Search

Your search keyword '"Stevens, Victoria L."' showing total 27 results
Start Over Author "Stevens, Victoria L." Language undetermined
27 results on '"Stevens, Victoria L."'

1. Duplex kinematics reduces both frontal advance and seismic moment deficit in the Himalaya

Author

Hu, Wan Lin, Stevens, Victoria L., Asian School of the Environment, and Earth Observatory of Singapore

Subjects
Himalayas, Geology, Geology [Science], Accretionary Wedge
Abstract

Duplexing plays important roles in the evolution of fold-and-thrust belts and accretionary wedges, and causes internal shortening of the system, which then impacts both rates of frontal advance and seismic-moment deficit. Nevertheless, the significance of this internal shortening has not yet been highlighted in previous studies in the Himalaya or elsewhere. We invoke geometric solutions to constrain the ratio of transferred slip (R; i.e., the ratio of updip slip to downdip slip) for the midcrustal ramp—the most active ramp within the midcrustal duplex—in the Himalayan wedge. We find that R is ∼0.9, and then used this ratio to calculate the accumulating seismic moment. The reduction in seismic-moment accumulation over the past 1000 yr along the entire Himalayan arc (∼2200 km) is equivalent to at least one ∼Mw 8.72 earthquake, and potentially reduces the seismic moment deficit by ∼23%–54%, which may reconcile the long-term unbalanced seismic moment in the Himalaya. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Research Foundation (NRF) Published version W.-L. Hu is supported by a Singapore International Graduate Award (SINGA) awarded by A*STAR, Singapore. V.L. Stevens was supported by the Claude Leon Postdoctoral Fellowship (South Africa). This research was also supported by a Singapore National Research Foundation (NRF) Investigatorship grant (award number NRFI05-2019- 0009) and the Earth Observatory of Singapore via its funding from the NRF Singapore and the Singapore Ministry of Education under the Research Centres of Excellence initiative.

Published
2022

2. A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium

Author

Midttun, Øivind, Ulvik, Arve, Meyer, Klaus, Zahed, Hana, Giles, Graham G., Manjer, Jonas, Sandsveden, Malte, Langhammer, Arnulf, Sørgjerd, Elin Pettersen, Behndig, Annelie F., Johansson, Mikael, Freedman, Neal D., Huang, Wen-Yi, Chen, Chu, Prentice, Ross, Stevens, Victoria L., Wang, Ying, Le Marchand, Loïc, Weinstein, Stephanie J., Cai, Qiuyin, Arslan, Alan A., Chen, Yu, Shu, Xiao-Ou, Zheng, Wei, Yuan, Jian-Min, Koh, Woon-Puay, Visvanathan, Kala, Sesso, Howard D., Zhang, Xuehong, Gaziano, J. Michael, Fanidi, Anouar, Robbins, Hilary A., Brennan, Paul, Johansson, Mattias, and Ueland, Per M.

Subjects
Cancer och onkologi, Multidisciplinary, Cancer and Oncology
Abstract

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan–NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

Published
2023

3. An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Author

Wu, Lang, Yang, Yaohua, Guo, Xingyi, Shu, Xiao Ou, Cai, Qiuyin, Shu, Xiang, Li, Bingshan, Tao, Ran, Wu, Chong, Nikas, Jason B., Sun, Yanfa, Zhu, Jingjing, Roobol, Monique J., Giles, Graham G., Brenner, Hermann, John, Esther M., Clements, Judith, Grindedal, Eli Marie, Park, Jong Y., Stanford, Janet L., Kote-Jarai, Zsofia, Haiman, Christopher A., Eeles, Rosalind A., Zheng, Wei, Long, Jirong, Henderson, Brian E., Schumacher, Fredrick R., Easton, Douglas, Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan M., Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Nordestgaard, Børge G., Li, Bingshan [0000-0003-2129-168X], Wu, Chong [0000-0002-8400-1785], Nikas, Jason B [0000-0001-9703-0422], Roobol, Monique J [0000-0001-6967-1708], Giles, Graham G [0000-0003-4946-9099], Park, Jong Y [0000-0002-6384-6447], Eeles, Rosalind A [0000-0002-3698-6241], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Hunter, DJ, consortium, PRACTICAL, Consortium, CRUK, Consortium, BPC3, Consortium, CAPS, Consortium, PEGASUS, and Urology

Subjects
0301 basic medicine, Male, General Physics and Astronomy, 02 engineering and technology, VARIANTS, urologic and male genital diseases, DISEASE, CRUK Consortium, Prostate cancer, BPC3 Consortium, Risk Factors, Epidemiology of cancer, GWAS, lcsh:Science, Cancer genetics, GENE-EXPRESSION, Genetics, Multidisciplinary, Methylation, 021001 nanoscience & nanotechnology, STATISTICS, Multidisciplinary Sciences, CpG site, DNA methylation, Science & Technology - Other Topics, 0210 nano-technology, SUSCEPTIBILITY LOCI, Science, Biology, Article, General Biochemistry, Genetics and Molecular Biology, PRACTICAL consortium, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, REVEALS, Genetic model, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Gene, Genetic Association Studies, Genetic association, Science & Technology, Models, Genetic, MORTALITY, Prostatic Neoplasms, General Chemistry, DNA Methylation, medicine.disease, CAPS Consortium, 030104 developmental biology, TISSUE, ANTIGEN LEVEL, Case-Control Studies, lcsh:Q, CpG Islands, PEGASUS Consortium
Abstract

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes., Genome wide association studies have identified multiple loci associated with risk of developing prostate cancer but the functional significance of many of these are unknown. Here, after generating models to predict methylation, the authors identify CpG methylation sites associated with prostate cancer.

Published
2021
Full Text
View/download PDF

4. Runs of homozygosity and testicular cancer risk

Author

Loveday, C, Sud, A, Litchfield, K, Levy, M, Holroyd, A, Broderick, P, Kote-Jarai, Z, Dunning, AM, Muir, K, Peto, J, Eeles, R, Easton, DF, Dudakia, D, Orr, N, Pashayan, N, Rustin, Gordon, Srihari, Narayanan N, Cole, David, Askill, Colin, Bertelli, Gianfilippo, Barber, James, Gilby, Ed, White, Jeff, Baybrooke, Jeremy, Leahy, Michael, Welch, Richard, Chakraborti, Prabir, Joffe, Johnathan, Brown, Richard, Faust, Guy, Simmonds, Peter, Mazhar, Danish, Stockdale, Andrew, Hrounda, David, Humber, Caroline, Appel, Wiebke, Hong, Anne, Howard, Grahame, Douglas, Fiona, Bloomfield, David, Butt, Mohammad, Kelly, Kay, Mehra, Rakesh, Rogers, Paul, Hatton, Matthew, Hennig, Ivo, McAteer, John, Savage, Philip, Seckl, Michael, Gale, Joanna, Clark, Peter, Woby, Steve, Rathmell, Adrian, Lamont, Alan, Sarwar, Naveed, Stuart, Nick, Chowdhury, Simon, Beesley, Sharon, Winkler, Mathius, Hamid, Abdel, Pathak, Sanjeev, Madhavan, Krishnaswamy, Highley, Martin, Money-Kryle, Julian, Brock, Cathryn, Sreenivasan, Thiagarajan, Henderson, Brian E, Haiman, Christopher A, Schumacher, Fredrick R, Al Olama, Ali Amin, Benlloch, Sara, Berndt, Sonja I, Conti, David V, Wiklund, Fredrik, Chanock, Stephen, Gapster, Susan, Stevens, Victoria L, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Geraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Ingles, Sue Ann, Rosenstein, Barry S, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Borge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Dominguez, Manuela Gago, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albrigh, Lisa, Pandha, Hardev, Thibodeau, Stephen N, Reid, A, Huddart, RA, Houlston, RS, Turnbull, C, and Urology

Subjects
Oncology, Male, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Runs of Homozygosity, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Endocrinology, testicular germ cell tumour, Risk Factors, Genotype, genetics, Andrology, 030219 obstetrics & reproductive medicine, Genome, Homozygote, Neoplasms, Germ Cell and Embryonal, Disease gene identification, homozygosity mapping, Life Sciences & Biomedicine, RECENT POSITIVE SELECTION, medicine.medical_specialty, Urology, Biology, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Testicular Neoplasms, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, cancer, Humans, Allele, GENOME-WIDE ASSOCIATION, SEX DETERMINATION, runs of homozygosity, Science & Technology, IDENTIFICATION, Cancer, recessive, medicine.disease, GERM-CELL TUMOR, CONSANGUINITY, Reproductive Medicine, Relative risk, genome-wide association studies, Genome-Wide Association Study
Abstract

