Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Selection and gene flow shape niche-associated variation in pheromone response
Lee, Daehan ; Zdraljevic, Stefan ; Cook, Daniel E. ; Frézal, Lise ; Hsu, Jung-Chen ; Sterken, Mark G. ; Riksen, Joost A.G. ; Wang, John ; Kammenga, Jan E. ; Braendle, Christian ; Félix, Marie-Anne ; Schroeder, Frank C. ; Andersen, Erik C. - \ 2019
Nature Ecology & Evolution 3 (2019). - ISSN 2397-334X - p. 1455 - 1463.
From quorum sensing in bacteria to pheromone signalling in social insects, chemical communication mediates interactions among individuals in local populations. In Caenorhabditis elegans, ascaroside pheromones can dictate local population density; high levels of pheromones inhibit the reproductive maturation of individuals. Little is known about how natural genetic diversity affects the pheromone responses of individuals from diverse habitats. Here, we show that a niche-associated variation in pheromone receptor genes contributes to natural differences in pheromone responses. We identified putative loss-of-function deletions that impair duplicated pheromone receptor genes (srg-36 and srg-37), which were previously shown to be lost in population-dense laboratory cultures. A common natural deletion in srg-37 arose recently from a single ancestral population that spread throughout the world; this deletion underlies reduced pheromone sensitivity across the global C. elegans population. We found that many local populations harbour individuals with a wild-type or a deletion allele of srg-37, suggesting that balancing selection has maintained the recent variation in this pheromone receptor gene. The two srg-37 genotypes are associated with niche diversity underlying boom-and-bust population dynamics. We hypothesize that human activities likely contributed to the gene flow and balancing selection of srg-37 variation through facilitating the migration of species and providing a favourable niche for the recently arisen srg-37 deletion.

Correction to: Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
Bien, Stephanie A. ; Su, Yu Ru ; Conti, David V. ; Harrison, Tabitha A. ; Qu, Conghui ; Guo, Xingyi ; Lu, Yingchang ; Albanes, Demetrius ; Auer, Paul L. ; Banbury, Barbara L. ; Berndt, Sonja I. ; Bézieau, Stéphane ; Brenner, Hermann ; Buchanan, Daniel D. ; Caan, Bette J. ; Campbell, Peter T. ; Carlson, Christopher S. ; Chan, Andrew T. ; Chang-Claude, Jenny ; Chen, Sai ; Connolly, Charles M. ; Easton, Douglas F. ; Feskens, Edith J.M. ; Gallinger, Steven ; Giles, Graham G. ; Gunter, Marc J. ; Hampe, Jochen ; Huyghe, Jeroen R. ; Hoffmeister, Michael ; Hudson, Thomas J. ; Jacobs, Eric J. ; Jenkins, Mark A. ; Kampman, Ellen ; Kang, Hyun Min ; Kühn, Tilman ; Küry, Sébastien ; Lejbkowicz, Flavio ; Marchand, Loic Le; Milne, Roger L. ; Li, Li ; Li, Christopher I. ; Lindblom, Annika ; Lindor, Noralane M. ; Martín, Vicente ; McNeil, Caroline E. ; Melas, Marilena ; Moreno, Victor ; Newcomb, Polly A. ; Offit, Kenneth ; Pharaoh, Paul D.P. ; Potter, John D. ; Qu, Chenxu ; Riboli, Elio ; Rennert, Gad ; Sala, Núria ; Schafmayer, Clemens ; Scacheri, Peter C. ; Schmit, Stephanie L. ; Severi, Gianluca ; Slattery, Martha L. ; Smith, Joshua D. ; Trichopoulou, Antonia ; Tumino, Rosario ; Ulrich, Cornelia M. ; Duijnhoven, Fränzel J.B. van; Guelpen, Bethany Van; Weinstein, Stephanie J. ; White, Emily ; Wolk, Alicja ; Woods, Michael O. ; Wu, Anna H. ; Abeçasis, Goncalo R. ; Casey, Graham ; Nickerson, Deborah A. ; Gruber, Stephen B. ; Hsu, Li ; Zheng, Wei ; Peters, Ulrike - \ 2019
Human Genetics 138 (2019)7. - ISSN 0340-6717 - p. 789 - 791.

Every author has erroneously been assigned to the affiliation “62”. The affiliation 62 belongs to the author Graham Casey.

Tracking global climate change adaptation among governments
Berrang-Ford, Lea ; Biesbroek, Robbert ; Ford, James D. ; Lesnikowski, Alexandra ; Tanabe, Andrew ; Wang, Frances M. ; Chen, Chen ; Hsu, Angel ; Hellmann, Jessica J. ; Pringle, Patrick ; Grecequet, Martina ; Amado, J.C. ; Huq, Saleemul ; Lwasa, Shuaib ; Heymann, S.J. - \ 2019
Nature Climate Change 9 (2019)6. - ISSN 1758-678X - p. 440 - 449.

The Paris Agreement and Katowice Climate Package articulate a clear mandate for all parties to undertake and document adaptation progress. Yet persistent challenges have prevented substantive developments in tracking adaptation and the assessment of adaptation actions and their outcomes. Here, we provide an overview of the challenges of adaptation tracking and propose a comprehensive conceptual framework for assessing adaptation progress by governments that is scalable over time and across contexts. The framework addresses the core components of adaptation assessment (vulnerability, goals and targets, adaptation efforts, and adaptation results) and characterizes subcomponents focused on adaptation effort (leadership, organizations and policy). In particular, we highlight how critical insights can be uncovered by systematically tracking policy efforts over time, and discusses novel approaches to data collection.

