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1. Rare Germline Variants in ATM Predispose to Prostate Cancer : A PRACTICAL Consortium Study

Author

PRACTICAL Consortium, Karlsson, Questa, Brook, Mark N, Dadaev, Tokhir, Wakerell, Sarah, Saunders, Edward J, Muir, Kenneth, Neal, David E, Giles, Graham G, MacInnis, Robert J, Thibodeau, Stephen N, McDonnell, Shannon K, Cannon-Albright, Lisa, Teixeira, Manuel R, Paulo, Paula, Cardoso, Marta, Huff, Chad, Li, Donghui, Yao, Yu, Scheet, Paul, Permuth, Jennifer B, Stanford, Janet L, Dai, James Y, Ostrander, Elaine A, Cussenot, Olivier, Cancel-Tassin, Géraldine, Hoegel, Josef, Herkommer, Kathleen, Schleutker, Johanna, Tammela, Teuvo L J, Rathinakannan, Venkat, Sipeky, Csilla, Wiklund, Fredrik, Grönberg, Henrik, Aly, Markus, Isaacs, William B, Dickinson, Jo L, FitzGerald, Liesel M, Chua, Melvin L K, Nguyen-Dumont, Tu, Schaid, Daniel J, Southey, Melissa C, Eeles, Rosalind A, Kote-Jarai, Zsofia, Tampere University, Department of Surgery, and Clinical Medicine

Subjects
Oncology, Male, medicine.medical_specialty, Urology, 030232 urology & nephrology, Disease, Ataxia Telangiectasia Mutated Proteins, urologic and male genital diseases, Targeted screening and therapy, Germline, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Internal medicine, Genetic predisposition, medicine, SNP, Humans, Radiology, Nuclear Medicine and imaging, Genetic Predisposition to Disease, Germ-Line Mutation, Variant Call Format, business.industry, Prostatic Neoplasms, Odds ratio, Priority Article, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Confidence interval, ddc, 030220 oncology & carcinogenesis, Surgery, ATM gene mutations, business
Abstract

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (

Published
2021

2. Additional file 3 of Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Author

Won-Chul Lee, Reuben, Alexandre, Hu, Xin, McGranahan, Nicholas, Runzhe Chen, Jalali, Ali, Negrao, Marcelo V., Hubert, Shawna M., Tang, Chad, Chia-Chin Wu, Lucas, Anthony San, Whijae Roh, Suda, Kenichi, Jihye Kim, Aik-Choon Tan, Peng, David H., Lu, Wei, Ximing Tang, Chi-Wan Chow, Fujimoto, Junya, Behrens, Carmen, Kalhor, Neda, Fukumura, Kazutaka, Coyle, Marcus, Thornton, Rebecca, Gumbs, Curtis, Li, Jun, Chang-Jiun Wu, Little, Latasha, Roarty, Emily, Xingzhi Song, J. Jack Lee, Sulman, Erik P., Rao, Ganesh, Swisher, Stephen, Lixia Diao, Wang, Jing, Heymach, John V., Huse, Jason T., Scheet, Paul, Wistuba, Ignacio I., Gibbons, Don L., P. Andrew Futreal, Jianhua Zhang, Gomez, Daniel, and Jianjun Zhang

Abstract

Additional file 3: Review history.

Published
2020
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3. Additional file 2 of Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Author

Won-Chul Lee, Reuben, Alexandre, Hu, Xin, McGranahan, Nicholas, Runzhe Chen, Jalali, Ali, Negrao, Marcelo V., Hubert, Shawna M., Tang, Chad, Chia-Chin Wu, Lucas, Anthony San, Whijae Roh, Suda, Kenichi, Jihye Kim, Aik-Choon Tan, Peng, David H., Lu, Wei, Ximing Tang, Chi-Wan Chow, Fujimoto, Junya, Behrens, Carmen, Kalhor, Neda, Fukumura, Kazutaka, Coyle, Marcus, Thornton, Rebecca, Gumbs, Curtis, Li, Jun, Chang-Jiun Wu, Little, Latasha, Roarty, Emily, Xingzhi Song, J. Jack Lee, Sulman, Erik P., Rao, Ganesh, Swisher, Stephen, Lixia Diao, Wang, Jing, Heymach, John V., Huse, Jason T., Scheet, Paul, Wistuba, Ignacio I., Gibbons, Don L., P. Andrew Futreal, Jianhua Zhang, Gomez, Daniel, and Jianjun Zhang

Abstract

Additional file 2: Supplementary Figs. S1-S22.

Published
2020
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4. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, M. D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette, Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeon, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Lee, Annette T., Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, Scleroderma Genetics Consortium., Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Myositis Genetics Consortium, and Scleroderma Genetics Consortium

Subjects
0301 basic medicine, Male, Lydia Becker Institute, PATHOGENESIS, PROTEIN, Arthritis, VARIANTS, medicine.disease_cause, Myositis Genetics Consortium, Autoimmunity, Scleroderma, Arthritis, Rheumatoid, 0302 clinical medicine, Scleroderma Genetics Consortium, Rheumatoid, MULTIPLE, Lupus Erythematosus, Systemic, Immunology and Allergy, Medicine, 2.1 Biological and endogenous factors, Aetiology, Genetics, autoimmunity, Family aggregation, Lim Kinases, ASSOCIATION, Single Nucleotide, Public Health and Health Services, Female, ARTHRITIS, Life Sciences & Biomedicine, alpha Karyopherins, Adult, medicine.medical_specialty, GENETICS, gene polymorphism, Quantitative Trait Loci, Clinical Sciences, Immunology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Autoimmune Disease, General Biochemistry, Genetics and Molecular Biology, White People, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Immune system, Rheumatology, Internal medicine, Rheumatic Diseases, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Humans, Genetic Predisposition to Disease, autoimmune diseases, Polymorphism, SCLEROSIS, COMMON, 030203 arthritis & rheumatology, Science & Technology, Scleroderma, Systemic, COMPLEX, Myositis, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Human Genome, Membrane Proteins, medicine.disease, Arthritis & Rheumatology, Repressor Proteins, 030104 developmental biology, Expression quantitative trait loci, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Human medicine, Gene polymorphism, business, Genome-Wide Association Study
Abstract

ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

Published
2019

5. Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage-specific gene Gprc5a

Author

Fujimoto, Junya, Nunomura-Nakamura, Sayuri, Liu, Yihua, Lang, Wenhua, McDowell, Tina, Jakubek, Yasminka, Ezzeddine, Dalia, Ochieng, Joshua Kapere, Petersen, Jason, Davies, Gareth, Fukuoka, Junya, Wistuba, Ignacio I., Ehli, Erik, Fowler, Jerry, Scheet, Paul, and Kadara, Humam

Subjects
Mice, Knockout, Lung Neoplasms, Nitrosamines, Adenocarcinoma of Lung, Adenocarcinoma, Article, Receptors, G-Protein-Coupled, Proto-Oncogene Proteins p21(ras), Mice, Mutation, Carcinogens, Animals, Humans, Cell Lineage, Genes, Tumor Suppressor
Abstract

Despite the urgency for prevention and treatment of lung adenocarcinoma (LUAD), we still do not know drivers in pathogenesis of the disease. Earlier work revealed that mice with knockout of the G-protein coupled receptor Gprc5a develop late onset lung tumors including LUADs. Here, we sought to further probe the impact of Gprc5a expression on LUAD pathogenesis. We first surveyed GPRC5A expression in human tissues and found that GPRC5A was markedly elevated in human normal lung relative to other normal tissues and was consistently down-regulated in LUADs. In sharp contrast to wild type littermates, Gprc5a-/- mice treated chronically with the nicotine-specific carcinogen NNK developed LUADs by six months following NNK exposure. Immunofluorescence analysis revealed that the LUADs exhibited abundant expression of surfactant protein C and lacked the clara cell marker Ccsp, suggesting that these LUADs originated from alveolar type II cells. Next, we sought to survey genome-wide alterations in the pathogenesis of Gprc5a-/- LUADs. Using whole exome sequencing, we found that carcinogen-induced LUADs exhibited markedly higher somatic mutation burdens relative to spontaneous tumors. All LUADs were found to harbor somatic mutations in the Kras oncogene (p. G12D or p. Q61R). In contrast to spontaneous lesions, carcinogen-induced Gprc5a-/- LUADs exhibited mutations (variants and copy number gain) in additional drivers (Atm, Kmt2d, Nf1, Trp53, Met, Ezh2). Our study underscores genomic alterations that represent early events in the development of Kras mutant LUAD following Gprc5a loss and tobacco carcinogen exposure and that may constitute targets for prevention and early treatment of this disease.

