• Acute phase inflammation is characterized by rapid changes in plasma/peritoneal fluid N-glycosylation in mice.

      Rombouts, Yoann; Jónasdóttir, Hulda S; Hipgrave Ederveen, Agnes L; Reiding, Karli R; Jansen, Bas C; Freysdottir, Jona; Hardardottir, Ingibjörg; Ioan-Facsinay, Andreea; Giera, Martin; Wuhrer, Manfred; [ 1 ] Leiden Univ, Med Ctr, Ctr Prote & Metab, Leiden, Netherlands [ 2 ] Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands [ 3 ] Univ Toulouse, CNRS, UPS, Inst Pharmacol & Biol Struct, Toulouse, France [ 4 ] Univ Iceland, Fac Med, Biomed Ctr, Sch Hlth Sci, Reykjavik, Iceland [ 5 ] Landspitali Natl Univ Hosp Iceland, Dept Immunol, Reykjavik, Iceland [ 6 ] Landspitali Natl Univ Hosp Iceland, Ctr Rheumatol Res, Reykjavik, Iceland [ 7 ] Vrije Univ Amsterdam, Div BioAnalyt Chem, Amsterdam, Netherlands (Springer, 2016-06)
      Murine zymosan-induced peritonitis is a widely used model for studying the molecular and cellular events responsible for the initiation, persistence and/or resolution of inflammation. Among these events, it is becoming increasingly evident that changes in glycosylation of proteins, especially in the plasma and at the site of inflammation, play an important role in the inflammatory response. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based glycosylation profiling, we investigated the qualitative and quantitative effect of zymosan-induced peritonitis on N-glycosylation in mouse plasma and peritoneal fluid. Our results show that both N-glycomes exhibit highly similar glycosylation patterns, consisting mainly of diantennary and triantennary complex type N-glycans with high levels (>95 %) of galactosylation and sialylation (mostly NeuGc) and a medium degree of core fucosylation (30 %). Moreover, MS/MS structural analysis, assisted by linkage-specific derivatization of sialic acids, revealed the presence of O-acetylated sialic acids as well as disialylated antennae ("branching sialylation") characterized by the presence of α2-6-linked NeuGc on the GlcNAc of the NeuGcα2-3-Galβ1-3-GlcNAc terminal motif. A significant decrease of (core) fucosylation together with an increase of both α2-3-linked NeuGc and "branching sialylation" were observed in N-glycomes of mice challenged with zymosan, but not in control mice injected with PBS. Importantly, substantial changes in glycosylation were already observed 12 h after induction of peritonitis, thereby demonstrating an unexpected velocity of the biological mechanisms involved.
    • Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

      Stacey, Simon N; Sulem, Patrick; Zanon, Carlo; Gudjonsson, Sigurjon A; Thorleifsson, Gudmar; Helgason, Agnar; Jonasdottir, Aslaug; Besenbacher, Soren; Kostic, Jelena P; Fackenthal, James D; Huo, Dezheng; Adebamowo, Clement; Ogundiran, Temidayo; Olson, Janet E; Fredericksen, Zachary S; Wang, Xianshu; Look, Maxime P; Sieuwerts, Anieta M; Martens, John W M; Pajares, Isabel; Garcia-Prats, Maria D; Ramon-Cajal, Jose M; de Juan, Ana; Panadero, Angeles; Ortega, Eugenia; Aben, Katja K H; Vermeulen, Sita H; Asadzadeh, Fatemeh; van Engelenburg, K C Anton; Margolin, Sara; Shen, Chen-Yang; Wu, Pei-Ei; Försti, Asta; Lenner, Per; Henriksson, Roger; Johansson, Robert; Enquist, Kerstin; Hallmans, Göran; Jonsson, Thorvaldur; Sigurdsson, Helgi; Alexiusdottir, Kristin; Gudmundsson, Julius; Sigurdsson, Asgeir; Frigge, Michael L; Gudmundsson, Larus; Kristjansson, Kristleifur; Halldorsson, Bjarni V; Styrkarsdottir, Unnur; Gulcher, Jeffrey R; Hemminki, Kari; Lindblom, Annika; Kiemeney, Lambertus A; Mayordomo, Jose I; Foekens, John A; Couch, Fergus J; Olopade, Olufunmilayo I; Gudbjartsson, Daniel F; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Johannsson, Oskar T; Stefansson, Kari; deCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.is (Public Library of Science, 2010-07)
      We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.
    • At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia.

