, R, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, Pg, Iglesias Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Batille, Ja, Marti, Gt, Hayward, N, Martin, N, Montgomery, G, Duffy, D, Whiteman, D, Gregor, Sm, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Ghiorzo, Paola, Bianchi, Giovanna, Pastorino, Lorenza, Bruno, William, Andreotti, Virginia, Queirolo, P, Spagnolo, Francesco, Mackie, R, Lang, J, Gruis, N, van Nieuwpoort, Fa, Out, C, Bergman, W, Kukutsch, N, Bavinck, Jnb, Bakker, B, van der Stoep, N, Ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jonsson, G, Borg, A, Harbst, K, Nielsen, K, Zander, As, Molvern, A, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Bressac de Paillerets, B, Demenais, F, Avril, Mf, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, D, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Hoiom, V, Freidman, E, Azizi, E, Baron Epel, O, Scope, A, Pavlotsky, F, Cohen Manheim, I, Laitman, Y, Harland, M, Randerson Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, Ma, Goldstein, Am, and Yang, X. r.

Subjects
0301 basic medicine, Male, Lung Neoplasms, Skin Neoplasms, General Physics and Astronomy, Genome-wide association study, VARIANTS, Histones, Skin cancer, RNA, Small Interfering, Melanoma, Telomerase, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Pancreas cancer, Regulation of gene expression, Genetics, Zinc finger, Gene knockdown, Multidisciplinary, Proteomics and Chromatin Biology, TRICL Consortium, Chromosome Mapping, GenoMEL Consortium, PANCREATIC-CANCER, Multidisciplinary Sciences, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Science & Technology - Other Topics, Chromosomes, Human, Pair 5, Female, Lung cancer, Signal Transduction, SUSCEPTIBILITY LOCI, Science, Locus (genetics), Single-nucleotide polymorphism, PROMOTES GROWTH, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, LUNG-CANCER, Testicular Neoplasms, Cell Line, Tumor, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, QUANTITATIVE PROTEOMICS, GENOME-WIDE ASSOCIATION, Gene, PanScan Consortium, Càncer de pell, Càncer de pàncrees, Alleles, Science & Technology, Kirurgi, HUMAN-CELLS, Telomere Homeostasis, Correction, General Chemistry, Molecular biology, TERT-CLPTM1L LOCUS, Telomere, Pancreatic Neoplasms, 030104 developmental biology, Genetic Loci, TELOMERE LENGTH, Càncer de pulmó, Surgery, Genètica, Genome-Wide Association Study, Transcription Factors
Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Published
2017

16. Appraising the causal relevance of DNA methylation for risk of lung cancer

Author

Battram, T, primary, Richmond, RC, additional, Baglietto, L, additional, Haycock, P, additional, Perduca, V, additional, Bojesen, S, additional, Gaunt, TR, additional, Hemani, G, additional, Guida, F, additional, Carreras-Torres, R, additional, Hung, R, additional, Amos, CI, additional, Freeman, JR, additional, Sandanger, TM, additional, Nøst, TH, additional, Nordestgaard, B, additional, Teschendorff, AE, additional, Polidoro, S, additional, Vineis, P, additional, Severi, G, additional, Hodge, A, additional, Giles, G, additional, Grankvist, K, additional, Johansson, MB, additional, Johansson, M, additional, Davey Smith, G, additional, and Relton, CL, additional

Published
2018
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17. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants

Author

Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC Jr, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, Italian PBC Genetics Study Group, Lazaridis KN, Seldin MF, Siminovitch KA, Almasio PL, Alvaro D, Andriulli A, Barlassina C, Battezzati PM, Benedetti A, Bragazzi M, Brunetto M, Bruno S, Caliari L, Casella G, Civardi F, Coco B, Colli A, Colombo M, Colombo S, Cursaro C, Crocè LS, Crosignani A, Donato F, Fabris L, Ferrari C, Floreani A, Fontana R, Galli A, Grattagliano I, Lazzari R, Macaluso F, Malinverno F, Marra F, Marzioni M, Mascia E, Mattalia A, Montanari R, Morini L, Morisco F, Niro GA, Picciotto A, Portincasa P, Prati D, Rosina F, Rossi S, Selmi C, Spinzi G, Strazzabosco M, Tarallo S, Tiribelli C, Toniutto P, Vinci M, Zuin M., ANDREONE, PIETRO, MURATORI, LUIGI, MURATORI, PAOLO, Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC Jr, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, Italian PBC Genetics Study Group, Lazaridis KN, Seldin MF, Siminovitch KA, Almasio PL, Alvaro D, Andreone P, Andriulli A, Barlassina C, Battezzati PM, Benedetti A, Bragazzi M, Brunetto M, Bruno S, Caliari L, Casella G, Civardi F, Coco B, Colli A, Colombo M, Colombo S, Cursaro C, Crocè LS, Crosignani A, Donato F, Fabris L, Ferrari C, Floreani A, Fontana R, Galli A, Grattagliano I, Lazzari R, Macaluso F, Malinverno F, Marra F, Marzioni M, Mascia E, Mattalia A, Montanari R, Morini L, Morisco F, Muratori L, Muratori P, Niro GA, Picciotto A, Portincasa P, Prati D, Rosina F, Rossi S, Selmi C, Spinzi G, Strazzabosco M, Tarallo S, Tiribelli C, Toniutto P, Vinci M, Zuin M., Juran, Bd, Hirschfield, Gm, Invernizzi, P, Atkinson, Ej, Li, Y, Xie, G, Kosoy, R, Ransom, M, Sun, Y, Bianchi, I, Schlicht, Em, Lleo, A, Coltescu, C, Bernuzzi, F, Podda, M, Lammert, C, Shigeta, R, Chan, Ll, Balschun, T, Marconi, M, Cusi, D, Heathcote, Ej, Mason, Al, Myers, Rp, Milkiewicz, P, Odin, Ja, Luketic, Va, Bacon, Br, Bodenheimer HC, Jr, Liakina, V, Vincent, C, Levy, C, Franke, A, Gregersen, Pk, Bossa, F, Gershwin, Me, Deandrade, M, Amos, Ci, Lazaridis, Kn, Seldin, Mf, Siminovitch, Ka, Morisco, Filomena, Italian PBC Genetics Study, Group, Juran, B, Hirschfield, G, Atkinson, E, Schlicht, E, Chan, L, Heathcote, E, Mason, A, Myers, R, Odin, J, Luketic, V, Bacon, B, Bodenheimer, H, Gregersen, P, Gershwin, M, Amos, C, Italian PBC Genetics Study, G, Lazaridis, K, Seldin, M, Siminovitch, K, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Crocè, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Fontana, R, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Malinverno, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Almasio, Pl, Battezzati, Pm, Croce', Saveria, Niro, Ga, Tiribelli, Claudio, and Zuin, M.