Published
2017

6. A Meta-Analytic Framework for Detection of Genetic Interactions

Author

Liu, Yulun, Chen, Yong, and Scheet, Paul

Subjects
Phenotype, Research Design, Epistasis, Genetic, Article, Genetic Association Studies
Abstract

With varying, but substantial, proportions of heritability remaining unexplained by summaries of single-SNP genetic variation, there is a demand for methods that extract maximal information from genetic association studies. One source of variation that is difficult to assess is genetic interactions. A major challenge for naive detection methods is the large number of possible combinations, with a requisite need to correct for multiple testing. Assumptions of large marginal effects, to reduce the search space, may be restrictive and miss higher order interactions with modest marginal effects. In this paper, we propose a new procedure for detecting gene-by-gene interactions through heterogeneity in estimated low-order (e.g., marginal) effect sizes by leveraging population structure, or ancestral differences, among studies in which the same phenotypes were measured. We implement this approach in a meta-analytic framework, which offers numerous advantages, such as robustness and computational efficiency, and is necessary when data-sharing limitations restrict joint analysis. We effectively apply a dimension reduction procedure that scales to allow searches for higher order interactions. For comparison to our method, which we term phylogenY-aware Effect-size Tests for Interactions (YETI), we adapt an existing method that assumes interacting loci will exhibit strong marginal effects to our meta-analytic framework. As expected, YETI excels when multiple studies are from highly differentiated populations and maintains its superiority in these conditions even when marginal effects are small. When these conditions are less extreme, the advantage of our method wanes. We assess the Type-I error and power characteristics of complementary approaches to evaluate their strengths and limitations.

Published
2016

7. Surveys of Subtle Allelic Imbalance in Tissue

Author

Scheet, Paul

Abstract

Somatically-acquired allelic imbalance (AI) is an established factor in cancer initiation and has recently been implicated as a marker for cancer risk. While DNA microarrays and next-generation sequencing are effective for whole-genome profiling of AI, in typical settings their sensitivities become extremely limited when the aberrant cell fraction (or tumor purity) is below 10-20%. Yet, this range may be critical for early detection and diagnostics, since often for such applications the samples of interest will be comprised of heterogeneous mixtures of cells with a large component of DNA from normal (i.e. the germline) rather than aberrant (e.g. the tumor) sources. Here we introduce a powerful haplotype-based computational technique (Vattathil & Scheet, 2013, Gen Res) and use it to characterize AI in several difficult settings. We start with a reanalysis of a study of over 35,000 samples of healthy tissue from recent genome-wide association studies and find a 2-fold higher rate of somatic mosaicism (within-individual genomic heterogeneity), which may indicate a wider applicability for the use of mosaicism as a biomarker for cancer risk. We next examine premalignant tissue, profiling polyps from individuals at risk for colorectal cancer to show subtle levels of AI across critical loci; we also demonstrate extensive mosaicism in the lung field (normal-appearing tissue surrounding the tumor), consistent with recent studies of expression (Kadara et. al., 2014, JNCI). Finally, we study lymph node tissue (of lung cancer patients), sampled via endobronchial ultrasound, and discover chromosomal aberrations in samples that were deemed negative by pathology review but that were ultimately determined to be positive following surgical extraction, thus demonstrating potential for molecular diagnostics.

Published
2015
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8. Selection signatures in worldwide sheep populations

Author

Fariello, Maria Ines, Servin, Bertrand, Tosser Klopp, Gwenola, Rupp, Rachel, Moreno, Carole, Cristobal, Magali San, Boitard, Simon, Arranz, Juan Jose, Banos, Georgios, Barendse, William, El Beltagy, Ahmedn, Benenwitz, Jorn, Bishop, Steven, Bunger, Lutz, Calvo, Jorge, Carta, Antonello, Cemal, Ibrahim, Ciani, Elena, Cockett, Noelle, Coltman, Dave, Dalrymple, Brian, D'Andrea, Mariasilvia, Distl, Ottmar, Drogemuller, Cord, Erhardt, Georg, Eythorsdottir, Emma, Gietzen, Kimberly, Gill, Clare, Gootwine, Elisha, Gupta, Vidya, Hanotte, Olivier, Hayes, Ben, Heaton, Michael, Hiendleder, Stefan, Jialin, Han, Kantanen, Juha, Kent, Matthew, Kijas, James, Larkin, Denis, Lenstra, Johannes A., Kui, Li, Longhurst, Terry, Runlin, Ma, Mcculloch, Russell, Machugh, David, Mcwilliam, Sean, Mcewan, John, Maddox, Jillian, Malek, Massoud, Mdomar, Faruque, Miltiadou, Despoina, Monteagudo Ibez, Luis V., Nicholas, Frank, Nowak, Kristen, Oddy, V. Hutton, Paiva, Samuel, Pardeshi, Varsha, Pemberton, Josephine, Pilla, Fabio, Porto Neto, Laercio R., Raadsma, Herman, Roberts, Cyril, San Cristobal, Magali, Sechi, Tiziana, Scheet, Paul, Shariflou, Mohammad, Silva, Pradeepa, Simianer, Henner, Slate, Jon, Tapio, Mikka, Vattathil, Selina, Whan, Vicki, Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of the Republic, Partenaires INRAE, Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Origine, structure et évolution de la biodiversité (OSEB), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Boitard, Simon, and Μιλτιάδου, Δέσποινα

Subjects
Genetics and Molecular Biology (all), Linkage disequilibrium, receptor, [SDV]Life Sciences [q-bio], Population genetics, Coat color, Adult height, Gene, Biochemistry, Genome, holstein cattle, artificial selection, missense mutation, genotype data, adult height, coat color, gene, genone, breed, 0302 clinical medicine, Gene Frequency, Natural Selection, Missense mutation, Animal Breeding, International HapMap Project, 610 Medicine & health, Animal Management, Genetics, 0303 health sciences, Multidisciplinary, 630 Agriculture, Agricultural Sciences, Artificial selection, Medicine (all), Agriculture, Single Nucleotide, Genomics, World wide, 590 Animals (Zoology), Medicine, Receptor, Research Article, Genetic Markers, Evolutionary Processes, Breeds, Science, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic, Animal Production, Animal and Dairy Science, Animals, [INFO]Computer Science [cs], Polymorphism, Selection, Genetic, Holstein cattle, Selection, Selection (genetic algorithm), 030304 developmental biology, Genetic diversity, Evolutionary Biology, Sheep, Biology and Life Sciences, Computational Biology, Genetic Variation, Genome Analysis, Agricultural and Biological Sciences (all), Haplotypes, Evolutionary biology, Genotype data, Adaptation, Animal Genetics, 030217 neurology & neurosurgery, Biochemistry, Genetics and Molecular Biology (all), Population Genetics
Abstract

International audience; The diversity of populations in domestic species offers great opportunities to study genome response to selection. The recently published Sheep HapMap dataset is a great example of characterization of the world wide genetic diversity in sheep. In this study, we re-analyzed the Sheep HapMap dataset to identify selection signatures in worldwide sheep populations. Compared to previous analyses, we made use of statistical methods that (i) take account of the hierarchical structure of sheep populations, (ii) make use of linkage disequilibrium information and (iii) focus specifically on either recent or older selection signatures. We show that this allows pinpointing several new selection signatures in the sheep genome and distinguishing those related to modern breeding objectives and to earlier post-domestication constraints. The newly identified regions, together with the ones previously identified, reveal the extensive genome response to selection on morphology, color and adaptation to new environments.

Published
2014

9. Association Between Autozygosity and Major Depression: Stratification Due to Religious Assortment

Author

Davies, Gareth, Hudziak, James, Brooks, Andrew, Sullivan, Patrick, de Geus, Eco, Penninx, Brenda, Smit, Johannes, Bartels, Meike, Hottenga, Jouke-Jan, Ehli, Erik, Boomsma, Dorret, Xiao, Xiangjun, Abdellaoui, Abdel, Willemsen, Gonneke, Smit, Dirk, and Scheet, Paul

Abstract

The effects of inbreeding on the health of offspring can be studied by measuring genome-wide autozygosity as the proportion of the genome in runs of homozygosity (Froh) and relate Froh to outcomes such as psychiatric phenotypes. To successfully conduct these studies, the main patterns of variation for genome-wide autozygosity between and within populations should be well understood and accounted for. Within population variation was investigated in the Dutch population by comparing autozygosity between religious and non-religious groups. The Netherlands have a history of societal segregation and assortment based on religious affiliation, which may have increased parental relatedness within religious groups. Religion has been associated with several psychiatric phenotypes, such as major depressive disorder (MDD). We investigated whether there is an association between autozygosity and MDD, and the extent to which this association can be explained by religious affiliation. All Froh analyses included adjustment for ancestry-informative principal components (PCs) and geographic factors.

