108 results on '"MacGregor, Stuart"'
Search Results
2. Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
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Lindström, Sara, Wang, Lu, Feng, Helian, Majumdar, Arunabha, Huo, Sijia, Macdonald, James, Harrison, Tabitha, Turman, Constance, Chen, Hongjie, Mancuso, Nicholas, Bammler, Theo, Consortium, Breast Cancer Association, Gallinger, Steve, Gruber, Stephen B, Gunter, Marc J, Le Marchand, Loic, Moreno, Victor, Offit, Kenneth, Study, Genetics And Epidemiology Of Colorectal Cancer Consortium Colorectal Transdisciplinary Study Colon Cancer Family Registry, De Vivo, Immaculata, O’Mara, Tracy A, Spurdle, Amanda B, Tomlinson, Ian, Consortium, Endometrial Cancer Association, Fitzgerald, Rebecca, Gharahkhani, Puya, Gockel, Ines, Jankowski, Janusz, Macgregor, Stuart, Schumacher, Johannes, Barnholtz-Sloan, Jill, Bondy, Melissa L, Houlston, Richard S, Jenkins, Robert B, Melin, Beatrice, Wrensch, Margaret, Brennan, Paul, Christiani, David C, Johansson, Mattias, Mckay, James, Aldrich, Melinda C, Amos, Christopher I, Landi, Maria Teresa, Tardon, Adonina, Consortium, International Lung Cancer, Bishop, D Timothy, Demenais, Florence, Goldstein, Alisa M, Iles, Mark M, Kanetsky, Peter A, Law, Matthew H, Consortium, Ovarian Cancer Association, Amundadottir, Laufey T, Stolzenberg-Solomon, Rachael, Wolpin, Brian M, Consortium, Pancreatic Cancer Cohort, Klein, Alison, Petersen, Gloria, Risch, Harvey, Consortium, The PRACTICAL Consortium Pancreatic Cancer Case-Control, Chanock, Stephen J, Purdue, Mark P, Scelo, Ghislaine, Pharoah, Paul, Kar, Siddhartha, Hung, Rayjean J, Pasaniuc, Bogdan, and Kraft, Peter
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Genetics ,Digestive Diseases ,Prevention ,Clinical Research ,Urologic Diseases ,Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Male ,Humans ,Genome-Wide Association Study ,Genetic Predisposition to Disease ,Neoplasms ,Risk Factors ,Transcriptome ,Polymorphism ,Single Nucleotide ,Breast Cancer Association Consortium ,Colorectal Transdisciplinary Study (CORECT) ,Colon Cancer Family Registry Study (CCFR) ,Genetics And Epidemiology Of Colorectal Cancer Consortium ,Endometrial Cancer Association Consortium ,International Lung Cancer Consortium ,Ovarian Cancer Association Consortium ,Pancreatic Cancer Cohort Consortium ,Pancreatic Cancer Case-Control Consortium (Panc4) ,The PRACTICAL Consortium ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundThe shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.MethodsWe collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.ResultsWe observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.ConclusionsOverall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
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- 2023
3. Discovery of genomic loci associated with sleep apnea risk through multi-trait GWAS analysis with snoring.
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Campos, Adrian, Ingold, Nathan, Huang, Yunru, Mitchell, Brittany, Kho, Pik-Fang, Han, Xikun, García-Marín, Luis, Ong, Jue-Sheng, Law, Matthew, Martin, Nicholas, Dong, Xianjun, Cuellar-Partida, Gabriel, MacGregor, Stuart, Aslibekyan, Stella, Rentería, Miguel, and Yokoyama, Jennifer
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GWAS ,genetics ,sleep apnea ,snoring ,Humans ,Genome-Wide Association Study ,Snoring ,Phenotype ,Sleep Apnea Syndromes ,Genomics ,Polymorphism ,Single Nucleotide - Abstract
STUDY OBJECTIVES: Despite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (NTotal = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal = 1 477 352; Ncases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method. RESULTS: Our SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions. CONCLUSION: Our study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.
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- 2023
4. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions
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Rahmioglu, Nilufer, Mortlock, Sally, Ghiasi, Marzieh, Møller, Peter L, Stefansdottir, Lilja, Galarneau, Geneviève, Turman, Constance, Danning, Rebecca, Law, Matthew H, Sapkota, Yadav, Christofidou, Paraskevi, Skarp, Sini, Giri, Ayush, Banasik, Karina, Krassowski, Michal, Lepamets, Maarja, Marciniak, Błażej, Nõukas, Margit, Perro, Danielle, Sliz, Eeva, Sobalska-Kwapis, Marta, Thorleifsson, Gudmar, Topbas-Selcuki, Nura F, Vitonis, Allison, Westergaard, David, Arnadottir, Ragnheidur, Burgdorf, Kristoffer S, Campbell, Archie, Cheuk, Cecilia SK, Clementi, Caterina, Cook, James, De Vivo, Immaculata, DiVasta, Amy, Dorien, O, Donoghue, Jacqueline F, Edwards, Todd, Fontanillas, Pierre, Fung, Jenny N, Geirsson, Reynir T, Girling, Jane E, Harkki, Paivi, Harris, Holly R, Healey, Martin, Heikinheimo, Oskari, Holdsworth-Carson, Sarah, Hostettler, Isabel C, Houlden, Henry, Houshdaran, Sahar, Irwin, Juan C, Jarvelin, Marjo-Riitta, Kamatani, Yoichiro, Kennedy, Stephen H, Kepka, Ewa, Kettunen, Johannes, Kubo, Michiaki, Kulig, Bartosz, Kurra, Venla, Laivuori, Hannele, Laufer, Marc R, Lindgren, Cecilia M, MacGregor, Stuart, Mangino, Massimo, Martin, Nicholas G, Matalliotaki, Charoula, Matalliotakis, Michail, Murray, Alison D, Ndungu, Anne, Nezhat, Camran, Olsen, Catherine M, Opoku-Anane, Jessica, Padmanabhan, Sandosh, Paranjpe, Manish, Peters, Maire, Polak, Grzegorz, Porteous, David J, Rabban, Joseph, Rexrode, Kathyrn M, Romanowicz, Hanna, Saare, Merli, Saavalainen, Liisu, Schork, Andrew J, Sen, Sushmita, Shafrir, Amy L, Siewierska-Górska, Anna, Słomka, Marcin, Smith, Blair H, Smolarz, Beata, Szaflik, Tomasz, Szyłło, Krzysztof, Takahashi, Atsushi, Terry, Kathryn L, Tomassetti, Carla, Treloar, Susan A, Vanhie, Arne, Vincent, Katy, Vo, Kim C, Werring, David J, Zeggini, Eleftheria, Zervou, Maria I, and Adachi, Sosuke
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Biological Sciences ,Genetics ,Contraception/Reproduction ,Clinical Research ,Endometriosis ,Prevention ,Pain Research ,Chronic Pain ,Infertility ,2.1 Biological and endogenous factors ,Aetiology ,Female ,Humans ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Pain ,Comorbidity ,DBDS Genomic Consortium ,FinnGen Study ,FinnGen Endometriosis Taskforce ,Celmatix Research Team ,23andMe Research Team ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
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- 2023
5. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer
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Quinn, Michael CJ, McCue, Karen, Shi, Wei, Johnatty, Sharon E, Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A, Glubb, Dylan M, Tyrer, Jonathan P, Armasu, Sebastian M, Ong, Jue-Sheng, Gharahkhani, Puya, Lu, Yi, Gao, Bo, Patch, Ann-Marie, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Edwards, Digna R Velez, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Dörk, Thilo, Dürst, Matthias, Modugno, Francesmary, Moysich, Kirsten, du Bois, Andreas, Pfisterer, Jacobus, Bauman, Klaus, Group, for the AGO Study, Karlan, Beth Y, Lester, Jenny, Cunningham, Julie M, Larson, Melissa C, McCauley, Bryan M, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus K, Hogdall, Estrid, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bjorge, Line, Webb, Penelope M, Group, for the OPAL Study, Friedlander, Michael, Pejovic, Tanja, Moffitt, Melissa, Glasspool, Rosalind, May, Taymaa, Ene, Gabrielle EV, Huntsman, David G, Woo, Michelle, Carney, Michael E, Hinsley, Samantha, Heitz, Florian, Fereday, Sian, Kennedy, Catherine J, Edwards, Stacey L, Winham, Stacey J, deFazio, Anna, Group, for Australian Ovarian Cancer Study, Pharoah, Paul DP, Goode, Ellen L, MacGregor, Stuart, and Chenevix-Trench, Georgia
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Prevention ,Human Genome ,Cancer ,Genetics ,Ovarian Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Autophagy-Related Protein-1 Homolog ,Biomarkers ,Tumor ,Carcinoma ,Ovarian Epithelial ,Female ,Gene Knockout Techniques ,Genome-Wide Association Study ,Humans ,Intracellular Signaling Peptides and Proteins ,Ovarian Neoplasms ,Polymorphism ,Single Nucleotide ,Progression-Free Survival ,AGO Study Group ,OPAL Study Group ,for Australian Ovarian Cancer Study Group ,Medical and Health Sciences ,Epidemiology ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.
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- 2021
6. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries
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Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, and Wiggs, Janey L
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Neurodegenerative ,Genetics ,Eye Disease and Disorders of Vision ,Aging ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Asian People ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Glaucoma ,Open-Angle ,Humans ,Polymorphism ,Single Nucleotide ,White People ,NEIGHBORHOOD consortium ,ANZRAG consortium ,Biobank Japan project ,FinnGen study ,UK Biobank Eye and Vision Consortium ,GIGA study group ,and Me Research Team - Abstract
Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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- 2021
7. A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus
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Hardcastle, Alison J, Liskova, Petra, Bykhovskaya, Yelena, McComish, Bennet J, Davidson, Alice E, Inglehearn, Chris F, Li, Xiaohui, Choquet, Hélène, Habeeb, Mahmoud, Lucas, Sionne EM, Sahebjada, Srujana, Pontikos, Nikolas, Lopez, Karla E Rojas, Khawaja, Anthony P, Ali, Manir, Dudakova, Lubica, Skalicka, Pavlina, Van Dooren, Bart TH, Geerards, Annette JM, Haudum, Christoph W, Faro, Valeria Lo, Tenen, Abi, Simcoe, Mark J, Patasova, Karina, Yarrand, Darioush, Yin, Jie, Siddiqui, Salina, Rice, Aine, Farraj, Layal Abi, Chen, Yii-Der Ida, Rahi, Jugnoo S, Krauss, Ronald M, Theusch, Elisabeth, Charlesworth, Jac C, Szczotka-Flynn, Loretta, Toomes, Carmel, Meester-Smoor, Magda A, Richardson, Andrea J, Mitchell, Paul A, Taylor, Kent D, Melles, Ronald B, Aldave, Anthony J, Mills, Richard A, Cao, Ke, Chan, Elsie, Daniell, Mark D, Wang, Jie Jin, Rotter, Jerome I, Hewitt, Alex W, MacGregor, Stuart, Klaver, Caroline CW, Ramdas, Wishal D, Craig, Jamie E, Iyengar, Sudha K, O’Brart, David, Jorgenson, Eric, Baird, Paul N, Rabinowitz, Yaron S, Burdon, Kathryn P, Hammond, Chris J, Tuft, Stephen J, and Hysi, Pirro G
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Human Genome ,Genetics ,Rare Diseases ,Eye Disease and Disorders of Vision ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Eye ,Australia ,Case-Control Studies ,Cell Differentiation ,Collagen ,Europe ,Extracellular Matrix ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Keratoconus ,Phenotype ,Polymorphism ,Single Nucleotide ,Risk Assessment ,Risk Factors - Abstract
Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.
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- 2021
8. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
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Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)
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Breast Cancer Association Consortium ,Barrett’s and Esophageal Adenocarcinoma Consortium ,Colon Cancer Family Registry ,Transdisciplinary Studies of Genetic Variation in Colorectal Cancer ,Endometrial Cancer Association Consortium ,Genetics and Epidemiology of Colorectal Cancer Consortium ,Melanoma Genetics Consortium ,Glioma International Case-Control Study ,International Lung Cancer Consortium ,Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium ,International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies ,Ovarian Cancer Association Consortium ,Oral Cancer GWAS ,Pancreatic Cancer Case-Control Consortium ,Pancreatic Cancer Cohort Consortium ,Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome ,Renal Cancer GWAS ,Testicular Cancer Consortium ,Animals ,Humans ,Neoplasms ,Genetic Predisposition to Disease ,Incidence ,Risk Assessment ,Risk Factors ,Multifactorial Inheritance ,Polymorphism ,Single Nucleotide ,Models ,Genetic ,Female ,Male ,Genome-Wide Association Study ,Human Genome ,Prevention ,Cancer ,Prostate Cancer ,Genetics ,Urologic Diseases ,2.1 Biological and endogenous factors - Abstract
Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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- 2020
9. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters
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Bonnemaijer, Pieter WM, Leeuwen, Elisabeth M van, Iglesias, Adriana I, Gharahkhani, Puya, Vitart, Veronique, Khawaja, Anthony P, Simcoe, Mark, Höhn, René, Cree, Angela J, Igo, Rob P, Gerhold-Ay, Aslihan, Nickels, Stefan, Wilson, James F, Hayward, Caroline, Boutin, Thibaud S, Polašek, Ozren, Aung, Tin, Khor, Chiea Chuen, Amin, Najaf, Lotery, Andrew J, Wiggs, Janey L, Cheng, Ching-Yu, Hysi, Pirro G, Hammond, Christopher J, Thiadens, Alberta AHJ, MacGregor, Stuart, Klaver, Caroline CW, and Duijn, Cornelia M van
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Genetics ,Eye Disease and Disorders of Vision ,Neurodegenerative ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Case-Control Studies ,Computational Biology ,Gene Expression Profiling ,Genetic Association Studies ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Glaucoma ,Humans ,Molecular Sequence Annotation ,Optic Disk ,Optic Nerve Diseases ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Quantitative Trait ,Heritable ,Signal Transduction ,International Glaucoma Genetics Consortium ,NEIGHBORHOOD consortium ,UK Biobank Eye and Vision Consortium ,Genome-wide association studies ,Optic nerve diseases - Abstract
A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
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- 2019
10. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
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Spracklen, Cassandra N, Karaderi, Tugce, Yaghootkar, Hanieh, Schurmann, Claudia, Fine, Rebecca S, Kutalik, Zoltan, Preuss, Michael H, Lu, Yingchang, Wittemans, Laura BL, Adair, Linda S, Allison, Matthew, Amin, Najaf, Auer, Paul L, Bartz, Traci M, Blüher, Matthias, Boehnke, Michael, Borja, Judith B, Bork-Jensen, Jette, Broer, Linda, Chasman, Daniel I, Chen, Yii-Der Ida, Chirstofidou, Paraskevi, Demirkan, Ayse, van Duijn, Cornelia M, Feitosa, Mary F, Garcia, Melissa E, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Guo, Xiuqing, Haesser, Jeffrey, Hansen, Torben, Harris, Tamara B, Highland, Heather M, Hong, Jaeyoung, Ikram, M Arfan, Ingelsson, Erik, Jackson, Rebecca, Jousilahti, Pekka, Kähönen, Mika, Kizer, Jorge R, Kovacs, Peter, Kriebel, Jennifer, Laakso, Markku, Lange, Leslie A, Lehtimäki, Terho, Li, Jin, Li-Gao, Ruifang, Lind, Lars, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mackey, David A, Mahajan, Anubha, Mangino, Massimo, Männistö, Satu, McCarthy, Mark I, McKnight, Barbara, Medina-Gomez, Carolina, Meigs, James B, Molnos, Sophie, Mook-Kanamori, Dennis, Morris, Andrew P, de Mutsert, Renee, Nalls, Mike A, Nedeljkovic, Ivana, North, Kari E, Pennell, Craig E, Pradhan, Aruna D, Province, Michael A, Raitakari, Olli T, Raulerson, Chelsea K, Reiner, Alex P, Ridker, Paul M, Ripatti, Samuli, Roberston, Neil, Rotter, Jerome I, Salomaa, Veikko, Sandoval-Zárate, America A, Sitlani, Colleen M, Spector, Tim D, Strauch, Konstantin, Stumvoll, Michael, Taylor, Kent D, Thuesen, Betina, Tönjes, Anke, Uitterlinden, Andre G, Venturini, Cristina, Walker, Mark, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Willems, Sara M, Willems van Dijk, Ko, Wilson, James G, Wu, Ying, Yao, Jie, Young, Kristin L, Langenberg, Claudia, and Frayling, Timothy M
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Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Human Genome ,Nutrition ,Obesity ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Cardiovascular ,Adiponectin ,Adipose Tissue ,Adolescent ,Adult ,Black or African American ,Aged ,Aged ,80 and over ,Exome ,Female ,Genetic Predisposition to Disease ,Hispanic or Latino ,Humans ,Lipids ,Male ,Middle Aged ,Phenotype ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,White People ,Young Adult ,adiponectin ,cardio metabolic traits ,exome ,genetics ,genome-wide association study ,lipids ,obesity ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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- 2019
11. Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability
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Pasman, Joëlle A, Verweij, Karin JH, Gerring, Zachary, Stringer, Sven, Sanchez-Roige, Sandra, Treur, Jorien L, Abdellaoui, Abdel, Nivard, Michel G, Baselmans, Bart ML, Ong, Jue-Sheng, Ip, Hill F, van der Zee, Matthijs D, Bartels, Meike, Day, Felix R, Fontanillas, Pierre, Elson, Sarah L, de Wit, Harriet, Davis, Lea K, MacKillop, James, Derringer, Jaime L, Branje, Susan JT, Hartman, Catharina A, Heath, Andrew C, van Lier, Pol AC, Madden, Pamela AF, Mägi, Reedik, Meeus, Wim, Montgomery, Grant W, Oldehinkel, AJ, Pausova, Zdenka, Ramos-Quiroga, Josep A, Paus, Tomas, Ribases, Marta, Kaprio, Jaakko, Boks, Marco PM, Bell, Jordana T, Spector, Tim D, Gelernter, Joel, Boomsma, Dorret I, Martin, Nicholas G, MacGregor, Stuart, Perry, John RB, Palmer, Abraham A, Posthuma, Danielle, Munafò, Marcus R, Gillespie, Nathan A, Derks, Eske M, and Vink, Jacqueline M
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Drug Abuse (NIDA only) ,Human Genome ,Brain Disorders ,Serious Mental Illness ,Genetics ,Schizophrenia ,Substance Misuse ,Mental Health ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,23andMe Research Team ,Substance Use Disorders Working Group of the Psychiatric Genomics Consortium ,International Cannabis Consortium ,Neurosciences ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.