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p

Published
2019

5. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V, Darst, Burcu F, Moss, Lilit C, Saunders, Edward J, Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R, Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N, Sahimi, Ali, Hoffmann, Thomas J, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bojesen, Stig E, Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M, Ghoussaini, Maya, Travis, Ruth C, Key, Tim J, Riboli, Elio, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J, Mucci, Lorelei A, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J, Penney, Kathryn L, Turman, Constance, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L, Ostrander, Elaine A, Geybels, Milan S, Koutros, Stella, Freeman, Laura E Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L, Hoover, Robert N, Machiela, Mitchell J, Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J, Zheng, Wei, Yeboah, Edward D, Mensah, James E, and Lu, Yong-Jie

Subjects
Male, Urologic Diseases, Aging, Quantitative Trait Loci, Medical and Health Sciences, Risk Factors, Clinical Research, Odds Ratio, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Genetic Predisposition to Disease, Aetiology, Cancer, Prevention, Prostate Cancer, Racial Groups, Human Genome, Prostatic Neoplasms, Molecular Sequence Annotation, Genomics, Middle Aged, Biological Sciences, Phenotype, Good Health and Well Being, Genetic Loci, Software, Genome-Wide Association Study, Statistical Distributions, Developmental Biology
Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Published
2021

6. An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Author

Wu, Lang, Yang, Yaohua, Guo, Xingyi, Shu, Xiao-Ou, Cai, Qiuyin, Shu, Xiang, Li, Bingshan, Tao, Ran, Wu, Chong, Nikas, Jason B., Sun, Yanfa, Zhu, Jingjing, Brenner, Hermann, John, Esther M., Clements, Judith, Grindedal, Eli Marie, Stanford, Janet L., Kote-Jarai, Zsofia, Haiman, Christopher A., Zheng, Wei, Long, Jirong, Eeles, Rosalind A., Henderson, Brian E., Schumacher, Fredrick R., Easton, Douglas, Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan M., Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Cybulski, Cezary, Nordestgaard, Børge G., Maier, Christiane, Kim, Jeri, Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Gamulin, Marija, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Dominguez, Manuela Gago, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Blot, William J., Riboli, Elio, Li, Bingshan [0000-0003-2129-168X], Wu, Chong [0000-0002-8400-1785], Nikas, Jason B. [0000-0001-9703-0422], Roobol, Monique J. [0000-0001-6967-1708], Giles, Graham G. [0000-0003-4946-9099], Park, Jong Y. [0000-0002-6384-6447], Eeles, Rosalind A. [0000-0002-3698-6241], Zheng, Wei [0000-0003-1226-070X], and Apollo - University of Cambridge Repository

Subjects
631/208, 631/67/68, article, 631/67/2324, urologic and male genital diseases
Abstract

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.

Published
2020
Full Text
View/download PDF

7. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Author

Hollis, Ben, Day, Felix R., Busch, Alexander S., Thompson, Deborah J., Soares, Ana Luiza G., Timmers, Paul R.H.J., Kwong, Alex, Easton, Doug F., Joshi, Peter K., Timpson, Nicholas J., Eeles, Rosalind A., Henderson, Brian E., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Nordestgaard, Børge G., Day, Felix R [0000-0003-3789-7651], Busch, Alexander S [0000-0003-4417-569X], Thompson, Deborah J [0000-0003-1465-5799], Soares, Ana Luiza G [0000-0003-2763-4647], Timmers, Paul R H J [0000-0002-5197-1267], Kwong, Alex [0000-0003-1953-2771], Easton, Doug F [0000-0003-2444-3247], Joshi, Peter K [0000-0002-6361-5059], Timpson, Nicholas J [0000-0002-7141-9189], Ong, Ken K [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, General Physics and Astronomy, Physiology, Genome-wide association study, Genome-wide association studies, Cohort Studies, 0302 clinical medicine, Endocrinology, Genetics research, Sexual Maturation, Young adult, lcsh:Science, RISK, Multidisciplinary, Age Factors, Mendelian Randomization Analysis, Effective sample size, Multidisciplinary Sciences, Pituitary hormones, Science & Technology - Other Topics, Female, Adult, Science, Longevity, Reproductive biology, Biology, Health outcomes, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, MENARCHE, 03 medical and health sciences, Young Adult, AGE, Mendelian randomization, Humans, Hair Color, Genetic association, Menarche, Science & Technology, MUTATIONS, Puberty, General Chemistry, 030104 developmental biology, METASTASIS, PIGMENTATION, lcsh:Q, 030217 neurology & neurosurgery, SKIN, Genome-Wide Association Study
Abstract

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes., Age at voice-breaking is used to determine puberty timing in men, recall of which is considered less accurate than age at first menarche in women. Here, the authors perform multi-trait GWAS for male puberty timing by including both age at voice breaking and age of first facial hair for improved phenotype definition and power.

Published
2020
Full Text
View/download PDF

8. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Author

Hollis, Ben, Day, Felix R., Busch, Alexander S., Thompson, Deborah J., Soares, Ana Luiza G., Timmers, Paul R. H. J., Kwong, Alex, Easton, Doug F., Joshi, Peter K., Timpson, Nicholas J., Ong, Ken K., Perry, John R. B., Eeles, Rosalind A., Henderson, Brian E., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Gago-Dominguez, Manuela, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Tilley, Wayne, Risbridger, Gail P., Horvath, Lisa, Taylor, Renea, Hayes, Vanessa, Butler, Lisa, Yeadon, Trina, Eckert, Allison, Saunders, Pamela, Haynes, Anne-Maree, Papargiris, Melissa, Srinivasan, Srilakshmi, Kedda, Mary-Anne, Moya, Leire, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Day, Felix R. [0000-0003-3789-7651], Busch, Alexander S. [0000-0003-4417-569X], Thompson, Deborah J. [0000-0003-1465-5799], Soares, Ana Luiza G. [0000-0003-2763-4647], Timmers, Paul R. H. J. [0000-0002-5197-1267], Kwong, Alex [0000-0003-1953-2771], Easton, Doug F. [0000-0003-2444-3247], Joshi, Peter K. [0000-0002-6361-5059], Timpson, Nicholas J. [0000-0002-7141-9189], Ong, Ken K. [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
631/443/494, 631/208/205/2138, 692/308/2056, 45/43, article, 692/163
Abstract

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.

Published
2020

9. Author Correction: Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Author

Sud, Amit, Thomsen, Hauke, Law, Philip J., Försti, Asta, da Silva Filho, Miguel Inacio, Holroyd, Amy, Broderick, Peter, Orlando, Giulia, Lenive, Oleg, Wright, Lauren, Cooke, Rosie, Easton, Douglas, Pharoah, Paul, Dunning, Alison, Peto, Julian, Canzian, Federico, Eeles, Rosalind, Kote-Jarai, Zsofia, Muir, Kenneth, Pashayan, Nora, Henderson, Brian E., Haiman, Christopher A., Benlloch, Sara, Schumacher, Fredrick R., Olama, Ali Amin Al, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry, Lu, Yong-Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Gago-Dominguez, Manuela, Roobol, Monique J., Menegaux, Florence, Hoffmann, Per, Nöthen, Markus M., Jöckel, Karl-Heinz, von Strandmann, Elke Pogge, Lightfoot, Tracy, Kane, Eleanor, Roman, Eve, Lake, Annette, Montgomery, Dorothy, Jarrett, Ruth F., Swerdlow, Anthony J., Engert, Andreas, Orr, Nick, Hemminki, Kari, and Houlston, Richard S.

Subjects
Science, Medizin, MEDLINE, General Physics and Astronomy, Genome-wide association study, Computational biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Disease susceptibility, immune system diseases, hemic and lymphatic diseases, Classical Hodgkin lymphoma, Humans, Genetic Predisposition to Disease, Author Correction, lcsh:Science, Alleles, HLA-DP beta-Chains, Multidisciplinary, Published Erratum, General Chemistry, Hodgkin Disease, Spelling, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Key (cryptography), lcsh:Q, Psychology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10−8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10−17), 6q23.3 (rs6928977, P = 4.62 × 10−11), 10p14 (rs3781093, P = 9.49 × 10−13), 13q34 (rs112998813, P = 4.58 × 10−8) and 16p13.13 (rs34972832, P = 2.12 × 10−8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response., Classical Hodgkin lymphoma is a cancer that originates in lymph nodes. Little is known about its genetic susceptibility. Here, the authors combined existing and new genome-wide association studies to identify risk loci for classical Hodgkin lymphoma at 6q22.33, and nodular sclerosis Hodgkin lymphoma at 3q28, 6q23.3, 10p14, 13q34, 16p13.13.