Published
2013
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10. A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John RB, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, Van Dam, Rob M, Van Haeften, Timon W, Van Herpt, Thijs, Van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin NA, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, Van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth JF, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda WJH, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, Center for Liver, Digestive and Metabolic Diseases (CLDM), Palmer, Nd, Mcdonough, Cw, Hicks, Pj, Roh, Bh, Wing, Mr, An, S, Hester, Jm, Cooke, Jn, Bostrom, Ma, Rudock, Me, Talbert, Me, Lewis, Jp, Diagram, Consortium, Magic, Investigator, Ferrara, A, Lu, L, Ziegler, Jt, Sale, Mm, Divers, J, Shriner, D, Adeyemo, A, Rotimi, Cn, Ng, Mc, Langefeld, Cd, Freedman, Bi, Bowden, Dw, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, Sladek, R., Medical Research Council (MRC), Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Langenberg, Claudia [0000-0002-5017-7344], Griffin, Simon [0000-0002-2157-4797], Wareham, Nicholas [0000-0003-1422-2993], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Apollo - University of Cambridge Repository, DIAGRAM Consortium, MAGIC Investigators, Johnson, T., Bergman, S., Bochud, M., Waeber, G., and Vollenweider, P.

Subjects
Netherlands Twin Register (NTR), Male, Adult, African Americans/genetics, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2/ethnology, Diabetes Mellitus, Type 2/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic, Medicin och hälsovetenskap, Linkage disequilibrium, Genetic Screens, endocrine system diseases, lcsh:Medicine, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Endocrinology, Genome Sequencing, lcsh:Science, Medicine(all), Genetics, African Americans, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Multidisciplinary, Agricultural and Biological Sciences(all), LARGE-SCALE ASSOCIATION, STAGE RENAL-DISEASE, COMMON VARIANTS, Genomics, Medicine, Research Article, SUSCEPTIBILITY LOCI, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, DIAGRAM Consortium, 03 medical and health sciences, MAGIC Investigators, SDG 3 - Good Health and Well-being, Genetic linkage, MD Multidisciplinary, Genome-Wide Association Studies, SNP, ddc:610, education, Genotyping, 030304 developmental biology, Diabetic Endocrinology, LINKAGE ANALYSIS, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, TCF7L2 GENE, Case-control study, Computational Biology, nutritional and metabolic diseases, Human Genetics, Diabetes Mellitus Type 2, Stage renal-disease, large-scale association, Susceptibility loci, Insulin-resistance, Fasting glucose, Tissue factor, Homeodomain protein, Linkage analysis, Common variants, TCF7L2 gene, Black or African American, Diabetes Mellitus, Type 2, TISSUE FACTOR, Genetics of Disease, HOMEODOMAIN PROTEIN, Genetic Polymorphism, lcsh:Q, Genome Expression Analysis, 030217 neurology & neurosurgery, Population Genetics, FASTING GLUCOSE
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012

11. Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers

Author

Gubjartsson, Daniel, Ducci, Francesca, Hansel, Nadia N., Jiang, Chenhui, Short, Susan E., Rosenberger, Albert, Scheet, Paul, Lyytikäinen, Leo-Pekka, Culverhouse, Robert, Vogelzangs, Nicole, Shaffer, John R., Stephens, Sarah H., Rawal, Rajesh, Saccone, Nancy L., Sun, Juzhong, Teumer, Alexander, Han, Younghun, Hartz, Sarah M., Franceschini, Nora, Keskitalo-Vuokko, Kaisu, Liu, Zhen, Coon, Hilary, Schwantes-An, Tae-Hwi, Vink, Jacqueline M., Michel, Martha, Wenzlaff, Angela S., Chen, LiShiun, Dueker, Nicole, Thompson, John R., Frank, Josef, Chen, Xiangning, and Geller, Frank

Subjects
education, mental disorders
Abstract

Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.

Published
2012
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12. A map of human genome variation from population-scale sequencing