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- 2019
12. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability
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Pasman, Joëlle A, Verweij, Karin JH, Gerring, Zachary, Stringer, Sven, Sanchez-Roige, Sandra, Treur, Jorien L, Abdellaoui, Abdel, Nivard, Michel G, Baselmans, Bart ML, Ong, Jue-Sheng, Ip, Hill F, van der Zee, Matthijs D, Bartels, Meike, Day, Felix R, Fontanillas, Pierre, Elson, Sarah L, the 23andMe Research Team, de Wit, Harriet, Davis, Lea K, MacKillop, James, The Substance Use Disorders Working Group of the Psychiatric Genomics Consortium, International Cannabis Consortium, Derringer, Jaime L, Branje, Susan JT, Hartman, Catharina A, Heath, Andrew C, van Lier, Pol AC, Madden, Pamela AF, Mägi, Reedik, Meeus, Wim, Montgomery, Grant W, Oldehinkel, AJ, Pausova, Zdenka, Ramos-Quiroga, Josep A, Paus, Tomas, Ribases, Marta, Kaprio, Jaakko, Boks, Marco PM, Bell, Jordana T, Spector, Tim D, Gelernter, Joel, Boomsma, Dorret I, Martin, Nicholas G, MacGregor, Stuart, Perry, John RB, Palmer, Abraham A, Posthuma, Danielle, Munafò, Marcus R, Gillespie, Nathan A, Derks, Eske M, and Vink, Jacqueline M
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Prevention ,Mental Health ,Schizophrenia ,Clinical Research ,Behavioral and Social Science ,Genetics ,Mental Illness ,Brain Disorders ,Serious Mental Illness ,Human Genome ,Drug Abuse (NIDA only) ,Women's Health ,Cannabinoid Research ,Substance Misuse ,2.1 Biological and endogenous factors ,Mental health ,Good Health and Well Being ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Cell Adhesion Molecules ,Databases ,Genetic ,Female ,Gene Expression Regulation ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Male ,Marijuana Abuse ,Mendelian Randomization Analysis ,Middle Aged ,Polymorphism ,Single Nucleotide ,Risk-Taking ,Young Adult ,23andMe Research Team ,Substance Use Disorders Working Group of the Psychiatric Genomics Consortium ,International Cannabis Consortium ,Neurosciences ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.
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- 2018
13. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.
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Pasman, Joëlle A, Verweij, Karin JH, Gerring, Zachary, Stringer, Sven, Sanchez-Roige, Sandra, Treur, Jorien L, Abdellaoui, Abdel, Nivard, Michel G, Baselmans, Bart ML, Ong, Jue-Sheng, Ip, Hill F, van der Zee, Matthijs D, Bartels, Meike, Day, Felix R, Fontanillas, Pierre, Elson, Sarah L, 23andMe Research Team, de Wit, Harriet, Davis, Lea K, MacKillop, James, Substance Use Disorders Working Group of the Psychiatric Genomics Consortium, International Cannabis Consortium, Derringer, Jaime L, Branje, Susan JT, Hartman, Catharina A, Heath, Andrew C, van Lier, Pol AC, Madden, Pamela AF, Mägi, Reedik, Meeus, Wim, Montgomery, Grant W, Oldehinkel, AJ, Pausova, Zdenka, Ramos-Quiroga, Josep A, Paus, Tomas, Ribases, Marta, Kaprio, Jaakko, Boks, Marco PM, Bell, Jordana T, Spector, Tim D, Gelernter, Joel, Boomsma, Dorret I, Martin, Nicholas G, MacGregor, Stuart, Perry, John RB, Palmer, Abraham A, Posthuma, Danielle, Munafò, Marcus R, Gillespie, Nathan A, Derks, Eske M, and Vink, Jacqueline M
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23andMe Research Team ,Substance Use Disorders Working Group of the Psychiatric Genomics Consortium ,International Cannabis Consortium ,Humans ,Marijuana Abuse ,Genetic Predisposition to Disease ,Cell Adhesion Molecules ,Risk-Taking ,Mental Health ,Schizophrenia ,Gene Expression Regulation ,Genotype ,Polymorphism ,Single Nucleotide ,Databases ,Genetic ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Genome-Wide Association Study ,Young Adult ,Mendelian Randomization Analysis ,Polymorphism ,Single Nucleotide ,Databases ,Genetic ,and over ,Prevention ,Human Genome ,Brain Disorders ,Drug Abuse ,Substance Abuse ,Genetics ,Clinical Research ,2.1 Biological and endogenous factors ,Cardiovascular ,Neurology & Neurosurgery ,Neurosciences ,Cognitive Sciences ,Psychology - Abstract
Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.
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- 2018
14. Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study
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Ong, Jue-Sheng, Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Martin, Nicholas G, Chenevix-Trench, Georgia, Quinn, Michael CJ, Cornelis, Marilyn C, Gharahkhani, Puya, Webb, Penelope M, MacGregor, Stuart, Bryne, Enda, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Swerdlow, Anthony J, Jones, Michael, Orr, Nicholas, Schoemaker, Minouk, Edwards, Digna Velez, Brenton, James, Benítez, Javier, García, María J, Rodriguez-Antona, Cristina, Rossing, Mary Anne, Fortner, Renée T, Riboli, Elio, Chang-Claude, Jenny, Eilber, Ursula, Wang-Gohrke, Shan, Yannoukakos, Drakoulis, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Duerst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Heitz, Florian, Karlan, Beth, Olsson, Håkan, Kjaer, Susanne K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Hildebrandt, Michelle AT, Liang, Dong, Wu, Xifeng, Le Marchand, Loic, Setiawan, V Wendy, Permuth, Jennifer B, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Willet, Walter, Missmer, Stacey, Bjorge, Line, Kopperud, Reidun K, Bischof, Katharina, Thomsen, Liv Cecilie Vestrheim, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, and Lissowska, Jolanta
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Epidemiology ,Health Sciences ,Clinical Research ,Ovarian Cancer ,Nutrition ,Rare Diseases ,Prevention ,Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Carcinoma ,Ovarian Epithelial ,Coffee ,Female ,Humans ,Mendelian Randomization Analysis ,Odds Ratio ,Ovarian Neoplasms ,Polymorphism ,Single Nucleotide ,Risk Factors ,Ovarian Cancer Association Consortium ,Statistics ,Public Health and Health Services ,Public health - Abstract
BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.
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- 2018
15. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets
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Cooke Bailey, Jessica N, Gharahkhani, Puya, Kang, Jae H, Butkiewicz, Mariusz, Sullivan, David A, Weinreb, Robert N, Aschard, Hugues, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Vajaranant, Thasarat S, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Craig, Jamie E, Burdon, Kathryn P, Hewitt, Alex W, Mackey, David A, Haines, Jonathan L, MacGregor, Stuart, Wiggs, Janey L, and Pasquale, Louis R
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Genetics ,Neurodegenerative ,Aging ,2.1 Biological and endogenous factors ,Aetiology ,Datasets as Topic ,Female ,Gene Frequency ,Genome-Wide Association Study ,Genotype ,Glaucoma ,Open-Angle ,Humans ,Intraocular Pressure ,Low Tension Glaucoma ,Male ,Metabolic Networks and Pathways ,Middle Aged ,Polymorphism ,Single Nucleotide ,Testosterone ,primary open-angle glaucoma ,testosterone ,genetics ,pathway analysis ,Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium ,Biological Sciences ,Medical and Health Sciences ,Ophthalmology & Optometry - Abstract
Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
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- 2018
16. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.
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Bailey, Jessica N Cooke, Gharahkhani, Puya, Kang, Jae H, Butkiewicz, Mariusz, Sullivan, David A, Weinreb, Robert N, Aschard, Hugues, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Vajaranant, Thasarat S, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Craig, Jamie E, Burdon, Kathryn P, Hewitt, Alex W, Mackey, David A, Haines, Jonathan L, MacGregor, Stuart, Wiggs, Janey L, Pasquale, Louis R, and Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium
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Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium ,Humans ,Glaucoma ,Open-Angle ,Testosterone ,Intraocular Pressure ,Gene Frequency ,Genotype ,Polymorphism ,Single Nucleotide ,Middle Aged ,Female ,Male ,Metabolic Networks and Pathways ,Genome-Wide Association Study ,Low Tension Glaucoma ,Datasets as Topic ,primary open-angle glaucoma ,testosterone ,genetics ,pathway analysis ,Glaucoma ,Open-Angle ,Polymorphism ,Single Nucleotide ,Biological Sciences ,Medical and Health Sciences ,Ophthalmology & Optometry - Abstract
Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
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- 2018
17. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma.
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King, Rebecca, Struebing, Felix L, Li, Ying, Wang, Jiaxing, Koch, Allison Ashley, Cooke Bailey, Jessica N, Gharahkhani, Puya, International Glaucoma Genetics Consortium, NEIGHBORHOOD Consortium, MacGregor, Stuart, Allingham, R Rand, Hauser, Michael A, Wiggs, Janey L, and Geisert, Eldon E
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International Glaucoma Genetics Consortium ,NEIGHBORHOOD Consortium ,Retinal Ganglion Cells ,Cornea ,Cells ,Cultured ,Animals ,Mice ,Inbred C57BL ,Mice ,Inbred DBA ,Mice ,Transgenic ,Humans ,Mice ,Glaucoma ,Disease Models ,Animal ,Genetic Predisposition to Disease ,Risk Factors ,Chromosome Mapping ,Apoptosis ,Pregnancy ,Polymorphism ,Single Nucleotide ,Female ,Male ,POU Domain Factors ,Embryo ,Mammalian ,Genome-Wide Association Study ,Genetic Loci ,Corneal Pachymetry ,Cells ,Cultured ,Disease Models ,Animal ,Embryo ,Mammalian ,Inbred C57BL ,Inbred DBA ,Transgenic ,Polymorphism ,Single Nucleotide ,Genetics ,Developmental Biology - Abstract
Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.
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- 2018
18. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
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Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study—GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Ophthalmology and Optometry ,Human Genome ,Rare Diseases ,Eye Disease and Disorders of Vision ,1.1 Normal biological development and functioning ,Underpinning research ,Eye ,ADAMTS Proteins ,Asian People ,Cornea ,Corneal Diseases ,Corneal Dystrophies ,Hereditary ,Decorin ,Ehlers-Danlos Syndrome ,Eye Diseases ,Hereditary ,Fibrillin-1 ,Gene Expression ,Genome ,Human ,Genome-Wide Association Study ,Glaucoma ,Open-Angle ,Humans ,Keratoconus ,Loeys-Dietz Syndrome ,Lumican ,Marfan Syndrome ,Mendelian Randomization Analysis ,Myopia ,Polymorphism ,Single Nucleotide ,Proteoglycans ,Quantitative Trait Loci ,Quantitative Trait ,Heritable ,Transforming Growth Factor beta2 ,White People ,Blue Mountains Eye Study—GWAS group ,NEIGHBORHOOD Consortium ,Wellcome Trust Case Control Consortium 2 - Abstract
Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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- 2018
19. The Genetics of Myopia
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Tedja, Milly S., Haarman, Annechien E. G., Meester-Smoor, Magda A., Verhoeven, Virginie J. M., Klaver, Caroline C. W., MacGregor, Stuart, Ang, Marcus, editor, and Wong, Tien Y., editor
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- 2020
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20. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci
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Glubb, Dylan M, Johnatty, Sharon E, Quinn, Michael CJ, O’Mara, Tracy A, Tyrer, Jonathan P, Gao, Bo, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Velez Edwards, Digna R, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Thompson, Pamela J, Dörk, Thilo, Dürst, Matthias, Modungo, Francesmary, Moysich, Kirsten, Heitz, Florian, du Bois, Andreas, Pfisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y, Lester, Jenny, Goode, Ellen L, Cunningham, Julie M, Winham, Stacey J, Larson, Melissa C, McCauley, Bryan M, Kjær, Susanne Krüger, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Salvesen, Helga B, Bjorge, Line, Webb, Penny M, Grant, Peter, Pejovic, Tanja, Moffitt, Melissa, Hogdall, Claus K, Hogdall, Estrid, Paul, James, Glasspool, Rosalind, Bernardini, Marcus, Tone, Alicia, Huntsman, David, Woo, Michelle, Group, AOCS, deFazio, Anna, Kennedy, Catherine J, Pharoah, Paul DP, MacGregor, Stuart, and Chenevix-Trench, Georgia
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Cancer ,Rare Diseases ,Prevention ,Genetics ,Ovarian Cancer ,Aetiology ,2.1 Biological and endogenous factors ,ovarian cancer outcome ,genetic association ,gene regulation ,meta-analysis ,Oncology and carcinogenesis - Abstract
We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p
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- 2017
21. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.