Published
2019

10. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Author

Schumacher, Fredrick R, Al Olama, Ali Amin, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Saunders, Edward J, Dadaev, Tokhir, Leongamornlert, Daniel, Anokian, Ezequiel, Cieza-Borrella, Clara, Goh, Chee, Brook, Mark N, Sheng, Xin, Fachal, Laura, Dennis, Joe, Tyrer, Jonathan, Muir, Kenneth, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Håkansson, Niclas, West, Catharine ML, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei A, Giovannucci, Edward, Andriole, Gerald L, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Beane Freeman, Laura E, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Stanford, Janet L, and Cybulski, Cezary

Subjects
Urologic Diseases, Risk, Male, Aging, Genotype, Breast and Prostate Cancer Cohort Consortium, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, urologic and male genital diseases, Medical and Health Sciences, Polymorphism, Single Nucleotide, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Polymorphism, Aetiology, Cancer, Canary PASS Investigators, Prostate Cancer, Human Genome, Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci, Profile Study, Australian Prostate Cancer BioResource, Prostatic Neoplasms, Single Nucleotide, Biological Sciences, IMPACT Study, Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, Cancer of the Prostate in Sweden, Genetic Loci, Case-Control Studies, Developmental Biology, Genome-Wide Association Study
Abstract

© 2018 The Author(s). Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

Published
2018

11. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Dadaev, Tokhir, Saunders, Edward J, Newcombe, Paul J, Anokian, Ezequiel, Leongamornlert, Daniel A, Brook, Mark N, Cieza-Borrella, Clara, Mijuskovic, Martina, Wakerell, Sarah, Olama, Ali Amin Al, Schumacher, Fredrick R, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Goh, Chee, Sheng, Xin, Zhang, Zhuo, Muir, Kenneth, Govindasami, Koveela, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Hakansson, Niclas, West, Catharine, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei, Giovannucci, Edward, Andriole, Gerald, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Freeman, Laura E Beane, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry, Kerns, Sarah, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, and Sellers, Thomas A

Subjects
Urologic Diseases, Risk, Male, Aging, Quantitative Trait Loci, European Continental Ancestry Group, Black People, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Polymorphism, Single Nucleotide, White People, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Polymorphism, Aetiology, Cancer, African Continental Ancestry Group, Prostate Cancer, Prevention, Human Genome, Prostatic Neoplasms, Chromosome Mapping, Bayes Theorem, Molecular Sequence Annotation, Single Nucleotide, Multivariate Analysis, Algorithms, Genome-Wide Association Study
Abstract

© 2018 The Author(s). Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Published
2018

12. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

Author

Vijayakrishnan, Jayaram, Studd, James, Broderick, Peter, Kinnersley, Ben, Holroyd, Amy, Law, Philip J., Kumar, Rajiv, Allan, James M., Harrison, Christine J., Moorman, Anthony V., Vora, Ajay, Roman, Eve, Rachakonda, Sivaramakrishna, Kinsey, Sally E., Sheridan, Eamonn, Thompson, Pamela D., Irving, Julie A., Koehler, Rolf, Hoffmann, Per, Nöthen, Markus M., Heilmann-Heimbach, Stefanie, Jöckel, Karl-Heinz, Easton, Douglas F., Pharaoh, Paul D.P., Dunning, Alison M., Peto, Julian, Canzian, Frederico, Swerdlow, Anthony, Eeles, Rosalind A., Kote-Jarai, ZSofia, Muir, Kenneth, Pashayan, Nora, Greaves, Mel, Zimmerman, Martin, Bartram, Claus R., Schrappe, Martin, Stanulla, Martin, Hemminki, Kari, Houlston, Richard S., Henderson, Brian E., Haiman, Christopher A., Benlloch, Sara, Schumacher, Fredrick R., Olama, Ali Amin Al, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry, Lu, Yong-Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Dominguez, Manuela Gago, Roobol, Monique J., Menegaux, Florence, and Urology

Subjects
Medizin
Abstract

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10⁻⁹, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10⁻⁸, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology. OA gold - CA extern

Published
2018

13. Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Author

Mancuso, Nicholas, Gayther, Simon, Gusev, Alexander, Zheng, Wei, Penney, Kathryn L., Kote-Jarai, Zsofia, Eeles, Rosalind, Freedman, Matthew, Haiman, Christopher, Pasaniuc, Bogdan, Henderson, Brian E., Benlloch, Sara, Schumacher, Fredrick R., Olama, Ali Amin Al, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry, Lu, Yong Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Park, Jong Y., Stanford, Janet L., Nordestgaard, Børge G., and Urology

Subjects
0301 basic medicine, Male, General Physics and Astronomy, Genome-wide association study, VARIANTS, urologic and male genital diseases, medicine.disease_cause, DISEASE, Transcriptome, Prostate cancer, 0302 clinical medicine, lcsh:Science, GENE-EXPRESSION, Prostate cancer risk, 0303 health sciences, Multidisciplinary, Manchester Cancer Research Centre, HERITABILITY, Prostatic Neoplasms/genetics, CARDIOVASCULAR RISK, 3. Good health, Multidisciplinary Sciences, CAUSAL GENES, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Medical Genetics, SUSCEPTIBILITY LOCI, Scale (ratio), Science, Urology, MEDLINE, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, SNP, Humans, Genetic Predisposition to Disease, FINNISH MEN, Gene, Medicinsk genetik, 030304 developmental biology, Genetic association, Science & Technology, business.industry, COMPLEX TRAITS, ResearchInstitutes_Networks_Beacons/mcrc, Alternative splicing, Cancer, Prostatic Neoplasms, General Chemistry, medicine.disease, 030104 developmental biology, YOUNG FINNS, Human genome, lcsh:Q, business, Carcinogenesis, Genome-Wide Association Study
Abstract

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci., Genome-wide association studies (GWAS) have identified hundreds of genomic risk regions for prostate cancer. Here, the authors perform a transcriptome wide association study (TWAS) by incorporating prostate cancer GWAS with gene expression data to identify potential novel prostate cancer risk loci and possible risk mechanisms.

Published
2018

14. Impaired functional vitamin B6 status is associated with increased risk of lung cancer

Author

Theofylaktopoulou, Despoina, Midttun, Øivind, Ueland, Per M., Meyer, Klaus, Fanidi, Anouar, Zheng, Wei, Shu, Xiao Ou, Xiang, Yong Bing, Prentice, Ross, Pettinger, Mary, Thomson, Cynthia A., Giles, Graham G., Hodge, Allison, Cai, Qiuyin, Blot, William J., Wu, Jie, Johansson, Mikael, Hultdin, Johan, Grankvist, Kjell, Stevens, Victoria L., McCullough, Marjorie M., Weinstein, Stephanie J., Albanes, Demetrius, Ziegler, Regina, Freedman, Neal D., Langhammer, Arnulf, Hveem, Kristian, Næss, Marit, Sesso, Howard D., Gaziano, J. Michael, Buring, Julie E., Lee, I. Min, Severi, Gianluca, Zhang, Xuehong, Stampfer, Meir J., Han, Jiali, Smith-Warner, Stephanie A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loic, Yuan, Jian Min, Wang, Renwei, Butler, Lesley M., Koh, Woon Puay, Gao, Yu Tang, Rothman, Nathaniel, Ericson, Ulrika, Sonestedt, Emily, Visvanathan, Kala, Jones, Miranda R., Relton, Caroline, Brennan, Paul, Johansson, Mattias, and Ulvik, Arve

Subjects
Male, Lung Cancer Cohort Consortium, Lung Neoplasms, pyridoxal 5′-phosphate, functional vitamin B6 marker, Middle Aged, Vitamin B 6, Article, Cohort Studies, xanthurenic acid [3-hydroxykynurenine], Risk Factors, Case-Control Studies, Carcinoma, Squamous Cell, Odds Ratio, Humans, Female, ICEP, Biomarkers, Aged
Abstract

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5′-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case–control study consisting of 5,364 matched case–control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4th vs. 1st) was 1.25 (95% confidence interval, 1.10–1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.