Author

Durbin, Richard M., Altshuler, David L., Abecasis, Gonçalo R., Bentley, David R., Chakravarti, Aravinda, Clark, Andrew G., Collins, Francis S., De La Vega, Francisco M., Donnelly, Peter, Egholm, Michael, Flicek, Paul, Gabriel, Stacey B., Gibbs, Richard A., Knoppers, Bartha M., Lander, Eric S., Lehrach, Hans, Mardis, Elaine R., McVean, Gil A., Nickerson, Debbie A., Peltonen, Leena, Schafer, Alan J., Sherry, Stephen T., Wang, Jun, Wilson, Richard K., Deiros, David, Metzker, Mike, Muzny, Donna, Reid, Jeff, Wheeler, David, Li, Jingxiang, Jian, Min, Li, Guoqing, Li, Ruiqiang, Liang, Huiqing, Tian, Geng, Wang, Bo, Wang, Jian, Wang, Wei, Yang, Huanming, Zhang, Xiuqing, Zheng, Huisong, Ambrogio, Lauren, Bloom, Toby, Cibulskis, Kristian, Fennell, Tim J., Jaffe, David B., Shefler, Erica, Sougnez, Carrie L., Gormley, Niall, Humphray, Sean, Kingsbury, Zoya, Koko-Gonzales, Paula, Stone, Jennifer, McKernan, Kevin J., Costa, Gina L., Ichikawa, Jeffry K., Lee, Clarence C., Sudbrak, Ralf, Borodina, Tatiana A., Dahl, Andreas, Davydov, Alexey N., Marquardt, Peter, Mertes, Florian, Nietfeld, Wilfiried, Rosenstiel, Philip, Schreiber, Stefan, Soldatov, Aleksey V., Timmermann, Bernd, Tolzmann, Marius, Affourtit, Jason, Ashworth, Dana, Attiya, Said, Bachorski, Melissa, Buglione, Eli, Burke, Adam, Caprio, Amanda, Celone, Christopher, Clark, Shauna, Conners, David, Desany, Brian, Gu, Lisa, Guccione, Lorri, Kao, Kalvin, Kebbel, Andrew, Knowlton, Jennifer, Labrecque, Matthew, McDade, Louise, Mealmaker, Craig, Minderman, Melissa, Nawrocki, Anne, Niazi, Faheem, Pareja, Kristen, Ramenani, Ravi, Riches, David, Song, Wanmin, Turcotte, Cynthia, Wang, Shally, Dooling, David, Fulton, Lucinda, Fulton, Robert, Weinstock, George, Burton, John, Carter, David M., Churcher, Carol, Coffey, Alison, Cox, Anthony, Palotie, Aarno, Quail, Michael, Skelly, Tom, Stalker, James, Swerdlow, Harold P., Turner, Daniel, De Witte, Anniek, Giles, Shane, Bainbridge, Matthew, Challis, Danny, Sabo, Aniko, Yu, Fuli, Yu, Jin, Fang, Xiaodong, Guo, Xiaosen, Li, Yingrui, Luo, Ruibang, Tai, Shuaishuai, Wu, Honglong, Zheng, Hancheng, Zheng, Xiaole, Zhou, Yan, Marth, Gabor T., Garrison, Erik P., Huang, Weichun, Indap, Amit, Kural, Deniz, Lee, Wan-Ping, Fung Leong, Wen, Quinlan, Aaron R., Stewart, Chip, Stromberg, Michael P., Ward, Alistair N., Wu, Jiantao, Lee, Charles, Mills, Ryan E., Shi, Xinghua, Daly, Mark J., DePristo, Mark A., Ball, Aaron D., Banks, Eric, Browning, Brian L., Garimella, Kiran V., Grossman, Sharon R., Handsaker, Robert E., Hanna, Matt, Hartl, Chris, Kernytsky, Andrew M., Korn, Joshua M., Li, Heng, Maguire, Jared R., McCarroll, Steven A., McKenna, Aaron, Nemesh, James C., Philippakis, Anthony A., Poplin, Ryan E., Price, Alkes, Rivas, Manuel A., Sabeti, Pardis C., Schaffner, Stephen F., Shlyakhter, Ilya A., Cooper, David N., Ball, Edward V., Mort, Matthew, Phillips, Andrew D., Stenson, Peter D., Sebat, Jonathan, Makarov, Vladimir, Ye, Kenny, Yoon, Seungtai C., Bustamante, Carlos D., Boyko, Adam, Degenhardt, Jeremiah, Gravel, Simon, Gutenkunst, Ryan N., Kaganovich, Mark, Keinan, Alon, Lacroute, Phil, Ma, Xin, Reynolds, Andy, Clarke, Laura, Cunningham, Fiona, Herrero, Javier, Keenen, Stephen, Kulesha, Eugene, Leinonen, Rasko, McLaren, William M., Radhakrishnan, Rajesh, Smith, Richard E., Zalunin, Vadim, Zheng-Bradley, Xiangqun, Korbel, Jan O., Stütz, Adrian M., Bauer, Markus, Keira Cheetham, R., Cox, Tony, Eberle, Michael, James, Terena, Kahn, Scott, Murray, Lisa, Ye, Kai, Fu, Yutao, Hyland, Fiona C. L., Manning, Jonathan M., McLaughlin, Stephen F., Peckham, Heather E., Sakarya, Onur, Sun, Yongming A., Tsung, Eric F., Batzer, Mark A., Konkel, Miriam K., Walker, Jerilyn A., Albrecht, Marcus W., Amstislavskiy, Vyacheslav S., Herwig, Ralf, Parkhomchuk, Dimitri V., Agarwala, Richa, Khouri, Hoda M., Morgulis, Aleksandr O., Paschall, Justin E., Phan, Lon D., Rotmistrovsky, Kirill E., Sanders, Robert D., Shumway, Martin F., Xiao, Chunlin, Auton, Adam, Iqbal, Zamin, Lunter, Gerton, Marchini, Jonathan L., Moutsianas, Loukas, Myers, Simon, Tumian, Afidalina, Knight, James, Winer, Roger, Craig, David W., Beckstrom-Sternberg, Steve M., Christoforides, Alexis, Kurdoglu, Ahmet A., Pearson, John V., Sinari, Shripad A., Tembe, Waibhav D., Haussler, David, Hinrichs, Angie S., Katzman, Sol J., Kern, Andrew, Kuhn, Robert M., Przeworski, Molly, Hernandez, Ryan D., Howie, Bryan, Kelley, Joanna L., Cord Melton, S., Li, Yun, Anderson, Paul, Blackwell, Tom, Chen, Wei, Cookson, William O., Ding, Jun, Min Kang, Hyun, Lathrop, Mark, Liang, Liming, Moffatt, Miriam F., Scheet, Paul, Sidore, Carlo, Snyder, Matthew, Zhan, Xiaowei, Zöllner, Sebastian, Awadalla, Philip, Casals, Ferran, Idaghdour, Youssef, Keebler, John, Stone, Eric A., Zilversmit, Martine, Jorde, Lynn, Xing, Jinchuan, Eichler, Evan E., Aksay, Gozde, Alkan, Can, Hajirasouliha, Iman, Hormozdiari, Fereydoun, Kidd, Jeffrey M., Cenk Sahinalp, S., Sudmant, Peter H., Chen, Ken, Chinwalla, Asif, Ding, Li, Koboldt, Daniel C., McLellan, Mike D., Wallis, John W., Wendl, Michael C., Zhang, Qunyuan, Albers, Cornelis A., Ayub, Qasim, Balasubramaniam, Senduran, Barrett, Jeffrey C., Chen, Yuan, Conrad, Donald F., Danecek, Petr, Dermitzakis, Emmanouil T., Hu, Min, Huang, Ni, Hurles, Matt E., Jin, Hanjun, Jostins, Luke, Keane, Thomas M., Quang Le, Si, Lindsay, Sarah, Long, Quan, MacArthur, Daniel G., Montgomery, Stephen B., Parts, Leopold, Tyler-Smith, Chris, Walter, Klaudia, Zhang, Yujun, Gerstein, Mark B., Snyder, Michael, Abyzov, Alexej, Balasubramanian, Suganthi, Bjornson, Robert, Du, Jiang, Grubert, Fabian, Habegger, Lukas, Haraksingh, Rajini, Jee, Justin, Khurana, Ekta, Lam, Hugo Y. K., Leng, Jing, Jasmine Mu, Xinmeng, Urban, Alexander E., Zhang, Zhengdong, Coafra, Cristian, Dinh, Huyen, Kovar, Christie, Lee, Sandy, Nazareth, Lynne, Wilkinson, Jane, Coffey, Allison, Scott, Carol, Gharani, Neda, Kaye, Jane S., Kent, Alastair, Li, Taosha, McGuire, Amy L., Ossorio, Pilar N., Rotimi, Charles N., Su, Yeyang, Toji, Lorraine H., Brooks, Lisa D., Felsenfeld, Adam L., McEwen, Jean E., Abdallah, Assya, Juenger, Christopher R., Clemm, Nicholas C., Duncanson, Audrey, Green, Eric D., Guyer, Mark S., Peterson, Jane L., The Wellcome Trust Sanger Institute [Cambridge], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Michigan [Ann Arbor], University of Michigan System, The 1000 Genomes Project Consortium, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Altshuler, David, Daly, Mark J., Grossman, Sharon Rachel, Jaffe, David B., Korn, Joshua M., and Dermitzakis, Emmanouil

Subjects
Male, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Pilot Projects, Chromosomes, Human, Y/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, ddc:576.5, 2. Zero hunger, Genetics, Recombination, Genetic, 0303 health sciences, Multidisciplinary, Genetics, Population/methods, Genomics, Polymorphism, Single Nucleotide/genetics, Recombination, Genetic/genetics, 3. Good health, Genetic Variation/genetics, Sequence Analysis, DNA/methods, Calibration, Female, Mutation/genetics, Genotype, Haplotypes/genetics, Biology, Instability, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Article, Selection, Genetic/genetics, Factor (chord), Evolution, Molecular, 03 medical and health sciences, Table (landform), Humans, Selection, Genetic, Genetic Association Studies, 030304 developmental biology, Genotype imputation, Chromosomes, Human, Y, Genome, Human, Computational Biology, Genetic Variation, Sequence Analysis, DNA, Genomics/methods, Genetics, Population, Haplotypes, Sample Size, wide association gene-expression recombination hotspots meiotic recombination genotype imputation rare variants haplotype map nucleotide diseases common, Mutation, Genome, Human/genetics, Trinucleotide repeat expansion, Sequence Alignment, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

April 1, 2011, The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother–father–child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10[superscript −8] per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research., Ministry of Science and Technology of the People's Republic of China (973 program no. 2011CB809200), National Natural Science Foundation (China) (30725008), National Natural Science Foundation (China) (30890032), National Natural Science Foundation (China) (30811130531), National Natural Science Foundation (China) (30221004), China (Chinese 863 program 2006AA02Z177), China (Chinese 863 program 2006AA02Z334), China (Chinese 863 program 2006AA02A302), China (Chinese 863 program 2009AA022707), National Institutes of Health (U.S.) (Grant U54HG2750), National Institutes of Health (U.S.) (Grant U01HG5208), National Institutes of Health (U.S.) (Grant U54HG3067)

Published
2010

13. Common variants at 30 loci contribute to polygenic dyslipidemia

Author

Tanaka, Toshiko, Galan, Pilar, Demissie, Serkalem, Schadt, Eric E, Surti, Aarti, Ferrucci, Luigi, Bennett, Derrick, Kubalanza, Kari A, Peloso, Gina M, Parish, Sarah, Zelenika, Diana, Voight, Benjamin F, Scott, Laura J, Kaplan, Lee, Clarke, Robert, Jackson, Anne U, Musunuru, Kiran, Laakso, Markku, Bonnycastle, Lori L, Bergman, Richard N, Kuusisto, Johanna, Swift, Amy J, Kathiresan, Sekar, Burtt, Noel P, Li, Yun, Crawford, Gabriel, Scheet, Paul, Willer, Cristen J, Sundvall, Jouko, Stringham, Heather M, Morken, Mario A, and Guiducci, Candace

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 × 10-8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10-15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Published
2009
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14. Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

Author

Timpson, Nicholas J., Scheet, Paul, Thorleifsson, Gudmar, Speliotes, Elizabeth K., Lim, Noha, Almgren, Peter, Lamina, Claudia, Randall, Joshua C., Bergman, Richard N., Qi, Lu, Zhao, Jing Hua, Drong, Alexander, Bandinelli, Stefania, Lyon, Helen N., Bonnycastle, Lori L., Heid, Iris M., Bennett, Amanda J., Willer, Cristen J., Soranzo, Nicole, Amin, Najaf, Aulchenko, Yurii S., Zillikens, M. Carola, Luan, Jian'an, Rivadeneira, Fernando, Sanna, Serena, Chanock, Stephen J., Bumpstead, Suzannah J., Jackson, Anne U., Steinthorsdottir, Valgerdur, Herrera, Blanca M., Chambers, John C., and Lindgren, Cecilia M.