The strengths and limitations of the SUSFANS metrics and models for assessing sustainable food and nutrition security in Europe : Deliverable No. D9.6
Latka, Catharina ; Kuiper, M.H. ; Heckelei, Thomas ; Havlík, Petr ; Frank, Stefan ; Dijk, M. van; Veer, P. van 't; Achterbosch, T.J. ; Hsu, S.H. - \ 2019
SUSFANS - 33 p.
The SUSFANS model toolbox comprises state-of-the-art foresight and newly developed diet models for a holistic sustainability and dietary assessment. The toolbox is ready to assess the food system transitions to support healthy and sustainable diets of EU citizens. A future research agenda for the modelling of food system properties is proposed regarding modelling of food supply, consumer choices, global impacts and for assessing and communicating complex model results.
Disentangling the genetics of lean mass
Karasik, David ; Zillikens, M.C. ; Hsu, Yi Hsiang ; Aghdassi, Ali ; Akesson, Kristina ; Amin, Najaf ; Barroso, Inês ; Bennett, David A. ; Bertram, Lars ; Bochud, Murielle ; Borecki, Ingrid B. ; Broer, Linda ; Buchman, Aron S. ; Byberg, Liisa ; Campbell, Harry ; Campos-Obando, Natalia ; Cauley, Jane A. ; Cawthon, Peggy M. ; Chambers, John C. ; Chen, Zhao ; Cho, Nam H. ; Choi, Hyung Jin ; Chou, Wen Chi ; Cummings, Steven R. ; Groot, Lisette C.P.G.M. De; Jager, Phillip L. De; Demuth, Ilja ; Diatchenko, Luda ; Econs, Michael J. ; Eiriksdottir, Gudny ; Enneman, Anke W. ; Eriksson, Joel ; Eriksson, Johan G. ; Estrada, Karol ; Evans, Daniel S. ; Feitosa, Mary F. ; Fu, Mao ; Gieger, Christian ; Grallert, Harald ; Gudnason, Vilmundur ; Lenore, Launer J. ; Hayward, Caroline ; Hofman, Albert ; Homuth, Georg ; Huffman, Kim M. ; Husted, Lise B. ; Illig, Thomas ; Ingelsson, Erik ; Ittermann, Till ; Jansson, John Olov ; Johnson, Toby ; Biffar, Reiner ; Jordan, Joanne M. ; Jula, Antti ; Karlsson, Magnus ; Khaw, Kay Tee ; Kilpeläinen, Tuomas O. ; Klopp, Norman ; Kloth, Jacqueline S.L. ; Koller, Daniel L. ; Kooner, Jaspal S. ; Kraus, William E. ; Kritchevsky, Stephen ; Kutalik, Zoltán ; Kuulasmaa, Teemu ; Kuusisto, Johanna ; Laakso, Markku ; Lahti, Jari ; Lang, Thomas ; Langdahl, Bente L. ; Lerch, Markus M. ; Lewis, Joshua R. ; Lill, Christina ; Lind, Lars ; Lindgren, Cecilia ; Liu, Yongmei ; Livshits, Gregory ; Ljunggren, Östen ; Loos, Ruth J.F. ; Lorentzon, Mattias ; Luan, Jian An ; Luben, Robert N. ; Malkin, Ida ; McGuigan, Fiona E. ; Medina-Gomez, Carolina ; Meitinger, Thomas ; Melhus, Håkan ; Mellström, Dan ; Michaëlsson, Karl ; Mitchell, Braxton D. ; Morris, Andrew P. ; Mosekilde, Leif ; Nethander, Maria ; Newman, Anne B. ; Oconnell, Jeffery R. ; Oostra, Ben A. ; Orwoll, Eric S. ; Palotie, Aarno ; Peacock, Munro ; Perola, Markus ; Peters, Annette ; Prince, Richard L. ; Psaty, Bruce M. ; Räikkönen, Katri ; Ralston, Stuart H. ; Ripatti, Samuli ; Rivadeneira, Fernando ; Robbins, John A. ; Rotter, Jerome I. ; Rudan, Igor ; Salomaa, Veikko ; Satterfield, Suzanne ; Schipf, Sabine ; Shin, Chan Soo ; Smith, Albert V. ; Smith, Shad B. ; Soranzo, Nicole ; Spector, Timothy D. ; StanÄ Áková, Alena ; Stefansson, Kari ; Steinhagen-Thiessen, Elisabeth ; Stolk, Lisette ; Streeten, Elizabeth A. ; Styrkarsdottir, Unnur ; Swart, Karin M.A. ; Thompson, Patricia ; Thomson, Cynthia A. ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Tikkanen, Emmi ; Tranah, Gregory J. ; Uitterlinden, André G. ; Duijn, Cornelia M. Van; Schoor, Natasja M. Van; Vandenput, Liesbeth ; Vollenweider, Peter ; Völzke, Henry ; Wactawski-Wende, Jean ; Walker, Mark ; J Wareham, Nicholas ; Waterworth, Dawn ; Weedon, Michael N. ; Wichmann, H.E. ; Widen, Elisabeth ; Williams, Frances M.K. ; Wilson, James F. ; Wright, Nicole C. ; Yerges-Armstrong, Laura M. ; Yu, Lei ; Zhang, Weihua ; Zhao, Jing Hua ; Zhou, Yanhua ; Nielson, Carrie M. ; Harris, Tamara B. ; Demissie, Serkalem ; Kiel, Douglas P. ; Ohlsson, Claes - \ 2019
American Journal of Clinical Nutrition 109 (2019)2. - ISSN 0002-9165 - p. 276 - 278.
body composition - body fat - meta-Analysis of genome-wide association studies - metabolic profile - skeletal muscle