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Sapkota, Yadav, Steinthorsdottir, Valgerdur, Morris, Andrew P, Fassbender, Amelie, Rahmioglu, Nilufer, De Vivo, Immaculata, Buring, Julie E, Zhang, Futao, Edwards, Todd L, Jones, Sarah, O, Dorien, Peterse, Daniëlle, Rexrode, Kathryn M, Ridker, Paul M, Schork, Andrew J, MacGregor, Stuart, Martin, Nicholas G, Becker, Christian M, Adachi, Sosuke, Yoshihara, Kosuke, Enomoto, Takayuki, Takahashi, Atsushi, Kamatani, Yoichiro, Matsuda, Koichi, Kubo, Michiaki, Thorleifsson, Gudmar, Geirsson, Reynir T, Thorsteinsdottir, Unnur, Wallace, Leanne M, iPSYCH-SSI-Broad Group, Yang, Jian, Velez Edwards, Digna R, Nyegaard, Mette, Low, Siew-Kee, Zondervan, Krina T, Missmer, Stacey A, D'Hooghe, Thomas, Montgomery, Grant W, Chasman, Daniel I, Stefansson, Kari, Tung, Joyce Y, and Nyholt, Dale R
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iPSYCH-SSI-Broad Group ,Humans ,Endometriosis ,Genetic Predisposition to Disease ,Gonadal Steroid Hormones ,Estrogen Receptor alpha ,Genotype ,Polymorphism ,Single Nucleotide ,Adult ,Aged ,Middle Aged ,Female ,Metabolic Networks and Pathways ,Genome-Wide Association Study ,Genetic Loci ,Genetics ,Pain Research ,Human Genome ,Contraception/Reproduction ,Clinical Research ,Prevention ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning - Abstract
Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P
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- 2017
22. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer
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French, Juliet D, Johnatty, Sharon E, Lu, Yi, Beesley, Jonathan, Gao, Bo, Kalimutho, Murugan, Henderson, Michelle J, Russell, Amanda J, Kar, Siddhartha, Chen, Xiaoqing, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, O’Reilly, Martin, Wang, Chen, Korbie, Darren J, Group, Australian Ovarian Cancer Study, Study, Australian Cancer, Lambrechts, Diether, Despierre, Evelyn, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Pisterer, Jacobus, Hillemanns, Peter, Nakanishi, Toru, Yatabe, Yasushi, Goodman, Marc T, Lurie, Galina, Matsuno, Rayna K, Thompson, Pamela J, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James M, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen M, Iversen, Ed, Weber, Rachel Palmieri, Brennan, Donal, Berchuck, Andrew, Pharoah, Paul, Harnett, Paul, Norris, Murray D, Haber, Michelle, Goode, Ellen L, Lee, Jason S, Khanna, Kum Kum, Meyer, Kerstin B, Chenevix-Trench, Georgia, deFazio, Anna, Edwards, Stacey L, MacGregor, Stuart, and Consortium, on behalf of the Ovarian Cancer Association
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Genetics ,Rare Diseases ,Human Genome ,Ovarian Cancer ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Apoptosis ,Biomarkers ,Tumor ,Cell Proliferation ,Chromatin Immunoprecipitation ,Cohort Studies ,Cystadenocarcinoma ,Serous ,Electrophoretic Mobility Shift Assay ,Enhancer Elements ,Genetic ,Fallopian Tube Neoplasms ,Female ,Follow-Up Studies ,Germ-Line Mutation ,Humans ,Ovarian Neoplasms ,Peritoneal Neoplasms ,Polymorphism ,Single Nucleotide ,Prognosis ,RNA ,Messenger ,Real-Time Polymerase Chain Reaction ,Reverse Transcriptase Polymerase Chain Reaction ,Survival Rate ,Transcription Factors ,Tumor Cells ,Cultured ,epithelial ovarian cancer ,progression free survival ,genome-wide association study ,PSIP1 ,chromosome conformation capture ,Australian Ovarian Cancer Study Group ,Australian Ovarian Cancer Study ,Ovarian Cancer Association Consortium ,Oncology and Carcinogenesis - Abstract
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
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- 2016
23. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
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Bailey, Jessica N Cooke, Loomis, Stephanie J, Kang, Jae H, Allingham, R Rand, Gharahkhani, Puya, Khor, Chiea Chuen, Burdon, Kathryn P, Aschard, Hugues, Chasman, Daniel I, Igo, Robert P, Hysi, Pirro G, Glastonbury, Craig A, Ashley-Koch, Allison, Brilliant, Murray, Brown, Andrew A, Budenz, Donald L, Buil, Alfonso, Cheng, Ching-Yu, Choi, Hyon, Christen, William G, Curhan, Gary, De Vivo, Immaculata, Fingert, John H, Foster, Paul J, Fuchs, Charles, Gaasterland, Douglas, Gaasterland, Terry, Hewitt, Alex W, Hu, Frank, Hunter, David J, Khawaja, Anthony P, Lee, Richard K, Li, Zheng, Lichter, Paul R, Mackey, David A, McGuffin, Peter, Mitchell, Paul, Moroi, Sayoko E, Perera, Shamira A, Pepper, Keating W, Qi, Qibin, Realini, Tony, Richards, Julia E, Ridker, Paul M, Rimm, Eric, Ritch, Robert, Ritchie, Marylyn, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Song, Yeunjoo E, Tamimi, Rulla M, Topouzis, Fotis, Viswanathan, Ananth C, Verma, Shefali Setia, Vollrath, Douglas, Wang, Jie Jin, Weisschuh, Nicole, Wissinger, Bernd, Wollstein, Gadi, Wong, Tien Y, Yaspan, Brian L, Zack, Donald J, Zhang, Kang, Study, EPIC-Norfolk Eye, Weinreb, Robert N, Pericak-Vance, Margaret A, Small, Kerrin, Hammond, Christopher J, Aung, Tin, Liu, Yutao, Vithana, Eranga N, MacGregor, Stuart, Craig, Jamie E, Kraft, Peter, Howell, Gareth, Hauser, Michael A, Pasquale, Louis R, Haines, Jonathan L, and Wiggs, Janey L
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Biological Sciences ,Genetics ,Eye Disease and Disorders of Vision ,Neurodegenerative ,Neurosciences ,Human Genome ,Aging ,Eye ,Ataxin-2 ,Forkhead Transcription Factors ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Glaucoma ,Open-Angle ,Humans ,Polymorphism ,Single Nucleotide ,Thioredoxin Reductase 2 ,ANZRAG Consortium ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
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- 2016
24. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium
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Johnatty, Sharon E, Group, on behalf of the Australian Ovarian Cancer Study, Tyrer, Jonathan P, Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B, Moysich, Kirsten B, Levine, Douglas A, Kiemeney, Lambertus A, Massuger, Leon FAG, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S, McGuire, Valerie, Rothstein, Joseph H, Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O, Wu, Anna H, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K, Spiewankiewicz, Beata, Goodman, Marc T, Wilkens, Lynne R, Carney, Michael E, Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Group, on behalf of the AGO Study, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C, Fogarty, Zachary C, Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L, Cunningham, Julie M, Vierkant, Robert A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Bandera, Elisa V, Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, and Pharoah, Paul DP
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Genetics ,Human Genome ,Precision Medicine ,Rare Diseases ,Women's Health ,Cancer Genomics ,Ovarian Cancer ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Alleles ,Carcinoma ,Ovarian Epithelial ,Computational Biology ,Female ,Genome-Wide Association Study ,Genotype ,Humans ,Kaplan-Meier Estimate ,Meta-Analysis as Topic ,Neoplasms ,Glandular and Epithelial ,Ovarian Neoplasms ,Patient Outcome Assessment ,Polymorphism ,Single Nucleotide ,Prognosis ,Quantitative Trait Loci ,AGO Study Group ,Australian Ovarian Cancer Study Group ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeChemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.Experimental designWe analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.ResultsFive SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)).ConclusionsWe have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.
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- 2015
25. Meta‐analysis of Genome‐Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology
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Springelkamp, Henriët, Mishra, Aniket, Hysi, Pirro G, Gharahkhani, Puya, Höhn, René, Khor, Chiea‐Chuen, Bailey, Jessica N Cooke, Luo, Xiaoyan, Ramdas, Wishal D, Vithana, Eranga, Koh, Victor, Yazar, Seyhan, Xu, Liang, Forward, Hannah, Kearns, Lisa S, Amin, Najaf, Iglesias, Adriana I, Sim, Kar‐Seng, Leeuwen, Elisabeth M, Demirkan, Ayse, der Lee, Sven, Loon, Seng‐Chee, Rivadeneira, Fernando, Nag, Abhishek, Sanfilippo, Paul G, Schillert, Arne, de Jong, Paulus TVM, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Consortium, NEIGHBORHOOD, Zhou, Tiger, Burdon, Kathryn P, Spector, Timothy D, Lackner, Karl J, Saw, Seang‐Mei, Vingerling, Johannes R, Teo, Yik‐Ying, Pasquale, Louis R, Wolfs, Roger CW, Lemij, Hans G, Tai, E‐Shyong, Jonas, Jost B, Cheng, Ching‐Yu, Aung, Tin, Jansonius, Nomdo M, Klaver, Caroline CW, Craig, Jamie E, Young, Terri L, Haines, Jonathan L, MacGregor, Stuart, Mackey, David A, Pfeiffer, Norbert, Wong, Tien‐Yin, Wiggs, Janey L, Hewitt, Alex W, Duijn, Cornelia M, and Hammond, Christopher J
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Aging ,Human Genome ,Eye Disease and Disorders of Vision ,Genetics ,Neurosciences ,Neurodegenerative ,Eye ,Asian People ,Genome-Wide Association Study ,Glaucoma ,Humans ,Optic Disk ,Optic Nerve Diseases ,Quantitative Trait Loci ,White People ,NEIGHBORHOOD Consortium ,GWAS ,cup area ,disc area ,glaucoma ,Public Health and Health Services ,Epidemiology - Abstract
Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
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- 2015
26. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.
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Springelkamp, Henriët, Höhn, René, Mishra, Aniket, Hysi, Pirro G, Khor, Chiea-Chuen, Loomis, Stephanie J, Bailey, Jessica N Cooke, Gibson, Jane, Thorleifsson, Gudmar, Janssen, Sarah F, Luo, Xiaoyan, Ramdas, Wishal D, Vithana, Eranga, Nongpiur, Monisha E, Montgomery, Grant W, Xu, Liang, Mountain, Jenny E, Gharahkhani, Puya, Lu, Yi, Amin, Najaf, Karssen, Lennart C, Sim, Kar-Seng, van Leeuwen, Elisabeth M, Iglesias, Adriana I, Verhoeven, Virginie JM, Hauser, Michael A, Loon, Seng-Chee, Despriet, Dominiek DG, Nag, Abhishek, Venturini, Cristina, Sanfilippo, Paul G, Schillert, Arne, Kang, Jae H, Landers, John, Jonasson, Fridbert, Cree, Angela J, van Koolwijk, Leonieke ME, Rivadeneira, Fernando, Souzeau, Emmanuelle, Jonsson, Vesteinn, Menon, Geeta, Blue Mountains Eye Study—GWAS group, Weinreb, Robert N, de Jong, Paulus TVM, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Ennis, Sarah, Thorsteinsdottir, Unnur, Burdon, Kathryn P, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Spector, Timothy D, Mirshahi, Alireza, Saw, Seang-Mei, Vingerling, Johannes R, Teo, Yik-Ying, Haines, Jonathan L, Wolfs, Roger CW, Lemij, Hans G, Tai, E-Shyong, Jansonius, Nomdo M, Jonas, Jost B, Cheng, Ching-Yu, Aung, Tin, Viswanathan, Ananth C, Klaver, Caroline CW, Craig, Jamie E, Macgregor, Stuart, Mackey, David A, Lotery, Andrew J, Stefansson, Kari, Bergen, Arthur AB, Young, Terri L, Wiggs, Janey L, Pfeiffer, Norbert, Wong, Tien-Yin, Pasquale, Louis R, Hewitt, Alex W, van Duijn, Cornelia M, and Hammond, Christopher J
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Blue Mountains Eye Study—GWAS group ,NEIGHBORHOOD Consortium ,Wellcome Trust Case Control Consortium 2 ,Optic Nerve ,Optic Disk ,Humans ,Glaucoma ,Case-Control Studies ,Gene Expression Profiling ,Gene Frequency ,Genotype ,Phenotype ,Polymorphism ,Single Nucleotide ,Asian Continental Ancestry Group ,European Continental Ancestry Group ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,Human Genome ,Genetics ,Neurodegenerative ,Eye Disease and Disorders of Vision ,Neurosciences ,2.1 Biological and endogenous factors ,Eye - Abstract
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
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- 2014
27. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.
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Hedditch, Ellen L, Gao, Bo, Russell, Amanda J, Lu, Yi, Emmanuel, Catherine, Beesley, Jonathan, Johnatty, Sharon E, Chen, Xiaoqing, Harnett, Paul, George, Joshy, Australian Ovarian Cancer Study Group, Williams, Rebekka T, Flemming, Claudia, Lambrechts, Diether, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Nakanishi, Toru, Yatabe, Yasushi, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susan K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen, Iversen, Ed, Weber, Rachel P, Berchuck, Andrew, Goode, Ellen, Bowtell, David D, Chenevix-Trench, Georgia, deFazio, Anna, Norris, Murray D, MacGregor, Stuart, Haber, Michelle, and Henderson, Michelle J
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Australian Ovarian Cancer Study Group ,Humans ,Neoplasms ,Glandular and Epithelial ,Cystadenocarcinoma ,Serous ,Ovarian Neoplasms ,ATP-Binding Cassette Transporters ,RNA ,Messenger ,Cell Movement ,Gene Expression Regulation ,Neoplastic ,Polymorphism ,Single Nucleotide ,Female ,Neoplastic Stem Cells ,Genome-Wide Association Study ,Kaplan-Meier Estimate ,Real-Time Polymerase Chain Reaction ,Neoplasm Grading ,ATP Binding Cassette Transporter 1 ,Carcinoma ,Ovarian Epithelial ,Ovarian Cancer ,Rare Diseases ,Biotechnology ,Genetics ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
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- 2014
28. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas
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Johnatty, Sharon E, Beesley, Jonathan, Gao, Bo, Chen, Xiaoqing, Lu, Yi, Law, Matthew H, Henderson, Michelle J, Russell, Amanda J, Hedditch, Ellen L, Emmanuel, Catherine, Fereday, Sian, Webb, Penelope M, Group, Australian Ovarian Cancer Study, Goode, Ellen L, Vierkant, Robert A, Fridley, Brooke L, Cunningham, Julie M, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Brown, Robert, Paul, Jim, Lambrechts, Sandrina, Despierre, Evelyn, Vergote, Ignace, Lester, Jenny, Karlan, Beth Y, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Bean, Yukie, Pejovic, Tanja, Levine, Douglas A, Goodman, Marc T, Camey, Michael E, Thompson, Pamela J, Lurie, Galina, Shildkraut, Joellen, Berchuck, Andrew, Terry, Kathryn L, Cramer, Daniel W, Norris, Murray D, Haber, Michelle, MacGregor, Stuart, deFazio, Anna, and Chenevix-Trench, Georgia
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Genetics ,Ovarian Cancer ,Rare Diseases ,Human Genome ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,ATP Binding Cassette Transporter ,Subfamily B ,ATP Binding Cassette Transporter ,Subfamily B ,Member 1 ,Antineoplastic Combined Chemotherapy Protocols ,Carboplatin ,Carcinoma ,Ovarian Epithelial ,Disease Progression ,Disease-Free Survival ,Drug Resistance ,Multiple ,Drug Resistance ,Neoplasm ,Female ,Humans ,Kaplan-Meier Estimate ,Neoplasms ,Glandular and Epithelial ,Ovarian Neoplasms ,Paclitaxel ,Pharmacogenetics ,Polymorphism ,Single Nucleotide ,Proportional Hazards Models ,Ovarian cancer ,Polymorphisms ,Outcome ,Chemotherapy ,ABCB1 ,Australian Ovarian Cancer Study Group ,Oncology and Carcinogenesis ,Paediatrics and Reproductive Medicine ,Oncology & Carcinogenesis - Abstract
ObjectiveABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).MethodsThe best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.ResultFine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.ConclusionOur study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.