Abstract

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

Published
2009
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15. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Author

Willer, Cristen J, Scheet, Paul, Prokopenko, Inga, McCarroll, Steven A, Soranzo, Nicole, Weedon, Michael N, Lim, Noha, Speliotes, Elizabeth K, Bingham, Sheila A, Bergman, Richard N, Li, Shengxu, Heid, Iris M, Bennett, Amanda, Wheeler, Eleanor, Jackson, Anne U, Berndt, Sonja I, Sanna, Serena, Qi, Lu, Lindgren, Cecilia M, Papadakis, Konstantinos, Elliott, Amanda L, Tanaka, Toshiko, Zhao, Jing Hua, Almgren, Peter, Roccasecca, Rosa Maria, Lettre, Guillaume, Timpson, Nicholas J, Jacobs, Leonie C, Randall, Joshua C, Lamina, Claudia, Loos, Ruth J F, and Lyon, Helen N

Abstract

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Published
2009
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16. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels

Author

Prokopenko, Inga, Langenberg, Claudia, Florez, Jose C., Saxena, Richa, Soranzo, Nicole, Thorleifsson, Gudmar, Loos, Ruth J.F., Manning, Alisa K., Jackson, Anne U., Aulchenko, Yurii, Potter, Simon C., Erdos, Michael R., Sanna, Serena, Hottenga, Jouke-Jan, Wheeler, Eleanor, Kaakinen, Marika, Lyssenko, Valeriya, Chen, Wei-Min, Ahmadi, Kourosh, Beckmann, Jacques S., Bergman, Richard N., Bochud, Murielle, Bonnycastle, Lori L., Buchanan, Thomas A., Cao, Antonio, Cervino, Alessandra, Coin, Lachlan, Collins, Francis S., Crisponi, Laura, de Geus, Eco JC, Dehghan, Abbas, Deloukas, Panos, Doney, Alex S F, Elliott, Paul, Freimer, Nelson, Gateva, Vesela, Herder, Christian, Hofman, Albert, Hughes, Thomas E., Hunt, Sarah, Illig, Thomas, Inouye, Michael, Isomaa, Bo, Johnson, Toby, Kong, Augustine, Krestyaninova, Maria, Kuusisto, Johanna, Laakso, Markku, Lim, Noha, Lindblad, Ulf, Lindgren, Cecilia M., McCann, Owen T., Mohlke, Karen L., Morris, Andrew D, Naitza, Silvia, Orrù, Marco, Palmer, Colin N A, Pouta, Anneli, Randall, Joshua, Rathmann, Wolfgang, Saramies, Jouko, Scheet, Paul, Scott, Laura J., Scuteri, Angelo, Sharp, Stephen, Sijbrands, Eric, Smit, Jan H., Song, Kijoung, Steinthorsdottir, Valgerdur, Stringham, Heather M., Tuomi, Tiinamaija, Tuomilehto, Jaakko, Uitterlinden, André G., Voight, Benjamin F., Waterworth, Dawn, Wichmann, H.-Erich, Willemsen, Gonneke, Witteman, Jacqueline CM, Yuan, Xin, Zhao, Jing Hua, Zeggini, Eleftheria, Schlessinger, David, Sandhu, Manjinder, Boomsma, Dorret I, Uda, Manuela, Spector, Tim D., Penninx, Brenda WJH, Altshuler, David, Vollenweider, Peter, Jarvelin, Marjo Riitta, Lakatta, Edward, Waeber, Gerard, Fox, Caroline S., Peltonen, Leena, Groop, Leif C., Mooser, Vincent, Cupples, L. Adrienne, Thorsteinsdottir, Unnur, Boehnke, Michael, Barroso, Inês, Van Duijn, Cornelia, Dupuis, Josée, Watanabe, Richard M., Stefansson, Kari, McCarthy, Mark I., Wareham, Nicholas J., Meigs, James B., and Abecasis, Goncalo R.

Subjects
Blood Glucose, Diabetes Mellitus, Type 2, Meta-Analysis as Topic, Receptor, Melatonin, MT2, Case-Control Studies, Quantitative Trait Loci, Receptors, Melatonin, Humans, Genetic Predisposition to Disease, Fasting, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

Published
2008

17. Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Author

Meneton, Pierre, Duren, William L, Scheet, Paul A, Heath, Simon C, Jackson, Anne U, Narisu, Narisu, Timpson, Nicholas J, Bonnycastle, Lori L, Maschio, Andrea, Busonero, Fabio, Shen, Haiqing, Clarke, Robert, Albai, Giuseppe, Chen, Wei-Min, Stringham, Heather M, Hercberg, Serge, Zelenika, Diana, Scuteri, Angelo, Strait, James, Scott, Laura J, Parish, Sarah, Bennett, Derrick, Morken, Mario A, Galan, Pilar, Watanabe, Richard M, Sundvall, Jouko, Najjar, Samer S, Li, Yun, Swift, Amy J, Sanna, Serena, Willer, Cristen J, and Mulas, Antonella

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Published
2008
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18. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals

Author

Dastani, Zari, Hivert, Marie-France, Timpson, Nicholas, Perry, John RB, Yuan, Xin, Scott, Robert A, Henneman, Peter, Heid, Iris M, Kizer, Jorge R, Lyytikäinen, Leo-Pekka, Fuchsberger, Christian, Tanaka, Toshiko, Morris, Andrew P, Small, Kerrin, Isaacs, Aaron, Beekman, Marian, Coassin, Stefan, Lohman, Kurt, Qi, Lu, Kanoni, Stavroula, Pankow, James S, Uh, Hae-Won, Wu, Ying, Bidulescu, Aurelian, Rasmussen-Torvik, Laura J, Greenwood, Celia MT, Ladouceur, Martin, Grimsby, Jonna, Manning, Alisa K, Liu, Ching-Ti, Kooner, Jaspal, Mooser, Vincent E, Vollenweider, Peter, Kapur, Karen A, Chambers, John, Wareham, Nicholas J, Langenberg, Claudia, Frants, Rune, Willems-Vandijk, Ko, Oostra, Ben A, Willems, Sara M, Lamina, Claudia, Winkler, Thomas W, Psaty, Bruce M, Tracy, Russell P, Brody, Jennifer, Chen, Ida, Viikari, Jorma, Kähönen, Mika, Pramstaller, Peter P, Evans, David M, St Pourcain, Beate, Sattar, Naveed, Wood, Andrew R, Bandinelli, Stefania, Carlson, Olga D, Egan, Josephine M, Böhringer, Stefan, Van Heemst, Diana, Kedenko, Lyudmyla, Kristiansson, Kati, Nuotio, Marja-Liisa, Loo, Britt-Marie, Harris, Tamara, Garcia, Melissa, Kanaya, Alka, Haun, Margot, Klopp, Norman, Wichmann, H-Erich, Deloukas, Panos, Katsareli, Efi, Couper, David J, Duncan, Bruce B, Kloppenburg, Margreet, Adair, Linda S, Borja, Judith B, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, Wilson, James G, Musani, Solomon, Guo, Xiuqing, Johnson, Toby, Semple, Robert, Teslovich, Tanya M, Allison, Matthew A, Redline, Susan, Buxbaum, Sarah G, Mohlke, Karen L, Meulenbelt, Ingrid, Ballantyne, Christie M, Dedoussis, George V, Hu, Frank B, Liu, Yongmei, Paulweber, Bernhard, Spector, Timothy D, Slagboom, P Eline, Ferrucci, Luigi, Jula, Antti, Perola, Markus, Raitakari, Olli, Florez, Jose C, Salomaa, Veikko, Eriksson, Johan G, Frayling, Timothy M, Hicks, Andrew A, Lehtimäki, Terho, Smith, George Davey, Siscovick, David S, Kronenberg, Florian, Van Duijn, Cornelia, Loos, Ruth JF, Waterworth, Dawn M, Meigs, James B, Dupuis, Josee, Richards, J Brent, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Hofmann, Oliver M, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, Van Dam, Rob M, Van Haeften, Timon W, Van Herpt, Thijs, Van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Morris, Andrew D, Palmer, Colin NA, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Pedersen, Oluf, Barroso, Inês, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, Van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Elliott, Paul, Rybin, Denis, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Lajunen, Taina, Doney, Alex, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sigurðsson, Gunnar, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Borecki, Ingrid B, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Procardis Consortium, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Penninx, Brenda WJH, Boomsma, Dorret I, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, MAGIC Investigators, GLGC Consortium, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Chasman, Daniel I, Johansen, Christopher T, Fouchier, Sigrid W, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Feitosa, Mary F, Orho-Melander, Marju, Melander, Olle, Li, Xiaohui, Li, Mingyao, Cho, Yoon Shin, Go, Min Jin, Kim, Young Jin, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Ong, Rick Twee-Hee, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Whitfield, John B, Thompson, John R, Surakka, Ida, Spector, Tim D, Smit, Johannes H, Sinisalo, Juha, Scott, James, Saharinen, Juha, Sabatti, Chiara, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Parker, Alex N, Pare, Guillaume, O'Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, McArdle, Wendy, Masson, David, Martin, Nicholas G, Marroni, Fabio, Lucas, Gavin, Luben, Robert, Lokki, Marja-Liisa, Lettre, Guillaume, Launer, Lenore J, Lakatta, Edward G, Laaksonen, Reijo, Kyvik, Kirsten O, König, Inke R, Khaw, Kay-Tee, Kaplan, Lee M, Johansson, Åsa, Janssens, A Cecile JW, Igl, Wilmar, Hovingh, G Kees, Hengstenberg, Christian, Havulinna, Aki S, Hastie, Nicholas D, Harris, Tamara B, Haritunians, Talin, Hall, Alistair S, Groop, Leif C, Gonzalez, Elena, Freimer, Nelson B, Erdmann, Jeanette, Ejebe, Kenechi G, Döring, Angela, Dominiczak, Anna F, Demissie, Serkalem, Deloukas, Panagiotis, De Faire, Ulf, Crawford, Gabriel, Chen, Yii-Der I, Caulfield, Mark J, Boekholdt, S Matthijs, Assimes, Themistocles L, Quertermous, Thomas, Seielstad, Mark, Wong, Tien Y, Tai, E-Shyong, Feranil, Alan B, Kuzawa, Christopher W, Taylor, Herman A, Gabriel, Stacey B, Holm, Hilma, Gudnason, Vilmundur, Krauss, Ronald M, Ordovas, Jose M, Munroe, Patricia B, Kooner, Jaspal S, Tall, Alan R, Hegele, Robert A, Kastelein, John JP, Schadt, Eric E, Strachan, David P, Reilly, Muredach P, Samani, Nilesh J, Schunkert, Heribert, Cupples, L Adrienne, Sandhu, Manjinder S, Ridker, Paul M, Rader, Daniel J, and Kathiresan, Sekar