Background Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age 2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
Bien, Stephanie A. ; Su, Yu-Ru ; Conti, David V. ; Harrison, Tabitha A. ; Qu, Conghui ; Guo, Xingyi ; Lu, Yingchang ; Albanes, Demetrius ; Auer, Paul L. ; Banbury, Barbara L. ; Berndt, Sonja I. ; Bézieau, Stéphane ; Brenner, Hermann ; Buchanan, Daniel D. ; Caan, Bette J. ; Campbell, Peter T. ; Carlson, Christopher S. ; Chan, Andrew T. ; Chang-Claude, Jenny ; Chen, Sai ; Connolly, Charles M. ; Easton, Douglas F. ; Feskens, Edith J.M. ; Gallinger, Steven ; Giles, Graham G. ; Gunter, Marc J. ; Hampe, Jochen ; Huyghe, Jeroen R. ; Hoffmeister, Michael ; Hudson, Thomas J. ; Jacobs, Eric J. ; Jenkins, Mark A. ; Kampman, Ellen ; Kang, Hyun Min ; Kühn, Tilman ; Küry, Sébastien ; Lejbkowicz, Flavio ; Marchand, Loic Le; Milne, Roger L. ; Li, Christopher I. ; Lindblom, Annika ; Lindor, Noralane M. ; Martín, Vicente ; McNeil, Caroline E. ; Melas, Marilena ; Moreno, Victor ; Newcomb, Polly A. ; Offit, Kenneth ; Pharaoh, Paul D.P. ; Potter, John D. ; Qu, Chenxu ; Riboli, Elio ; Rennert, Gad ; Sala, Núria ; Schafmayer, Clemens ; Scacheri, Peter C. ; Schmit, Stephanie L. ; Severi, Gianluca ; Slattery, Martha L. ; Smith, Joshua D. ; Trichopoulou, Antonia ; Tumino, Rosario ; Ulrich, Cornelia M. ; Duijnhoven, Fränzel J.B. van; Guelpen, Bethany Van; Weinstein, Stephanie J. ; White, Emily ; Wolk, Alicja ; Woods, Michael O. ; Wu, Anna H. ; Abecasis, Goncalo R. ; Casey, Graham ; Nickerson, Deborah A. ; Gruber, Stephen B. ; Hsu, Li ; Zheng, Wei ; Peters, Ulrike - \ 2019
Human Genetics 138 (2019)4. - ISSN 0340-6717 - p. 307 - 326.
Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10− 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10− 4, replication P = 6.7 × 10− 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
Breeding progress and preparedness for mass-scale deployment of perennial lignocellulosic biomass crops switchgrass, miscanthus, willow and poplar
Clifton-Brown, John ; Harfouche, Antoine ; Casler, Michael D. ; Dylan Jones, Huw ; Macalpine, William J. ; Murphy-Bokern, Donal ; Smart, Lawrence B. ; Adler, Anneli ; Ashman, Chris ; Awty-Carroll, Danny ; Bastien, Catherine ; Bopper, Sebastian ; Botnari, Vasile ; Brancourt-Hulmel, Maryse ; Chen, Zhiyong ; Clark, Lindsay V. ; Cosentino, Salvatore ; Dalton, Sue ; Davey, Chris ; Dolstra, Oene ; Donnison, Iain ; Flavell, Richard ; Greef, Joerg ; Hanley, Steve ; Hastings, Astley ; Hertzberg, Magnus ; Hsu, Tsai Wen ; Huang, Lin S. ; Iurato, Antonella ; Jensen, Elaine ; Jin, Xiaoli ; Jørgensen, Uffe ; Kiesel, Andreas ; Kim, Do Soon ; Liu, Jianxiu ; McCalmont, Jon P. ; McMahon, Bernard G. ; Mos, Michal ; Robson, Paul ; Sacks, Erik J. ; Sandu, Anatolii ; Scalici, Giovanni ; Schwarz, Kai ; Scordia, Danilo ; Shafiei, Reza ; Shield, Ian ; Slavov, Gancho ; Stanton, Brian J. ; Swaminathan, Kankshita ; Trindade, Luisa M. - \ 2019
Global change biology Bioenergy 11 (2019)1. - ISSN 1757-1693 - p. 118 - 151.
bioenergy - feedstocks - lignocellulose - M. sacchariflorus - M. sinensis - Miscanthus - Panicum virgatum - perennial biomass crop - Populus spp. - Salix spp.

Genetic improvement through breeding is one of the key approaches to increasing biomass supply. This paper documents the breeding progress to date for four perennial biomass crops (PBCs) that have high output–input energy ratios: namely Panicum virgatum (switchgrass), species of the genera Miscanthus (miscanthus), Salix (willow) and Populus (poplar). For each crop, we report on the size of germplasm collections, the efforts to date to phenotype and genotype, the diversity available for breeding and on the scale of breeding work as indicated by number of attempted crosses. We also report on the development of faster and more precise breeding using molecular breeding techniques. Poplar is the model tree for genetic studies and is furthest ahead in terms of biological knowledge and genetic resources. Linkage maps, transgenesis and genome editing methods are now being used in commercially focused poplar breeding. These are in development in switchgrass, miscanthus and willow generating large genetic and phenotypic data sets requiring concomitant efforts in informatics to create summaries that can be accessed and used by practical breeders. Cultivars of switchgrass and miscanthus can be seed-based synthetic populations, semihybrids or clones. Willow and poplar cultivars are commercially deployed as clones. At local and regional level, the most advanced cultivars in each crop are at technology readiness levels which could be scaled to planting rates of thousands of hectares per year in about 5 years with existing commercial developers. Investment in further development of better cultivars is subject to current market failure and the long breeding cycles. We conclude that sustained public investment in breeding plays a key role in delivering future mass-scale deployment of PBCs.