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- 2013
29. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error
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Cheng, Ching-Yu, Schache, Maria, Ikram, M Kamran, Young, Terri L, Guggenheim, Jeremy A, Vitart, Veronique, MacGregor, Stuart, Verhoeven, Virginie JM, Barathi, Veluchamy A, Liao, Jiemin, Hysi, Pirro G, Bailey-Wilson, Joan E, St. Pourcain, Beate, Kemp, John P, McMahon, George, Timpson, Nicholas J, Evans, David M, Montgomery, Grant W, Mishra, Aniket, Wang, Ya Xing, Wang, Jie Jin, Rochtchina, Elena, Polasek, Ozren, Wright, Alan F, Amin, Najaf, van Leeuwen, Elisabeth M, Wilson, James F, Pennell, Craig E, van Duijn, Cornelia M, de Jong, Paulus TVM, Vingerling, Johannes R, Zhou, Xin, Chen, Peng, Li, Ruoying, Tay, Wan-Ting, Zheng, Yingfeng, Chew, Merwyn, Error and Myopia, Consortium for Refractive, Cohort, 1958 British Birth, Rahi, Jugnoo S, cohort, Aichi, Yoshimura, Nagahisa, Yamashiro, Kenji, Miyake, Masahiro, ALIENOR, Delcourt, Cécile, Maubaret, Cecilia, ALSPAC, Williams, Cathy, Northstone, Kate, Ring, Susan M, Davey-Smith, George, ANZRAG, Craig, Jamie E, Burdon, Kathryn P, Fogarty, Rhys D, AREDS1a, Iyengar, Sudha K, Igo, Robert P, Chew, Emily, Janmahasathian, Sarayut, AREDS1b, AREDS1c, Stambolian, Dwight, Wilson, Joan E Bailey, BATS, Lu, Yi, Study, Beijing Eye, Jonas, Jost B, Xu, Liang, Saw, Seang-Mei, BMES, Baird, Paul N, Mitchell, Paul, CIEMS, Nangia, Vinay, CROATIA-Korčula, Hayward, Caroline, CROATIA-Split, Campbell, Harry, CROATIA-Vis, Rudan, Igor, Vatavuk, Zoran, DCCT, Paterson, Andrew D, Hosseini, S Mohsen, GWAS, FECD Fuchs Dystrophy, Fondran, Jeremy R, Study, Myopia, Feng, Sheng, and Study, Erasmus Rucphen Family
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Allied Health and Rehabilitation Science ,Health Sciences ,Ophthalmology and Optometry ,Human Genome ,Eye Disease and Disorders of Vision ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Eye ,Adolescent ,Adult ,Aged ,Asian People ,Axial Length ,Eye ,Eye Proteins ,Female ,Gene Expression ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Refractive Errors ,Signal Transduction ,White People ,Consortium for Refractive Error and Myopia ,Fuchs' Genetics Multi-Center Study Group ,Wellcome Trust Case Control Consortium 2 ,Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions ,and Complications Research Group ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
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- 2013
30. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size
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Macgregor, Stuart, Hewitt, Alex W, Hysi, Pirro G, Ruddle, Jonathan B, Medland, Sarah E, Henders, Anjali K, Gordon, Scott D, Andrew, Toby, McEvoy, Brian, Sanfilippo, Paul G, Carbonaro, Francis, Tah, Vikas, Li, Yi Ju, Bennett, Sonya L, Craig, Jamie E, Montgomery, Grant W, Tran-Viet, Khanh-Nhat, Brown, Nadean L, Spector, Timothy D, Martin, Nicholas G, Young, Terri L, Hammond, Christopher J, and Mackey, David A
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Eye Disease and Disorders of Vision ,Neurosciences ,Human Genome ,Clinical Research ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Eye ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Australia ,Basic Helix-Loop-Helix Transcription Factors ,Blindness ,Child ,Child ,Preschool ,Genome-Wide Association Study ,Humans ,Membrane Proteins ,Middle Aged ,Optic Disk ,Optic Nerve ,Polymorphism ,Single Nucleotide ,Twins ,United Kingdom ,Young Adult ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.
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- 2010
31. Evaluation of Association of HNF1B Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies
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Elliott, Katherine S, Zeggini, Eleftheria, McCarthy, Mark I, Gudmundsson, Julius, Sulem, Patrick, Stacey, Simon N, Thorlacius, Steinunn, Amundadottir, Laufey, Grönberg, Henrik, Xu, Jianfeng, Gaborieau, Valerie, Eeles, Rosalind A, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Muir, Kenneth, Hwang, Shih-Jen, Spitz, Margaret R, Zanke, Brent, Carvajal-Carmona, Luis, Brown, Kevin M, Hayward, Nicholas K, Macgregor, Stuart, Tomlinson, Ian PM, Lemire, Mathieu, Amos, Christopher I, Murabito, Joanne M, Isaacs, William B, Easton, Douglas F, Brennan, Paul, Barkardottir, Rosa B, Gudbjartsson, Daniel F, Rafnar, Thorunn, Hunter, David J, Chanock, Stephen J, Stefansson, Kari, and Ioannidis, John PA
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Epidemiology ,Health Services and Systems ,Health Sciences ,Oncology and Carcinogenesis ,Human Genome ,Aging ,Urologic Diseases ,Prostate Cancer ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Cooperative Behavior ,Databases ,Genetic ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Hepatocyte Nuclear Factor 1-beta ,Humans ,Neoplasms ,Polymorphism ,Single Nucleotide ,Australian Melanoma Family Study Investigators ,PanScan Consortium ,General Science & Technology - Abstract
BackgroundGenome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only.Methodology/principal findingsIn a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p
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- 2010
32. Identification of a genetic variant associated with treatment outcome in ovarian cancer: the potential role of cholesterol metabolism as a determinant of response to chemotherapy
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Chenevix-Trench Georgia, Lu Yi, Johnatty Sharon, Gamazon Eric, Beesley Jonathan, Chen Xiaoqing, Gao Bo, Harnett Paul, Stephanie Huang R, Despierre Evelyn, Heitz Florian, Hogdall Estrid, Hogdall Claus, Brown Robert, Moyisch Kirsten, Fasching Peter, Goode Ellen, Russell Amanda, Henderson Michelle, Haber Michelle, Dolan Eileen, Macgregor Stuart, and deFazio Anna
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Genetics ,QH426-470 - Published
- 2012
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33. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
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Duffy, David L, Zhu, Gu, Xin, Li, Sanna, Marianna, Iles, Mark M, Jacobs, Leonie C, Evans, David M, Yazar, Seyhan, Beesley, Jonathan, Law, Matthew H, Kraft, Peter, Visconti, Alessia, Taylor, John C, Lui, Fan, Wright, Margaret J, Henders, Anjali K, Bowdler, Lisa, Glass, Dan, Ikram, Arfan M, Uitterlinden, André G, Madden, Pamela A, Heath, Andrew C, Nelson, Elliot C, Green, Adele C, Chanock, Stephen, Barrett, Jennifer H, Brown, Matthew A, Hayward, Nicholas K, Macgregor, Stuart, Sturm, Richard A, Hewitt, Alex W, Kayser, Manfred, Hunter, David J, Newton Bishop, Julia A, Spector, Timothy D, Montgomery, Grant W, Mackey, David A, Smith, George Davey, Nijsten, Tamar E, Bishop, D Timothy, Bataille, Veronique, Falchi, Mario, Han, Jiali, Martin, Nicholas, G, Lee, Je, Brossard, M, Moses, Ek, Song, F, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Scarrà, Gb, Brown, Km, Dębniak, T, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Schulze, Hj, Dunning, Am, Demenais, F, Amos, Ci., Apollo - University of Cambridge Repository, Dermatology, Genetic Identification, Epidemiology, Internal Medicine, and Consortium, Melanoma Gwas
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0301 basic medicine ,Skin Neoplasms ,Medizin ,General Physics and Astronomy ,Genome-wide association study ,Receptors, G-Protein-Coupled ,0302 clinical medicine ,Guanine Nucleotide Exchange Factors ,lcsh:Science ,skin and connective tissue diseases ,Melanoma ,Telomerase ,Genetics ,0303 health sciences ,Nevus, Pigmented ,Stem Cell Factor ,Multidisciplinary ,Microfilament Proteins ,Nuclear Proteins ,RNA-Binding Proteins ,Genetic Pleiotropy ,Microphthalmia-associated transcription factor ,3. Good health ,030220 oncology & carcinogenesis ,Cytochrome P-450 CYP1B1 ,Interferon Regulatory Factors ,Medical genetics ,PPARGC1B ,Dock8 ,medicine.medical_specialty ,Science ,Telomere-Binding Proteins ,Single-nucleotide polymorphism ,Nerve Tissue Proteins ,Biology ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Histone Deacetylases ,White People ,Group VI Phospholipases A2 ,03 medical and health sciences ,Genetic predisposition ,Pigmented Nevus ,medicine ,Nevus ,Humans ,Genetic Predisposition to Disease ,neoplasms ,030304 developmental biology ,General Chemistry ,medicine.disease ,Repressor Proteins ,MicroRNAs ,030104 developmental biology ,Cutaneous melanoma ,RNA ,lcsh:Q ,Carrier Proteins ,IRF4 ,Genome-Wide Association Study - Abstract
The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.
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- 2018
34. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
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Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Shi, Jianxin, Mai, Xu, Goldstein, Alisa M., Trower, Adam J., Bishop, D. Timothy, Iles, Mark M., Duffy, David L., Macgregor, Stuart, Amundadottir, Laufey T., Law, Matthew H., Loftus, Stacie K., Pavan, William J., Brown, Kevin M., Lee, Je, Brossard, M, Martin, Ng, Moses, Ek, Song, F, Barrett, Jh, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Taylor, Jc, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Bianchi Scarrà, G, Dȩbniak, T, Duffy, Dl, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Montgomery, Gw, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Wu, W, Qureshi, Aa, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Hayward, Nk, Han, J, Schulze, Hj, Dunning, Am, Bishop, Jan, Demenais, F, Amos, Ci, Macgregor, S, Iles, Mm, Barnabas, Bb, Bouffard, Gg, Brooks, Sy, Coleman, H, Dekhtyar, L, Guan, X, Ho, Sl, Legaspi, R, Maduro, Ql, Masiello, Ca, Mcdowell, Jc, Montemayor, C, Mullikin, Jc, Park, M, Riebow, Nl, Schandler, K, Schmidt, B, Sison, C, Smith, R, Stantripop, S, Thomas, Jw, Thomas, Pj, Vemulapalli, M, and Young, Ac.
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0301 basic medicine ,Hemeproteins ,Linkage disequilibrium ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Quantitative trait locus ,Melanocyte ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,03 medical and health sciences ,Heme-Binding Proteins ,0302 clinical medicine ,Genetics ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Genetic Predisposition to Disease ,Melanoma ,Genetics (clinical) ,Cells, Cultured ,Genetic association ,Research ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Expression quantitative trait loci ,Interferon Regulatory Factors ,Melanocytes ,Carrier Proteins - Abstract
Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
- Published
- 2018
35. GAIA: An easy-to-use web-based application for interaction analysis of case-control data
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Macgregor Stuart and Khan Imtiaz A
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Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background The advent of cheap, large scale genotyping has led to widespread adoption of genetic association mapping as the tool of choice in the search for loci underlying susceptibility to common complex disease. Whilst simple single locus analysis is relatively trivial to conduct, this is not true of more complex analysis such as those involving interactions between loci. The importance of testing for interactions between loci in association analysis has been highlighted in a number of recent high profile publications. Results Genetic Association Interaction Analysis (GAIA) is a web-based application for testing for statistical interactions between loci. It is based upon the widely used case-control study design for genetic association analysis and is designed so that non-specialists may routinely apply tests for interaction. GAIA allows simple testing of both additive and additive plus dominance interaction models and includes permutation testing to appropriately correct for multiple testing. The application will find use both in candidate gene based studies and in genome-wide association studies. For large scale studies GAIA includes a screening approach which prioritizes loci (based on the significance of main effects at one or both loci) for further interaction analysis. Conclusion GAIA is available at http://www.bbu.cf.ac.uk/html/research/biostats.htm
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- 2006
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36. Gene Discovery Using Twins.
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Duffy, David, Sturm, Rick, Zhu, Gu, MacGregor, Stuart, Evans, David, Medland, Sarah, and Gillespie, Nathan
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TWINS ,SKIN cancer ,EYE color ,MELANOMA ,GENE expression ,GENE mapping ,NEVUS ,HISTORY ,SKIN tumors ,SYMPTOMS ,ANIMAL coloration ,GENETIC techniques ,PHENOTYPES ,EPIDEMIOLOGICAL research - Abstract
One of Nick's key early achievements at QIMR was to establish a twin study on melanoma risk factors. The Brisbane Twin Nevus Study (BTNS) had an initial focus on nevus (mole) count in adolescents but, reflecting Nick's broad interests, expanded in scope enormously over the decades. In the skin cancer arena, BTNS was essential to genetic discoveries in melanoma, eye color and pigmentation. Later studies amassed data on thousands of phenotypes, ranging from molecular phenotypes such as gene expression to studies where gene mapping findings in adolescents turned out to have translational potential in late-onset diseases. Nick's twin data have formed the basis for an enormous range of discoveries, with Nick and his colleagues continuing to capitalize on these data. [ABSTRACT FROM AUTHOR]
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- 2020
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37. Potential influence of socioeconomic status on genetic correlations between alcohol consumption measures and mental health.
- Author
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Marees, Andries T., Smit, Dirk J. A., Ong, Jue-Sheng, MacGregor, Stuart, An, Jiyuan, Denys, Damiaan, Vorspan, Florence, van den Brink, Wim, and Derks, Eske M.
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ALCOHOL drinking ,GENETICS ,GENOMES ,MENTAL health ,MENTAL illness ,REGRESSION analysis ,PHENOTYPES ,SOCIOECONOMIC factors ,HEALTH & social status - Abstract
Background. Frequency and quantity of alcohol consumption are metrics commonly used to measure alcohol consumption behaviors. Epidemiological studies indicate that these alcohol consumption measures are differentially associated with (mental) health outcomes and socioeconomic status (SES). The current study aims to elucidate to what extent genetic risk factors are shared between frequency and quantity of alcohol consumption, and how these alcohol consumption measures are genetically associated with four broad phenotypic categories: (i) SES; (ii) substance use disorders; (iii) other psychiatric disorders; and (iv) psychological/personality traits. Methods. Genome-Wide Association analyses were conducted to test genetic associations with alcohol consumption frequency (N = 438 308) and alcohol consumption quantity (N = 307 098 regular alcohol drinkers) within UK Biobank. For the other phenotypes, we used genome-wide association studies summary statistics. Genetic correlations (r
g ) between the alcohol measures and other phenotypes were estimated using LD score regression. Results. We found a substantial genetic correlation between the frequency and quantity of alcohol consumption (rg = 0.52). Nevertheless, both measures consistently showed opposite genetic correlations with SES traits, and many substance use, psychiatric, and psychological/personality traits. High alcohol consumption frequency was genetically associated with high SES and low risk of substance use disorders and other psychiatric disorders, whereas the opposite applies for high alcohol consumption quantity. Conclusions. Although the frequency and quantity of alcohol consumption show substantial genetic overlap, they consistently show opposite patterns of genetic associations with SES-related phenotypes. Future studies should carefully consider the potential influence of SES on the shared genetic etiology between alcohol and adverse (mental) health outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2020
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38. Genome-wide association study identifies WNT7B as a novel locus for central corneal thickness in Latinos
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Gao, Xiaoyi, Nannini, Drew R., Corrao, Kristen, Torres, Mina, Chen, Yii Der I., Fan, Bao J., Wiggs, Janey L., Taylor, Kent D., Gauderman, W. James, Rotter, Jerome I., Varma, Rohit, Aung, Tin, Burdon, Kathryn P., Cheng, Ching Yu, Craig, Jamie E., Cree, Angela J., Gharahkhani, Puya, Hammond, Christopher J., Hewitt, Alex W., Höhn, René, Hysi, Pirro, Gonzalez, Adriana I.Iglesias, Jonas, Jost, Khawaja, Anthony, Khor, Chiea Cheun, Klaver, Caroline C.W., Pasutto, Francesca, MacGregor, Stuart, Mackey, David, Mitchell, Paul, Mishra, Aniket, Pang, Calvin, Pasquale, Louis R., Springelkamp, Henriette, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, van Duijn, Cornelia M., Viswanathan, Ananth, Vitart, Veronique, Wojciechowski, Robert, Wong, Tien, Young, Terrri L., Zeller, Tanja, Ophthalmology, Epidemiology, and Obstetrics & Gynecology
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0301 basic medicine ,Adult ,Male ,genetic structures ,Corneal Pachymetry ,Genotype ,Genetic genealogy ,Population ,Genome-wide association study ,Single-nucleotide polymorphism ,Biology ,Keratoconus ,Polymorphism, Single Nucleotide ,Cornea ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Genetics ,Humans ,1000 Genomes Project ,education ,Molecular Biology ,Genetics (clinical) ,Genetic association ,Aged ,education.field_of_study ,Association Studies Articles ,Glaucoma ,General Medicine ,Hispanic or Latino ,Middle Aged ,Los Angeles ,Genetic architecture ,eye diseases ,Wnt Proteins ,030104 developmental biology ,Genetic Loci ,Female ,sense organs ,Imputation (genetics) ,Glaucoma, Open-Angle ,Genome-Wide Association Study - Abstract
The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (~730K markers) or the Illumina Hispanic/SOL BeadChip (~2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P=6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1 and ZNF469 (P < 1.25E-3). These findings provide further insight into the genetic architecture of CCT and illustrate that the use of minority groups in GWAS will help identify additional loci.