Subjects
2. Zero hunger, Male, Waist-Hip Ratio, Cholesterol, HDL, Gene Expression, Glucose Tolerance Test, Polymorphism, Single Nucleotide, White People, 3. Good health, Black or African American, Asian People, Diabetes Mellitus, Type 2, Humans, Female, Genetic Predisposition to Disease, Adiponectin, Insulin Resistance, Metabolic Networks and Pathways, Genome-Wide Association Study
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

20. Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Author

Swift, Amy J., Collins, Rory, Maschio, Andrea, Uda, Manuela, Tuomilehto, Jaakko, Collins, Francis S., Zelenika, Diana, Meneton, Pierre, Stringham, Heather M., Morken, Mario A., Mohlke, Karen, Clarke, Robert, Mulas, Antonella, Narisu, Narisu, Albai, Giuseppe, Strait, James, Scheet, Paul A., Scuteri, Angelo, Lawlor, Debbie A., Lathrop, G. Mark, Bennett, Derrick, Davey-Smith, George, Watanabe, Richard M., Busonero, Fabio, Duren, William L., Cao, Antonio, Boehnke, Michael, Timpson, Nicholas J., Shuldiner, Alan R., Sanna, Serena, Galan, Pilar, Schlessinger, David, Li, Yun, Abecasis, Goncalo R., Chen, Wei-Min, Sundvall, Jouko, Willer, Cristen J., Ebrahim, Shah, Heath, Simon C., Bonnycastle, Lori L., Ben-Shlomo, Yoav, Lakatta, Edward, Shen, Haiqing, Nagaraja, Ramaiah, Jackson, Anne U., Scott, Laura J., Najjar, Samer S., Bergman, Richard N., Parish, Sarah, and Hercberg, Serge

Subjects
lipids (amino acids, peptides, and proteins), 3. Good health
Abstract

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

21. Population structure, migration and diversifying selection in the Netherlands

Author

Sullivan, Patrick F, Brooks, Andrew, Willemsen, Gonneke, van Beijsterveldt, Toos, Scheet, Paul, Nivard, Michel G, Xiao, Xiangjun, Hottenga, Jouke-Jan, Davies, Gareth E, Penninx, Brenda W J H, Knijff, Peter de, Boomsma, Dorret I, de Geus, Eco J, Hu, Yueshan, Ehli, Erik A, Abdellaoui, Abdel, and Hudziak, James J

Subjects
10. No inequality
Abstract

Genetic variation in a population can be summarized through principal component analysis (PCA) on genome-wide data. PCs derived from such analyses are valuable for genetic association studies, where they can correct for population stratification. We investigated how to capture the genetic population structure in a well-characterized sample from the Netherlands and in a worldwide data set and examined whether (1) removing long-range linkage disequilibrium (LD) regions and LD-based SNP pruning significantly improves correlations between PCs and geography and (2) whether genetic differentiation may have been influenced by migration and/or selection. In the Netherlands, three PCs showed significant correlations with geography, distinguishing between: (1) North and South; (2) East and West; and (3) the middle-band and the rest of the country. The third PC only emerged with minimized LD, which also significantly increased correlations with geography for the other two PCs. In addition to geography, the Dutch North–South PC showed correlations with genome-wide homozygosity (r=0.245), which may reflect a serial-founder effect due to northwards migration, and also with height (♂: r=0.142, ♀: r=0.153). The divergence between subpopulations identified by PCs is partly driven by selection pressures. The first three PCs showed significant signals for diversifying selection (545 SNPs - the majority within 184 genes). The strongest signal was observed between North and South for the functional SNP in HERC2 that determines human blue/brown eye color. Thus, this study demonstrates how to increase ancestry signals in a relatively homogeneous population and how those signals can reveal evolutionary history.

22. Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Author

Nauck, Matthias, Shuldiner, Alan, Gudnason, Vilmundur, Dupuis, Josée, Salomaa, Veikko, Snieder, Harold, Völzke, Henry, Ferrucci, Luigi, Peltonen, Leena, Ballantyne, Christie M., Koenig, Wolfgang, Soranzo, Nicole, Guo, Xiuqing, Scheet, Paul, Naitza, Silvia, Freimer, Nelson B., Benjamin, Emelia J., Kettunen, Johannes, Folsom, Aaron R., Schnabel, Renate B., Sarin, Antti Pekka, Sijbrands, Eric J.G., Zee, Robert Y.L., Sun, Wei, Uitterlinden, Andre G., Rotter, Jerome I., Spector, Timothy D., Liu, Yongmei, Smith, Nicholas L., Psaty, Bruce M., Barbalic, Maja, Homuth, Georg, Yamamoto, Jennifer F., Paré, Guillaume, Boerwinkle, Eric, Willemsen, Gonneke, Nolte, Ilja M., Wallaschofski, Henri, Alizadeh, Behrooz Z., Surakka, Ida, Hayward, Caroline, Teumer, Alexander, Järvelin, Marjo Riitta, Greiser, Karin H., Dehghan, Abbas, Eiriksdottir, Gudny, Van Duijn, Cornelia M., Pouta, Anneli, Vasan, Ramachandran S., Campbell, Harry, Harris, Tamara B., Boomsma, Dorret I., Ripatti, Samuli, Larson, Martin G., Schlessinger, David, Hofman, Albert, Sundvall, Jouko, Pankow, James, De Geus, Eco J.C., Siscovick, David S., Thiery, Joachim, Wilson, James F., Hoogeveen, Ron C., Ruokonen, Aimo, Badola, Sunita, Thorand, Barbara, Keaney, John F., Gibson, Quince D., Radke, Dörte, Chasman, Daniel I., Guralnik, Jack, Hicks, Andrew A., Uda, Manuela, Elliott, Paul, Werdan, Karl, Ridker, Paul M., Fontes, João D., Gieger, Christian, Vitart, Veronique, Rose, Lynda M., Bates, David, Xiao, Xiangjun, Jamshidi, Yalda, Tanaka, Toshiko, Rudock, Megan E., Baumert, Jens, Pellikka, Niina, Rice, Kenneth, Rudan, Igor, Tsui, Kim, Bis, Joshua C., Smith, Albert V., Parker, Alexander N., Kuss, Oliver, Aspelund, Thor, Willems Van Dijk, Ko, Penninx, Brenda W., Coresh, Joe, Perola, Markus, Young, Lauren, Buring, Julie E., Fuchsberger, Christian, Witteman, Jacqueline C.M., Pramstaller, Peter P., Astor, Brad C., Lu, Chen, Nambi, Vijay, Launer, Lenore J., Tracy, Russell P., Bandinelli, Stefania, Henneman, Peter, Strachan, David P., Meyer Zu Schwabedissen, Henriette E., and Kavousi, Maryam

Subjects
2. Zero hunger, 3. Good health
Abstract

C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We aimed to identify genetic variants that are associated with CRP levels.

24. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Global BPgen Consrotium, Sovio, Ulla, Shuldiner, Alan R., Dedoussis, George V., Bonnycastle, Lori L., Hercberg, Serge, Chen, Yii-Der Ida, Visvikis-Siest, Sophie, Kumari, Meena, Meneton, Pierre, Ariyurek, Yavuz, Egan, Josephine M., Ben-Shlomo, Yoav, Forouhi, Nita G., Graessler, Jurgen, Rudan, Igor, Pedersen, Nancy L., Lindgren, Cecilia M., Chines, Peter, Stringham, Heather M., Meisinger, Christa, Pattaro, Cristian, Vogelzangs, Nicole, DIAGRAM Consortium, Illig, Thomas, Langenberg, Claudia, Zethelius, Bjorn, Sayer, Avan Aihie, Laakso, Markku, Li, Man, Clarke, Robert, Isomaa, Bo, McAteer, Jarred B., Doney, Alex, Pedersen, Oluf, Jorgensen, Torben, Bottcher, Yvonne, Ebrahim, Shah, Schwarz, Peter, Lecoeur, Cecile, Psaty, Bruce M., Shrader, Peter, Knight, Beatrice, Beilby, John P., Gieger, Christian, Ripatti, Samuli, Zhao, Jing Hua, Herder, Christian, Morken, Mario A., Kesaniemi, Y. Antero, Orru, Marco, Mitchell, Braxton D., Thorand, Barbara, Lyssenko, Valeriya, Manning, Alisa K., Sethupathy, Praveen, Meyre, David, Hansen, Torben, Rayner, Nigel W., Hammond, Naomi, Timpson, Nicholas J., Sanna, Serena, Brunner, Eric, Zhai, Guangju, Witteman, Jacqueline C.M., Rybin, Denis, Cornelis, Marilyn, Zabena, Carina, Willemson, Gonneke, Kaakinen, Marika, Perry, John R.B., Zelenika, Diana, Walters, G. Bragi, Heath, Simon C., Oostra, Ben A., Salomaa, Veikko, Ward, Kim L., van Dijk, Ko Willems, Williams, Gordon H., Karpe, Fredrik, Wagner, Peter J., Magi, Reedik, Fischer-Rosinsky, Antje, Hallmans, Goran, Lajunen, Taina, Qi, Lu, Navarro, Paul, Grallert, Harald, Pramstaller, Peter Paul, Kaprio, Jaakko, Smith, Nicholas L., Hayward, Caroline, Sandbaek, Annelli, Sparso, Thomas, Dina, Christian, Paolisso, Giuseppe, Wright, Alan F., Mangino, Massimo, Henneman, Peter, Smith, George Davey, Boerwinkle, Eric, Prokopenko, Inga, Jackson, Anne U., Grarup, Niels, Walley, Andrew, Hofman, Albert, Hadjadj, Samy, Hu, Frank B., Hung, Joe, Li, Yun, Gwilliam, Rhian, Thorleifsson, Gudmar, Singleton, Andrew, Ardlie, Kristin, Kivimaki, Mika, Syvanen, Ann-Christine, Zillikens, M. Carola, Day, Ian N.M., Rice, Kenneth, Silander, Kaisa, Bergmann, Sven, Simpson, Laila, Scott, Laura J., Melzer, David, Neville, Matthew J., Watkins, Hugh, Ingelsson, Erik, Lathrop, G. Mark, Scheet, Paul, Hottenga, Jouke Jan, Song, Kijoung, Benediktsson, Rafn, de Geus, Eco J. C., Le Bacquer, Olivier, Hillman, David R., Koskinen, Seppo, Frants, Rune, Lind, Lars, Kanoni, Stavroula, Sandhu, Manjinder, Crawford, Gabe, Sigurdsson, Gunnar, Pfeiffer, Andreas F.H., Pattou, Francois, Pankow, James S., Wilson, James F., Bennett, Amanda J., Dupuis, Josee, Potter, Simon C., Elliott, Amanda, Province, Michael A., Perola, Markus, Serrano-Rios, Manuel, Kyvik, Kirsten Ohm, Yarnell, John W.G., Pakyz, Ruth, Johnson, Paul R.V., Borch-Johnsen, Knut, Saxena, Richa, Steinthorsdottir, Valgerdur, Tanaka, Toshiko, Campbell, Harry, Barter, Philip, Franzosi, Maria Grazia, GIANT Consortium, Han, Xijing, Cavalcanti-Proenca, Christine, Glazer, Nicole L., Kovacs, Peter, Stumvoll, Michael, Syddall, Holly, Hingorani, Aroon D., Morris, Andrew P., O'Connell, Jeffrey, Payne, Felicity, Galan, Pilar, Rivadeneira, Fernando, Wild, Sarah H., McPherson, Ruth, Sijbrands, Eric J.G., Hicks, Andrew A., Dehghan, Abbas, Elliott, Paul, Cooper, Matthew N., Sharp, Stephen J., Balkau, Beverley, Voight, Benjamin F., Roden, Michael, Tuomi, Tiinamaija, Franklin, Christopher S., Swift, Amy, Pichler, Irene, Narisu, Narisu, Goodarzi, Mark O., Franks, Paul W., An, Ping, Bumpstead, Suzannah J., Bochud, Murielle, Rathmann, Wolfgang, Randall, Joshua, Bouatia-Naji, Nabila, von Hoek, Mandy, Kuusisto, Johanna, Sampson, Michael J., Wichmann, H. Erich, Vitart, Veronique, Tichet, Jean, Spranger, Joachim, Fedson, Annette C., Waeber, Gerard, Wheeler, Eleanor, Polasek, Ozren, Coin, Lachlan J.M., Varma, Dhiraj, Pearson, Daniel, Hartikainen, Anna-Liisa, Loos, Ruth J.F., Grundy, Scott, Martinez-Larrad, Maria Teresa, Jula, Antti, Palmer, Colin N.A., Mukherjee, Sutapa, Bornstein, Stefan R., Gyllensten, Ulf, Roccasecca, Rosa Maria, Johnson, Toby, Crisponi, Laura, Weedon, Michael N., Hamsten, Anders, Bonnefond, Amelie, Nathan, David M., Silveira, Angela, Borecki, Ingrid B., Hassanali, Neelam, Pouta, Anneli, Fox, Caroline S., Cooper, Cyrus, McCulloch, Laura J., Hattersley, Andrew T., Seedorf, Udo, Zeggini, Eleftheria, Lawlor, Debbie A., Uitterlinden, Andre G., Rocheleau, Ghislain, Kao, W.H. Linda, Goel, Anuj, Palmer, Lyel J., Magnusson, Patrik K.E., Shields, Beverley, Tonjes, Anke, Soranzo, Nicole, Groves, Christopher J., Gloyn, Anna L., Charpentier, Guillaume, Erdos, Michael R., Posthuma, Danielle, Marmot, Michael, Morris, Andrew D., Luan, Jian'an, Delplanque, Jerome, Naitza, Silvia, Mahley, Robert, McCarroll, Steven A., Hui, Jennie, Rolandsson, Olov, and Peden, John F.