A research roadmap for quantifying non-state and subnational climate mitigation action
Hsu, Angel ; Höhne, Niklas ; Kuramochi, Takeshi ; Roelfsema, Mark ; Weinfurter, Amy ; Xie, Yihao ; Lütkehermöller, Katharina ; Chan, Sander ; Corfee-Morlot, Jan ; Drost, Philip ; Faria, Pedro ; Gardiner, Ann ; Gordon, David J. ; Hale, Thomas ; Hultman, Nathan E. ; Moorhead, John ; Reuvers, Shirin ; Setzer, Joana ; Singh, Neelam ; Weber, Christopher ; Widerberg, Oscar - \ 2019
Nature Climate Change 9 (2019)1. - ISSN 1758-678X - p. 11 - 17.

Non-state and subnational climate actors have become central to global climate change governance. Quantitatively assessing climate mitigation undertaken by these entities is critical to understand the credibility of this trend. In this Perspective, we make recommendations regarding five main areas of research and methodological development related to evaluating non-state and subnational climate actions: defining clear boundaries and terminology; use of common methodologies to aggregate and assess non-state and subnational contributions; systematically dealing with issues of overlap; estimating the likelihood of implementation; and addressing data gaps.

Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma : interim results and correlations with CD4+ T-lymphocyte counts
Bota, Daniela A. ; Chung, Jinah ; Dandekar, Manisha ; Carrillo, Jose A. ; Kong, Xiao Tang ; Fu, Beverly D. ; Hsu, Frank Pk ; Schönthal, Axel H. ; Hofman, Florence M. ; Chen, Thomas C. ; Zidovetzki, Raphael ; Pretto, Chrystel ; Strik, Ankie ; Schijns, Virgil E.J.C. ; Stathopoulos, Apostolos - \ 2018
JAMA Oncology 7 (2018)3. - ISSN 2374-2437 - p. CNS22 - CNS22.
allogeneic - autologous - bevacizumab - CD4+ T lymphocyte - ERC1671 - GBM - GBM vaccine - glioma surgery - immunotherapy

AIM: ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors.

METHODS: In this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine® or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.

CONCLUSION: The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.