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- 2016
39. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium
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Johnatty, Sharon E., Tyrer, Jonathan P., Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Lambrechts, Diether, Nieuwenhuysen, Els Van, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A., Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B., Moysich, Kirsten B., Levine, Douglas A., Kiemeney, Lambertus A., Massuger, Leon F.A.G., Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S., McGuire, Valerie, Rothstein, Joseph H., Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J., Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O., Wu, Anna H., Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Spiewankiewicz, Beata, Goodman, Marc T., Wilkens, Lynne R., Carney, Michael E., Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C., Fogarty, Zachary C., Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L., Cunningham, Julie M., Vierkant, Robert A., Schildkraut, Joellen M., Iversen, Edwin S., Terry, Kathryn L., Cramer, Daniel W., Bandera, Elisa V., Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, deFazio, Anna, Pharoah, Paul D.P., Goode, Ellen L., Webb, Penelope M., and Chenevix-Trench, Georgia
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Oncology ,Cancer Research ,Genome-wide association study ,AGO Study Group ,Kaplan-Meier Estimate ,Carcinoma, Ovarian Epithelial ,Bioinformatics ,chemistry.chemical_compound ,Neoplasms ,Ovarian Epithelial ,2.1 Biological and endogenous factors ,Neoplasms, Glandular and Epithelial ,Aetiology ,Cancer ,Ovarian Neoplasms ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,Glandular and Epithelial ,Single Nucleotide ,Prognosis ,Ovarian Cancer ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Female ,Australian Ovarian Cancer Study Group ,medicine.medical_specialty ,Genotype ,Quantitative Trait Loci ,Oncology and Carcinogenesis ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Article ,Rare Diseases ,Meta-Analysis as Topic ,Clinical Research ,Internal medicine ,Carcinoma ,medicine ,Genetics ,SNP ,Humans ,Progression-free survival ,Oncology & Carcinogenesis ,Polymorphism ,Alleles ,business.industry ,Human Genome ,Computational Biology ,medicine.disease ,Carboplatin ,Patient Outcome Assessment ,Regimen ,Orphan Drug ,chemistry ,Ovarian cancer ,business ,Genome-Wide Association Study - Abstract
Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.
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- 2015
40. Genetic studies of body mass index yield new insights for obesity biology
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Ebrahim, S., Eriksson, JG., Fauser, BC., Ferreli, L., Folsom, AR., Garcia, ME., Hall, P., Haller, T., Hankinson, SE., Hass, M., Heath, AC., Janssens, AC., Karasik, D., Keyzer, J., Kiel, DP., Lahti, J., Lai, S., Laisk, T., Laven, JS., Liu, J., Lopez, LM., Louwers, YV., Marongiu, M., Klaric, IM., Masciullo, C., McKnight, B., Medland, SE., Melzer, D., Newman, AB., Paré, G., Peeters, PH., Plump, AS., Pop, VJ., Räikkönen, K., Salumets, A., Smith, JA., Stacey, SN., Starr, JM., Stathopoulou, MG., Styrkarsdottir, U., Tenesa, A., Thorand, B., Tryggvadottir, L., Tsui, K., van Dam RM., van Gils CH., van Nierop, P., Vink, JM., Voorhuis, M., Wallaschofski, H., Widen, E., Wijnands-van Gent CJ., Yerges-Armstrong, LM., Zgaga, L., Zillikens, MC., Zygmunt, M., Arnold, AM., Buring, JE., Crisponi, L., Demerath, EW., Hunter, DJ., Schlessinger, D., Streeten, EA., Murray, A., Murabito, JM., Visser, JA., Lunetta, KL., Elks, CE., Cousminer, DL., Feenstra, B., Koller, DL., Lin, P., van Wingerden SW., Smith, EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Eriksson, J., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Peacock, M., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., van Meurs JB., Weedon, MN., Wichmann, H., Young, L., Bierut, LJ., Boyd, HA., Econs, MJ., Van T'Hooft, Ferdinand M., Njølstad, Inger, Abecasis, Gonçalo R., Barroso, Inɥ, The MIGEN Consortium, Investigator, Casari, GIORGIO NEVIO, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Locke, A, Kahali, B, Berndt, S, Justice, A, Pers, T, Day, F, Powell, C, Vedantam, S, Buchkovich, M, Yang, J, Croteau-Chonka, D, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Magi, R, Randall, J, Winkler, T, Wood, A, Workalemahu, T, Faul, J, Smith, J, Zhao, J, Zhao, W, Chen, J, Fehrmann, R, Hedman, A, Karjalainen, J, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, J, Bragg-Gresham, J, Buyske, S, Demirkan, A, Deng, G, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Goel, A, Gong, J, Jackson, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Leach, I, Medina-Gomez, C, Medland, S, Nalls, M, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Shungin, D, Stancakova, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet-Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Isaacs, A, Albrecht, E, Arnlov, J, Arscott, G, Attwood, A, Bandinelli, S, Barrett, A, Bas, I, Bellis, C, Bennett, A, Berne, C, Blagieva, R, Bluher, M, Bohringer, S, Bonnycastle, L, Bottcher, Y, Boyd, H, Bruinenberg, M, Caspersen, I, Chen, Y, Clarke, R, Daw, E, de Craen, A, Delgado, G, Dimitriou, M, Doney, A, Eklund, N, Estrada, K, Eury, E, Folkersen, L, Fraser, R, Garcia, M, Geller, F, Giedraitis, V, Gigante, B, Go, A, Golay, A, Goodall, A, Gordon, S, Gorski, M, Grabe, H, Grallert, H, Grammer, T, Grassler, J, Gronberg, H, Groves, C, Gusto, G, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heard-Costa, N, Helmer, Q, Hengstenberg, C, Holmen, O, Hottenga, J, James, A, Jeff, J, Johansson, A, Jolley, J, Juliusdottir, T, Kinnunen, L, Koenig, W, Koskenvuo, M, Kratzer, W, Laitinen, J, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindstrom, J, Lo, K, Lobbens, S, Lorbeer, R, Lu, Y, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Mclachlan, S, Menni, C, Merger, S, Mihailov, E, Milani, L, Moayyeri, A, Monda, K, Morken, M, Mulas, A, Muller, G, Muller-Nurasyid, M, Musk, A, Nagaraja, R, Nothen, M, Nolte, I, Pilz, S, Rayner, N, Renstrom, F, Rettig, R, Ried, J, Ripke, S, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Scott, W, Seufferlein, T, Shi, J, Smith, A, Smolonska, J, Stanton, A, Steinthorsdottir, V, Stirrups, K, Stringham, H, Sundstrom, J, Swertz, M, Swift, A, Syvanen, A, Tan, S, Tayo, B, Thorand, B, Thorleifsson, G, Tyrer, J, Uh, H, Vandenput, L, Verhulst, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Warren, H, Waterworth, D, Weedon, M, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Brennan, E, Choi, M, Dastani, Z, Drong, A, Eriksson, P, Franco-Cereceda, A, Gadin, J, Gharavi, A, Goddard, M, Handsaker, R, Huang, J, Karpe, F, Kathiresan, S, Keildson, S, Kiryluk, K, Kubo, M, Lee, J, Liang, L, Lifton, R, Ma, B, Mccarroll, S, Mcknight, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Okada, Y, Perry, J, Dorajoo, R, Reinmaa, E, Salem, R, Sandholm, N, Scott, R, Stolk, L, Takahashi, A, Van't Hooft, F, Vinkhuyzen, A, Westra, H, Zheng, W, Zondervan, K, Heath, A, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Bovet, P, Campbell, H, Caulfield, M, Cesana, G, Chakravarti, A, Chasman, D, Chines, P, Collins, F, Crawford, D, Cupples, L, Cusi, D, Danesh, J, de Faire, U, Den Ruijter, H, Dominiczak, A, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Felix, S, Ferrannini, E, Ferrieres, J, Ford, I, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gejman, P, Gieger, C, Gottesman, O, Gudnason, V, Gyllensten, U, Hall, A, 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J, Ramos, R, Williams, G, Nathan, D, Macrae, C, Berglund, G, Asselta, R, Duga, S, Spreafico, M, Daly, M, Nemesh, J, Korn, J, Surti, A, Gianniny, L, Parkin, M, Burtt, N, Gabriel, S, Wright, B, Ball, S, Schunkert, I, Linsel-Nitschke, P, Lieb, W, Fischer, M, Grosshennig, A, Preuss, M, Scholz, M, Chen, Z, Wilensky, R, Matthai, W, Qasim, A, Hakonarson, H, Devaney, J, Pichard, A, Kent, K, Satler, L, Lindsay, J, Waksman, R, Knouff, C, Scheffold, T, Berger, K, Huge, A, Martinelli, N, Olivieri, O, Corrocher, R, Xie, C, Ahmadi, K, Ainali, C, Bataille, V, Bell, J, Buil, A, Dermitzakis, E, Dimas, A, Durbin, R, Glass, D, Hassanali, N, Ingle, C, Knowles, D, Krestyaninova, M, Lowe, C, Meduri, E, Di Meglio, P, Montgomery, S, Nestle, F, Nica, A, Nisbet, J, O'Rahilly, S, Parts, L, Potter, S, Sekowska, M, Shin, S, Surdulescu, G, Travers, M, Tsaprouni, L, Tsoka, S, Wilk, A, Yang, T, Higashio, J, Williams, R, Nato, A, Ambite, J, Deelman, E, Manolio, T, Heiss, G, Taylor, K, Avery, C, Graff, M, Lin, D, 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Liu, J, Lopez, L, Louwers, Y, Marongiu, M, Klaric, I, Masciullo, C, Melzer, D, Newman, A, Pare, G, Peeters, P, Pop, V, Raikkonen, K, Salumets, A, Stacey, S, Starr, J, Stathopoulou, M, Styrkarsdottir, U, Tenesa, A, Tryggvadottir, L, Tsui, K, van Dam, R, van Gils, C, van Nierop, P, Vink, J, Voorhuis, M, Widen, E, Wijnands-Van Gent, C, Yerges-Armstrong, L, Zgaga, L, Zygmunt, M, Buring, J, Crisponi, L, Demerath, E, Streeten, E, Murray, A, Visser, J, Lunetta, K, Elks, C, Cousminer, D, Koller, D, Lin, P, Smith, E, Warrington, N, Alavere, H, Berenson, G, Blackburn, H, Busonero, F, Chen, W, Couper, D, Easton, D, Foroud, T, Kilpelainen, T, Li, S, Murray, S, Ness, A, Northstone, K, Peacock, M, Pennell, C, Pharoah, P, Rafnar, T, Rice, J, Ring, S, Schork, N, Segre, A, Sovio, U, Srinivasan, S, Tammesoo, M, van Meurs, J, Young, L, Bierut, L, Econs, M, The ADIPOGen Consortium, The AGEN-BMI Working Group, The CARDIOGRAMplusC4D Consortium, The CKDGen Consortium, The GLGC, The ICBP, The MAGIC Investigators, The MuTHER Consortium, The MIGen Consortium, The PAGE Consortium, The ReproGen Consortium, The GENIE Consortium, The International Endogene Consortium, Berndt, Sonja I, Justice, Anne E, Hyppönen, Elina Tuulikki, Epidemiology and Data Science, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
- Subjects
Male ,LOCI ,Genome-wide association study ,Continental Population Groups/genetics ,VARIANTS ,Body Mass Index ,Insulin Secretion ,Insulin ,Age Factor ,Adiposity ,ddc:616 ,Adipogenesis ,Genetic Predisposition to Disease/genetics ,Synapse ,3. Good health ,Continental Population Group ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,GENOME-WIDE ASSOCIATIONPROVIDES INSIGHTSGLYCEMIC TRAITSLOCIMETAANALYSISVARIANTSINDIVIDUALSHIPPOCAMPALARCHITECTURETOPIRAMATE ,ddc:500 ,Adipogenesis/genetics ,Single Nucleotide/genetics ,Age Factors ,Continental Population Groups ,Energy Metabolism ,Europe ,Female ,Genetic Predisposition to Disease ,Glutamic Acid ,Humans ,Obesity ,Polymorphism, Single Nucleotide ,Quantitative Trait Loci ,Synapses ,Genome-Wide Association Study ,Multidisciplinary ,genetics [Adiposity] ,Human ,Socio-culturale ,genetics [Energy Metabolism] ,ta3111 ,genetic, body mass index, obesity ,SDG 3 - Good Health and Well-being ,GLYCEMIC TRAITS ,genetics [Continental Population Groups] ,Genetic variability ,Polymorphism ,GENOME-WIDE ASSOCIATION ,genetics [Adipogenesis] ,METAANALYSIS ,Genetic association ,Adipogenesi ,genetics [Quantitative Trait Loci] ,ta1184 ,metabolism [Glutamic Acid] ,ta1182 ,PATHWAYS ,metabolism [Synapses] ,ta3121 ,medicine.disease ,metabolism [Insulin] ,Adiposity/genetics ,Clinical Medicine ,Quantitative Trait Loci/genetics ,Body mass index ,HUMAN HEIGHT ,BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Synapses/metabolism ,Medizin ,Obesity/genetics ,Bioinformatics ,genetic basis ,Obesity/metabolism ,genetics [Obesity] ,body mass index (BMI) ,genetics [Genetic Predisposition to Disease] ,ethnology [Europe] ,2. Zero hunger ,Genetics ,ARCHITECTURE ,Genetics of obesity ,Medicine (all) ,Single Nucleotide ,Polymorphism, Single Nucleotide/genetics ,Insulin/metabolism/secretion ,Glutamic Acid/metabolism ,genetics [Polymorphism, Single Nucleotide] ,EXPRESSION ,Insulin/metabolism ,PROVIDES INSIGHTS ,genetics [Racial Groups] ,Biology ,Obesity/genetics/metabolism ,Europe/ethnology ,metabolism [Obesity] ,Mendelian randomization ,medicine ,Energy Metabolism/genetics ,body mass, genetic analysis, obesity ,Klinisk medicin - Abstract
Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
- Published
- 2015
41. New genetic loci link adipose and insulin biology to body fat distribution
- Author