Subjects
3. Good health
Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

25. NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality

Author

Carsten A. Böger, Mathias Gorski, Gearoid M. McMahon, Huichun Xu, Yen-Pei C. Chang, Peter J. van der Most, Gerjan Navis, Ilja M. Nolte, Martin H. de Borst, Weihua Zhang, Benjamin Lehne, Marie Loh, Sian-Tsung Tan, Eric Boerwinkle, Morgan E. Grams, Peggy Sekula, Man Li, Beth Wilmot, James G. Moon, Paul Scheet, Francesco Cucca, Xiangjun Xiao, Leo-Pekka Lyytikäinen, Graciela Delgado, Tanja B. Grammer, Marcus E. Kleber, Sanaz Sedaghat, Fernando Rivadeneira, Tanguy Corre, Zoltan Kutalik, Sven Bergmann, Carrie M. Nielson, Priya Srikanth, Alexander Teumer, Martina Müller-Nurasyid, Anne Catharina Brockhaus, Arne Pfeufer, Wolfgang Rathmann, Annette Peters, Martha Matsumoto, Mariza de Andrade, Elizabeth J. Atkinson, Cassianne Robinson-Cohen, Ian H. de Boer, Shih-Jen Hwang, Iris M. Heid, Martin Gögele, Maria Pina Concas, Toshiko Tanaka, Stefania Bandinelli, Mike A. Nalls, Andrew Singleton, Salman M. Tajuddin, Adebowale Adeyemo, Jie Zhou, Ayo Doumatey, Shannon McWeeney, Joanne Murabito, Nora Franceschini, Michael Flessner, Michael Shlipak, James G. Wilson, Guanjie Chen, Charles N. Rotimi, Alan B. Zonderman, Michele K. Evans, Luigi Ferrucci, Olivier Devuyst, Mario Pirastu, Alan Shuldiner, Andrew A. Hicks, Peter Paul Pramstaller, Bryan Kestenbaum, Sharon L.R. Kardia, Stephen T. Turner, LifeLines Cohort Study, Tamara Ellefson Briske, Christian Gieger, Konstantin Strauch, Christa Meisinger, Thomas Meitinger, Uwe Völker, Matthias Nauck, Henry Völzke, Peter Vollenweider, Murielle Bochud, Gerard Waeber, Mika Kähönen, Terho Lehtimäki, Winfried März, Abbas Dehghan, Oscar H. Franco, Andre G. Uitterlinden, Albert Hofman, Herman A. Taylor, John C. Chambers, Jaspal S. Kooner, Caroline S. Fox, Robert Hitzemann, Eric S. Orwoll, Cristian Pattaro, David Schlessinger, Anna Köttgen, Harold Snieder, Afshin Parsa, David M. Cohen, Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Life Course Epidemiology (LCE), Value, Affordability and Sustainability (VALUE), Groningen Institute for Organ Transplantation (GIOT), Böger, Carsten A., Gorski, Mathia, Mcmahon, Gearoid M., Xu, Huichun, Chang, Yen Pei C., Van Der Most, Peter J., Navis, Gerjan, Nolte, Ilja M., De Borst, Martin H., Zhang, Weihua, Lehne, Benjamin, Loh, Marie, Tan, Sian Tsung, Boerwinkle, Eric, Grams, Morgan E., Sekula, Peggy, Li, Man, Wilmot, Beth, Moon, James G., Scheet, Paul, Cucca, Francesco, Xiao, Xiangjun, Lyytikäinen, Leo Pekka, Delgado, Graciela, Grammer, Tanja B., Kleber, Marcus E., Sedaghat, Sanaz, Rivadeneira, Fernando, Corre, Tanguy, Kutalik, Zoltan, Bergmann, Sven, Nielson, Carrie M., Srikanth, Priya, Teumer, Alexander, Müller Nurasyid, Martina, Brockhaus, Anne Catharina, Pfeufer, Arne, Rathmann, Wolfgang, Peters, Annette, Matsumoto, Martha, De Andrade, Mariza, Atkinson, Elizabeth J., Robinson Cohen, Cassianne, De Boer, Ian H., Hwang, Shih Jen, Heid, Iris M., Gögele, Martin, Concas, MARIA PINA, Tanaka, Toshiko, Bandinelli, Stefania, Nalls, Mike A., Singleton, Andrew, Tajuddin, Salman M., Adeyemo, Adebowale, Zhou, Jie, Doumatey, Ayo, Mcweeney, Shannon, Murabito, Joanne, Franceschini, Nora, Flessner, Michael, Shlipak, Michael, Wilson, James G., Chen, Guanjie, Rotimi, Charles N., Zonderman, Alan B., Evans, Michele K., Ferrucci, Luigi, Devuyst, Olivier, Pirastu, Mario, Shuldiner, Alan, Hicks, Andrew A., Pramstaller, Peter Paul, Kestenbaum, Bryan, Kardia, Sharon L. R., Turner, Stephen T., Study, Lifelines Cohort, Briske, Tamara Ellefson, Gieger, Christian, Strauch, Konstantin, Meisinger, Christa, Meitinger, Thoma, Völker, Uwe, Nauck, Matthia, Völzke, Henry, Vollenweider, Peter, Bochud, Murielle, Waeber, Gerard, Kähönen, Mika, Lehtimäki, Terho, März, Winfried, Dehghan, Abba, Franco, Oscar H., Uitterlinden, Andre G., Hofman, Albert, Taylor, Herman A., Chambers, John C., Kooner, Jaspal S., Fox, Caroline S., Hitzemann, Robert, Orwoll, Eric S., Pattaro, Cristian, Schlessinger, David, Köttgen, Anna, Snieder, Harold, Parsa, Afshin, and Cohen, David M.

Subjects
0301 basic medicine, medicine.medical_specialty, hyponatremia, Body water, Water-Electrolyte Imbalance, PROTEIN, human genetics, Genome-wide association study, Biology, 03 medical and health sciences, Plasma, NFAT5, Internal medicine, Gene expression, Genetic variation, Transcriptional regulation, medicine, Humans, human genetic, CELL-TYPES, GENE-EXPRESSION, Genetics, IDENTIFICATION, hypernatremia, Sodium-Bicarbonate Symporter, Sodium-Bicarbonate Symporters, Sodium, PRIMARY-CARE, 1103 Clinical Sciences, General Medicine, Urology & Nephrology, water-electrolyte balance, Plasma osmolality, Human Genetics, Hypernatremia, Hyponatremia, Water-electrolyte Balance, 030104 developmental biology, Endocrinology, Basic Research, NEPHROGENIC DIABETES-INSIPIDUS, Genome-Wide Association Study, Genetic Loci, Nephrology, Expression quantitative trait loci, TRANSCRIPTION FACTOR-BINDING, INAPPROPRIATE ANTIDIURESIS, INTRONIC ENHANCERS, Human
Abstract

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P-6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 3 x 10-5), with combined stages 1 and 2 genomewide significance of P=5.6 x 10-10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous systemand relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Published
2017

26. Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome

Author

Eduardo Vilar, Florencia McAllister, Maria Teresa Catanese, Erick Riquelme, Elisa Scarselli, F. Anthony San Lucas, Scott Kopetz, Maria Grazia Diodoro, Patrick M. Lynch, Alfredo Nicosia, Reagan M. Barnett, Kyle Chang, Guido Leoni, Ernest T. Hawk, Y. Nancy You, Melissa W. Taggart, Jason Roszik, Paul Scheet, Federica Mori, Ester Borras, Laura Reyes-Uribe, Chang, Kyle, Taggart, Melissa W., Reyes-Uribe, Laura, Borras, Ester, Riquelme, Erick, Barnett, Reagan M., Leoni, Guido, Anthony San Lucas, F., Catanese, Maria T., Mori, Federica, Diodoro, Maria G., Nancy You, Y., Hawk, Ernest T., Roszik, Jason, Scheet, Paul, Kopetz, Scott, Nicosia, Alfredo, Scarselli, Elisa, Lynch, Patrick M., Mcallister, Florencia, and Vilar, Eduardo

Subjects
Adenoma, Male, 0301 basic medicine, Cancer Research, LAG3, medicine.medical_treatment, Colonic Polyps, Familial adenomatous polyposis, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Carcinoma, Humans, Original Investigation, business.industry, Gene Expression Profiling, Cancer, Immunotherapy, Middle Aged, Prognosis, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, 030104 developmental biology, Oncology, Hyperplastic Polyp, 030220 oncology & carcinogenesis, Cancer research, Female, Colorectal Neoplasms, business, Precancerous Conditions, Biomarkers, Follow-Up Studies
Abstract

IMPORTANCE: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. OBJECTIVE: To characterize the immune profile of premalignant lesions from a cohort of patients with LS. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. MAIN OUTCOMES AND MEASURES: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. RESULTS: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling). CONCLUSIONS AND RELEVANCE: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.

Published
2018

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