Therapeutic immunization against glioblastoma
Schijns, Virgil E.J.C. ; Pretto, Chrystel ; Strik, Anna M. ; Gloudemans-Rijkers, Rianne ; Deviller, Laurent ; Pierre, Denis ; Chung, Jinah ; Dandekar, Manisha ; Carrillo, Jose A. ; Kong, Xiao Tang ; Fu, Beverly D. ; Hsu, Frank P.K. ; Hofman, Florence M. ; Chen, Thomas C. ; Zidovetzki, Raphael ; Bota, Daniela A. ; Stathopoulos, Apostolos - \ 2018
International Journal of Molecular Sciences 19 (2018)9. - ISSN 1661-6596
Allogenic - Autologous - Brain tumor - Glioma tumor - Immunotherapy - Therapeutic vaccine
Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient’s immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation.
Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
Jiang, Xia ; O'Reilly, Paul F. ; Aschard, Hugues ; Hsu, Yi Hsiang ; Richards, J.B. ; Dupuis, Josée ; Ingelsson, Erik ; Karasik, David ; Pilz, Stefan ; Berry, Diane ; Kestenbaum, Bryan ; Zheng, Jusheng ; Luan, Jianan ; Sofianopoulou, Eleni ; Streeten, Elizabeth A. ; Albanes, Demetrius ; Lutsey, Pamela L. ; Yao, Lu ; Tang, Weihong ; Econs, Michael J. ; Wallaschofski, Henri ; Völzke, Henry ; Zhou, Ang ; Power, Chris ; McCarthy, Mark I. ; Michos, Erin D. ; Boerwinkle, Eric ; Weinstein, Stephanie J. ; Freedman, Neal D. ; Huang, Wen Yi ; Schoor, Natasja M. van; Velde, Nathalie van der; Groot, Lisette C.P.G.M. de; Enneman, Anke ; Cupples, L.A. ; Booth, Sarah L. ; Vasan, Ramachandran S. ; Liu, Ching Ti ; Zhou, Yanhua ; Ripatti, Samuli ; Ohlsson, Claes ; Vandenput, Liesbeth ; Lorentzon, Mattias ; Eriksson, Johan G. ; Shea, M.K. ; Houston, Denise K. ; Kritchevsky, Stephen B. ; Liu, Yongmei ; Lohman, Kurt K. ; Ferrucci, Luigi ; Peacock, Munro ; Gieger, Christian ; Beekman, Marian ; Slagboom, Eline ; Deelen, Joris ; Deelen, Joris ; Heemst, Diana van; Kleber, Marcus E. ; März, Winfried ; Boer, Ian H. De; Wood, Alexis C. ; Rotter, Jerome I. ; Rich, Stephen S. ; Robinson-Cohen, Cassianne ; Heijer, Martin Den; Jarvelin, Marjo Riitta ; Jarvelin, Marjo Riitta ; Cavadino, Alana ; Cavadino, Alana ; Joshi, Peter K. ; Wilson, James F. ; Hayward, Caroline ; Lind, Lars ; Michaëlsson, Karl ; Trompet, Stella ; Zillikens, M.C. ; Uitterlinden, Andre G. ; Rivadeneira, Fernando - \ 2018
Nature Communications 9 (2018)1. - ISSN 2041-1723
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 -9 at rs8018720 in SEC23A, and P = 1.9×10 -14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
Zillikens, M.C. ; Demissie, Serkalem ; Hsu, Yi Hsiang ; Yerges-Armstrong, Laura M. ; Chou, Wen Chi ; Stolk, Lisette ; Livshits, Gregory ; Broer, Linda ; Johnson, Toby ; Koller, Daniel L. ; Kutalik, Zoltán ; Luan, J. ; Malkin, Ida ; Ried, Janina S. ; Smith, Albert V. ; Thorleifsson, Gudmar ; Vandenput, Liesbeth ; Hua Zhao, Jing ; Zhang, Weihua ; Aghdassi, Ali ; Åkesson, Kristina ; Amin, Najaf ; Baier, Leslie J. ; Barroso, Inês ; Bennett, David A. ; Bertram, Lars ; Biffar, Rainer ; Bochud, Murielle ; Boehnke, Michael ; Borecki, Ingrid B. ; Buchman, Aron S. ; Byberg, Liisa ; Campbell, Harry ; Campos Obanda, Natalia ; Cauley, Jane A. ; Cawthon, Peggy M. ; Cederberg, Henna ; Chen, Zhao ; Cho, Nam H. ; Jin Choi, Hyung ; Claussnitzer, Melina ; Collins, Francis ; Cummings, Steven R. ; Jager, Philip L. De; Demuth, Ilja ; Dhonukshe-Rutten, Rosalie A.M. ; Diatchenko, Luda ; Eiriksdottir, Gudny ; Enneman, Anke W. ; Erdos, Mike ; Eriksson, Johan G. ; Eriksson, Joel ; Estrada, Karol ; Evans, Daniel S. ; Feitosa, Mary F. ; Fu, Mao ; Garcia, Melissa ; Gieger, Christian ; Girke, Thomas ; Glazer, Nicole L. ; Grallert, Harald ; Grewal, Jagvir ; Han, Bok Ghee ; Hanson, Robert L. ; Hayward, Caroline ; Hofman, Albert ; Hoffman, Eric P. ; Homuth, Georg ; Hsueh, Wen Chi ; Hubal, Monica J. ; Hubbard, Alan ; Huffman, Kim M. ; Husted, Lise B. ; Illig, Thomas ; Ingelsson, Erik ; Ittermann, Till ; Jansson, John Olov ; Jordan, Joanne M. ; Jula, Antti ; Karlsson, Magnus ; Khaw, Kay Tee ; Kilpeläinen, Tuomas O. ; Klopp, Norman ; Kloth, Jacqueline S.L. ; Koistinen, Heikki A. ; Kraus, William E. ; Kritchevsky, Stephen ; Kuulasmaa, Teemu ; Kuusisto, Johanna ; Laakso, Markku ; Lahti, Jari ; Lang, Thomas ; Langdahl, Bente L. ; Launer, Lenore J. ; Lee, Jong Young ; Lerch, Markus M. ; Lewis, Joshua R. ; Lind, Lars ; Lindgren, Cecilia ; Liu, Yongmei ; Liu, Tian ; Liu, Youfang ; Ljunggren, Östen ; Lorentzon, Mattias ; Luben, Robert N. ; Maixner, William ; McGuigan, Fiona E. ; Medina-Gomez, Carolina ; Meitinger, Thomas ; Melhus, Håkan ; Mellström, Dan ; Melov, Simon ; Michaëlsson, Karl ; Mitchell, Braxton D. ; Morris, Andrew P. ; Mosekilde, Leif ; Newman, Anne ; Nielson, Carrie M. ; O'Connell, Jeffrey R. ; Oostra, Ben A. ; Orwoll, Eric S. ; Palotie, Aarno ; Parker, Stephen C.J. ; Peacock, Munro ; Perola, Markus ; Peters, Annette ; Polasek, Ozren ; Prince, Richard L. ; Räikkönen, Katri ; Ralston, Stuart H. ; Ripatti, Samuli ; Robbins, John A. ; Rotter, Jerome I. ; Rudan, Igor ; Salomaa, Veikko ; Satterfield, Suzanne ; Schadt, Eric E. ; Schipf, Sabine ; Scott, Laura ; Sehmi, Joban ; Shen, Jian ; Soo Shin, Chan ; Sigurdsson, Gunnar ; Smith, Shad ; Soranzo, Nicole ; Stančáková, Alena ; Steinhagen-Thiessen, Elisabeth ; Streeten, Elizabeth A. ; Styrkarsdottir, Unnur ; Swart, Karin M.A. ; Tan, Sian Tsung ; Tarnopolsky, Mark A. ; Thompson, Patricia ; Thomson, Cynthia A. ; Thorsteinsdottir, Unnur ; Tikkanen, Emmi ; Tranah, Gregory J. ; Tuomilehto, Jaakko ; Schoor, Natasja M. van; Verma, Arjun ; Vollenweider, Peter ; Völzke, Henry ; Wactawski-Wende, Jean ; Walker, Mark ; Weedon, Michael N. ; Welch, Ryan ; Wichmann, H.E. ; Widen, Elisabeth ; Williams, Frances M.K. ; Wilson, James F. ; Wright, Nicole C. ; Xie, Weijia ; Yu, Lei ; Zhou, Yanhua ; Chambers, John C. ; Döring, Angela ; Duijn, Cornelia M. van; Econs, Michael J. ; Gudnason, Vilmundur ; Kooner, Jaspal S. ; Psaty, Bruce M. ; Spector, Timothy D. ; Stefansson, Kari ; Rivadeneira, Fernando ; Uitterlinden, André G. ; Wareham, Nicholas J. ; Ossowski, Vicky ; Waterworth, Dawn ; Loos, Ruth J.F. ; Karasik, David ; Harris, Tamara B. ; Ohlsson, Claes ; Kiel, Douglas P. - \ 2017
Nature Communications 8 (2017)1. - ISSN 2041-1723 - 1 p.