      Hansen, Thomas; Ingason, Andrés; Djurovic, Srdjan; Melle, Ingrid; Fenger, Mogens; Gustafsson, Omar; Jakobsen, Klaus D; Rasmussen, Henrik B; Tosato, Sarah; Rietschel, Marcella; Frank, Josef; Owen, Mike; Bonetto, Chiara; Suvisaari, Jaana; Thygesen, Johan Hilge; Pétursson, Hannes; Lönnqvist, Jouko; Sigurdsson, Engilbert; Giegling, Ina; Craddock, Nick; O'Donovan, Michael C; Ruggeri, Mirella; Cichon, Sven; Ophoff, Roel A; Pietiläinen, Olli; Peltonen, Leena; Nöthen, Markus M; Rujescu, Dan; St Clair, David; Collier, David A; Andreassen, Ole A; Werge, Thomas; Mental Health Centre Sct. Hans, Copenhagen University Hospital, Research Institute of Biological Psychiatry, Roskilde, Denmark; Copenhagen University, Center for Pharmacogenomics, Copenhagen, Denmark. (Elsevier, 2011-07-01)
      BACKGROUND: Schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication. METHODS: Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel-Haenszel test. RESULTS: One type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01-1.14, p = .033). CONCLUSION: The association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity.
    • Biochemical characterization of human gluconokinase and the proposed metabolic impact of gluconic acid as determined by constraint based metabolic network analysis.

      Rohatgi, Neha; Nielsen, Tine Kragh; Bjørn, Sara Petersen; Axelsson, Ivar; Paglia, Giuseppe; Voldborg, Bjørn Gunnar; Palsson, Bernhard O; Rolfsson, Óttar; Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Iceland, Biomed Ctr, Reykjavik, Iceland, Univ Copenhagen, Fac Hlth Sci, Ctr Prot Res, Copenhagen, Denmark (Public Library Science, 2014)
      The metabolism of gluconate is well characterized in prokaryotes where it is known to be degraded following phosphorylation by gluconokinase. Less is known of gluconate metabolism in humans. Human gluconokinase activity was recently identified proposing questions about the metabolic role of gluconate in humans. Here we report the recombinant expression, purification and biochemical characterization of isoform I of human gluconokinase alongside substrate specificity and kinetic assays of the enzyme catalyzed reaction. The enzyme, shown to be a dimer, had ATP dependent phosphorylation activity and strict specificity towards gluconate out of 122 substrates tested. In order to evaluate the metabolic impact of gluconate in humans we modeled gluconate metabolism using steady state metabolic network analysis. The results indicate that significant metabolic flux changes in anabolic pathways linked to the hexose monophosphate shunt (HMS) are induced through a small increase in gluconate concentration. We argue that the enzyme takes part in a context specific carbon flux route into the HMS that, in humans, remains incompletely explored. Apart from the biochemical description of human gluconokinase, the results highlight that little is known of the mechanism of gluconate metabolism in humans despite its widespread use in medicine and consumer products.
    • Biomarkers defining the metabolic age of red blood cells during cold storage.

      Paglia, Giuseppe; D'Alessandro, Angelo; Rolfsson, Óttar; Sigurjónsson, Ólafur E; Bordbar, Aarash; Palsson, Sirus; Nemkov, Travis; Hansen, Kirk C; Gudmundsson, Sveinn; Palsson, Bernhard O; [ 1 ] European Acad Bozen Bolzano, Ctr Biomed, Via Galvani 31, I-39100 Bolzano, Italy [ 2 ] Univ Colorado Denver, Sch Med, Dept Biochem & Mol Genet, Aurora, CO USA [ 3 ] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland [ 4 ] Landspitali Univ Hosp, Blood Bank, Reykjavik, Iceland   Organization-Enhanced Name(s)      Landspitali National University Hospital [ 5 ] Reykjavik Unvers, Sch Sci & Engn, Reykjavik, Iceland [ 6 ] Sinopia Biosci, San Diego, CA USA (Amer Soc Hematology, 2016-09-29)
      Metabolomic investigations of packed red blood cells (RBCs) stored under refrigerated conditions in saline adenine glucose mannitol (SAGM) additives have revealed the presence of 3 distinct metabolic phases, occurring on days 0-10, 10-18, and after day 18 of storage. Here we used receiving operating characteristics curve analysis to identify biomarkers that can differentiate between the 3 metabolic states. We first recruited 24 donors and analyzed 308 samples coming from RBC concentrates stored in SAGM and additive solution 3. We found that 8 extracellular compounds (lactic acid, nicotinamide, 5-oxoproline, xanthine, hypoxanthine, glucose, malic acid, and adenine) form the basis for an accurate classification/regression model and are able to differentiate among the metabolic phases. This model was then validated by analyzing an additional 49 samples obtained by preparing 7 new RBC concentrates in SAGM. Despite the technical variability associated with RBC processing strategies, verification of these markers was independently confirmed in 2 separate laboratories with different analytical setups and different sample sets. The 8 compounds proposed here highly correlate with the metabolic age of packed RBCs, and can be prospectively validated as biomarkers of the RBC metabolic lesion.
    • Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer.

      Siena, Salvatore; Sartore-Bianchi, Andrea; Di Nicolantonio, Federica; Balfour, Julia; Bardelli, Alberto; Osped Niguarda Ca Granda, Falck Div Med Oncol, Dept Oncol, I-20162 Milan, Italy, Univ Turin, Sch Med, Mol Genet Lab, Inst Canc Res & Treatment, Turin, Italy, Inst Mol Oncol, Fdn Italiana Ric Cancro, Milan, Italy (Oxford Univ Press, 2009-10-07)
      The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be present in 35%-45% of patients with colorectal cancer, have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment. In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment, although these additional biomarkers require further validation before incorporation into clinical practice. Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance. The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer.
    • Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

      Dunning, Alison M; Michailidou, Kyriaki; Kuchenbaecker, Karoline B; Thompson, Deborah; French, Juliet D; Beesley, Jonathan; Healey, Catherine S; Kar, Siddhartha; Pooley, Karen A; Lopez-Knowles, Elena; Dicks, Ed; Gronwald, Jacek; Huzarski, Tomasz; Barkardottir, Rosa B; Laframboise, Rachel; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Park, Sue Kyung; Hills, Margaret; Cox, Angela; Lindor, Noralane; Couch, Fergus J; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Singer, Christian F; Rappaport, Christine; Phelan, Catherine M; Greene, Mark H; Cross, Simon S; Jarosz, Monika; Mai, Phuong L; Rennert, Gad; Imyanitov, Evgeny N; Hulick, Peter J; Phillips, Kelly-Anne; Piedmonte, Marion; Mulligan, Anna Marie; Glendon, Gord; Bojesen, Anders; Blot, William; Thomassen, Mads; Drury, Suzie; Caligo, Maria A; Yoon, Sook-Yee; Friedman, Eitan; Laitman, Yael; Borg, Ake; von Wachenfeldt, Anna; Ehrencrona, Hans; Rantala, Johanna; Cai, Qiuyin; Olopade, Olufunmilayo I; Ganz, Patricia A; Canisius, Sander; Nussbaum, Robert L; Gayther, Simon A; Nathanson, Katherine L; Domchek, Susan M; Arun, Banu K; Mitchell, Gillian; Karlan, Beth Y; Ghoussaini, Maya; Lester, Jenny; Maskarinec, Gertraud; Woolcott, Christy; Bolla, Manjeet K; Scott, Christopher; Stone, Jennifer; Apicella, Carmel; Tamimi, Rulla; Luben, Robert; Khaw, Kay-Tee; Perkins, Barbara J; Helland, Åslaug; Haakensen, Vilde; Dowsett, Mitch; Pharoah, Paul D P; Dennis, Joe; Simard, Jacques; Hall, Per; García-Closas, Montserrat; Vachon, Celine; Chenevix-Trench, Georgia; Shah, Mitul; Antoniou, Antonis C; Easton, Douglas F; Edwards, Stacey L; Wang, Qin; Hopper, John L; Southey, Melissa C; Broeks, Annegien; Schmidt, Marjanka K; Lophatananon, Artitaya; Muir, Kenneth; Choi, Ji-Yeob; Beckmann, Matthias W; Fasching, Peter A; Dos-Santos-Silva, Isabel; Peto, Julian; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Kang, Daehee; Bojesen, Stig E; Flyger, Henrik; González-Neira, Anna; Perez, Jose I A; Anton-Culver, Hoda; Eunjung, Lee; Arndt, Volker; Brenner, Hermann; Meindl, Alfons; Schmutzler, Rita K; Lee, Soo Chin; Brauch, Hiltrud; Hamann, Ute; Aittomäki, Kristiina; Blomqvist, Carl; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natasha; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Barrowdale, Daniel; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-Chen; Wu, Anna H; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Hartman, Mikael; Olson, Janet E; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Henderson, Brian E; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Nord, Silje; Borresen-Dale, Anne-Lise; Kabisch, Maria; Kristensen, Vessela; Long, Jirong; Zheng, Wei; Pylkäs, Katri; Winqvist, Robert; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; Figueroa, Jonine; Torres, Diana; Sherman, Mark E; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; van den Ouweland, Ans M W; Humphreys, Keith; Gao, Yu-Tang; Shu, Xiao-Ou; Jakubowska, Anna; Lubinski, Jan; Brennan, Paul; Sangrajrang, Suleeporn; Ambrosone, Christine B; Toland, Amanda E; Shen, Chen-Yang; Sinnott-Armstrong, Nicholas A; Wu, Pei-Ei; Orr, Nick; Swerdlow, Anthony; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Kapuscinski, Miroslav; John, Esther M; Terry, Mary Beth; Daly, Mary B; Sallari, Richard C; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ejlertsen, Bent; Hansen, Thomas V O; Hillman, Kristine M; Osorio, Ana; Benitez, Javier; Rando, Rachel; Weitzel, Jeffrey N; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Papi, Laura; Ottini, Laura; Konstantopoulou, Irene; Kaufmann, Susanne; Apostolou, Paraskevi; Garber, Judy; Rashid, Muhammad Usman; Frost, Debra; Izatt, Louise; Ellis, Steve; Godwin, Andrew K; Arnold, Norbert; Niederacher, Dieter; Rhiem, Kerstin; Sivakumaran, Haran; Bogdanova-Markov, Nadja; Sagne, Charlotte; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Sinilnikova, Olga M; Mazoyer, Sylvie; Isaacs, Claudine; Claes, Kathleen B M; De Leeneer, Kim; de la Hoya, Miguel; Moradi Marjaneh, Mahdi; Caldes, Trinidad; Nevanlinna, Heli; Khan, Sofia; Mensenkamp, Arjen R; Hooning, Maartje J; Rookus, Matti A; Kwong, Ava; Olah, Edith; Diez, Orland; Brunet, Joan; Lee, Jason S; Pujana, Miquel Angel; [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany [ 58 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 59 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Basis Genet Risk & Genet Testing, Milan, Italy [ 60 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 61 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 62 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 63 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 64 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia [ 65 ] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia [ 66 ] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 67 ] Univ Oslo, Inst Clin Med, Oslo, Norway [ 68 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 69 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA [ 70 ] Univ Oulu, NordLab Oulu Univ Hosp, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 71 ] Univ Oulu, NordLab Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland [ 72 ] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 73 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 74 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 75 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 76 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 77 ] Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands [ 78 ] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands [ 79 ] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands [ 80 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 81 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 82 ] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands [ 83 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 84 ] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England [ 85 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 86 ] Int Epidemiol Inst, Rockville, MD USA [ 87 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 88 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 89 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 90 ] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore [ 91 ] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore [ 92 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 93 ] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore [ 94 ] Pontificia Univ Javerianar, Inst Human Genet, Bogota, Colombia [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France [ 97 ] Natl Canc Inst, Bangkok, Thailand [ 98 ] Roswell Pk Canc Inst, Buffalo, NY 14263 USA [ 99 ] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 100 ] China Med Univ, Sch Publ Hlth, Taichung, Taiwan [ 101 ] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan [ 102 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England [ 103 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 104 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 105 ] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 106 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 107 ] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA [ 108 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 109 ] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA [ 110 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 111 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 112 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 113 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 114 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 115 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 116 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 117 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 118 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain [ 119 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 120 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain [ 121 ] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA [ 122 ] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA [ 123 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 124 ] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy [ 125 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 126 ] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy [ 127 ] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece [ 128 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 129 ] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan [ 130 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England [ 131 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 132 ] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany [ 133 ] Univ Dusseldorf, Dusseldorf, Germany [ 134 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 135 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany [ 136 ] Univ Munster, Inst Human Genet, D-48149 Munster, Germany [ 137 ] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France [ 138 ] Inst Curie, Dept Tumour Biol, Paris, France [ 139 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 140 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France [ 141 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 142 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 143 ] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain [ 144 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 145 ] Univ Helsinki, Cent Hosp, Helsinki, Finland [ 146 ] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands [ 147 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands [ 148 ] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands [ 149 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 150 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 151 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 152 ] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain [ 153 ] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 154 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain [ 155 ] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland   Organization-Enhanced Name(s)      Landspitali National University Hospital     University of Iceland [ 156 ] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland [ 157 ] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada [ 158 ] Univ Laval, Quebec City, PQ, Canada [ 159 ] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada [ 160 ] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy [ 161 ] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal [ 162 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 163 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 164 ] McGill Univ, Program Canc Genet, Montreal, PQ, Canada [ 165 ] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic [ 166 ] Masaryk Univ, Fac Med, Brno, Czech Republic [ 167 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 168 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria [ 169 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 170 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA [ 171 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 172 ] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel [ 173 ] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 174 ] NN Petrov Oncol Res Inst, St Petersburg, Russia [ 175 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 176 ] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia [ 177 ] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA [ 178 ] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada [ 179 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada [ 180 ] Vejle Hosp, Dept Clin Genet, Vejle, Denmark [ 181 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark [ 182 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 183 ] Univ Hosp Pisa, Pisa, Italy [ 184 ] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia [ 185 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 186 ] Lund Univ, Dept Oncol, Lund, Sweden [ 187 ] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden [ 188 ] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden [ 189 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 190 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 191 ] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 192 ] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 193 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 194 ] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA [ 195 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 196 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 197 ] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia [ 198 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 199 ] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA [ 200 ] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada [ 201 ] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia [ 202 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 203 ] Harvard Univ, Sch Med, Boston, MA USA [ 204 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 205 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA [ 206 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England (Nature Publishing Group, 2016-04)
      We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
    • Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5--a population-based study.