Published
2017

15. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

Author

Ng, Maggie CY, Graff, Mariaelisa, Lu, Yingchang, Justice, Anne E, Mudgal, Poorva, Liu, Ching-Ti, Young, Kristin, Yanek, Lisa R, Feitosa, Mary F, Wojczynski, Mary K, Rand, Kristin, Brody, Jennifer A, Cade, Brian E, Dimitrov, Latchezar, Duan, Qing, Guo, Xiuqing, Lange, Leslie A, Nalls, Michael A, Okut, Hayrettin, Tajuddin, Salman M, Tayo, Bamidele O, Vedantam, Sailaja, Bradfield, Jonathan P, Chen, Guanjie, Chen, Wei-Min, Chesi, Alessandra, Irvin, Marguerite R, Padhukasahasram, Badri, Smith, Jennifer A, Zheng, Wei, Allison, Matthew A, Ambrosone, Christine B, Bandera, Elisa V, Bartz, Traci M, Berndt, Sonja I, Bernstein, Leslie, Blot, William J, Bottinger, Erwin P, Carpten, John, Chanock, Stephen J, Chen, Yii-Der Ida, Conti, David V, Cooper, Richard S, Fornage, Myriam, Freedman, Barry I, Garcia, Melissa, Goodman, Phyllis J, Hsu, Yu-Han H, Hu, Jennifer, Huff, Chad D, Ingles, Sue A, John, Esther M, Kittles, Rick, Klein, Eric, Li, Jin, McKnight, Barbara, Nayak, Uma, Nemesure, Barbara, Ogunniyi, Adesola, Olshan, Andrew, Press, Michael F, Rohde, Rebecca, Rybicki, Benjamin A, Salako, Babatunde, Sanderson, Maureen, Shao, Yaming, Siscovick, David S, Stanford, Janet L, Stevens, Victoria L, Stram, Alex, Strom, Sara S, Vaidya, Dhananjay, Witte, John S, Yao, Jie, Zhu, Xiaofeng, Ziegler, Regina G, Zonderman, Alan B, Adeyemo, Adebowale, Ambs, Stefan, Cushman, Mary, Faul, Jessica D, Hakonarson, Hakon, Levin, Albert M, Nathanson, Katherine L, Ware, Erin B, Weir, David R, Zhao, Wei, Zhi, Degui, Bone Mineral Density in Childhood Study (BMDCS) Group, Arnett, Donna K, Grant, Struan FA, Kardia, Sharon LR, Oloapde, Olufunmilayo I, Rao, DC, Rotimi, Charles N, Sale, Michele M, Williams, L Keoki, Zemel, Babette S, Becker, Diane M, Borecki, Ingrid B, and Copenhaver, Gregory P

Subjects
Male, European Continental Ancestry Group, Black People, White People, Linkage Disequilibrium, Body Mass Index, Gene Frequency, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Obesity, Aetiology, Polymorphism, Bone Mineral Density in Childhood Study (BMDCS) Group, African Continental Ancestry Group, Adiposity, Anthropometry, Waist-Hip Ratio, Serine Endopeptidases, Human Genome, Chromosome Mapping, Single Nucleotide, Female, Transcription Factor 7-Like 2 Protein, Genome-Wide Association Study, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (

Published
2017

16. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

Author

Rand, Kristin A, Song, Chi, Dean, Eric, Serie, Daniel J, Curtin, Karen, Sheng, Xin, Hu, Donglei, Huff, Carol Ann, Bernal-Mizrachi, Leon, Tomasson, Michael H, Ailawadhi, Sikander, Singhal, Seema, Pawlish, Karen, Peters, Edward S, Bock, Cathryn H, Stram, Alex, Van Den Berg, David J, Edlund, Christopher K, Conti, David V, Zimmerman, Todd, Hwang, Amie E, Huntsman, Scott, Graff, John, Nooka, Ajay, Kong, Yinfei, Pregja, Silvana L, Berndt, Sonja I, Blot, William J, Carpten, John, Casey, Graham, Chu, Lisa, Diver, W Ryan, Stevens, Victoria L, Lieber, Michael R, Goodman, Phyllis J, Hennis, Anselm JM, Hsing, Ann W, Mehta, Jayesh, Kittles, Rick A, Kolb, Suzanne, Klein, Eric A, Leske, Cristina, Murphy, Adam B, Nemesure, Barbara, Neslund-Dudas, Christine, Strom, Sara S, Vij, Ravi, Rybicki, Benjamin A, Stanford, Janet L, Signorello, Lisa B, Witte, John S, Ambrosone, Christine B, Bhatti, Parveen, John, Esther M, Bernstein, Leslie, Zheng, Wei, Olshan, Andrew F, Hu, Jennifer J, Ziegler, Regina G, Nyante, Sarah J, Bandera, Elisa V, Birmann, Brenda M, Ingles, Sue A, Press, Michael F, Atanackovic, Djordje, Glenn, Martha J, Cannon-Albright, Lisa A, Jones, Brandt, Tricot, Guido, Martin, Thomas G, Kumar, Shaji K, Wolf, Jeffrey L, Deming Halverson, Sandra L, Rothman, Nathaniel, Brooks-Wilson, Angela R, Rajkumar, S Vincent, Kolonel, Laurence N, Chanock, Stephen J, Slager, Susan L, Severson, Richard K, Janakiraman, Nalini, Terebelo, Howard R, Brown, Elizabeth E, De Roos, Anneclaire J, Mohrbacher, Ann F, Colditz, Graham A, Giles, Graham G, Spinelli, John J, Chiu, Brian C, Munshi, Nikhil C, Anderson, Kenneth C, Levy, Joan, Zonder, Jeffrey A, Orlowski, Robert Z, Lonial, Sagar, Camp, Nicola J, Vachon, Celine M, Ziv, Elad, Stram, Daniel O, and Hazelett, Dennis J

Subjects
Adult, Male, Epidemiology, Transmembrane Activator and CAML Interactor Protein, Black People, Protein Serine-Threonine Kinases, Medical and Health Sciences, White People, Rare Diseases, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Aged, Cancer, Polycomb Repressive Complex 1, Human Genome, Single Nucleotide, Hematology, Middle Aged, Repressor Proteins, Genetic Loci, Female, Multiple Myeloma, Genome-Wide Association Study
Abstract

BackgroundGenome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.MethodsWe performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.ResultsWe found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.ImpactA subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

Published
2016

17. Tolerance of glycosylphosphatidylinositol (GPI)-specific phospholipase D overexpression by Chinese hamster ovary cell mutants with aberrant GPI biosynthesis

Author

Du, Xiaohan, Cai, Jiewei, Zhou, Jian-zhong, Stevens, Victoria L, and Low, Martin G

Subjects
DNA, Complementary, Base Sequence, Glycosylphosphatidylinositols, Phosphatidylinositol Diacylglycerol-Lyase, Gene Expression, CHO Cells, Cell Biology, Transfection, Biochemistry, carbohydrates (lipids), Mice, Cricetinae, Type C Phospholipases, Mutation, Phospholipase D, Animals, Cattle, lipids (amino acids, peptides, and proteins), Molecular Biology, Research Article
Abstract

Mammalian glycosylphosphatidylinositol (GPI)-specific phospholipase D (GPI-PLD) is capable of releasing GPI-anchored proteins by cleavage of the GPI moiety. A previous study indicated that overexpression of GPI-PLD in mouse RAW 264.7 monocytes/macrophages could be cytotoxic, since survivors of stable transfections had enzymic activity no higher than untransfected cells [Du and Low (2001) Infect. Immun. 69, 3214–3223]. We investigated this phenomenon by transfecting bovine GPI-PLD cDNA stably into Chinese hamster ovary (CHO) cells using a bi-cistronic expression system. The surviving transfectants showed an unchanged cellular level of GPI-PLD, supporting the cytotoxicity hypothesis. However, when using a CHO mutant defective in the second step of GPI biosynthesis as host, the expression level of GPI-PLD in stable transfectants was increased by 2.5-fold compared with untransfected or empty-vector-transfected cells. To identify the mechanism, we studied another CHO cell mutant (G9PLAP.D5), which seems to be defective at a later stage in GPI biosynthesis. In sharp contrast with wild-type cells, GPI-PLD activity in G9PLAP.D5 transfected with bovine GPI-PLD cDNA was 100-fold higher than untransfected or empty-vector-transfected cells. This was accompanied by a significant release of alkaline phosphatase into the medium and a decrease in membrane-associated alkaline phosphatase. Taken together, our results indicate that overexpression of GPI-PLD is lethal to wild-type cells, possibly by catalysing the overproduction of GPI-derived toxic substances. We propose that cells with abnormal GPI biosynthesis/processing can escape the toxic effect of these substances.