A correction to this article has been published and is linked from the HTML version of this article.

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
Zillikens, M.C. ; Demissie, Serkalem ; Hsu, Yi Hsiang ; Yerges-Armstrong, Laura M. ; Chou, Wen Chi ; Stolk, Lisette ; Livshits, Gregory ; Broer, Linda ; Johnson, Toby ; Koller, Daniel L. ; Kutalik, Zoltán ; Luan, J.A. ; Malkin, Ida ; Ried, Janina S. ; Smith, Albert V. ; Thorleifsson, Gudmar ; Vandenput, Liesbeth ; Hua Zhao, Jing ; Zhang, Weihua ; Aghdassi, Ali ; Åkesson, Kristina ; Amin, Najaf ; Baier, Leslie J. ; Barroso, Inês ; Bennett, David A. ; Bertram, Lars ; Biffar, Rainer ; Bochud, Murielle ; Boehnke, Michael ; Borecki, Ingrid B. ; Buchman, Aron S. ; Byberg, Liisa ; Campbell, Harry ; Campos Obanda, Natalia ; Cauley, Jane A. ; Cawthon, Peggy M. ; Cederberg, Henna ; Chen, Zhao ; Cho, Nam H. ; Jin Choi, Hyung ; Claussnitzer, Melina ; Collins, Francis ; Cummings, Steven R. ; Jager, Philip L. De; Demuth, Ilja ; Dhonukshe-Rutten, Rosalie A.M. ; DIatchenko, Luda ; Eiriksdottir, Gudny ; Enneman, Anke W. ; Erdos, Mike ; Eriksson, Johan G. ; Eriksson, Joel ; Estrada, Karol ; Evans, Daniel S. ; Feitosa, Mary F. ; Fu, Mao ; Garcia, Melissa ; Gieger, Christian ; Girke, Thomas ; Glazer, Nicole L. ; Grallert, Harald ; Grewal, Jagvir ; Han, Bok Ghee ; Hanson, Robert L. ; Hayward, Caroline ; Hofman, Albert ; Hoffman, Eric P. ; Homuth, Georg ; Hsueh, Wen Chi ; Hubal, Monica J. ; Hubbard, Alan ; Huffman, Kim M. ; Husted, Lise B. ; Illig, Thomas ; Ingelsson, Erik ; Ittermann, Till ; Jansson, John Olov ; Jordan, Joanne M. ; Jula, Antti ; Karlsson, Magnus ; Khaw, Kay Tee ; Kilpelaïnen, Tuomas O. ; Klopp, Norman ; Kloth, Jacqueline S.L. ; Koistinen, Heikki A. ; Kraus, William E. ; Kritchevsky, Stephen ; Kuulasmaa, Teemu ; Kuusisto, Johanna ; Laakso, Markku ; Lahti, Jari ; Lang, Thomas ; Langdahl, Bente L. ; Launer, Lenore J. ; Lee, Jong Young ; Lerch, Markus M. ; Lewis, Joshua R. ; Lind, Lars ; Lindgren, Cecilia M. ; Liu, Yongmei ; Liu, Tian ; Liu, Youfang ; Ljunggren, Östen ; Lorentzon, Mattias ; Luben, Robert N. ; Maixner, William ; McGuigan, Fiona E. ; Medina-Gomez, Carolina ; Meitinger, Thomas ; Melhus, Håkan ; Mellström, Dan ; Melov, Simon ; Michaëlsson, Karl ; Mitchell, Braxton D. ; Morris, Andrew P. ; Mosekilde, Leif ; Newman, Anne ; Nielson, Carrie M. ; O'Connell, Jeffrey R. ; Oostra, Ben A. ; Orwoll, Eric S. ; Palotie, Aarno ; Parker, Stephan ; Peacock, Munro ; Perola, Markus ; Peters, Annette ; Polasek, Ozren ; Prince, Richard L. ; Raïkkönen, Katri ; Ralston, Stuart H. ; Ripatti, Samuli ; Robbins, John A. ; Rotter, Jerome I. ; Rudan, Igor ; Salomaa, Veikko ; Satterfield, Suzanne ; Schadt, Eric E. ; Schipf, Sabine ; Scott, Laura ; Sehmi, Joban ; Shen, Jian ; Soo Shin, Chan ; Sigurdsson, Gunnar ; Smith, Shad ; Soranzo, Nicole ; Stančáková, Alena ; Steinhagen-Thiessen, Elisabeth ; Streeten, Elizabeth A. ; Styrkarsdottir, Unnur ; Swart, Karin M.A. ; Tan, Sian Tsung ; Tarnopolsky, Mark A. ; Thompson, Patricia ; Thomson, Cynthia A. ; Thorsteinsdottir, Unnur ; Tikkanen, Emmi ; Tranah, Gregory J. ; Tuomilehto, Jaakko ; Schoor, Natasja M. van; Verma, Arjun ; Vollenweider, Peter ; Völzke, Henry ; Wactawski-Wende, Jean ; Walker, Mark ; Weedon, Michael N. ; Welch, Ryan ; Wichman, H.E. ; Widen, Elisabeth ; Williams, Frances M.K. ; Wilson, James F. ; Wright, Nicole C. ; Xie, Weijia ; Yu, Lei ; Zhou, Yanhua ; Chambers, John C. ; Döring, Angela ; Duijn, Cornelia M. Van; Econs, Michael J. ; Gudnason, Vilmundur ; Kooner, Jaspal S. ; Psaty, Bruce M. ; Spector, Timothy D. ; Stefansson, Kari ; Rivadeneira, Fernando ; Uitterlinden, André G. ; Wareham, Nicholas J. ; Ossowski, Vicky ; Waterworth, Dawn M. ; Loos, Ruth J.F. ; Karasik, David ; Harris, Tamara B. ; Ohlsson, Claes ; Kiel, Douglas P. - \ 2017
Nature Communications 8 (2017)1. - ISSN 2041-1723
Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis
Manousaki, Despoina ; Dudding, Tom ; Haworth, Simon ; Hsu, Yi Hsiang ; Liu, Ching Ti ; Medina-Gómez, Carolina ; Voortman, Trudy ; Velde, Nathalie Van Der; Melhus, Håkan ; Vandenput, Liesbeth ; Noordam, Raymond ; Forgetta, Vincenzo ; Greenwood, Celia M.T. ; Biggs, Mary L. ; Psaty, Bruce M. ; Rotter, Jerome I. ; Zemel, Babette S. ; Mitchell, Jonathan A. ; Taylor, Bruce ; Lorentzon, Mattias ; Karlsson, Magnus ; Jaddoe, Vincent W.V. ; Tiemeier, Henning ; Campos-Obando, Natalia ; Franco, Oscar H. ; Utterlinden, Andre G. ; Broer, Linda ; Schoor, Natasja M. van; Ham, Annelies C. ; Ikram, Arfan M.A. ; Karasik, David ; Mutsert, Renée De; Rosendaal, Frits R. ; Heijer, Martin den; Wang, Thomas J. ; Lind, Lars ; Orwoll, Eric S. ; Mook-Kanamori, Dennis O. ; Michaëlsson, Karl ; Kestenbaum, Bryan ; Ohlsson, Claes ; Mellström, Dan ; Groot, Lisette C.P.G.M. de; Grant, Struan F.A. ; Kiel, Douglas P. ; Zillikens, M.C. ; Rivadeneira, Fernando ; Sawcer, Stephen ; Timpson, Nicholas J. ; Richards, J.B. - \ 2017