Subjects
MULTILOCUS GENOTYPE DATA, PRIMARY BILIARY CIRRHOSIS, PBC, 0302 clinical medicine, Gene Frequency, MED/12 - GASTROENTEROLOGIA, HLA Antigens, REGULATORY T-CELLS, RHEUMATOID-ARTHRITIS, VITAMIN-D, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetics, CLASSICAL HLA ALLELES, 0303 health sciences, Liver Cirrhosis, Biliary, PBC, HLA alleles, Association Studies Articles, CELIAC-DISEASE, General Medicine, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, GENETIC RISK, 3. Good health, Chromosomes, Human, Pair 1, SINGLE NUCLEOTIDE POLYMORPHISMS, 030211 gastroenterology & hepatology, Chromosomes, Human, Pair 7, GENETIC ANALYSES, Genotype, Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Humans, SNP, Genetic Predisposition to Disease, Allele, Molecular Biology, Allele frequency, Alleles, 030304 developmental biology, Chromosomes, Human, Pair 13, Haplotype, Epistasis, Genetic, Genetic Loci, Case-Control Studies, Imputation (genetics)
Abstract

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

Published
2012

18. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis

Author

Italian PBC Genetics Study Group, Seldin, Mf, Gershwin, Me, Podda, M, de Bakker PI, Cusi, D, Siminovitch, Ka, Gregersen, Pk, Amos, Ci, Bossa, F, Franke, A, Shigeta, R, Lleo, A, Kosoy, R, Raychaudhuri, S, Ransom, M, Invernizzi, P, Almasio, Pl, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, Mc, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, Ls, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Marra, F, Marzioni, M, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Moroni, L, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Prisco, C, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M., Invernizzi P, Ransom M, Raychaudhuri S, Kosoy R, Lleo A, Shigeta R, Franke A, Bossa F, Amos CI, Gregersen PK, Siminovitch KA, Cusi D, de Bakker PI, Podda M, Gershwin ME, Seldin MFAlmasio PL, Alvaro D, Andreone P, Andriulli A, Barlassina C, Benedetti A, Bernuzzi F, Bianchi I, Bragazzi MC, Brunetto M, Bruno S, Caliari L, Casella G, Civardi F, Coco B, Colli A, Colombo M, Colombo S, Cursaro C, Croce LS, Crosignani A, Donato F, Fabris L, Ferrari C, Floreani A, Galli A, Grattagliano I, Lazzari R, Macaluso F, Marra F, Marzioni M, Mattalia A, Montanari R, Morini L, Morisco F, Moroni L, Muratori L, Muratori P, Niro G, Picciotto A, Portincasa P, Prati D, Prisco C, Rosina F, Rossi S, Selmi C, Spinzi G, Strazzabosco M, Tarallo S, Tiribelli C, Toniutto P, Vinci M, Zuin M., Invernizzi, P., Ransom, M., Raychaudhuri, S., Kosoy, R., Lleo, A., Shigeta, R., Franke, A, Bossa, F., Amos, Ci, Gregersen, Pk, Siminovitch, Ka, Cusi, D., de Bakker, Pi, Podda, M, Gershwin, Me, Seldin, Mf, The Italian PBC Genetics Study, Group, Croce', Saveria, Tiribelli, Claudio, Invernizzi, P, Ransom, M, Raychaudhuri, S, Kosoy, R, Lleo, A, Shigeta, R, Bossa, F, Cusi, D, Morisco, Filomena, Italian PBC Genetics Study, Group, Amos, C, Gregersen, P, Siminovitch, K, de Bakker, P, Gershwin, M, Seldin, M, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Marra, F, Marzioni, M, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Moroni, L, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Prisco, C, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, and Zuin, M

Subjects
AUTOIMMUNITY, PRIMARY BILIARY CIRRHOSIS, genetic risk, imputation, 0302 clinical medicine, Primary biliary cirrhosis, Gene Frequency, MED/12 - GASTROENTEROLOGIA, immune system diseases, Risk Factors, Genetic risk, skin and connective tissue diseases, HLA-DRB1, Genetics (clinical), HLA-DP beta-Chains, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Liver Cirrhosis, Biliary, antigen binding pocket, Italy, HLA-DRB1 Chain, 030211 gastroenterology & hepatology, Case-Control Studie, antigen-binding pocket, Human, musculoskeletal diseases, risk allele, European Continental Ancestry Group, Immunology, Autoimmune Diseases, autoimmune disease, Biology, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Allele, 030304 developmental biology, Autoimmune disease, Oligonucleotide Array Sequence Analysi, Risk Factor, HLA polymorfism, PBC, HLA-DRB1, HLA-DPB1, Hla association, medicine.disease, HLA-DP beta-Chain, Case-Control Studies, Risk allele, Imputation (genetics), Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.Genes and Immunity advance online publication, 10 May 2012; doi:10.1038/gene.2012.17.