      Gatta, Gemma; Botta, Laura; Rossi, Silvia; Aareleid, Tiiu; Bielska-Lasota, Magdalena; Clavel, Jacqueline; Dimitrova, Nadya; Jakab, Zsuzsanna; Kaatsch, Peter; Lacour, Brigitte; Mallone, Sandra; Marcos-Gragera, Rafael; Minicozzi, Pamela; Sánchez-Pérez, Maria-José; Sant, Milena; Santaquilani, Mariano; Stiller, Charles; Tavilla, Andrea; Trama, Annalisa; Visser, Otto; Peris-Bonet, Rafael; [ 1 ] FDN IRCCS Ist Nazl Tumori, Evaluat Epidemiol Unit, I-20133 Milan, Italy, [ 2 ] FDN IRCCS Ist Nazl Tumori, Analyt Epidemiol & Hlth Impact Unit, I-20133 Milan, Italy [ 3 ] Ist Super Sanita, Ctr Nazl Epidemiol, I-00161 Rome, Italy [ 4 ] Natl Inst Hlth Dev, Dept Epidemiol & Biostat, Tallinn, Estonia [ 5 ] Natl Inst Hyg, Natl Inst Publ Hlth, PL-00791 Warsaw, Poland [ 6 ] Univ Paris Sud, INSERM UMRS1018, Villejuif, France [ 7 ] Natl Registry Childhood Hematopoiet Malignancies, Villejuif, France [ 8 ] CHU, French Natl Registry Childhood Solid Tumours, Nancy, France [ 9 ] Natl Oncol Hosp, Bulgarian Natl Canc Registry, Sofia, Bulgaria [ 10 ] Semmelweis Univ, Dept Pediat 2, Hungarian Childhood Canc Registry, H-1085 Budapest, Hungary [ 11 ] Johannes Gutenberg Univ Mainz, Inst Med Biostat Epidemiol & Informat, German Childhood Canc Registry, D-55122 Mainz, Germany [ 12 ] Epidemiol Unit, Girona, Spain [ 13 ] Girona Canc Registry, Oncol Coordinat Plan, Dept Hlth, Girona, Spain [ 14 ] Catalan Inst Oncol, Girona, Spain [ 15 ] Escuela Andaluza Salud Publ, Granada, Spain [ 16 ] CIBER Epidemiol & Salud Publ, Madrid, Spain [ 17 ] Inst Invest Biosanitaria Granada, Granada, Spain [ 18 ] Univ Oxford, Childhood Canc Res Grp, Oxford, England [ 19 ] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands (Elsevier Science Inc, 2014-01)
      Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007.
    • Clozapine treatment and discontinuation in Iceland: A national longitudinal study using electronic patient records.

      Ingimarsson, Oddur; MacCabe, James H; Haraldsson, Magnús; Jónsdóttir, Halldóra; Sigurdsson, Engilbert; [ 1 ] Univ Iceland, Sch Hlth Sci, Fac Med, Reykjavik, Iceland [ 2 ] Landspitali Univ Hosp, Mental Hlth Serv, IS-101 Reykjavik, Iceland   Organization-Enhanced Name(s)      Landspitali National University Hospital [ 3 ] Kings Coll London, London WC2R 2LS, England [ 4 ] South London & Maudsley NHS Fdn Trust, Bethlem Royal Hosp, Natl Psychosis Unit, London, England (Taylor & Francis Ltd, 2016-08)
      Clozapine is the only drug approved for treatment-resistant schizophrenia. There is evidence that clozapine is underutilized.