American Journal of Human Genetics 101 (2017)2. - ISSN 0002-9297 - p. 227 - 238.
GWAS - Low-frequency genetic variants - Multiple sclerosis - Vitamin D
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
Big data has big potential for applications to climate change adaptation
Ford, James D. ; Tilleard, Simon E. ; Berrang-Ford, Lea ; Araos, Malcolm ; Biesbroek, Robbert ; Lesnikowski, Alexandra C. ; MacDonald, Graham K. ; Hsu, Angel ; Chen, Chen ; Bizikova, Livia - \ 2016
Proceedings of the National Academy of Sciences of the United States of America 113 (2016)39. - ISSN 0027-8424 - p. 10729 - 10732.
The capacity to collect and analyze massive amounts
of data is transforming research in the natural and social
sciences (1). And yet, the climate change adaptation
community has largely overlooked these developments.
Here, we examine how “big data” can inform adaptation
research and decision-making and outline what’s
needed from the adaptation community to maximize
this opportunity. We contend that careful application
of big data could revolutionize our understanding of
how to manage the risks of climate change.
An expanded evaluation of protein function prediction methods shows an improvement in accuracy
Jiang, Yuxiang ; Oron, Tal Ronnen ; Clark, Wyatt T. ; Bankapur, Asma R. ; Andrea, Daniel D'; Lepore, Rosalba ; Funk, Christopher S. ; Kahanda, Indika ; Verspoor, Karin M. ; Ben-Hur, Asa ; Koo, Da Chen Emily ; Penfold-Brown, Duncan ; Shasha, Dennis ; Youngs, Noah ; Bonneau, Richard ; Lin, Alexandra ; Sahraeian, Sayed M.E. ; Martelli, Pier Luigi ; Profiti, Giuseppe ; Casadio, Rita ; Cao, Renzhi ; Zhong, Zhaolong ; Cheng, Jianlin ; Altenhoff, Adrian ; Skunca, Nives ; Dessimoz, Christophe ; Dogan, Tunca ; Hakala, Kai ; Kaewphan, Suwisa ; Mehryary, Farrokh ; Salakoski, Tapio ; Ginter, Filip ; Fang, Hai ; Smithers, Ben ; Oates, Matt ; Gough, Julian ; Törönen, Petri ; Koskinen, Patrik ; Holm, Liisa ; Chen, Ching Tai ; Hsu, Wen Lian ; Bryson, Kevin ; Cozzetto, Domenico ; Minneci, Federico ; Jones, David T. ; Chapman, Samuel ; BKC, Dukka ; Khan, Ishita K. ; Kihara, Daisuke ; Ofer, Dan ; Rappoport, Nadav ; Stern, Amos ; Cibrian-Uhalte, Elena ; Denny, Paul ; Foulger, Rebecca E. ; Hieta, Reija ; Legge, Duncan ; Lovering, Ruth C. ; Magrane, Michele ; Melidoni, Anna N. ; Mutowo-Meullenet, Prudence ; Pichler, Klemens ; Shypitsyna, Aleksandra ; Li, Biao ; Zakeri, Pooya ; ElShal, Sarah ; Tranchevent, Léon Charles ; Das, Sayoni ; Dawson, Natalie L. ; Lee, David ; Lees, Jonathan G. ; Sillitoe, Ian ; Bhat, Prajwal ; Nepusz, Tamás ; Romero, Alfonso E. ; Sasidharan, Rajkumar ; Yang, Haixuan ; Paccanaro, Alberto ; Gillis, Jesse ; Sedeño-Cortés, Adriana E. ; Pavlidis, Paul ; Feng, Shou ; Cejuela, Juan M. ; Goldberg, Tatyana ; Hamp, Tobias ; Richter, Lothar ; Salamov, Asaf ; Gabaldon, Toni ; Marcet-Houben, Marina ; Supek, Fran ; Gong, Qingtian ; Ning, Wei ; Zhou, Yuanpeng ; Tian, Weidong ; Falda, Marco ; Fontana, Paolo ; Lavezzo, Enrico ; Toppo, Stefano ; Ferrari, Carlo ; Giollo, Manuel ; Piovesan, Damiano ; Tosatto, Silvio C.E. ; Pozo, Angela del; Fernández, José M. ; Maietta, Paolo ; Valencia, Alfonso ; Tress, Michael L. ; Benso, Alfredo ; Carlo, Stefano Di; Politano, Gianfranco ; Savino, Alessandro ; Rehman, Hafeez Ur ; Re, Matteo ; Mesiti, Marco ; Valentini, Giorgio ; Bargsten, Joachim W. ; Dijk, Aalt-Jan van; Gemovic, Branislava ; Glisic, Sanja ; Perovic, Vladmir ; Veljkovic, Veljko ; Veljkovic, Nevena ; Almeida-e-Silva, Danillo C. ; Vencio, Ricardo Z.N. ; Sharan, Malvika ; Vogel, Jörg ; Kansakar, Lakesh ; Zhang, Shanshan ; Vucetic, Slobodan ; Wang, Zheng ; Sternberg, Michael J.E. ; Wass, Mark N. ; Huntley, Rachael P. ; Martin, Maria J. ; O'Donovan, Claire ; Robinson, Peter N. ; Moreau, Yves ; Tramontano, Anna ; Babbitt, Patricia C. ; Brenner, Steven E. ; Linial, Michal ; Orengo, Christine A. ; Rost, Burkhard ; Greene, Casey S. ; Mooney, Sean D. ; Friedberg, Iddo ; Radivojac, Predrag - \ 2016
Genome Biology 17 (2016)1. - ISSN 1474-7596
Disease gene prioritization - Protein function prediction