Published
2012

19. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

Author

Miller, FW, Cooper, RG, Vencovský, J, Rider, LG, Danko, K, Wedderburn, LR, Lundberg, IE, Pachman, LM, Reed, AM, Ytterberg, SR, Padyukov, L, Selva-O'Callaghan, A, Radstake, TR, Isenberg, DA, Chinoy, H, Ollier, WE, O'Hanlon, TP, Peng, B, Lee, A, Lamb, JA, Chen, W, Amos, CI, and Gregersen, PK

Subjects
Orvostudományok, Klinikai orvostudományok
Abstract

OBJECTIVE: To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of

Published
2016

20. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†

Author

Amos, Ci, Wang, Le, Lee, Je, Gershenwald, Je, Chen, Wv, Fang, S, Kosoy, R, Zhang, M, Qureshi, Aa, Vattathil, S, Schacherer, Cw, Gardner, Jm, Wang, Y, Bishop, Dt, Barrett, Jh, Macgregor, S, Hayward, Nk, Martin, Ng, Duffy, Dl, Mann, Gj, Cust, A, Hopper, J, Brown, Km, Grimm, Ea, Xu, Y, Han, Y, Jing, K, Mchugh, C, Laurie, Cc, Doheny, Kf, Pugh, Ew, Seldin, Mf, Han, J, Wei, Q, Genomel, Investigators, Mega Investigators, Q., AMFS Investigators Mann GJ, Hopper, Jl, Aitken, Jf, Armstrong, Bk, Giles, Gg, Kefford, Rf, Cust, Ae, Jenkins, Ma, Schmid, H, Aguilera, P, Badenas, C, Carrera, C, Cuellar, F, Gabriel, D, Martinez, E, Gonzalez, M, Iglesias, P, Malvehy, J, Marti Laborda, R, Mila, M, Ogbah, Z, Butille, Ja, Puig, S, Alós, L, Arance, A, Arguís, P, Campo, A, Castel, T, Conill, C, Palou, J, Rull, R, Sánchez, M, Vidal Sicart, S, Vilalta, A, Vilella, R, Montgomery, Gw, Whiteman, Dc, Whiteman, D, Webb, P, Green, A, Parsons, P, Purdie, D, Hayward, N, Landi, Mt, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Bianchi, Giovanna, Ghiorzo, Paola, Pastorino, Lorenza, Bruno, William, Battistuzzi, Linda, Gargiulo, Sara, Nasti, Sabina, Gliori, S, Origone, Paola, Andreotti, V, Queirolo, P, Mackie, R, Lang, J, Bishop, Ja, Affleck, P, Harrison, J, Iles, Mm, Randerson Moor, J, Harland, M, Taylor, Jc, Whittaker, L, Kukalizch, K, Leake, S, Karpavicius, B, Haynes, S, Mack, T, Chan, M, Taylor, Y, Davies, J, King, P, Gruis, Na, van Nieuwpoort FA, Out, C, van der Drift, C, Bergman, W, Kukutsch, N, Bavinck, Jn, Bakker, B, van der Stoep, N, ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Olsson, H, Ingvar, C, Jönsson, G, Borg, Å, Måsbäck, A, Lundgren, L, Baeckenhorn, K, Nielsen, K, Casslén, As, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Molven, A, Avril, Mf, Bressac de Paillerets, B, Chaudru, V, Chateigner, N, Corda, E, Jeannin, P, Lesueur, F, de Lichy, M, Maubec, E, Mohamdi, H, Demenais, F, Andry Benzaquen, P, Bachollet, B, Bérard, F, Berthet, P, Boitier, F, Bonadona, V, Bonafé, Jl, Bonnetblanc, Jm, Cambazard, F, Caron, O, Caux, F, Chevrant Breton, J, Chompret, A, Dalle, S, Demange, L, Dereure, O, Doré, Mx, Doutre, Ms, Dugast, C, Faivre, L, Grange, F, Humbert, P, Joly, P, Kerob, D, Lasset, C, Leccia, Mt, Lenoir, G, Leroux, D, Levang, J, Lipsker, D, Mansard, S, Martin, L, Martin Denavit, T, Mateus, C, Michel, Jl, Morel, P, Olivier Faivre, L, Perrot, Jl, Robert, C, Ronger Savle, S, Sassolas, B, Souteyrand, P, Stoppa Lyonnet, D, Thomas, L, Vabres, P, Wierzbicka, E, Elder, D, Kanetsky, P, Knorr, J, Ming, M, Mitra, N, Ruffin, A, Van Belle, P, Debniak, T, Lubiński, J, Mirecka, A, Ertmański, S, Novakovic, S, Hocevar, M, Peric, B, Cerkovnik, P, Höiom, V, Hansson, J, Holland, Ea, Azizi, E, Galore Haskel, G, Friedman, E, Baron Epel, O, Scope, A, Pavlotsky, F, Yakobson, E, Cohen Manheim, I, Laitman, Y, Milgrom, R, Shimoni, I, and Kozlovaa, E.

Subjects
Genetic Markers, Candidate gene, Skin Neoplasms, Ubiquitin-Protein Ligases, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Genetics, Eye color, Guanine Nucleotide Exchange Factors, Humans, SNP, Genetic Predisposition to Disease, Melanoma, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Pigmentation, Association Studies Articles, General Medicine, 3. Good health, Chromosomes, Human, Pair 1, Genetic Loci, Genetic marker, Case-Control Studies, 030220 oncology & carcinogenesis, Cutaneous melanoma, Genome-Wide Association Study
Abstract

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.