Published
2001

18. The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study

Author

Johansson, Mattias, Carreras-Torres, Robert, Scelo, Ghislaine, Purdue, Mark P, Mariosa, Daniela, Muller, David C, Timpson, Nicolas J, Haycock, Philip C, Brown, Kevin M, Wang, Zhaoming, Ye, Yuanqing, Hofmann, Jonathan N, Foll, Matthieu, Gaborieau, Valerie, Machiela, Mitchell J, Colli, Leandro M, Li, Peng, Garnier, Jean-Guillaume, Blanche, Helene, Boland, Anne, Burdette, Laurie, Prokhortchouk, Egor, Skryabin, Konstantin G, Yeager, Meredith, Radojevic-Skodric, Sanja, Ognjanovic, Simona, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Mukeriya, Anush, Rascu, Stefan, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Weiderpass, Elisabete, Ljungberg, Börje, Tumkur Sitaram, Raviprakash, Häggström, Christel, Bruinsma, Fiona, Jordan, Susan J, Severi, Gianluca, Winship, Ingrid, Hveem, Kristian, Vatten, Lars J, Fletcher, Tony, Larsson, Susanna C, Wolk, Alicja, Banks, Rosamonde E, Selby, Peter J, Easton, Douglas F, Andreotti, Gabriella, Beane Freeman, Laura E, Koutros, Stella, Männistö, Satu, Weinstein, Stephanie, Clark, Peter E, Edwards, Todd L, Lipworth, Loren, Gapstur, Susan M, Stevens, Victoria L, Carol, Hallie, Freedman, Matthew L, Pomerantz, Mark M, Cho, Eunyoung, Wilson, Kathryn M, Gaziano, J Michael, Sesso, Howard D, Freedman, Neal D, Parker, Alexander S, Eckel-Passow, Jeanette E, Huang, Wen-Yi, Kahnoski, Richard J, Lane, Brian R, Noyes, Sabrina L, Petillo, David, Teh, Bin Tean, Peters, Ulrike, White, Emily, Anderson, Garnet L, Johnson, Lisa, Luo, Juhua, Buring, Julie, Lee, I-Min, Chow, Wong-Ho, Moore, Lee E, Eisen, Timothy, Henrion, Marc, Larkin, James, Barman, Poulami, Leibovich, Bradley C, Choueiri, Toni K, Lathrop, G Mark, Deleuze, Jean-Francois, Gunter, Marc, McKay, James D, Wu, Xifeng, Houlston, Richard S, Chanock, Stephen J, Relton, Caroline, Richards, J Brent, Martin, Richard M, Davey Smith, George, and Brennan, Paul

Subjects
2. Zero hunger, Blood Glucose, Genetic Markers, Male, Blood Pressure, Mendelian Randomization Analysis, urologic and male genital diseases, Lipids, Kidney Neoplasms, Body Mass Index, Diabetes Mellitus, Type 2, Risk Factors, Humans, Insulin, Female, Obesity, Carcinoma, Renal Cell, Genome-Wide Association Study
Abstract

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

19. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

Author

Purdue, Mark P., Johansson, Mattias, Zelenika, Diana, Toro, Jorge R., Scelo, Ghislaine, Moore, Lee E., Prokhortchouk, Egor, Wu, Xifeng, Kiemeney, Lambertus A., Gaborieau, Valerie, Jacobs, Kevin B., Allen, Naomi E., Bueno de Mesquita, H. Bas, Peeters, Petra H. M., Trichopoulos, Dimitrios, Linseisen, Jakob, Ljungberg, Börje, Overvad, Kim, Tjønneland, Anne, Romieu, Isabelle, Riboli, Elio, Mukeria, Anush, Shangina, Oxana, Stevens, Victoria L., Thun, Michael J., Diver, W. Ryan, Gapstur, Susan M., Pharoah, Paul D. P., Easton, Douglas F., Albanes, Demetrius, Weinstein, Stephanie J., Virtamo, Jarmo, Vatten, Lars, Hveem, Kristian, Njølstad, Inger, Tell, Grethe, Stoltenberg, Camilla, Kumar, Rajiv, Koppova, Kvetoslava, Cussenot, Olivier, Benhamou, Simone, Oosterwijk, Egbert, Vermeulen, Sita H., Aben, Katja K., van der Marel, Saskia L., Ye, Yuanqing, Wood, Christopher G., Pu, Xia, Mazur, Alexander M., Boulygina, Eugenia S., Chekanov, Nikolai N., Foglio, Mario, Lechner, Doris, Gut, Ivo, Heath, Simon, Blanche, Hélène, Hutchinson, Amy, Thomas, Gilles, Wang, Zhaoming, Yeager, Meredith, Fraumeni, Joseph F., Skryabin, Konstantin G., McKay, James D., Rothman, Nathaniel, Chanock, Stephen J., Lathrop, Mark, Brennan, Paul, Chow, Wong-Ho, Zaridze, David, Matveev, Vsevolod, Lubinski, Jan, Trubicka, Joanna, Szeszenia-Dabrowska, Neonila, Lissowska, Jolanta, Rudnai, Péter, Fabianova, Eleonora, Bucur, Alexandru, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Boffetta, Paolo, Colt, Joanne S., Davis, Faith G., Schwartz, Kendra L., Banks, Rosamonde E., Selby, Peter J., Harnden, Patricia, Berg, Christine D., Hsing, Ann W., Grubb III, Robert L., Boeing, Heiner, Vineis, Paolo, Clavel-Chapelon, Françoise, Palli, Domenico, Tumino, Rosario, Krogh, Vittorio, Panico, Salvatore, Duell, Eric J., Quirós, J. Ramón, Sánchez, María José, Navarro, Carmen, Ardanaz, Eva, Dorronsoro, Miren, and Khaw, Kay-Tee

Subjects
Genòmica, Kidney cancer, Genomics, Càncer de ronyó
Abstract

We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r(2) = 0.99 in controls), rs11894252 (P = 1.8 x 10(-8)) and rs7579899 (P = 2.3 x 10(-9)), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 x 10(-14)). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 x 10(-8)). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

20. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer (vol 46, pg 736, 2014)

Author

Wang, Yufei, Mckay, James D., Rafnar, Thorunn, Wang, Zhaoming, Timofeeva, Maria N., Broderick, Peter, Zong, Xuchen, Laplana, Marina, Wei, Yongyue, Han, Younghun, Lloyd, Amy, Delahaye-Sourdeix, Manon, Chubb, Daniel, Gaborieau, Valerie, Wheeler, William, Chatterjee, Nilanjan, Thorleifsson, Gudmar, Sulem, Patrick, Liu, Geoffrey, Kaaks, Rudolf, Henrion, Marc, Kinnersley, Ben, Vallee, Maxime, Calvez-Kelm, Florence Le, Stevens, Victoria L., Gapstur, Susan M., Chen, Wei V., Zaridze, David, Szeszenia-Dabrowska, Neonilia, Lissowska, Jolanta, Rudnai, Peter, Fabianova, Eleonora, Mates, Dana, Vladimir Bencko, Foretova, Lenka, Janout, Vladimir, Krokan, Hans E., Gabrielsen, Maiken Elvestad, Skorpen, Frank, Vatten, Lars, Njolstad, Inger, Chen, Chu, Goodman, Gary, Benhamou, Simone, Vooder, Tonu, Vaelk, Kristjan, Nelis, Mari, Metspalu, Andres, Lener, Marcin, Lubinski, Jan, Johansson, Mattias, Vineis, Paolo, Agudo, Antonio, Clavel-Chapelon, Francoise, Bueno-De-Mesquita, H. Bas, Trichopoulos, Dimitrios, Khaw, Kay-Tee, Johansson, Mikael, Weiderpass, Elisabete, Tjonneland, Anne, Riboli, Elio, Lathrop, Mark, Scelo, Ghislaine, Albanes, Demetrius, Caporaso, Neil E., Ye, Yuanqing, Gu, Jian, Wu, Xifeng, Spitz, Margaret R., Dienemann, Hendrik, Rosenberger, Albert, Su, Li, Matakidou, Athena, Eisen, Timothy, Stefansson, Kari, Risch, Angela, Chanock, Stephen J., Christiani, David C., Hung, Rayjean J., Brennan, Paul, Landi, Maria Teresa, Houlston, Richard S., and Amos, Christopher I.

21. A Meta-Analysis of Genome-Wide Association Studies of Multiple Myeloma in Persons of African Ancestry [African-American Multiple Myeloma Study (AAMMS)] Identifies Suggestive Risk Variants

Author

Du, Zhaohui, Weinhold, Niels, David J Van Den Berg, Hwang, Amie, Sheng, Xin, Hom, Victor, Ailawadhi, Sikander, Nooka, Ajay K., Singhal, Seema, Pawlish, Karen, Peters, Edward S., Bock, Cathryn, Mohrbacher, Ann, Stram, Alexander, Hu, Donglei, Graff, John, Berndt, Sonja I., Blot, William J., Carpten, John David, Casey, Graham, Stevens, Victoria L., Kittles, Rick, Phyllis, Goodman, Hennis, Anselm, Klein, Eric A., Nemesure, Barbara, Rybicki, Benjamin A., Stanford, Janet, Witte, John, Ambrosone, Christine B., John, Esther M., Bernstein, Leslie, Stroup, Antoinette, Olshan, Andrew, Zheng, Wei, Hu, Jennifer J., Ziegler, Regina, Nyante, Sarah J., Bandera, Elisa, Ingles, Sue Ann, Mehta, Jayesh, Colditz, Graham A., Tomasson, Michael, Fiala, Mark A., Terebelo, Howard, Janakiraman, Nalini, Kolonel, Laurence, Le Marchand, Loic, Anderson, Kenneth C., Ziv, Elad, Chiu, Brian C. -H, Conti, David, Stram, Daniel, Vij, Ravi, Bernal-Mizrachi, Leon, Zonder, Jeffrey A., Morgan, Gareth J., Huff, Carol Ann, Orlowski, Robert Z., Lonial, Sagar, Haiman, Christopher A., and Cozen, Wendy

22. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V, Darst, Burcu F, Moss, Lilit C, Saunders, Edward J, Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R, Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N, Sahimi, Ali, Hoffmann, Thomas J, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bojesen, Stig E, Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M, Ghoussaini, Maya, Travis, Ruth C, Key, Tim J, Riboli, Elio, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J, Mucci, Lorelei A, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J, Penney, Kathryn L, Turman, Constance, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L, Ostrander, Elaine A, Geybels, Milan S, Koutros, Stella, Freeman, Laura E Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L, Hoover, Robert N, Machiela, Mitchell J, Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J, Zheng, Wei, Yeboah, Edward D, Mensah, James E, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, West, Catharine ML, Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M, Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A, Stern, Mariana C, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Teixeira, Manuel R, Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T, Fontham, Elizabeth TH, Mohler, James, Taylor, Jack A, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C, Huff, Chad D, Strom, Sara S, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J, Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A, Hsing, Ann W, Kittles, Rick A, Murphy, Adam B, Logothetis, Christopher J, Kim, Jeri, Neuhausen, Susan L, Steele, Linda, Ding, Yuan Chun, Isaacs, William B, Nemesure, Barbara, Hennis, Anselm JM, Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F, Lin, Daniel W, Fowke, Jay H, Neslund-Dudas, Christine, Rybicki, Benjamin A, Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van Den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A, Aukim-Hastie, Claire, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Srivastava, Shiv, Cullen, Jennifer C, Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J, Jenster, Guido, Van Schaik, Ron HN, Hu, Jennifer J, Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I, Van Den Eeden, Stephen K, Easton, Douglas F, Chanock, Stephen J, Cook, Michael B, Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S, Eeles, Rosalind A, Kote-Jarai, Zsofia, and Haiman, Christopher A

Subjects
Male, Genetic Loci, Risk Factors, Racial Groups, Odds Ratio, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Molecular Sequence Annotation, Neoplasm Invasiveness, Middle Aged, 3. Good health, Genome-Wide Association Study
Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

23. Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author

Matejcic, Marco, Saunders, Edward J, Dadaev, Tokhir, Brook, Mark N, Wang, Kan, Sheng, Xin, Olama, Ali Amin Al, Schumacher, Fredrick R, Ingles, Sue A, Govindasami, Koveela, Benlloch, Sara, Berndt, Sonja I, Albanes, Demetrius, Koutros, Stella, Muir, Kenneth, Stevens, Victoria L, Gapstur, Susan M, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Kraft, Peter, Cancel-Tassin, Géraldine, Sorensen, Karina D, Maehle, Lovise, Grindedal, Eli M, Strom, Sara S, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Rosenstein, Barry, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Bensen, Jeanette T, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Børge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Gago-Dominguez, Manuela, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa A, Pandha, Hardev, Thibodeau, Stephen N, Schaid, Daniel J, PRACTICAL (Prostate Cancer Association Group To Investigate Cancer-Associated Alterations In The Genome) Consortium, Wiklund, Fredrik, Chanock, Stephen J, Easton, Douglas F, Eeles, Rosalind A, Kote-Jarai, Zsofia, Conti, David V, and Haiman, Christopher A

Subjects
Genetic Markers, Male, Genotype, Chromosome Mapping, Prostatic Neoplasms, Risk Assessment, White People, 3. Good health, Haplotypes, Risk Factors, Case-Control Studies, Humans, Genetic Predisposition to Disease, Disease Susceptibility, Chromosomes, Human, Pair 8
Abstract

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

24. Detectable clonal mosaicism and its relationship to aging and cancer

Author

Jacobs, Kevin B., Yeager, Meredith, Zhou, Weiyin, Wacholder, Sholom, Wang, Zhaoming, Rodriguez-Santiago, Benjamin, Hutchinson, Amy, Deng, Xiang, Liu, Chenwei, Horner, Marie-Josephe, Cullen, Michael, Liao, Linda, Schwartz, Ann G., McNeill, Lorna H., Schwenn, Molly, Figueroa, Jonine D., Henderson, Brian E., Shu, Xiao-Ou, Zeleniuch-Jacquotte, Anne, Wiencke, John K., Gonzalez, Juan R., Gallinger, Steven, Fan, Jin-Hu, Thomas, Gilles, Wrensch, Margaret, Savage, Sharon A., Silverman, Debra T., Amos, Christopher I., Tang, Ze-Zhong, Sierrasesúmaga, Luis, Consonni, Dario, Albanes, Demetrius, Trichopoulos, Dimitrios, Olson, Sara H., Chow, Wong-Ho, Krogh, Vittorio, Beane Freeman, Laura, Kratz, Christian P., Holly, Elizabeth A., Blot, William J., Hallmans, Göran, Peters, Ulrike, Duell, Eric J., Brinton, Louise A., Yu, Herbert, Hoover, Robert N., Caporaso, Neil E ., Bertazzi, Pier Alberto, Chanock, Stephen J., Erickson, Ralph L., Elena, Joanne W., Visvanathan, Kala, Tobias, Geoffrey S., Rothman, Nathaniel, Gross, Myron D., Hassan, Manal, Chang, Kenneth, Cotterchio, Michelle, Johnson, Alison, Moore, Lee E., Rajaraman, Preetha, Purdue, Mark, Klein, Alison P., Wheeler, William, Wentzensen, Nicolas, Tjønneland, Anne, Arslan, Alan A., Petersen, Gloria, Chatterjee, Nilanjan, Canzian, Federico, Goggins, Michael, Landi, Maria Teresa, Kurtz, Robert C., Graubard, Barry I., Kovaks, Joseph, Marenne, Gaelle, Dean, Michael C., Giovannucci, Edward L., Wunder, Jay S., Andrulis, Irene L., Butler, Mary A., Jenab, Mazda, Bueno de Mesquita, H. Bas, Marchand, Loic Le, Carreon, Tania, Goldin, Lynn, Virtamo, Jarmo, Ruder, Avima M., Peplonska, Beata, Burdett, Laurie, Sampson, Joshua, Gorlick, Richard G., Fuchs, Charles S., Chung, Charles C., Barkauskas, Donald A., Taylor, Philip R., Haiman, Christopher A., Hunter, David J., Gapstur, Susan M., Giles, Graham G., White, Emily, Mendelsohn, Julie B., Zheng, Wei, Lissowska, Jolanta, Amundadottir, Laufey, Andersson, Ulrika, Davis, Faith G., Freedman, Neal D., Boutron-Ruault, Marie-Christine, LaCroix, Andrea, Rabe, Kari G., Hankinson, Susan E., Bracci, Paige M., McKean-Cowdin, Roberta, Weinstein, Stephanie J., Mandelson, Margaret T., Gao, Yu-Tang, Kolonel, Laurence N., Harris, Curtis C., Teras, Lauren T., Fraumeni Jr., Joseph F., Greene, Mark H., Sesso, Howard D., Mirabello, Lisa, Schwartz, Kendra L., Risch, Harvey A., Abnet, Christian C., Prokunina-Olsson, Ludmila, Garcia Closas, Montserrat, Michaud, Dominique S., Stevens, Victoria L., Signorello, Lisa B., Tucker, Margaret, Ding, Ti, Aldrich, Melinda C., Stram, Daniel, Kraft, Peter, Pérez Jurado, Luis A., Berg, Christine D., Hoffman Bolton, Judith A., Koh, Woon-Puay, Buring, Julie E., Ziegler, Regina G., Bock, Cathryn H., McWilliams, Robert R., Feychting, Maria, Goldstein, Alisa M., Hartge, Patricia, Johansen, Christoffer, Hu, Nan, Patiño García, Ana, Rotunno, Melissa, Gillanders, Elizabeth M., Rybicki, Benjamin A., Spitz, Margaret R., Riboli, Elio, Gaziano, J. Michael, Epstein, Caroline G., Khaw, Kay-Tee, Inskip, Peter D., Melin, Beatrice S., Severi, Gianluca, McGlynn, Katherine A., Wolpin, Brian M., Henriksson, Roger, Stolzenberg-Solomon, Rachael Z., Qiao, You-Lin, Gaudet, Mia M., Wu, Xifeng, Berndt, Sonja I., Yu, Kai, Hsing, Ann W., Landgren, Annelie, Wolk, Alicja, Xiang, Yong-Bing, Ahlbom, Anders, Cook, Michael B., Black, Amanda, Baris, Dalsu, Yuan, Jian-Min, Li, Donghui, Malats, Núria, Jiao, Li, Kogevinas, Manolis, Kooperberg, Charles, Villa, Olaya, Real, Francisco X., Zanetti, Krista A., and Schumacher, Fredrick