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Zgaga, L., Zygmunt, M., Arnold, AM., Buring, JE., Crisponi, L., Demerath, EW., Hunter, DJ., Schlessinger, D., Murray, A., Murabito, JM., Visser, JA., Lunetta, KL., Elks, CE., Cousminer, DL., Feenstra, B., Lin, P., van Wingerden SW., Smith, EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., Weedon, MN., Wichmann, H., Young, L., Zhuang, WV., Bierut, LJ., Boyd, HA., Department of Clinical Sciences, Lund University [Lund], Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Umeå University, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Sciences, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Laboratory of Image Science and Technology [Nanjing] (LIST), Southeast University [Jiangsu]-School of Computer Science and Engineering, Limnology, Ecology, Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Institute of Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, King‘s College London, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Department of Pharmacy Sciences, Creighton University Medical Center, Medical Department III, Universität Leipzig, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Public Health and Clinical Medicine, Medstar Research Institute, Genetics and Pathology, Finnish Institute of Occupational Health, Epidemiology, University Medical Centre Groningen, Departments of Microbiology & Molecular Genetics and Molecular Biology & Biochemistry, University of California [Irvine] (UC Irvine), Department of Odontology, Cariology, Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Division of Cardiology, Geneva University Hospital (HUG), Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Anaesthesia and Intensive care, Royal Aberdeen Childrens Hospital, UCL Institute of neurology, UCL Institute of Neurology, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Department of Genetics, University of Groningen [Groningen], deCODE Genetics, deCODE genetics [Reykjavik], Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Department of Nutrition-Dietetics, Harokopio University of Athens, Yale School of Medicine [New Haven, Connecticut] (YSM), National Heart and Lung Institute (NHLI), Imperial College London, Queensland Institute of Medical Research, Concord Hospital, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Dept. Atherosclerose, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), Department of Public Health & Primary Care, University of Cambridge [UK] (CAM), Department of cardiology, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Internal Medicine, University of Pisa - Università di Pisa, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Health Sciences Research Institute, Warwick, Department of Nephrology, University Medical Center, University of Groningen, Institute of Genetic Epidemiology, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Executive Board, Polycystic Kidney Disease Charity (PKD Charity)-Ciliopathy Alliance-International Alliance, Department of Zoology, University of Otago [Dunedin, Nouvelle-Zélande], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, 5 University Street, Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Unit for Molecular Epidemiology, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Epidemiology and Biostatistics, Department of Life Course and Services, National Institute for Health and Welfare [Helsinki], Department of Epidemiology and Public Health, Queen's University [Belfast] (QUB), Interdisciplinary Center of Clinical Research, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, University of Hawai‘i [Mānoa] (UHM), Department of Clinical Chemistry, University of Tampere [Finland]-Tampere University Hospital, Chronic Disease Epidemiology and Prevention Unit, Université Laval [Québec] (ULaval), Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, Interdisciplinary Center for Psychiatric Epidemiology, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Department of Clinical Physiology, Turku University Hospital (TYKS), Brigham and Women's Hospital [Boston], Department of Chronic Disease Prevention, Department of Cardiovascular Sciences [Leicester], University of Leicester, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Maastricht University [Maastricht], Institute of Social and Preventive Medicine, Lausanne University Hospital, Carl Gustav Carus University Hospital, Recherches en Psychopathologie, nouveaux symptômes et lien social (EA 4050), Université de Poitiers-Université de Brest (UBO)-Université Catholique de l'Ouest (UCO)-Université de Rennes 2 (UR2), Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of child and adolescent psychiatry, Institute for Medical Informatics, Biometry, and Epidemiology, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Peter MacCallum Cancer Center, Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, MRC epidemiology Unit, Institute of Epidemiology, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Oncology, Queensland Brain Institute, University of Queensland [Brisbane], Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital [Boston], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Lund University Diabetes Centre-Lund University [Lund], Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Technical University of Denmark [Lyngby] (DTU), Université de Lausanne (UNIL), Universität Duisburg-Essen [Essen], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California [Berkeley], University of California-University of California, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universität Leipzig [Leipzig], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California [Irvine] (UCI), German Research Center for Environmental Health, University of Bonn, Czech Academy of Sciences [Prague] (ASCR), Yale University School of Medicine, University of Oxford [Oxford], German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Laval University, Laval University [Québec], Turku University Hospital, Lausanne university hospital, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Helmholtz-Zentrum München (HZM), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Internal Medicine, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Medical Informatics, Obstetrics & Gynecology, Lund University [Lund]-Lund University Diabetes Centre, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institute of Medicine-University of Gothenburg (GU), Signalisation et Transports Ioniques Membranaires ( STIM ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Laboratory of Image Science and Technology [Nanjing] ( LIST ), Department of Medical Epidemiology and Biostatistics ( MEB ), University of Lausanne, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC, Space Sciences Laboratory [Berkeley] ( SSL ), Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), University of Leipzig, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Epidemiology [Neuherberg] ( EPI ), University of California [Irvine] ( UCI ), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Geneva University Hospital ( HUG ), Bonn Universität [Bonn], Indian Institute of Technology Kanpur ( IIT Kanpur ), The University of North Carolina at Chapel Hill, Université de Bonn, Wellcome Trust Sanger Institute, Harvard University School of Public Health, Czech Academy of Sciences [Prague] ( ASCR ), deCODE genetics, University of Groningen [Groningen]-University Medical Center Groningen-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Yale School of Medicine, National Heart and Lung Institute ( NHLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, University Medical Center Groningen, University of Cambridge [UK] ( CAM ), Wellcome Trust Centre for Human Genetics, University of Pisa [Pisa], University of Cambridge [UK] ( CAM ) -Institute of Metabolic Science, German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), University of Otago, University of Greifswald, University College of London [London] ( UCL ), National Institute for Health and Welfare, Queen's University [Belfast] ( QUB ), University of Hawaii at Manoa ( UHM ), University of Gothenburg ( GU ) -Institute of Medicine, Recherches en Psychopathologie, nouveaux symptômes et lien social ( EA 4050 ), Université de Poitiers-Université de Brest ( UBO ) -Université Catholique de l'Ouest-Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Finland Institute for Molecular Medicine ( FIMM ), Georgia Prevention Institute, Netherlands Consortium for Healthy Aging, Helmholtz-Zentrum München ( HZM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Massachusetts General Hospital, Children's Hospital, Boston, Broad Institute, Cambridge, MA, The University of North Carolina at Chapel Hill-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Shungin D, Winkler TW, Adipogen, Consortium, Cardiogramplusc4d, Consortium, Ckdgen, Consortium, Gefos, Consortium, Genie, Consortium, Glgc, Icbp, International, Endogene Consortium, Lifelines, Cohort Study, Magic, Investigator, Muther, Consortium, Consortium, Page, ReproGen Consortium, Amouyel P, D'Adamo, ADAMO PIO, Gasparini, Paolo, Shungin, Dmitry, Winkler, Thomas W, Croteau-Chonka, Damien C, Ferreira, Teresa, Hypponen, Elina, Mohlke, Karen L, ADIPOGEN Consortium, Int Endogene Consortium, Lee Kong Chian School of Medicine (LKCMedicine), Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, Université de Tours-Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, Tayo, B, Thorand, B, Thorleifsson, G, Tomaschitz, A, Troffa, C, Van Oort, F, Verweij, N, Vonk, J, Waite, L, Wennauer, R, Wilsgaard, T, Wojczynski, M, Wong, A, Zhang, Q, Zhao, J, Brennan, E, Choi, M, Eriksson, P, Folkersen, L, Franco Cereceda, A, Gharavi, A, Hedman, A, Hivert, M, Huang, J, Kanoni, S, Karpe, F, Keildson, S, Kiryluk, K, Liang, L, Lifton, R, Ma, B, Mcknight, A, Mcpherson, R, Metspalu, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Olsson, C, Perry, J, Reinmaa, E, Salem, R, Sandholm, N, Schadt, E, Scott, R, Stolk, L, Vallejo, E, Westra, H, Zondervan, K, Amouyel, P, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Brown, M, Burnier, M, Campbell, H, Chakravarti, A, Chines, P, Claudi Boehm, S, Collins, F, Crawford, D, Danesh, J, De Faire, U, De Geus, E, Dörr, M, Erbel, R, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gieger, C, Gudnason, V, Haiman, C, Harris, T, Hattersley, A, Heliövaara, M, Hicks, A, Hingorani, A, Hoffmann, W, Hofman, A, Homuth, G, Humphries, S, Hyppönen, E, Illig, T, Jarvelin, M, Johansen, B, Jousilahti, P, Jula, A, Kaprio, J, Kee, F, Keinanen Kiukaanniemi, S, Kooner, J, Kooperberg, C, Kovacs, P, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lyssenko, V, Männistö, S, Marette, A, Matise, T, Mckenzie, C, Mcknight, B, Musk, A, Möhlenkamp, S, Morris, A, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Palmer, L, Penninx, B, Peters, A, Pramstaller, P, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ridker, P, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Shuldiner, A, Staessen, J, Steinthorsdottir, V, Stolk, R, Strauch, K, Tönjes, A, Tremblay, A, Tremoli, E, Vohl, M, Völker, U, Vollenweider, P, Wilson, J, Witteman, J, Adair, L, Bochud, M, Boehm, B, Bornstein, S, Bouchard, C, Cauchi, S, Caulfield, M, Chambers, J, Chasman, D, Cooper, R, Dedoussis, G, Ferrucci, L, Froguel, P, Grabe, H, Hamsten, A, Hui, J, Hveem, K, Jöckel, K, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, März, W, Munroe, P, Njolstad, I, Oostra, B, Pedersen, N, Perola, M, Pe'Russe, L, Peters, U, Power, C, Quertermous, T, Rauramaa, R, Rivadeneira, F, Saaristo, T, Saleheen, D, Sinisalo, J, Slagboom, P, Snieder, H, Spector, T, Thorsteinsdottir, U, Stumvoll, M, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Van Der Harst, P, Veronesi, G, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Abecasis, G, Assimes, T, Berndt, S, Boehnke, M, Borecki, I, Deloukas, P, Franke, L, Frayling, T, Groop, L, Hunter, D, Kaplan, R, O'Connell, J, Qi, L, Schlessinger, D, Strachan, D, Stefansson, K, Van Duijn, C, Willer, C, Visscher, P, Yang, J, Hirschhorn, J, Zillikens, M, Mccarthy, M, Speliotes, E, North, K, Fox, C, Barroso, I, Franks, P, Ingelsson, E, Heid, I, Loos, R, Cupples, L, Lindgren, C, Mohlke, K, Dastani, Z, Timpson, N, Yuan, X, Henneman, P, Kizer, J, Lyytikainen, L, Fuchsberger, C, Small, K, Coassin, S, Lohman, K, Pankow, J, Uh, H, Wu, Y, Bidulescu, A, Rasmussen Torvik, L, Greenwood, C, Ladouceur, M, Grimsby, J, Manning, A, Mooser, V, Kapur, K, Frants, R, Willemsvan vanDijk, K, Willems, S, Psaty, B, Tracy, R, Brody, J, Chen, I, Viikari, J, Kähönen, M, Evans, D, St Pourcain, B, Sattar, N, Carlson, O, Egan, J, van Heemst, D, Kedenko, L, Nuotio, M, Loo, B, Kanaya, A, Haun, M, Klopp, N, Katsareli, E, Couper, D, Duncan, B, Kloppenburg, M, Borja, J, Musani, S, Guo, X, Semple, R, Teslovich, T, Allison, M, Redline, S, Buxbaum, S, Meulenbelt, I, Ballantyne, C, Hu, F, Paulweber, B, Florez, J, Smith, G, Siscovick, D, Kronenberg, F, van Duijn, C, Waterworth, D, Meigs, J, Dupuis, J, Richards, J, Willenborg, C, Thompson, J, Erdmann, J, Goldstein, B, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Lundmark, P, Lyytikäinen, L, Rafelt, S, Tikkanen, E, Van Zuydam, N, Voight, B, Ziegler, A, Altshuler, D, Balmforth, A, Braund, P, Burgdorf, C, Cox, D, Dimitriou, M, Do, R, El Mokhtari, N, Fontanillas, P, Hager, J, Han, B, Kang, H, Kessler, T, Knowles, J, Kolovou, G, Langford, C, Lokki, M, Lundmark, A, Meisinger, C, Melander, O, Maouche, S, Nikus, K, Peden, J, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Basart, H, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Gauguier, D, Goodall, A, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kim, H, Laaksonen, R, Ouwehand, W, Parish, S, Park, J, Rader, D, Shah, S, Stark, K, Trégouët, D, Virtamo, J, Wallentin, L, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Hovingh, G, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, O'Donnell, C, Reilly, M, Collins, R, Kathiresan, S, Roberts, R, Schunkert, H, Pattaro, C, Köttgen, A, Garnaas, M, Böger, C, Chen, M, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, M, O'Seaghdha, C, Glazer, N, Struchalin, M, Li, G, Johnson, A, Gierman, H, Hwang, S, Atkinson, E, Cornelis, M, Chouraki, V, Holliday, E, Sorice, R, Deshmukh, H, Ulivi, S, Chu, A, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Launer, L, Aspelund, T, Eiriksdottir, G, Mitchell, B, Schmidt, H, Cavalieri, M, Rao, M, de Andrade, M, Turner, S, Ding, J, Andrews, J, Freedman, B, Döring, A, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, H, Igl, W, Zaboli, G, Wild, S, Wright, A, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Endlich, K, Ernst, F, Kroemer, H, Nauck, M, Stracke, S, Völzke, H, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, J, Ruggiero, D, Bergmann, S, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Robino, A, Giulianini, F, Krämer, B, Portas, L, Ford, I, Buckley, B, Adam, M, Thun, G, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, S, Gasparini, P, Pirastu, M, Jukema, J, Probst Hensch, N, Toniolo, D, Coresh, J, Schmidt, R, Kardia, S, Curhan, G, Gyllensten, U, Franke, A, Rettig, R, Parsa, A, Goessling, W, Kao, W, de Boer, I, Peralta, C, Akylbekova, E, Kramer, H, van der Harst, P, Arking, D, Franceschini, N, Hernandez, D, Townsend, R, Lumley, T, Kestenbaum, B, Haritunians, T, Waeber, G, Lu, X, Leak, T, Aasarød, K, Skorpen, F, Baumert, J, Devuyst, O, Mychaleckyj, J, Hallan, S, Navis, G, Shlipak, M, Bull, S, Paterson, A, Rotter, J, Beckmann, J, Dreisbach, A, Styrkarsdottir, U, Evangelou, E, Hsu, Y, Duncan, E, Ntzani, E, Oei, L, Albagha, O, Kemp, J, Koller, D, Minster, R, Vandenput, L, Willner, D, Xiao, S, Yerges Armstrong, L, Zheng, H, Alonso, N, Kammerer, C, Kaptoge, S, Leo, P, Wilson, S, Aalto, V, Alen, M, Aragaki, A, Center, J, Dailiana, Z, Duggan, D, Garcia