Published
2011

21. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, M, Bishop, DT, Lee, JE, Brossard, M, Martin, NG, Moses, EK, Song, F, Barrett, JH, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Taylor, JC, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, MF, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Duffy, DL, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NE, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, GenoMEL Consortium, Essen-Heidelberg Investigators, The SDH Study Group, Q-MEGA and QTWIN Investigators, AMFS Investigators, ATHENS Melanoma Study Group, Landi, MT, Lang, J, Lathrop, M, Lubinski, J, Mackie, RM, Mann, GJ, Molvern, A, Montgomery, GW, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Qureshi, AA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Hayward, NK, Han, J, Schulze, HJ, Dunning, AM, Newton-Bishop, JA, Demenais, F, Amos, CI, MacGregor, S, Iles, MM, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Candidate gene, Skin Neoplasms, Medizin, Single-nucleotide polymorphism, Genome-wide association study, Biology, Genome, Polymorphism, Single Nucleotide, Article, Polymorphism (computer science), ATHENS Melanoma Study Group, Genetics, Chromosomes, Human, Humans, Genetic Predisposition to Disease, AMFS Investigators, Melanoma, Genetic association, 11 Medical And Health Sciences, 06 Biological Sciences, GenoMEL Consortium, Human genetics, 3. Good health, Genetic Loci, Case-Control Studies, SDH Study Group, Expression quantitative trait loci, Q-MEGA and QTWIN Investigators, Essen-Heidelberg Investigators, Developmental Biology, Genome-Wide Association Study
Abstract

© 2015 Nature America, Inc. All rights reserved.Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10-8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Published
2015

22. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Author

Cordell, HJ, Han, Y, Mells, GF, Li, Y, Hirschfield, GM, Greene, CS, Xie, G, Juran, BD, Zhu, D, Qian, DC, Floyd, JAB, Morley, KI, Prati, D, Lleo, A, Cusi, D, Gershwin, ME, Anderson, CA, Lazaridis, KN, Invernizzi, P, Seldin, MF, Sandford, RN, Amos, CI, Siminovitch, KA, Schlicht, EM, Lammert, C, Atkinson, EJ, Chan, LL, De Andrade, M, Balschun, T, Mason, AL, Myers, RP, Zhang, J, Milkiewicz, P, Qu, J, Odin, JA, Luketic, VA, Bacon, BR, Bodenheimer, HC, Liakina, V, Vincent, C, Levy, C, Gregersen, PK, Almasio, PL, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Battezzati, PM, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, MC, Brunetto, M, Bruno, S, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Crocè, LS, Crosignani, A, Donato, MF, Elia, G, Fabris, L, Ferrari, C, Floreani, A, Foglieni, B, Fontana, R, Galli, A, Lazzari, R, Macaluso, F, Malinverno, F, Marra, F, Marzioni, M, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Mousa Hani, S, Muratori, L, Muratori, P, Niro, GA, Palmieri, VO, Picciotto, A, Podda, M, Portincasa, P, Ronca, V, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, and Spreafico, M

Subjects
MD Multidisciplinary
Abstract

© 2015 Macmillan Publishers Limited. All rights reserved.Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined

Published
2015

23. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies

Author

Kar, Sp, Seldin, Mf, Chen, W, Lu, E, Hirschfield, Gm, Invernizzi, P, Heathcote, J, Cusi, D, Almasio, Pl, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, Ls, Crosignani, A, Donato, F, Elia, G, Fabris, L, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Lleo, A, Macaluso, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Podda, M, Portincasa, P, Prati, D, Raggi, C, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Strazzabosco, M, Tarallo, Sonia, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Gershwin, Me, Siminovitch, Ka, Amos, Ci, Tarallo, S, Zuin, M., S. P., Kar, M. F., Seldin, W., Chen, E., Lu, G. M., Hirschfield, P., Invernizzi, J., Heathcote, D., Cusi, t. I., Pbc, P. L., Almasio, D., Alvaro, P., Andreone, A., Andriulli, C., Barlassina, A., Benedetti, F., Bernuzzi, I., Bianchi, M., Bragazzi, M., Brunetto, S., Bruno, L., Caliari, G., Casella, B., Coco, A., Colli, M., Colombo, S., Colombo, C., Cursaro, Croce', Saveria, A., Crosignani, F., Donato, G., Elia, L., Fabri, A., Floreani, A., Galli, I., Grattagliano, R., Lazzari, A., Lleo, F., Macaluso, F., Marra, M., Marzioni, E., Mascia, A., Mattalia, R., Montanari, L., Morini, F., Morisco, L., Muratori, P., Muratori, G., Niro, A., Picciotto, M., Podda, P., Portincasa, D., Prati, C., Raggi, F., Rosina, S., Rossi, I., Sogno, G., Spinzi, M., Strazzabosco, S., Tarallo, M., Tarocchi, Tiribelli, Claudio, P., Toniutto, M., Vinci, M., Zuin, M. E., Gershwin, K. A., Siminovitch, C. I., Amos, SP Kar, MF Seldin, W Chen, E Lu, GM Hirschfield, P Invernizzi, J Heathcote, D Cusi, the Italian PBC Genetics Study Group [.., P Andreone, L Muratori, P Muratori, ], ME Gershwin, KA Siminovitch, CI Amos, Kar, S, Seldin, M, Chen, W, Lu, E, Hirschfield, G, Invernizzi, P, Heathcote, J, Cusi, D, the Italian PBC Genetics Study, G, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, L, Crosignani, A, Donato, F, Elia, G, Fabris, L, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Lleo, A, Macaluso, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G., P, A, Podda, M, Portincasa, P, Prati, D, Raggi, C, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Strazzabosco, M, Tarallo, S, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Gershwin, M, Siminovitch, K, Amos, C, Kar, Sp, Seldin, Mf, Hirschfield, Gm, Almasio, Pl, Morisco, Filomena, Niro, G, Picciotto, A, Gershwin, Me, Siminovitch, Ka, Amos, Ci, and the Italian PBC Genetics Study, Group