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
Zheng, H. ; Forgetta, V. ; Hsu, Y.H. ; Estrada, K. ; Rosello-Diez, A. ; Groot, C.P.G.M. de - \ 2015
Nature 526 (2015). - ISSN 0028-0836 - p. 112 - 117.
The extent to which low-frequency (minor allele frequency (MAF) between 1–5%) and rare (MAF¿=¿1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants1, 2, 3, 4, 5, 6, 7, 8, as well as rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal¿=¿53,236) and fracture (ntotal¿=¿508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n¿=¿2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n¿=¿3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n¿=¿26,534), and de novo replication genotyping (n¿=¿20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF¿=¿1.6%, replication effect size¿=¿+0.20 s.d., Pmeta¿=¿2¿×¿10-14), which was also associated with a decreased risk of fracture (odds ratio¿=¿0.85; P¿=¿2¿×¿10-11; ncases¿=¿98,742 and ncontrols¿=¿409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF¿=¿1.2%, replication effect size¿=¿+0.41 s.d., Pmeta¿=¿1¿×¿10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
Moayyeri, A. ; Hsu, Y.H. ; Karasik, D. ; Dhonukshe-Rutten, R.A.M. ; Groot, C.P.G.M. de - \ 2014
Human Molecular Genetics 23 (2014)11. - ISSN 0964-6906 - p. 3054 - 3068.
x-ray absorptiometry - quantitative ultrasound - mineral density - osteoporosis - fracture - risk - densitometry - phenotypes - calcaneus - women
Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P <5 × 10-8) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P <8.23 × 10-14). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P <5 × 10-6 also had the expected direction of association with any fracture (P <0.05), including three SNPs with P <0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
Movement of entomophagous arthropods in agricultural landscapes: links to pest suppression
Schellhorn, N.A. ; Bianchi, F.J.J.A. ; Hsu, C.L. - \ 2014
Annual Review of Entomology 59 (2014). - ISSN 0066-4170 - p. 559 - 581.
different spatial scales - parasitoid diadegma-semiclausum - conservation biological-control - ephemeral crop habitats - mark-recapture data - natural enemies - foraging behavior - egg parasitoids - flight activity - cereal fields
Entomophagous arthropods can provide valuable biological control services, but they need to fulfill their life cycle in agricultural landscapes often dominated by ephemeral and disturbed habitats. In this environment, movement is critical to escape from disturbances and to find resources scattered in space and time. Despite considerable research effort in documenting species movement and spatial distribution patterns, the quantification of arthropod movement has been hampered by their small size and the variety of modes of movement that can result in redistribution at different spatial scales. In addition, insight into how movement influences in-field population processes and the associated biocontrol services is limited because emigration and immigration are often confounded with local-scale population processes. More detailed measurements of the habitat functionality and movement processes are needed to better understand the interactions between species movement traits, disturbances, the landscape context, and the potential for entomophagous arthropods to suppress economically important pests.
Nonlinear Amplification of a Supramolecular Complex at a Multivalent Interface
Hsu, S.H. ; Yilmaz, M.D. ; Reinhoudt, D.N. ; Velders, A.H. ; Huskens, J. - \ 2013
Angewandte Chemie-International Edition 52 (2013)2. - ISSN 1433-7851 - p. 714 - 719.
self-assembled monolayers - molecular printboards - chemistry - binding - membrane - nanostructures - organization - selection - discrete - peptides
Competition with a monovalent cyclodextrin host (blue cones) in solution drives the multivalent binding of a Eu3+ complex and a sensitizer molecule to cyclodextrin monolayers through a nonlinear self-assembly process. Adamantyl groups (light-blue spheres) are attached to the EDTA ligand (black) and the antenna molecule (orange), which has a carboxylate group for coordination to the Eu3+ ion (yellow or red in free or complexed form, respectively).
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