Giralt, N, Giroux, S, Hocking, L, Husted, L, Jameson, K, Khusainova, R, Kim, G, Koromila, T, Kruk, M, Laaksonen, M, Lacroix, A, Lee, S, Leung, P, Lewis, J, Masi, L, Mencej Bedrac, S, Nguyen, T, Nogues, X, Patel, M, Prezelj, J, Scollen, S, Siggeirsdottir, K, Svensson, O, Trummer, O, van Schoor, N, Woo, J, Zhu, K, Balcells, S, Brandi, M, Cheng, S, Christiansen, C, Cooper, C, Frost, M, Goltzman, D, González Macías, J, Karlsson, M, Khusnutdinova, E, Koh, J, Kollia, P, Langdahl, B, Leslie, W, Lips, P, Ljunggren, Ö, Lorenc, R, Marc, J, Mellström, D, Obermayer Pietsch, B, Olmos, J, Pettersson Kymmer, U, Reid, D, Riancho, J, Rousseau, F, Tang, N, Urreizti, R, Van Hul, W, Zarrabeitia, M, Castano Betancourt, M, Herrera, L, Ingvarsson, T, Johannsdottir, H, Kwan, T, Li, R, Luben, R, Medina Gómez, C, Palsson, S, Reppe, S, Sigurdsson, G, van Meurs, J, Verlaan, D, Williams, F, Zhou, Y, Gautvik, K, Raychaudhuri, S, Cauley, J, Clark, G, Cummings, S, Danoy, P, Dennison, E, Eastell, R, Eisman, J, Jackson, R, Jones, G, Khaw, K, Mccloskey, E, Nandakumar, K, Peacock, M, Pols, H, Prince, R, Reid, I, Robbins, J, Sambrook, P, Sham, P, Tylavsky, F, Econs, M, Kung, A, Reeve, J, Streeten, E, Karasik, D, Ralston, S, Ioannidis, J, Kiel, D, Forsblom, C, Isakova, T, Mckay, G, Williams, W, Sadlier, D, Mäkinen, V, Swan, E, Boright, A, Ahlqvist, E, Keller, B, Huang, H, Ahola, A, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkilä, O, Hietala, K, Kytö, J, Lahermo, P, Lehto, M, Österholm, A, Parkkonen, M, Pitkäniemi, J, Rosengård Bärlund, M, Saraheimo, M, Sarti, C, Söderlund, J, Soro Paavonen, A, Syreeni, A, Thorn, L, Tikkanen, H, Tolonen, N, Tryggvason, K, Wadén, J, Gill, G, Prior, S, Guiducci, C, Mirel, D, Taylor, A, Hosseini, M, Parving, H, Rossing, P, Tarnow, L, Ladenvall, C, Alhenc Gelas, F, Lefebvre, P, Rigalleau, V, Roussel, R, Tregouet, D, Maestroni, A, Maestroni, S, Falhammar, H, Gu, T, Möllsten, A, Cimponeriu, D, Mihai, I, Mota, M, Mota, E, Serafinceanu, C, Stavarachi, M, Hanson, R, Nelson, R, Kretzler, M, Panduru, N, Gu, H, Brismar, K, Zerbini, G, Hadjadj, S, Marre, M, Lajer, M, Waggott, D, Savage, D, Bain, S, Martin, F, Godson, C, Groop, P, Maxwell, A, Sengupta, S, Peloso, G, Ganna, A, Mora, S, Chang, H, Den Hertog, H, Donnelly, L, Fraser, R, Freitag, D, Gurdasani, D, Kaakinen, M, Kettunen, J, Li, X, Montasser, M, Petersen, A, Saxena, R, Service, S, Sidore, C, Surakka, I, Van den Herik, E, Volcik, K, Asiki, G, Been, L, Bolton, J, Bonnycastle, L, Burnett, M, Cesana, G, Elliott, P, Eyjolfsson, G, Goodarzi, M, Gravito, M, Hartikainen, A, Hung, Y, Jones, M, Kaleebu, P, Kastelein, J, Kim, E, Komulainen, P, Lin, S, Nieminen, T, Nsubuga, R, Olafsson, I, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Ruokonen, A, Seeley, J, Silander, K, Stančáková, A, Tiret, L, van Pelt, L, Wainwright, N, Wijmenga, C, Willemsen, G, Young, E, Bennett, F, Boomsma, D, Bovet, P, Chen, Y, Feranil, A, Freimer, N, Hsiung, C, Järvelin, M, Kesäniemi, A, Koudstaal, P, Krauss, R, Kyvik, K, Martin, N, Meneton, P, Moilanen, L, Njølstad, I, Price, J, Sanghera, D, Sheu, W, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Rich, S, Johnson, L, Larson, M, Levy, D, Newton Cheh, C, O'Reilly, P, Palmas, W, Rice, K, Snider, H, Tobin, M, Verwoert, G, Pihur, V, Heath, S, Sõber, S, Arora, P, Zhang, F, Lucas, G, Milaneschi, Y, Parker, A, Fava, C, Fox, E, Go, M, Sjögren, M, Vinay, D, Alexander, M, Tabara, Y, Shaw Hawkins, S, Whincup, P, Shi, G, Seielstad, M, Sim, X, Nguyen, K, Matullo, G, Gaunt, T, Onland Moret, N, Cooper, M, Platou, C, Org, E, Hardy, R, Dahgam, S, Palmen, J, Kuznetsova, T, Uiterwaal, C, Adeyemo, A, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, N, Chang, Y, Steinle, N, Grobbee, D, Morrison, A, Najjar, S, Hadley, D, Connell, J, Day, I, Lawlor, D, Lawrence, R, Ongen, H, Li, Y, Young, J, Bis, J, Chaturvedi, N, Islam, M, Jafar, T, Kulkarni, S, Grässler, J, Howard, P, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Weder, A, Sun, Y, Scott, L, Peltonen, L, Vartiainen, E, Brand, S, Wang, T, Burton, P, Artigas, M, Dong, Y, Wang, X, Zhu, H, Rudock, M, Heckbert, S, Smith, N, Wiggins, K, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, C, Rosengren, A, Thelle, D, Corsi, A, Singleton, A, Hilton, G, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Cho, Y, Scott, J, Sehmi, J, Hedblad, B, Nilsson, P, Stanèáková, A, Raffel, L, Yao, J, Schwartz, S, Ikram, M, Longstreth W., J, Mosley, T, Seshadri, S, Shrine, N, Wain, L, Morken, M, Laitinen, J, Zitting, P, Cooper, J, van Gilst, W, Janipalli, C, Mani, K, Yajnik, C, Mattace Raso, F, Lakatta, E, Orru, M, Scuteri, A, Ala Korpela, M, Kangas, A, Soininen, P, Tukiainen, T, Würtz, P, Ong, R, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Zhai, G, Meschia, J, Sharma, P, Terzic, J, Kumar, M, Denniff, M, Zukowska Szczechowska, E, Wagenknecht, L, Fowkes, F, Charchar, F, Rotimi, C, Bots, M, Brand, E, Talmud, P, Nyberg, F, Laan, M, van der Schouw, Y, Casas, J, Vineis, P, Ganesh, S, Wong, T, Tai, E, Morris, R, Dominiczak, A, Marmot, M, Miki, T, Chandak, G, Zhu, X, Elosua, R, Soranzo, N, Sijbrands, E, Uda, M, Vasan, R, Anderson, C, Gordon, S, Guo, Q, Henders, A, Lambert, A, Kraft, P, Kennedy, S, Macgregor, S, Missmer, S, Painter, J, Roseman, F, Treloar, S, Wallace, L, Alizadeh, B, de Boer, R, Boezen, H, van der Klauw, M, Ormel, J, Postma, D, Rosmalen, J, Slaets, J, Lagou, V, Welch, R, Wheeler, E, Rehnberg, E, Lecoeur, C, Johnson, P, Hottenga, J, Salo, P, Bielak, L, Zhao, W, Horikoshi, M, Navarro, P, Chen, H, Rybin, D, Song, K, An, P, Marullo, L, Jansen, H, Edkins, S, Varga, T, Oksa, H, Antonella, M, Kong, A, Herder, C, Antti, J, Miljkovic, I, Atalay, M, Kiess, W, Smit, J, Campbell, S, Fowkes, G, Rathmann, W, Maerz, W, Watanabe, R, de Geus, E, Toenjes, A, Peyser, P, Körner, A, Cucca, F, Balkau, B, Bouatia Naji, N, Ahmadi, K, Ainali, C, Bataille, V, Bell, J, Buil, A, Dermitzakis, E, Dimas, A, Durbin, R, Glass, D, Hassanali, N, Hedman, Å, Ingle, C, Knowles, D, Krestyaninova, M, Lowe, C, Meduri, E, di Meglio, P, Montgomery, S, Nestle, F, Nica, A, Nisbet, J, O'Rahilly, S, Parts, L, Potter, S, Sekowska, M, Shin, S, Surdulescu, G, Travers, M, Tsaprouni, L, Tsoka, S, Wilk, A, Higashio, J, Williams, R, Nato, A, Ambite, J, Manolio, T, Hindorff, L, Heiss, G, Taylor, K, Avery, C, Graff, M, Lin, D, Quibrera, M, Cochran, B, Kao, L, Umans, J, Cole, S, Maccluer, J, Person, S, Gross, M, Fornage, M, Durda, P, Jenny, N, Patsy, B, Arnold, A, Buzkova, P, Haines, J, Murdock, D, Glenn, K, Brown Gentry, K, Thornton Wells, T, Dumitrescu, L, Jeff, J, Bush, W, Mitchell, S, Goodloe, R, Boston, J, Malinowski, J, Restrepo, N, Oetjens, M, Fowke, J, Zheng, W, Spencer, K, Pendergrass, S, Wilkens, L, Park, L, Tiirikainen, M, Kolonel, L, Lim, U, Cheng, I, Wang, H, Shohet, R, Stram, D, Henderson, B, Monroe, K, Schumacher, F, Anderson, G, Carlson, C, Prentice, R, Wu, C, Carty, C, Gong, J, Rosse, S, Young, A, Haessler, J, Kocarnik, J, Lin, Y, Kuller, L, He, C, Sulem, P, Barbalic, M, Broer, L, Byrne, E, Gudbjartsson, D, Mcardle, P, Porcu, E, van Wingerden, S, Zhuang, W, Lauc, L, Broekmans, F, Burri, A, Chanock, S, Chen, C, Corre, T, Coviello, A, D'Adamo, P, Davies, G, Deary, I, Ebrahim, S, Fauser, B, Ferreli, L, Folsom, A, Hall, P, Hankinson, S, Hass, M, Heath, A, Janssens, A, Keyzer, J, Lahti, J, Lai, S, Laisk, T, Laven, J, Liu, J, Lopez, L, Louwers, Y, Marongiu, M, Klaric, I, Masciullo, C, Medland, S, Melzer, D, Newman, A, Paré, G, Peeters, P, Pop, V, Räikkönen, K, Salumets, A, Smith, J, Stacey, S, Starr, J, Stathopoulou, M, Tenesa, A, Tryggvadottir, L, Tsui, K, van Dam, R, van Gils, C, van Nierop, P, Vink, J, Voorhuis, M, Wallaschofski, H, Widen, E, Wijnands van Gent, C, Zgaga, L, Zygmunt, M, Buring, J, Crisponi, L, Demerath, E, Murray, A, Visser, J, Lunetta, K, Elks, C, Cousminer, D, Feenstra, B, Lin, P, Smith, E, Warrington, N, Alavere, H, Berenson, G, Blackburn, H, Busonero, F, Chen, W, Easton, D, Foroud, T, Geller, F, Kilpeläinen, T, Li, S, Melbye, M, Murray, J, Murray, S, Ness, A, Northstone, K, Pennell, C, Pharoah, P, Rafnar, T, Rice, J, Ring, S, Schork, N, Segrè, A, Sovio, U, Srinivasan, S, Tammesoo, M, Tyrer, J, Weedon, M, Young, L, Bierut, L, Boyd, H, Psychiatry, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
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Adipose Tissue/metabolism ,Male ,genetic association ,subcutaneous fat ,Transcription, Genetic ,Adipocytes ,Adipogenesis ,Adipose Tissue ,Age Factors ,Body Mass Index ,Continental Population Groups ,Epigenesis, Genetic ,Europe ,Female ,Genome, Human ,Humans ,Insulin ,Insulin Resistance ,Models, Biological ,Neovascularization, Physiologic ,Obesity ,Polymorphism, Single Nucleotide ,Quantitative Trait Loci ,Sex Characteristics ,Waist-Hip Ratio ,Body Fat Distribution ,Genome-Wide Association Study ,Multidisciplinary ,Insulin Resistance/genetics ,Genome-wide association study ,Continental Population Groups/genetics ,genetic analysis ,heritability ,gene cluster ,Science::Biological sciences::Human anatomy and physiology [DRNTU] ,0302 clinical medicine ,high density lipoprotein cholesterol ,Models ,genetics [Insulin Resistance] ,histone modification ,Age Factor ,insulin receptor ,0303 health sciences ,Adipocyte ,Human/genetics ,CARDIOGRAMplusC4D Consortium ,ADIPOGENIC DIFFERENTIATION ,genetic correlation ,body fat ,Continental Population Group ,priority journal ,5 trisphosphate 3 phosphatase ,GEFOS Consortium ,meta analysis (topic) ,Science & Technology - Other Topics ,ddc:500 ,transcription regulation ,Adipogenesis/genetics ,Single Nucleotide/genetics ,Human ,medicine.medical_specialty ,Waist ,phosphatidylinositol 3 ,European ,ta3111 ,genetic regulation ,Article ,developmental biology ,03 medical and health sciences ,MAGIC Investigators ,transcription initiation site ,SDG 3 - Good Health and Well-being ,Genetic ,genomics ,GLYCEMIC TRAITS ,genetics [Continental Population Groups] ,Polymorphism ,GENOME-WIDE ASSOCIATION ,Physiologic ,genetics [Adipogenesis] ,Adipocytes/metabolism ,Europe/ethnology ,Genome, Human/genetics ,Insulin/metabolism ,Neovascularization, Physiologic/genetics ,Obesity/genetics ,Polymorphism, Single Nucleotide/genetics ,Quantitative Trait Loci/genetics ,Transcription, Genetic/genetics ,Genetic/genetics ,Adipogenesi ,Science & Technology ,adiponectin ,[ SDV ] Life Sciences [q-bio] ,vasculotropin ,genetics [Quantitative Trait Loci] ,ta1184 ,Racial Groups ,ta1182 ,gene mapping ,ta3121 ,triacylglycerol blood level ,medicine.disease ,Biological ,major clinical study ,amino acid sequence ,metabolism [Insulin] ,Endocrinology ,metabolism [Adipocytes] ,genetic loci, insulin, body fat ,GLGC ,International Endogene Consortium ,metabolism [Adipose Tissue] ,Body mass index ,HUMAN HEIGHT ,Epigenesis ,LifeLines Cohort Study ,ReproGen Consortium ,BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,tissue level ,Physiologic/genetics ,[SDV]Life Sciences [q-bio] ,Medizin ,Adipose tissue ,low density lipoprotein cholesterol ,PAGE Consortium ,COMMON SNPS ,angiogenesis ,Waist–hip ratio ,genetics [Obesity] ,MESH: Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio ,single nucleotide polymorphism ,fat ,genetic variability ,molecular biology ,body mass index (BMI) ,ethnology [Europe] ,peroxisome proliferator activated receptor ,2. Zero hunger ,Genetics ,Genome ,Single Nucleotide ,waist circumference ,insulin ,phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase ,triacylglycerol ,vasculotropin, developmental biology ,gene expression ,genome ,numerical model, adipocyte ,adipose tissue ,body fat distribution ,body mass ,female ,gene locus ,gene structure ,hip circumference ,human ,insulin resistance ,lipoprotein blood level ,male ,obesity ,protein protein interaction ,sex difference ,waist hip ratio ,Multidisciplinary Sciences ,genetics [Transcription, Genetic] ,genetics [Polymorphism, Single Nucleotide] ,ADIPOGen Consortium ,genetics [Neovascularization, Physiologic] ,Transcription ,SUSCEPTIBILITY LOCI ,General Science & Technology ,ICBP ,030209 endocrinology & metabolism ,Biology ,adipocyte ,MESH : Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio ,MESENCHYMAL STEM-CELLS ,GENIE Consortium ,SEXUAL-DIMORPHISM ,Insulin resistance ,Internal medicine ,medicine ,genetics [Genome, Human] ,ABDOMINAL ADIPOSITY ,Neovascularization ,030304 developmental biology ,FALSE DISCOVERY ,CKDGen Consortium ,Sex Characteristic ,MuTHER Consortium ,numerical model - Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P
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- 2015
42. Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium.
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Polimanti, Renato, Gelernter, Joel, Mbarek, Hamdi, Agrawal, Arpana, Edenberg, Howard J., Lewis, Cathryn M., Sullivan, Patrick F., Wray, Naomi R., Peterson, Roseann E., Edwards, Alexis C., Gillespie, Nathan A., Kendler, Kenneth S., Maes, Hermine H., Ong, Jue-Sheng, MacGregor, Stuart, Clarke, Toni-Kim, Frank, Josef, Streit, Fabian, Gerring, Zachary, and Derks, Eske M.
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ALCOHOLISM ,ATTRIBUTION (Social psychology) ,STATISTICAL correlation ,MENTAL depression ,ALCOHOL drinking ,GENETICS ,PSYCHIATRY ,REGRESSION analysis ,DESCRIPTIVE statistics - Abstract
Background: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. Methods: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). Results: Positive genetic correlation was observed between MD and AD (rg
MD−AD = + 0.47, P = 6.6 × 10−10 ). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14 ) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7 ), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10 ) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6 ). There was no evidence for reverse causation. Conclusion: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts. [ABSTRACT FROM AUTHOR]- Published
- 2019
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43. Association Between Population Density and Genetic Risk for Schizophrenia.