Subjects
Male, Linkage disequilibrium, PRIMARY BILIARY CIRRHOSIS, Genome-wide association study, VARIANTS, Linkage Disequilibrium, Cohort Studies, ACTIVATION, Primary biliary cirrhosis, Gene Frequency, MED/12 - GASTROENTEROLOGIA, Databases, Genetic, SENSORS, Genetics (clinical), Genetics, Liver Cirrhosis, Biliary, Middle Aged, EPITHELIAL-MESENCHYMAL TRANSITION, hedgehog signaling, Hedgehog signaling pathway, Algorithm, Italy, DISEASES, Female, Algorithms, TRAITS, Human, Signal Transduction, Canada, Genotype, Immunology, EPITHELIAL-MESENCHYMAL TRANSITION, CELLS, ACTIVATION, GENE, IDENTIFICATION, RESPONSES, VARIANTS, DISEASES, SENSORS, TRAITS, autoimmune disease, Biology, Polymorphism, Single Nucleotide, linear combination test, Article, Autoimmune Diseases, Meta-Analysis as Topic, medicine, Humans, Genetic Predisposition to Disease, phosphatidylinositol signaling, KEGG, Allele frequency, Genetic association, IDENTIFICATION, medicine.disease, GENE, Multiple comparisons problem, PBC, genome wide association, CELLS, Cohort Studie, Genome-Wide Association Study, RESPONSES
Abstract

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P

Published
2013

24. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer (vol 41, pg 991, 2009)

Author

Wu, X, Ye, Y, Kiemeney, LA, Sulem, P, Rafnar, T, Matullo, G, Seminara, D, Yoshida, T, Saeki, N, Andrew, AS, Dinney, CP, Czerniak, B, Zhang, Z-F, Kiltie, AE, Bishop, DT, Vineis, P, Porru, S, Buntinx, F, Kellen, E, Zeegers, MP, Kumar, R, Rudnai, P, Gurzau, E, Koppova, K, Mayordomo, JI, Sanchez, M, Saez, B, Lindblom, A, de Verdier, P, Steineck, G, Mills, GB, Schned, A, Chang, S-C, Lin, J, Chang, DW, Hale, KS, Majewski, T, Grossman, HB, Thorlacius, S, Thorsteinsdottir, U, Aben, KKH, Witjes, JA, Stefansson, K, Amos, CI, Karagas, MR, Gu, J, Guarrera, S, and Polidoro, S

Published
2009

25. Erratum: Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer (Nature Genetics) (2009) 41 (991-995))

Author

Wu, X, Ye, Y, Kiemeney, LA, Sulem, P, Rafnar, T, Matullo, G, Seminara, D, Yoshida, T, Saeki, N, Andrew, AS, Dinney, CP, Czerniak, B, Zhang, Z-F, Kiltie, AE, Bishop, DT, Vineis, P, Porru, S, Buntinx, F, Kellen, E, Zeegers, MP, Kumar, R, Rudnai, P, Gurzau, E, Koppova, K, Mayordomo, JI, Sanchez, M, Saez, B, Lindblom, A, De Verdier, P, Steineck, G, Mills, GB, Schned, A, Chang, S-C, Lin, J, Chang, DW, Hale, KS, Majewski, T, Grossman, HB, Thorlacius, S, Thorsteinsdottir, U, Aben, KKH, Witjes, JA, Stefansson, K, Amos, CI, Karagas, MR, and Gu, J

Published
2009

26. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer

Author

Wu, X, Ye, Y, Kiemeney, La, Sulem, P, Rafnar, T, Matullo, G, Seminara, D, Yoshida, T, Saeki, N, Andrew, As, Dinney, Cp, Czerniak, B, Zhang, Z, Kiltie, Ae, Bishop, Dt, Vineis, P, Porru, Stefano, Buntinx, F, Kellen, E, Zeegers, Mp, Kumar, R, Rudnai, P, Gurzau, E, Koppova, K, Mayordomo, Ji, Sanchez, M, Saez, B, Lindblom, A, DE VERDIER, P, Steinek, G, Mills, Gb, Schned, A, Chang, Sc, Lin, J, Chang, Dw, Hale, Ks, Majewski, T, Grossman, Hb, Thorlacius, S, Thorsterindottir, U, Aben, Kkh, Witjes, Ja, Stefansson, K, Amos, Ci, Karagas, Mr, and Gu, J.

Published
2009

27. BIRTH-ORDER, DELIVERY ROUTE, AND CONCORDANCE IN THE TRANSMISSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 FROM MOTHERS TO TWINS

Author

DULIEGE, AM, AMOS, CI, FELTON, S, BIGGAR, RJ, ZIEGLER, J, CRUIKSHANK, M, LEVY, J, MEATES, MA, GIBB, D, MAYAUX, MJ, TEGLAS, JP, LAURENT, C, BLANCHE, S, ROUZIOUX, C, HELLINGGIESE, G, MATTNER, U, HOEGER, PH, CONLON, T, GRIFFIN, E, DEMARIA, A, BENEDETTO, A, PRINCIPI, N, GIAQUINTO, C, GIANCOMELLI, A, MOK, J, CASABONA, J, FORTUNY, C, URIZ, S, PEREZ, JM, TUSETRUIZ, MC, LEON, P, ELORZA, JFY, CANOSA, C, BRANDLE, B, SEGER, R, NADAL, D, IRION, O, WYLER, CA, DAVIS, P, LALLEMANT, M, LALLEMANTLECOEUR, S, HITIMANA, DG, LEPAGE, P, VANDEPERRE, P, DABIS, F, MARUM, L, NDUGWA, C, TINDYEBWA, D, ACENG, E, MMIRO, F, SUTONGAS, T, OLNESS, K, LAPOINTE, N, RUBINSTEIN, A, BURGE, D, STECHENBERG, BW, COOPER, E, REGAN, AM, SHIPKOWITZ, S, WIZNIA, A, BRUNELL, PA, COURVILLE, T, RUTSTEIN, R, MCINTOSH, K, PETRU, A, OLEARY, M, CHURCH, J, TAYLOR, S, SQUIRES, J, MALLORY, M, YOGEV, R, RAKUSAN, T, PLUMLEY, S, SHELTON, MM, WILFERT, C, LANE, B, ABRAMS, EJ, RANA, S, CHANDAVASU, O, PUVABANDITSIN, S, CHOW, JH, SHAH, K, NACHMAN, S, ONEILL, R, SELWYN, P, SHOENBAUM, E, BARZILAI, A, WARFORD, R, AHERN, L, PAHWA, S, PNUGOTI, N, GARCIATRIAS, DE, BAKSHI, S, LANDESMAN, S, MENDEZ, H, MOROSO, G, MENDEZBAUTISTA, RD, FIKRIG, S, BELMAN, A, KLINE, MW, HANSON, C, EDELSON, P, HINDS, G, VANDYKE, R, CLARK, R, WARA, DW, MANIO, EB, JOHNSON, G, WELLS, L, JOHNSON, JP, ALGER, L, LUZURIAGA, K, MASTRUCCI, T, SUNKUTU, MR, RODRIGUEZ, Z, DOYLE, M, REUBEN, J, BRYSON, Y, DILLON, M, SIMPSON, BJ, ANDIMAN, W, URIBE, P, Klauke, B., and University of Groningen