    • CNVs conferring risk of autism or schizophrenia affect cognition in controls.

      Stefansson, Hreinn; Meyer-Lindenberg, Andreas; Steinberg, Stacy; Magnusdottir, Brynja; Morgen, Katrin; Arnarsdottir, Sunna; Bjornsdottir, Gyda; Walters, G Bragi; Jonsdottir, Gudrun A; Doyle, Orla M; Tost, Heike; Grimm, Oliver; Kristjansdottir, Solveig; Snorrason, Heimir; Davidsdottir, Solveig R; Gudmundsson, Larus J; Jonsson, Gudbjorn F; Stefansdottir, Berglind; Helgadottir, Isafold; Haraldsson, Magnus; Jonsdottir, Birna; Thygesen, Johan H; Schwarz, Adam J; Didriksen, Michael; Stensbøl, Tine B; Brammer, Michael; Kapur, Shitij; Halldorsson, Jonas G; Hreidarsson, Stefan; Saemundsen, Evald; Sigurdsson, Engilbert; Stefansson, Kari; deCODE genetics/Amgen, Sturlugata 8, IS-101 Reykjavík, Iceland, Central Institute of Mental Health, University of Heidelberg Medical Faculty Mannheim, 68159 Mannheim, Germany, Landspitali, Department of Psychiatry, National University Hospital, IS-101 Reykjavík, Iceland, Central Institute of Mental Health, University of Heidelberg Medical Faculty Mannheim, 68159 Mannheim, Germany, Institute of Psychiatry, King's College, 16 De Crespigny Park, London SE5 8AF, UK, University of Iceland, Faculty of Medicine, University of Iceland, IS-101 Reykjavík, Iceland, Röntgen Domus, Egilsgötu 3, IS-101 Reykjavík, Iceland, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Research Institute of Biological Psychiatry, Boserupvej 2, DK-4000 Roskilde, Denmark, Tailored Therapeutics, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center DC 1940, Indianapolis, Indiana 46285, USA, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark, The State Diagnostic and Counselling Centre, Digranesvegur 5, IS-200 Kópavogur, Iceland (NPG, 2014)
      In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
    • Common variant at 16p11.2 conferring risk of psychosis.

      Steinberg, S; de Jong, S; Mattheisen, M; Costas, J; Demontis, D; Jamain, S; Pietiläinen, O P H; Lin, K; Papiol, S; Huttenlocher, J; Sigurdsson, E; Stefanovski, B; Durmishi, N; Pejovic Milovancevic, M; Lecic Tosevski, D; Silagadze, T; Naneishvili, N; Mikeladze, N; Surguladze, S; Vincent, J B; Farmer, A; Corvin, A; Mitchell, P B; Wright, A; Schofield, P R; Fullerton, J M; Montgomery, G W; Martin, N G; Rubino, I A; van Winkel, R; Kenis, G; De Hert, M; Gill, M; Réthelyi, J M; Bitter, I; Terenius, L; Jönsson, E G; Bakker, S; van Os, J; Jablensky, A; Leboyer, M; Bramon, E; Powell, J; Morris, D; Murray, R; O'Neill, F A; Kendler, K; Riley, B; Craddock, N; Owen, M J; O'Donovan, M C; Thorsteinsdottir, U; Vassos, E; Kong, A; Ehrenreich, H; Carracedo, A; Golimbet, V; Andreassen, O A; Børglum, A D; Mors, O; Mortensen, P B; Werge, T; Ophoff, R A; Giegling, I; Nöthen, M M; Rietschel, M; Cichon, S; Ruggeri, M; Tosato, S; Palotie, A; St Clair, D; Rujescu, D; Collier, D A; Stefansson, H; Breuer, R; Stefansson, K; Fraser, G; Walker, N; Melle, I; Djurovic, S; Agartz, I; Tuulio-Henriksson, A; Suvisaari, J; Lönnqvist, J; Paunio, T; Olsen, L; Hansen, T; Ingason, A; Pirinen, M; Strengman, E; Hougaard, D M; Orntoft, T; Didriksen, M; Hollegaard, M V; Nordentoft, M; Abramova, L; Kaleda, V; Arrojo, M; Sanjuán, J; Arango, C; Etain, B; Bellivier, F; Méary, A; Schürhoff, F; Szoke, A; Ribolsi, M; Magni, V; Siracusano, A; Sperling, S; Rossner, M; Christiansen, C; Kiemeney, L A; Franke, B; van den Berg, L H; Veldink, J; Curran, S; Bolton, P; Poot, M; Staal, W; Rehnstrom, K; Kilpinen, H; Freitag, C M; Meyer, J; Magnusson, P; Saemundsen, E; Martsenkovsky, I; Bikshaieva, I; Martsenkovska, I; Vashchenko, O; Raleva, M; Paketchieva, K; deCODE Genet, IS-101 Reykjavik, Iceland Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA Univ Bonn, Inst Genom Math, Bonn, Germany Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany CHUS, Galician Fdn Genom Med SERGAS, Santiago De Compostela, Spain Aarhus Univ, Dept Biomed, Aarhus, Denmark Aarhus Univ, iSEQ, Ctr Integrat Sequencing, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark Fdn FondaMental, Creteil, France Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland Wellcome Trust Sanger Inst, Cambridge, England South London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr Mental Hlth, Dept Neurosci, London, England Kings Coll London, London, England DFG Res Ctr Mol Physiol Brain CMPB, Gottingen, Germany Max Planck Inst Expt Med, Div Clin Neurosci, D-37075 Gottingen, Germany Univ Tubingen, Inst Human Genet, Dept Med Genet, Tubingen, Germany Natl Univ Hosp Reykjavik, Dept Psychiat, Reykjavik, Iceland Univ Iceland, Sch Med, Reykjavik, Iceland Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Res Ctr, London, England Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-80539 Munich, Germany Heidelberg Univ, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany Univ Aberdeen, Dept Mental Hlth, Royal Cornhill Hosp, Aberdeen, Scotland Ravenscraig Hosp, Greenock, Scotland [Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, Div Mental Hlth & Addict,Oslo Univ Hosp, Oslo, Norway Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki, Finland Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland Univ Helsinki, Cent Hosp, Helsinki, Finland Natl Inst Hlth & Welf THL, Publ Hlth Genom Unit, Helsinki, Finland Univ Copenhagen, Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, Roskilde, Denmark Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands Statens Serum Inst, Dept Clin Biochem Immunol & Genet, Sect Neonatal Screening & Hormones, DK-2300 Copenhagen, Denmark Aarhus Univ Hosp, Dept Mol Med, DK-8000 Aarhus, Denmark H Lundbeck & Co AS, Synapt Transmiss, Copenhagen, Denmark Copenhagen Univ Hosp, Psychiat Ctr Copenhagen, Copenhagen, Denmark Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia CHUS, Serv Psychiat, Santiago De Compostela, Spain Univ Valencia, Network Ctr Biomed Res Mental Hlth CIBERSAM, Unit Psychiat, Fac Med, Valencia, Spain Univ Complutense, Hosp Gen Univ Gregorio Maranon, IiSGM, CIBERSAM, E-28040 Madrid, Spain Hop H Mondor A Chenevier, AP HP, Creteil, France Univ Paris Est, Fac Med, Creteil, France Univ Roma Tor Vergata, Dept Neurosci, Sect Psychiat, Rome, Italy Max Planck Inst Expt Med, Dept Neurogenet, D-37075 Gottingen, Germany Nord Biosci, Herlev, Denmark Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol & Biostat, NL-6525 ED Nijmegen, Netherlands Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands Kings Coll London, Inst Psychiat, Dept Child & Adolescent Psychiat, London, England Radboud Univ Nijmegen, Dept Cognit Neurosci, NL-6525 ED Nijmegen, Netherlands Goethe Univ Frankfurt, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-60054 Frankfurt, Germany Univ Trier, Dept Neurobehav Genet, Trier, Germany Natl Univ Hosp Reykjavik, Dept Child & Adolescent Psychiat, Reykjavik, Iceland State Diagnost & Counseling Ctr, Kopavogur, Iceland Ukrainian Res Inst Social Forens Psychiat & Drug, Dept Child Adolescent Psychiat & Med Social Rehab, Kiev, Ukraine Univ Skopje, Dept Child & Adolescent Psychiat, Skopje, Macedonia Inst Mental Hlth, Belgrade, Serbia Univ Belgrade, Fac Med, Belgrade, Serbia Tbilisi State Med Univ TSMU, Dept Psychiat & Drug Addict, Tbilisi, Rep of Georgia Ilia State Univ, Social & Affect Neurosci Lab, Tbilisi, Rep of Georgia Ctr Addict & Mental Hlth CAMH, Mol Neuropsychiat & Dev Lab, Toronto, ON, Canada Prince Wales Hosp, Black Dog Inst, Randwick, NSW 2031, Australia Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia Neurosci Res Australia, Sydney, NSW, Australia Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia Queensland Inst Med