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Colodro-Conde, Lucía, Whitfield, John B., Gordon, Scott, Neale, Rachel E., MacGregor, Stuart, Olsen, Catherine M., Whiteman, David C., Medland, Sarah E., Martin, Nicholas G., Couvy-Duchesne, Baptiste, Yang, Jian, McGrath, John J., Kemper, Kathryn E., Yengo, Loic, Zheng, Zhili, Trzaskowski, Maciej, Streit, Fabian, Rietschel, Marcella, de Zeeuw, Eveline L., and Nivard, Michel G.
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POPULATION density ,GENETICS ,SCHIZOPHRENIA risk factors ,ENVIRONMENTAL risk ,GENOTYPE-environment interaction - Abstract
Importance: Urban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased genetic risk tend to live in urban/dense areas.Objective: To assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk.Design, Setting, and Participants: Four large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018.Exposures: Polygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models.Main Outcomes and Measures: Population density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested.Results: The QIMR participants (15 544; 10 197 [65.6%] women; mean [SD] age, 54.4 [13.2] years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 [54.3%] women; age, 65.7 [8.0] years; NTR: 11 212; 6727 [60.0%] women; age, 48.6 [17.5] years; and QSKIN: 15 726; 8602 [54.7%] women; age, 57.0 [7.9] years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations.Conclusions and Relevance: The results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions. [ABSTRACT FROM AUTHOR]- Published
- 2018
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44. Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma.
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Zhou, Tiger, Souzeau, Emmanuelle, Sharma, Shiwani, Landers, John, Mills, Richard, Goldberg, Ivan, Healey, Paul R., Graham, Stuart, Hewitt, Alex W., Mackey, David A., Galanopoulos, Anna, Casson, Robert J., Ruddle, Jonathan B., Ellis, Jonathan, Leo, Paul, Brown, Matthew A., MacGregor, Stuart, Lynn, David J., Burdon, Kathryn P., and Craig, Jamie E.
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EXOMES ,EYE development ,PROTEIN folding ,OPEN-angle glaucoma ,CELL membranes ,HOMEOSTASIS - Abstract
Purpose: To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants. Methods: A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB. Results: POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10–7, corrected p = 3.28×10–4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10–5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10–4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG. Conclusion: This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis. [ABSTRACT FROM AUTHOR]
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- 2017
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45. A Novel Approach for Pathway Analysis of GWAS Data Highlights Role of BMP Signaling and Muscle Cell Differentiation in Colorectal Cancer Susceptibility.
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Mishra, Aniket and MacGregor, Stuart
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COLON cancer diagnosis , *BONE morphogenetic proteins , *MUSCLE cells , *CANCER cell differentiation , *GENETICS of colon cancer , *DISEASE susceptibility , *CELL metabolism , *CELL differentiation , *CELLS , *COLON tumors , *DATABASES , *GENE mapping , *GENES , *GENETIC polymorphisms , *GENETICS , *SEQUENCE analysis ,RECTUM tumors - Abstract
Genome-wide association studies (GWAS) have revolutionized the field of gene mapping. As the GWAS field matures, it is becoming clear that for many complex traits, a proportion of the missing heritability is attributable to common variants of individually small effect. Detecting these small effects individually can be difficult, and statistical power would be increased if relevant variants could be grouped together for testing. Here, we propose a VEGAS2Pathway approach that aggregates association strength of individual markers into pre-specified biological pathways. It accounts for gene size and linkage disequilibrium between markers using simulations from the multivariate normal distribution. Pathway size is taken into account via a resampling approach. Importantly, since the approach only requires summary data, the method can easily be applied in all GWASs, including meta-analysis, singleton-based, family-based, and DNA-pooling-based designs. This approach is implemented in a user-friendly web page https://vegas2.qimrberghofer.edu.au and a command line tool. The web implementation uses gene-sets from the gene ontology (GO), curated gene-sets from MSigDB (containing canonical pathways and gene-sets from BIOCARTA, REACTOME, KEGG databases), PANTHER, and pathway commons databases, enabling analysis of a wide range of complex traits. We applied this method on a colorectal cancer GWAS meta-analysis data set (10,934 cases, 12,328 controls) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). We report statistically significant enrichment of association signal for the ‘BMP signaling’ and ‘muscle cell differentiation’ pathways, suggesting a possible role for these pathways onto the risk of colorectal cancer. [ABSTRACT FROM PUBLISHER]
- Published
- 2017
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46. Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.
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Jwu Jin Khong, Burdon, Kathryn P., Yi Lu, Laurie, Kate, Leonardos, Lefta, Baird, Paul N., Sahebjada, Srujana, Walsh, John P., Gajdatsy, Adam, Ebeling, Peter R., Hamblin, Peter Shane, Wong, Rosemary, Forehan, Simon P., Fourlanos, Spiros, Roberts, Anthony P., Doogue, Matthew, Selva, Dinesh, Montgomery, Grant W., Macgregor, Stuart, and Craig, Jamie E.
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GRAVES' disease ,GENOMES ,AUTOIMMUNE diseases ,GENETICS ,RATING - Abstract
Background: Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. Results: Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10
-8 ). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10-4 . Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. Conclusions: Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation. [ABSTRACT FROM AUTHOR]- Published
- 2016
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- View/download PDF
47. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets
- Author
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Cooke Bailey, Jessica N., Gharahkhani, Puya, Kang, Jae H., Butkiewicz, Mariusz, Sullivan, David A., Weinreb, Robert N., Aschard, Hugues, Allingham, R. Rand, Ashley-Koch, Allison, Lee, Richard K., Moroi, Sayoko E., Brilliant, Murray H., Wollstein, Gadi, Schuman, Joel S., Fingert, John H., Budenz, Donald L., Realini, Tony, Gaasterland, Terry, Scott, William K., Singh, Kuldev, Sit, Arthur J., Igo, Robert P., Song, Yeunjoo E., Hark, Lisa, Ritch, Robert, Rhee, Douglas J., Vollrath, Douglas, Zack, Donald J., Medeiros, Felipe, Vajaranant, Thasarat S., Chasman, Daniel I., Christen, William G., Pericak-Vance, Margaret A., Liu, Yutao, Kraft, Peter, Richards, Julia E., Rosner, Bernard A., Hauser, Michael A., Craig, Jamie E., Burdon, Kathryn P., Hewitt, Alex W., Mackey, David A., Haines, Jonathan L., MacGregor, Stuart, Wiggs, Janey L., and Pasquale, Louis R.
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primary open-angle glaucoma ,testosterone ,genetics ,pathway analysis - Abstract
Purpose Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
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- 2018
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48. Sweet Taste Perception is Associated with Body Mass Index at the Phenotypic and Genotypic Level.
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Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Ong, Jue-Sheng, Breslin, Paul A. S., Reed, Danielle R., MacGregor, Stuart, Gharahkhani, Puya, Martin, Nicholas G., Rentería, Miguel E., and Rentería, Miguel E
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TWINS ,SWEETNESS (Taste) ,TASTE perception ,BODY mass index ,LONGITUDINAL method ,GENETIC correlations ,GENETICS ,SIBLINGS ,CLINICAL trials ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,SWEETENERS ,TASTE ,PHENOTYPES ,EVALUATION research ,GENOTYPES - Abstract
Investigations on the relationship between sweet taste perception and body mass index (BMI) have been inconclusive. Here, we report a longitudinal analysis using a genetically informative sample of 1,576 adolescent Australian twins to explore the relationship between BMI and sweet taste. First, we estimated the phenotypic correlations between perception scores for four different sweet compounds (glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame) and BMI. Then, we computed the association between adolescent taste perception and BMI in early adulthood (reported 9 years later). Finally, we used twin modeling and polygenic risk prediction analysis to investigate the genetic overlap between BMI and sweet taste perception. Our findings revealed that BMI in early adulthood was significantly associated with each of the sweet perception scores, with the strongest correlation observed in aspartame with r = 0.09 (p = .007). However, only limited evidence of association was observed between sweet taste perception and BMI that was measured at the same time (in adolescence), with the strongest evidence of association observed for glucose with a correlation coefficient of r = 0.06 (p = .029) and for aspartame with r = 0.06 (p = .035). We found a significant (p < .05) genetic correlation between glucose and NHDC perception and BMI. Our analyses suggest that sweet taste perception in adolescence can be a potential indicator of BMI in early adulthood. This association is further supported by evidence of genetic overlap between the traits, suggesting that some BMI genes may be acting through biological pathways of taste perception. [ABSTRACT FROM AUTHOR]
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- 2016
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49. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
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Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Angelantonio, Emanuele Di, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, Rasheed, Asif, Raulerson, Chelsea K, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Ridker, Paul M, Rivas, Manuel A, Robertson, Neil R, Robino, Antonietta, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Blair H, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van Duijn, Cornelia M, Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M Carola, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CH, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira, Fernando, Borecki, Ingrid B, Pospisilik, J Andrew, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, Mohlke, Karen L, Rotter, Jerome I, Kutalik, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Young, Kristin L [0000-0003-0070-6145], Mahajan, Anubha [0000-0001-5585-3420], Winkler, Thomas W [0000-0003-0292-5421], Locke, Adam E [0000-0001-6227-198X], Medina-Gomez, Carolina [0000-0001-7999-5538], Giri, Ayush [0000-0002-7786-4670], Ng, Maggie CY [0000-0002-4133-2007], Heard-Costa, Nancy L [0000-0001-9730-0306], Manning, Alisa K [0000-0003-0247-902X], Alam, Dewan S [0000-0002-2051-3837], Amouyel, Philippe [0000-0001-9088-234X], Bergmann, Sven [0000-0002-6785-9034], Boehnke, Michael [0000-0002-6442-7754], Butterworth, Adam S [0000-0002-6915-9015], Caulfield, Mark J [0000-0001-9295-3594], Collins, Francis S [0000-0002-1023-7410], de Bakker, Paul IW [0000-0001-7735-7858], Dennis, Joe G [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Elliott, Paul [0000-0002-7511-5684], Evangelou, Evangelos [0000-0002-5488-2999], Giedraitis, Vilmantas [0000-0003-3423-2021], Girotto, Giorgia [0000-0003-4507-6589], Grarup, Niels [0000-0001-5526-1070], Gustafsson, Stefan [0000-0001-5894-0351], Hansen, Torben [0000-0001-8748-3831], Hayward, Caroline [0000-0002-9405-9550], Howson, Joanna MM [0000-0001-7618-0050], Ikram, M Arfan [0000-0003-0372-8585], Jackson, Anne U [0000-0002-9672-2547], Justesen, Johanne M [0000-0002-0484-8522], Kovacs, Peter [0000-0002-0290-5423], Kuulasmaa, Kari [0000-0003-2165-1411], Langenberg, Claudia [0000-0002-5017-7344], Lin, Li-An [0000-0003-2731-1346], Linneberg, Allan [0000-0002-0994-0184], Liu, Ching-Ti [0000-0002-0703-0742], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], MacGregor, Stuart [0000-0001-6731-8142], McCarthy, Mark I [0000-0002-4393-0510], Morgan, Anna [0000-0001-6290-445X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Munroe, Patricia B [0000-0002-4176-2947], Narisu, Narisu [0000-0002-8483-1156], Neville, Matt [0000-0002-6004-5433], Reilly, Dermot F [0000-0002-9456-1364], Rudan, Igor [0000-0001-6993-6884], Saleheen, Danish [0000-0001-6193-020X], Salomaa, Veikko [0000-0001-7563-5324], Sim, Xueling [0000-0002-1233-7642], Small, Kerrin S [0000-0003-4566-0005], Smith, Blair H [0000-0002-5362-9430], Smith, Jennifer A [0000-0002-3575-5468], Southam, Lorraine [0000-0002-7546-9650], Stefansson, Kari [0000-0003-1676-864X], Stirrups, Kathleen E [0000-0002-6823-3252], Stringham, Heather M [0000-0002-2991-6392], Teumer, Alexander [0000-0002-8309-094X], Thompson, Deborah J [0000-0003-1465-5799], Vestergaard, Henrik [0000-0003-3090-269X], Vitart, Veronique [0000-0002-4991-3797], Wang, Carol A [0000-0002-4301-3974], Wessel, Jennifer [0000-0002-7031-0085], Willer, Cristen J [0000-0001-5645-4966], Zeggini, Eleftheria [0000-0003-4238-659X], Rivadeneira, Fernando [0000-0001-9435-9441], Pospisilik, J Andrew [0000-0002-9745-0977], Deloukas, Panos [0000-0001-9251-070X], Mohlke, Karen L [0000-0001-6721-153X], Kutalik, Zoltán [0000-0001-8285-7523], Loos, Ruth JF [0000-0002-8532-5087], Lindgren, Cecilia M [0000-0002-4903-9374], Apollo - University of Cambridge Repository, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Medical and Clinical Psychology, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele Di, Dörr, Marcu, Drenos, Fotio, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Girotto, Giorgia, Gorski, Mathia, Grallert, Harald, Grarup, Niel, Grove, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’An, Lyytikäinen, Leo-Pekka, Macgregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., Mccarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome I., Kutalik, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Epidemiology and Data Science, and VU University medical center
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Exome/genetics ,Male ,ReproGen Consortium ,Adipose tissue ,Genome-wide association study ,Type 2 diabetes ,White adipose tissue ,Body Mass Index ,Animals ,Body Fat Distribution ,Case-Control Studies ,Drosophila ,Exome ,Female ,Gene Frequency ,Genetic Predisposition to Disease ,Genetic Variation ,Genome-Wide Association Study ,Homeostasis ,Humans ,Lipids ,Proteins ,Risk Factors ,Waist-Hip Ratio ,0302 clinical medicine ,Hyperlipidemia ,Body fat distribution ,2. Zero hunger ,Genetics ,0303 health sciences ,INSULIN-RESISTANCE ,ADIPOCYTE DIFFERENTIATION ,CHD Exome+ Consortium ,Genetic Predisposition to Disease/genetics ,Drosophila/genetics ,RS11209026 POLYMORPHISM ,KINASE 7 ,1184 Genetics, developmental biology, physiology ,T2D-Genes Consortium ,11 Medical And Health Sciences ,Body Fat Distribution/methods ,RECEPTOR ALK7 ,ADIPOSE-TISSUE ,Gene Frequency/genetics ,Genetic Variation/genetics ,InterAct ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,genetic association study ,RNA splicing ,Proteins/genetics ,Genome-Wide Association Study/methods ,Lipid particle ,ExomeBP Consortium ,WAIST CIRCUMFERENCE ,Waist-Hip Ratio/methods ,Biology ,EPIC-CVD Consortium ,Article ,MAGIC Investigators ,03 medical and health sciences ,Homeostasis/genetics ,Lipids/genetics ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Global Lipids Genetic Consortium ,Risk factor ,GENOME-WIDE ASSOCIATION ,ABDOMINAL ADIPOSITY ,Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ,Gene ,030304 developmental biology ,06 Biological Sciences ,medicine.disease ,Minor allele frequency ,GoT2D Genes Consortium ,genetics research ,TYPE-2 DIABETES SUSCEPTIBILITY ,3111 Biomedicine ,Body mass index ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Body fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology, and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants., Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.
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50. Genetic Loci for Retinal Arteriolar Microcirculation.
- Author
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Sim, Xueling, Jensen, Richard A., Ikram, M. Kamran, Cotch, Mary Frances, Li, Xiaohui, MacGregor, Stuart, Xie, Jing, Smith, Albert Vernon, Boerwinkle, Eric, Mitchell, Paul, Klein, Ronald, Klein, Barbara E. K., Glazer, Nicole L., Lumley, Thomas, McKnight, Barbara, Psaty, Bruce M., de Jong, Paulus T. V. M., Hofman, Albert, Rivadeneira, Fernando, and Uitterlinden, Andre G.
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RETINAL blood supply ,LOCUS (Genetics) ,MICROCIRCULATION ,HYPERTENSION ,GENETIC epidemiology ,CHROMOSOMES ,HEALTH outcome assessment ,ATHEROSCLEROSIS - Abstract
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10
−8 . This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined. [ABSTRACT FROM AUTHOR]- Published
- 2013
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