Subjects
RISK, HIV-1 INFECTION, ANTIBODIES, WOMEN, INFANTS, CHILDREN, POLYMERASE CHAIN-REACTION, DIAGNOSIS, LABOR, SECRETIONS
Abstract

Background: We evaluated data from prospectively identified twins to understand better the mechanisms and covariates of mother-to-infant transmission of human immunodeficiency virus (HIV). Methods: Using data obtained from an international collaboration and multivariate quasilikelihood modeling, we assessed concordance, birth order, route of delivery, and other factors for HIV infection in 115 prospectively studied twin pairs born to HIV-infected women. Actuarial methods were used to evaluate overall survival and survival free of acquired immunodeficiency syndrome for HIV-infected twins. Results: Infection with HIV occurred in 35% of vaginally delivered firstborn (A) twins, 16% of cesarean-delivered A twins, 15% of vaginally delivered second-born (B) twins, and 8% of cesarean-delivered B twins. In a multivariate model, the adjusted odds ratios for HIV infection were 11.8 (confidence interval: 3.1 to 45.3) for concordance of infection with the co-twin, 2.8 (confidence interval: 1.6 to 5.0) for A versus B twins, and 2.7 (confidence interval: 1.1 to 6.6) for vaginally delivered versus cesarean-delivered twins. Among A twins, 52% (lower confidence limit: 6%) of the transmission risk was related to vaginal delivery, Comparing vaginally delivered A twins (infants most exposed to vaginal mucus and blood) to cesarean-delivered B twins (infants least exposed), 76% (lower confidence limit: 48%) of the transmission risk was related to vaginal exposure. Infected B twins had slightly reduced Quetelet indexes and more rapid development of illnesses related to acquired immunodeficiency syndrome. Conclusions: These results indicate that HIV infection of B twins occurs predominantly in utero, whereas infection of A twins (and, by implication, singletons) occurs predominantly intrapartum, We propose that intrapartum transmission is responsible for the majority of pediatric HIV infections and that reducing exposure to HIV in the birth canal may reduce transmission of the virus from mother to infant.

Published
1995

30. Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.

Author

Wu X, Ye Y, Rosell R, Amos CI, Stewart DJ, Hildebrandt MA, Roth JA, Minna JD, Gu J, Lin J, Buch SC, Nukui T, Ramirez Serrano JL, Taron M, Cassidy A, Lu C, Chang JY, Lippman SM, Hong WK, and Spitz MR

Abstract

Background: Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).Methods: To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.Results: SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).Conclusion: These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients. [ABSTRACT FROM AUTHOR]

Published
2011
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31. Nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk among African Americans: a case-control study.

Author

Amos CI, Gorlov IP, Dong Q, Wu X, Zhang H, Lu EY, Scheet P, Greisinger AJ, Mills GB, Spitz MR, Amos, Christopher I, Gorlov, Ivan P, Dong, Qiong, Wu, Xifeng, Zhang, Huifeng, Lu, Emily Y, Scheet, Paul, Greisinger, Anthony J, Mills, Gordon B, and Spitz, Margaret R

Abstract

Genome-wide association studies of white persons with lung cancer have identified a region of extensive linkage disequilibrium on chromosome 15q25.1 that appears to be associated with both risk for lung cancer and smoking dependence. Because studying African American persons, who exhibit lower levels of linkage disequilibrium in this region, may identify additional loci that are associated with lung cancer, we genotyped 34 single-nucleotide polymorphisms (SNPs) in this region (including LOC123688, PSMA4, CHRNA5, CHRNA3, and CHRNB4 genes) in 467 African American patients with lung cancer and 388 frequency-matched African American control subjects. Associations of SNPs in LOC123688 (rs10519203; odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.25 to 2.05, P = .00016), CHRNA5 (rs2036527; OR = 1.67, 95% CI = 1.26 to 2.21, P = .00031), and CHRNA3 (rs1051730; OR = 1.81, 95% CI = 1.26 to 2.59, P = .00137) genes with lung cancer risk reached Bonferroni-corrected levels of statistical significance (all statistical tests were two-sided). Joint logistic regression analysis showed that rs684513 (OR = 0.47, 95% CI = 0.31 to 0.71, P = .0003) in CHRNA5 and rs8034191 (OR = 1.76, 95% CI = 1.23 to 2.52, P = .002) in LOC123688 were also associated with risk. The functional A variant of rs1696698 in CHRNA5 had the strongest association with lung cancer (OR = 1.98, 95% CI = 1.25 to 3.11, P = .003). These SNPs were primarily associated with increased risk for lung adenocarcinoma histology and were only weakly associated with smoking phenotypes. Thus, among African American persons, multiple loci in the region of chromosome 15q25.1 appear to be strongly associated with lung cancer risk. [ABSTRACT FROM AUTHOR]

Published
2010
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33. The chromosome 7q region association with rheumatoid arthritis in females in a british population is not replicated in a North American case-control series.