Subjects
Aging, Envelliment, Càncer, Cancer
Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

25. Shared heritability and functional enrichment across six solid cancers

Author

Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, DeFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, Ganz, Patricia A, Garber, Judy, García-Sáenz, José A, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, Goode, Ellen L, Goodman, Marc T, Goodman, Gary, Grankvist, Kjell, Greene, Mark H, Gronberg, Henrik, Gronwald, Jacek, Guénel, Pascal, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hamdy, Freddie C, Hamilton, Robert J, Hampe, Jochen, Haugen, Aage, Heitz, Florian, Herrero, Rolando, Hillemanns, Peter, Hoffmeister, Michael, Høgdall, Estrid, Hong, Yun-Chul, Hopper, John L, Houlston, Richard, Hulick, Peter J, Hunter, David J, Huntsman, David G, Idos, Gregory, Imyanitov, Evgeny N, Ingles, Sue Ann, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Jenkins, Mark A, Johansson, Mattias, Johansson, Mikael, John, Esther M, Joshi, Amit D, Kaneva, Radka, Karlan, Beth Y, Kelemen, Linda E, Kühl, Tabea, Khaw, Kay-Tee, Khusnutdinova, Elza, Kibel, Adam S, Kiemeney, Lambertus A, Kim, Jeri, Kjaer, Susanne K, Knight, Julia A, Kogevinas, Manolis, Kote-Jarai, Zsofia, Koutros, Stella, Kristensen, Vessela N, Kupryjanczyk, Jolanta, Lacko, Martin, Lam, Stephan, Lambrechts, Diether, Landi, Maria Teresa, Lazarus, Philip, Le, Nhu D, Lee, Eunjung, Lejbkowicz, Flavio, Lenz, Heinz-Josef, Leslie, Goska, Lessel, Davor, Lester, Jenny, Levine, Douglas A, Li, Li, Li, Christopher I, Lindblom, Annika, Lindor, Noralane M, Liu, Geoffrey, Loupakis, Fotios, Lubiński, Jan, Maehle, Lovise, Maier, Christiane, Mannermaa, Arto, Marchand, Loic Le, Margolin, Sara, May, Taymaa, McGuffog, Lesley, Meindl, Alfons, Middha, Pooja, Miller, Austin, Milne, Roger L, MacInnis, Robert J, Modugno, Francesmary, Montagna, Marco, Moreno, Victor, Moysich, Kirsten B, Mucci, Lorelei, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L, Neal, David E, Ness, Andrew R, Neuhausen, Susan L, Nevanlinna, Heli, Newcomb, Polly A, Newcomb, Lisa F, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Nordestgaard, Børge G, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olama, Ali Amin Al, Olopade, Olufunmilayo I, Olshan, Andrew F, Olsson, Håkan, Osorio, Ana, Pandha, Hardev, Park, Jong Y, Pashayan, Nora, Parsons, Michael T, Pejovic, Tanja, Penney, Kathryn L, Peters, Wilbert HM, Phelan, Catherine M, Phipps, Amanda I, Plaseska-Karanfilska, Dijana, Pring, Miranda, Prokofyeva, Darya, Radice, Paolo, Stefansson, Kari, Ramus, Susan J, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Van Rensburg, Elizabeth J, Riggan, Marjorie J, Risch, Harvey A, Risch, Angela, Roobol, Monique J, Rosenstein, Barry S, Rossing, Mary Anne, De Ruyck, Kim, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schabath, Matthew B, Schleutker, Johanna, Schmidt, Marjanka K, Setiawan, V Wendy, Shen, Hongbing, Siegel, Erin M, Sieh, Weiva, Singer, Christian F, Slattery, Martha L, Sorensen, Karina Dalsgaard, Southey, Melissa C, Spurdle, Amanda B, Stanford, Janet L, Stevens, Victoria L, Stintzing, Sebastian, Stone, Jennifer, Sundfeldt, Karin, Sutphen, Rebecca, Swerdlow, Anthony J, Tajara, Eloiza H, Tangen, Catherine M, Tardon, Adonina, Taylor, Jack A, Teare, M Dawn, Teixeira, Manuel R, Terry, Mary Beth, Terry, Kathryn L, Thibodeau, Stephen N, Thomassen, Mads, Bjørge, Line, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Townsend, Paul A, Travis, Ruth C, Tung, Nadine, Tworoger, Shelley S, Ulrich, Cornelia M, Usmani, Nawaid, Vachon, Celine M, Van Nieuwenhuysen, Els, Vega, Ana, Aguado-Barrera, Miguel Elías, Wang, Qin, Webb, Penelope M, Weinberg, Clarice R, Weinstein, Stephanie, Weissler, Mark C, Weitzel, Jeffrey N, West, Catharine ML, White, Emily, Whittemore, Alice S, Wichmann, H-Erich, Wiklund, Fredrik, Winqvist, Robert, Wolk, Alicja, Woll, Penella, Woods, Michael, Wu, Anna H, Wu, Xifeng, Yannoukakos, Drakoulis, Zheng, Wei, Zienolddiny, Shanbeh, Ziogas, Argyrios, Zorn, Kristin K, Lane, Jacqueline M, Saxena, Richa, Thomas, Duncan, Hung, Rayjean J, Diergaarde, Brenda, McKay, James, Peters, Ulrike, Hsu, Li, García-Closas, Montserrat, Eeles, Rosalind A, Chenevix-Trench, Georgia, Brennan, Paul J, Haiman, Christopher A, Simard, Jacques, Easton, Douglas F, Gruber, Stephen B, Pharoah, Paul DP, Price, Alkes L, Pasaniuc, Bogdan, Amos, Christopher I, Kraft, Peter, and Lindström, Sara

Subjects
Male, Ovarian Neoplasms, Lung Neoplasms, Mental Disorders, Smoking, Inheritance Patterns, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 3. Good health, Neoplasm Proteins, Phenotype, Head and Neck Neoplasms, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

26. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Dadaev, Tokhir, Saunders, Edward J, Newcombe, Paul J, Anokian, Ezequiel, Leongamornlert, Daniel A, Brook, Mark N, Cieza-Borrella, Clara, Mijuskovic, Martina, Wakerell, Sarah, Olama, Ali Amin Al, Schumacher, Fredrick R, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Goh, Chee, Sheng, Xin, Zhang, Zhuo, Muir, Kenneth, Govindasami, Koveela, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Hakansson, Niclas, West, Catharine, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei, Giovannucci, Edward, Andriole, Gerald, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Freeman, Laura E Beane, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry, Kerns, Sarah, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Stanford, Janet L, Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Ostrander, Elaine A, Geybels, Milan S, Nordestgaard, Børge G, Nielsen, Sune F, Weisher, Maren, Bisbjerg, Rasmus, Røder, Martin Andreas, Iversen, Peter, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Maier, Christiane, Luedeke, Manuel, Schnoeller, Thomas, Kim, Jeri, Logothetis, Christopher J, John, Esther M, Teixeira, Manuel R, Paulo, Paula, Cardoso, Marta, Neuhausen, Susan L, Steele, Linda, Ding, Yuan Chun, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Lin, Daniel W, Newcomb, Lisa F, Lessel, Davor, Gamulin, Marija, Kulis, Tomislav, Kaneva, Radka, Usmani, Nawaid, Slavov, Chavdar, Mitev, Vanio, Parliament, Matthew, Singhal, Sandeep, Claessens, Frank, Joniau, Steven, Van Den Broeck, Thomas, Larkin, Samantha, Townsend, Paul A, Aukim-Hastie, Claire, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Roobol, Monique J, Jenster, Guido, Van Schaik, Ron HN, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, Xu, Jianfeng, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Lindstrom, Sara, Turman, Constance, Ma, Jing, Hunter, David J, Riboli, Elio, Siddiq, Afshan, Canzian, Federico, Kolonel, Laurence N, Le Marchand, Loic, Hoover, Robert N, Machiela, Mitchell J, Kraft, Peter, PRACTICAL (Prostate Cancer Association Group To Investigate Cancer-Associated Alterations In The Genome) Consortium, Freedman, Matthew, Wiklund, Fredrik, Chanock, Stephen, Henderson, Brian E, Easton, Douglas F, Haiman, Christopher A, Eeles, Rosalind A, Conti, David V, and Kote-Jarai, Zsofia

Subjects
Male, Risk, Quantitative Trait Loci, Black People, Chromosome Mapping, Prostatic Neoplasms, Bayes Theorem, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, White People, 3. Good health, Multivariate Analysis, Humans, Genetic Predisposition to Disease, Algorithms, Genome-Wide Association Study
Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

27. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study

Author

Elisabete Weiderpass, J. Brent Richards, Peter Selby, Emily White, Peng Li, Ghislaine Scelo, David C. Muller, Garnet L. Anderson, Nicholas J. Timpson, David Zaridze, Mattias Johansson, Poulami Barman, Laura E. Beane Freeman, Alexander S. Parker, Simone Benhamou, Mark P. Purdue, Ingrid Winship, Victoria L. Stevens, Wong-Ho Chow, Valerie Gaborieau, Neal D. Freedman, Jean-François Deleuze, Juhua Luo, Philip C Haycock, Kevin M. Brown, Todd L. Edwards, Jeanette E. Eckel-Passow, Tony Fletcher, Ulrike Peters, Anush Mukeriya, Christel Häggström, Fiona Bruinsma, Timothy Eisen, Richard J. Kahnoski, George Davey Smith, I-Min Lee, Laurie Burdette, Lisa Johnson, Hallie Carol, Alicja Wolk, Jolanta Lissowska, Zhaoming Wang, Stephen J. Chanock, Yuanqing Ye, Sabrina L. Noyes, Jan Lubinski, Marie Navratilova, Matthew L. Freedman, Xifeng Wu, Ivana Holcatova, Stella Koutros, Vladimir Janout, Richard S. Houlston, James D. McKay, Toni K. Choueiri, Anne Boland, Susanna C. Larsson, Rosamonde E. Banks, Gabriella Andreotti, Sanja Radojevic-Skodric, Egor Prokhortchouk, Eunyoung Cho, Stefan Rascu, Paul Brennan, Hélène Blanché, David Petillo, James Larkin, Konstantin G. Skryabin, Börje Ljungberg, Marc J. Gunter, Viorel Jinga, Howard D. Sesso, Matthieu Foll, Brian R. Lane, Peter Rudnai, Jean-Guillaume Garnier, J. Michael Gaziano, Geraldine Cancel-Tassin, Caroline L Relton, Julie E. Buring, Meredith Yeager, Raviprakash T. Sitaram, Kristian Hveem, Loren Lipworth, Olivier Cussenot, Bin Tean Teh, Robert Carreras-Torres, Peter E. Clark, Vladimir Bencko, Simona Ognjanovic, Mark Pomerantz, Stephanie J. Weinstein, Mitchell J. Machiela, G. Mark Lathrop, Dana Mates, Lenka Foretova, Gianluca Severi, Bradley C. Leibovich, Leandro M. Colli, Daniela Mariosa, Marc Henrion, Satu Männistö, Susan J. Jordan, Kathryn M. Wilson, Richard M. Martin, Eleonora Fabianova, Jonathan N. Hofmann, Lars J. Vatten, Susan M. Gapstur, Cezary Cybulski, Wen-Yi Huang, Douglas F. Easton, Lee E. Moore, Cancer Research UK, Carreras-Torres, Robert [0000-0002-2925-734X], Timpson, Nicolas J [0000-0002-7141-9189], Haycock, Philip C [0000-0001-5001-3350], Brown, Kevin M [0000-0002-8558-6711], Machiela, Mitchell J [0000-0001-6538-9705], Li, Peng [0000-0002-0682-9819], Radojevic-Skodric, Sanja [0000-0002-5395-8285], Holcatova, Ivana [0000-0002-1366-0337], Mates, Dana [0000-0002-6219-9807], Mukeriya, Anush [0000-0002-6847-9295], Fabianova, Eleonora [0000-0002-5519-8427], Jinga, Viorel [0000-0001-7632-5328], Cancel-Tassin, Geraldine [0000-0002-9583-6382], Cussenot, Olivier [0000-0002-9912-0533], Weiderpass, Elisabete [0000-0003-2237-0128], Bruinsma, Fiona [0000-0002-9356-2015], Jordan, Susan J [0000-0002-4566-1414], Severi, Gianluca [0000-0001-7157-419X], Winship, Ingrid [0000-0001-8535-6003], Fletcher, Tony [0000-0003-3385-200X], Larsson, Susanna C [0000-0003-0118-0341], Wolk, Alicja [0000-0001-7387-6845], Banks, Rosamonde E [0000-0002-0042-8715], Beane Freeman, Laura E [0000-0003-1294-4124], Weinstein, Stephanie [0000-0002-3834-1535], Edwards, Todd L [0000-0003-4318-6119], Gapstur, Susan M [0000-0002-1934-2110], Stevens, Victoria L [0000-0003-0259-4407], Carol, Hallie [0000-0001-8890-9785], Pomerantz, Mark M [0000-0003-4914-1157], Freedman, Neal D [0000-0003-0074-1098], Huang, Wen-Yi [0000-0002-4440-3368], Petillo, David [0000-0001-7234-4644], Anderson, Garnet L [0000-0001-5087-7837], Moore, Lee E [0000-0002-5957-8283], Henrion, Marc [0000-0003-1242-839X], Barman, Poulami [0000-0002-4604-9868], Choueiri, Toni K [0000-0002-9201-3217], McKay, James D [0000-0002-1787-3874], Richards, J Brent [0000-0002-3746-9086], Martin, Richard M [0000-0002-7992-7719], Davey Smith, George [0000-0002-1407-8314], Brennan, Paul [0000-0002-0518-8714], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, Male, Physiology, Epidemiology, Blood Pressure, Genome-wide association study, 030204 cardiovascular system & hematology, urologic and male genital diseases, Bioinformatics, Biochemistry, Vascular Medicine, Body Mass Index, Endocrinology, Mathematical and Statistical Techniques, 0302 clinical medicine, Risk Factors, Renal cell carcinoma, Medicine and Health Sciences, Insulin, Medicine, 030212 general & internal medicine, 2. Zero hunger, Cancer Risk Factors, Statistics, Public Health, Global Health, Social Medicine and Epidemiology, Mendelian Randomization Analysis, Genomics, 11 Medical And Health Sciences, General Medicine, Lipids, Kidney Neoplasms, 3. Good health, Oncology, Physiological Parameters, Physical Sciences, Female, ICEP, Research Article, Genetic Markers, medicine.medical_specialty, Research and Analysis Methods, Instrumental Variable Analysis, Carcinomas, 03 medical and health sciences, General & Internal Medicine, Mendelian randomization, Genome-Wide Association Studies, Genetics, Carcinoma, Humans, VDP::Medisinske Fag: 700, Obesity, Statistical Methods, Carcinoma, Renal Cell, Diabetic Endocrinology, Cancer och onkologi, business.industry, Body Weight, Renal Cell Carcinoma, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Cancer, Human Genetics, Genome Analysis, medicine.disease, Hormones, VDP::Medical disciplines: 700, Genitourinary Tract Tumors, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Diabetes Mellitus, Type 2, Medical Risk Factors, Cancer and Oncology, Etiology, business, Mathematics, Genome-Wide Association Study
Abstract

Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Using mendelian randomization approaches, Paul Brennan and colleagues reveal an association between 12 obesity-related factors, including insulin and the development of renal cell carcinoma., Author summary Why was this study done? Traditional observational studies wherein putative risk factors are measured directly have found several obesity-related factors associated with increased risk of renal cell carcinoma (RCC). Traditional observational studies are subject to confounding and reverse causation and have not been able to disentangle which obesity-related risk factors directly influence RCC risk. This study used an alternative methodology commonly referred to as mendelian randomization (MR). MR circumvents many of the inherent limitations of traditional observational study by use of genetic proxies of putative risk factors when evaluating their associations with disease risk, as they are not subject to reverse causation and are less likely to be confounded by other risk factors. What did the researchers do and find? First, we used large-scale genome-wide association studies (GWAS) to identify genetic variants associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose. Second, these genetic variants were used as proxies for the above-mentioned risk factors and evaluated in relation RCC risk using GWAS data from 10,000 RCC patients and 20,000 control participants. Based on these genetic data, we found that multiple measures of obesity, as well as diastolic blood pressure (DBP) and fasting insulin, are associated with RCC risk. In contrast, we found little evidence for an association with RCC risk for systolic blood pressure (SBP), circulating lipids, overall diabetes, or fasting glucose. What do these findings mean? This study provided robust and confirmatory evidence of an important role of obesity as an important risk factor of RCC. Further confirmatory evidence was found for elevated DBP as a risk factor of RCC, but it is not clear why DBP rather than SBP is important in RCC. The study, to our knowledge, provided novel evidence of an important role of circulating insulin in RCC etiology. This study provided some novel insights into the pathways involved in mediating the risk increase in RCC that is caused by obesity, most notably through insulin and DBP, but further research is needed to fully elucidate the important relationship between obesity and RCC.

Published
2019

Catalog

Books, media, physical & digital resources
See catalog results