Author

Korman BD, Seldin MF, Taylor KE, Le JM, Lee AT, Plenge RM, Amos CI, Criswell LA, Gregersen PK, Kastner DL, and Remmers EF

Abstract

OBJECTIVE: The single-nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population. METHODS: DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole-genome SNP data (772 cases and 1,213 controls). RESULTS: We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P = 0.0073), and rs11765576 showed association with RA in both the NARAC (P = 0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole-genome subset, neither SNP showed significant association with RA after correction for population stratification. CONCLUSION: While 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false-positive disease associations. [ABSTRACT FROM AUTHOR]

Published
2009
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34. Smoking-related genomic signatures in non-small cell lung cancer.

Author

Massion PP, Zou Y, Chen H, Jiang A, Coulson P, Amos CI, Wu X, Wistuba I, Wei Q, Shyr Y, Spitz MR, Massion, Pierre P, Zou, Yong, Chen, Heidi, Jiang, Aixiang, Coulson, Peter, Amos, Christopher I, Wu, Xifeng, Wistuba, Ignacio, and Wei, Qingyi

Abstract

Rationale: Tobacco smoking is responsible for 85% of all lung cancers. To further our understanding of the molecular pathogenesis of lung cancer, we determined whether smoking history leads to the emergence of specific genomic alterations found in non-small cell lung cancer (NSCLC).Objectives: To identify gene copy number alterations in NSCLCs associated with smoking history or DNA repair capacity.Methods: Seventy-five NSCLCs were selected for this study from patients with current, none, or past smoking history, including pack year information. Tissue sections were microdissected, and DNA was extracted, purified, and labeled by random priming before hybridization onto bacterial artificial chromosome (BAC) arrays. Normalized ratios were correlated with smoking history and DNA repair capacity was measured by an in vitro lymphocyte assay in the same patients.Measurements and Main Results: We identified smoking-related genomic signatures in NSCLCs that could be predicted with an overall 74% accuracy. Lung tumors arising from current-smokers had the greatest number of copy number alterations. The genomic regions most significantly associated with smoking were located within 60 regions and were functionally associated with genes controlling the M phase of the cell cycle, the segregation of chromosomes, and the methylation of DNA. Verification of the data is provided from data in the public domain and by quantitative real-time polymerase chain reaction. The associations between genomic abnormalities and DNA repair capacity did not reach statistical significance.Conclusions: These findings indicate that smoking history leaves a specific genomic signature in the DNA of lung tumors and suggest that these alterations may reflect new molecular pathways to cancer development. [ABSTRACT FROM AUTHOR]

Published
2008
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35. The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.

Author

Spitz MR, Amos CI, Dong Q, Lin J, Wu X, Spitz, Margaret R, Amos, Christopher I, Dong, Qiong, Lin, Jie, and Wu, Xifeng

Abstract

Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies, with no consensus as to the relative impact of the variants on the propensity to smoke vs a direct carcinogenic effect. To further explore our hypothesis that these variants are indeed associated with both cancer causation and nicotine dependence, we performed a more detailed analysis of the association of these putative risk genotypes with smoking phenotype, as well as in lifetime never smokers, and in other smoking-related cancers. We demonstrate a statistically significant association of the variants with both nicotine dependence, as well as lung cancer phenotypes, including earlier age at lung cancer onset. The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects, nor in other smoking-related cancers (bladder and renal). Thus, we conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk. [ABSTRACT FROM AUTHOR]

Published
2008
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40. Rheumatoid arthritis association with the FCRL3 -169C polymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population.

Author

Newman WG, Zhang Q, Liu X, Walker E, Ternan H, Owen J, Johnson B, Greer W, Mosher DP, Maksymowych WP, Bykerk VP, Keystone EC, Amos CI, and Siminovitch KA

Abstract

OBJECTIVE: Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls. METHODS: A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined. RESULTS: An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD. CONCLUSION: Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals. [ABSTRACT FROM AUTHOR]

Published
2006
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43. Support for previously identified alcoholism susceptibility Loci in a cohort selected for smoking behavior.

Author

Wilhelmsen KC, Swan GE, Cheng LS, Lessov-Schlaggar CN, Amos CI, Feiler HS, Hudmon KS, Ring HZ, Andrews JA, Tildesley E, Benowitz NL, and Hops H

Abstract

BACKGROUND: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior. METHODS: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality. RESULTS: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies. CONCLUSIONS: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition. [ABSTRACT FROM AUTHOR]

Published
2005
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44. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.

Author

Huizinga TWJ, Amos CI, van der Helm-van Mil AHM, Chen W, van Gaalen FA, Jawaheer D, Schreuder GMT, Wener M, Breedveld FC, Ahmad N, Lum RF, de Vries RRP, Gregersen PK, Toes REM, and Criswell LA

Abstract

OBJECTIVE: The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. METHODS: HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. RESULTS: For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. CONCLUSION: HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype. [ABSTRACT FROM AUTHOR]

Published
2005
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45. Relationship between plasma carotenoids and prostate cancer.

Author

Chang S, Erdman JW Jr., Clinton SK, Vadiveloo M, Strom SS, Yamamura Y, Duphorne CM, Spitz MR, Amos CI, Contois JH, Gu X, Babaian RJ, Scardino PT, and Hursting SD

Abstract

Carotenoids, particularly lycopene, are thought to decrease prostate cancer risk, but the relationship between plasma carotenoid concentrations and risk in various populations has not been well characterized. Comparing 118 non-Hispanic Caucasian men mainly from southeast Texas with nonmetastatic prostate cancer with 52 healthy men from the same area, we conducted a case-control analysis evaluating associations between risk and plasma levels of total carotenoids, beta-cryptoxanthin, alpha- and trans-beta-carotene, lutein and zeaxanthin, total lycopenes, trans-lycopene, total cis-lycopenes, and cis-lycopene isoforms 1, 2, 3, and 5. Risk for men with high plasma levels of alpha-carotene, trans-beta-carotene, beta-cryptoxanthin, and lutein and zeaxanthin was less than half that for those with lower levels. In contrast, we observed no significant associations for total lycopenes, all-trans-lycopene, and cis-lycopene isomer peaks 2, 3, and 5, although high levels of cis-lycopene isomer peak 1 were inversely associated with risk. Analysis of men with aggressive disease (Gleason scores of > or =7, n = 88) vs. less aggressive cases (Gleason scores of <7, n = 30) failed to reveal significant associations between carotenoid levels and the risk of diagnosis with aggressive disease. These findings suggest that, in these men, higher circulating levels of alpha-cryptoxanthin, alpha-carotene, trans-beta-carotene, and lutein and zeaxanthin may contribute to lower prostate cancer risk but not to disease progression. [ABSTRACT FROM AUTHOR]

Published
2005
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46. Deletion in poly(ADP-ribose)polymerase pseudogene and lung cancer risk.

Author

Wu, X, Hsu, TC, Cao, S, Lee, JJ, Amos, CI, and Spitz, MR

Abstract

The poly(ADP-ribose)polymerase (PADPRP) gene has been implicated in carcinogenesis through its role in DNA repair, replication and recombination. A two-allele polymorphism in the chromosome 13 PADPRP pseudogene has been studied in several racial groups. It has been suggested that the B allele, which results from a 193-bp deletion in the gene, predisposes to myeloma in Blacks. We assessed the association between chromosome 13 PADPRP pseudogene genotype, mutagen sensitivity (a marker reflecting host DNA repair capability), cigarette smoking, and lung cancer risk in a minority lung cancer case-control study. The chromosome 13 PADPRP pseudogene polymorphism was detected by polymerase chain reaction-based analysis. Mutagen sensitivity was measured by an in vitro assay that quantified bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures. We examined 121 cases (80 African-Americans and 41 Mexican-Americans) with previously untreated lung cancer and 171 matched controls. Our results suggested that the distribution of the PADPRP pseudogene genotype frequencies was significantly different among African-American and Mexican-American controls (P <0.001). The susceptibility genotype (i.e. at least one B allele) was found in 82.5% of African-American cases, 79.4% of African-American controls, 53.7% of Mexican-American cases, and 32.5% of Mexican-American controls. The odds ratios (OR) and 95% confidence intervals for the PADPRP susceptibility genotypes were 2.3 (95% CI = 0.7-8.0) and 3.2 (95% CI = 1.0-10.3) for African-Americans and Mexican-Americans respectively, after adjustment by age, sex, pack-years and mutagen sensitivity. Patients with the susceptibility genotype appeared to have more mutagen-induced breaks than did patients with the other genotype. Only adenocarcinoma was significantly associated with the PADPRP susceptibility genotype (OR = 3.8). Mutagen sensitivity ( 1 break/cell) was significantly associated with lung cancer risk for both ethnic groups with increased ORs of above three-fold. On stratified analysis, synergistic interactions were noted for the PADPRP susceptibility genotype, mutagen sensitivity and smoking status. In Mexican-Americans, the ORs for PADPRP susceptibility genotype, mutagen sensitivity and both risk factors combined were 1,3, 2.7 and 17.1 respectively. The combined OR for the PADPRP susceptibility genotype and smoking status was 15.6. Therefore, this polymorphism appears to be associated with lung cancer risk. However, it is likely that no single genotype is sufficiently predictive of risk and that a panel of susceptibility markers is needed to define the high-risk subgroup. [ABSTRACT FROM PUBLISHER]

Published
1998
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47. The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis.

Author

Brown, MA, Rudwaleit, M, Pile, KD, Kennedy, LG, Shatford, J, Amos, CI, Siminovitch, K, Rubin, L, Calin, A, and Wordsworth, BP

Abstract

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda  1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis. [ABSTRACT FROM PUBLISHER]

Published
1998
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49. Association analysis identifies 65 new breast cancer risk loci

Author

Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF

Subjects
ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

50. The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Amos, CI, Dennis, J, Wang, Z, Byun, J, Schumacher, FR, Gayther, SA, Casey, G, Hunter, DJ, Sellers, TA, Gruber, SB, Dunning, AM, Michailidou, K, Fachal, L, Doheny, K, Spurdle, AB, Li, Y, Xiao, X, Romm, J, Pugh, E, Coetzee, GA, Hazelett, DJ, Bojesen, SE, Caga-Anan, C, Haiman, CA, Kamal, A, Luccarini, C, Tessier, D, Vincent, D, Bacot, F, Van Den Berg, DJ, Nelson, S, Demetriades, S, Goldgar, DE, Couch, FJ, Forman, JL, Giles, GG, Conti, DV, Bickeböller, H, Risch, A, Waldenberger, M, Brüske-Hohlfeld, I, Hicks, BD, Ling, H, McGuffog, L, Lee, A, Kuchenbaecker, K, Soucy, P, Manz, J, Cunningham, JM, Butterbach, K, Kote-Jarai, Z, Kraft, P, FitzGerald, L, Lindström, S, Adams, M, McKay, JD, Phelan, CM, Benlloch, S, Kelemen, LE, Brennan, P, Riggan, M, O'Mara, TA, Shen, H, Shi, Y, Thompson, DJ, Goodman, MT, Nielsen, SF, Berchuck, A, Laboissiere, S, Schmit, SL, Shelford, T, Edlund, CK, Taylor, JA, Field, JK, Park, SK, Offit, K, Thomassen, M, Schmutzler, R, Ottini, L, Hung, RJ, Marchini, J, Amin Al Olama, A, Peters, U, Eeles, RA, Seldin, MF, Gillanders, E, Seminara, D, Antoniou, AC, Pharoah, PDP, Chenevix-Trench, G, Chanock, SJ, Simard, J, and Easton, DF

Subjects
Male, Genotype, Genetic Variation, Prognosis, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Neoplasms, Prevalence, Humans, Female, Genetic Predisposition to Disease, Selection, Genetic, Genome-Wide Association Study
Abstract

BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.

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