Res, Brisbane, Qld 4006, Australia Catholic Univ Louvain, Univ Psychiat Ctr, Kortenberg, Belgium Maastricht Univ, European Grad Sch Neurosci EURON,Med Ctr, Sch Mental Hlth & Neurosci,Dept Psychiat & Psycho, South Limburg Mental Hlth Res & Teaching Network, Maastricht, Netherlands Semmelweis Univ, Dept Psychiat & Psychotherapy, H-1085 Budapest, Hungary Karolinska Hosp & Inst, HUBIN Project, Dept Clin Neurosci, Stockholm, Sweden Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands Maastricht Univ, Dept Psychiat, Med Ctr, Maastricht, Netherlands Univ Western Australia, Graylands Hosp, CCRN, Perth, WA 6009, Australia UCL, Mental Hlth Sci Unit, London, England UCL, Inst Cognit Neurosci, London, England South London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr Mental Hlth, Dept Psychosis Studies, London, England Trinity Coll Dublin, Sch Med, Neuropsychiat Genet Res Grp, Dublin, Ireland Queens Univ Belfast, Dept Psychiat, Belfast, Antrim, North Ireland Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales Univ Santiago de Compostela, Biomed Network Res Ctr Rare Dis CIBERER, Galician Fdn Genom Med, Genom Med Grp, Santiago De Compostela, Spain Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark German Ctr Neurodegenerat Disorders DZNE, Bonn, Germany Univ Bonn, Inst Human Genet, Bonn, Germany Inst Neurosci & Med INM 1, Julich, Germany Univ Verona, Sect Psychiat, I-37100 Verona, Italy Broad Inst MIT & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA USA Univ Helsinki, Dept Med Genet, Helsinki, Finland Univ Cent Hosp, Helsinki, Finland Univ Halle Wittenberg, Dept Psychiat, D-06108 Halle, Germany Eli Lilly & Co Ltd, Erl Wood Manor, Windlesham, Surrey, England (Nature Publishing Group, 2014-01)
      Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).
    • A common variant at 8q24.21 is associated with renal cell cancer.

      Gudmundsson, Julius; Sulem, Patrick; Gudbjartsson, Daniel F; Masson, Gisli; Petursdottir, Vigdis; Hardarson, Sverrir; Gudjonsson, Sigurjon A; Johannsdottir, Hrefna; Helgadottir, Hafdis Th; Stacey, Simon N; Magnusson, Olafur Th; Helgason, Hannes; Panadero, Angeles; van der Zanden, Loes F; Aben, Katja K H; Vermeulen, Sita H; Oosterwijk, Egbert; Kong, Augustine; Mayordomo, Jose I; Sverrisdottir, Asgerdur; Jonsson, Eirikur; Gudbjartsson, Tomas; Einarsson, Gudmundur V; Kiemeney, Lambertus A; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Stefansson, Kari; DeCODE Genet Inc AMGEN, IS-101 Reykjavik, Iceland, Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland, Ciudad Coria Hosp, Div Med Oncolol, Coria 10800, Spain, Radboud Univ Nijmegen Med Ctr, Dept Hlth Evidence, NL-6500 HB Nijmegen, Netherlands, Comprehens Canc Ctr Netherlands, Dept Canc Registry & Res, NL-3501 DB Utrecht, Netherlands, Radboud Univ Nijmegen Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Radboud Univ Nijmegen Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands, Univ Zaragoza, Div Med Oncol, E-50009 Zaragoza, Spain, Landspitali Univ Hosp, Dept Oncol, IS-101 Reykjavik, Iceland, Landspitali Univ Hosp, Dept Urol, IS-101 Reykjavik, Iceland, Landspitali Univ Hosp, Dept Surg, IS-101 Reykjavik, Iceland, Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland (Nature Publishing Group, 2013)
      Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.
    • Common variants at VRK2 and TCF4 conferring risk of schizophrenia.

      Steinberg, Stacy; de Jong, Simone; Andreassen, Ole A; Werge, Thomas; Børglum, Anders D; Mors, Ole; Mortensen, Preben B; Gustafsson, Omar; Costas, Javier; Pietiläinen, Olli P H; Demontis, Ditte; Papiol, Sergi; Huttenlocher, Johanna; Mattheisen, Manuel; Breuer, René; Vassos, Evangelos; Giegling, Ina; Fraser, Gillian; Walker, Nicholas; Tuulio-Henriksson, Annamari; Suvisaari, Jaana; Lönnqvist, Jouko; Paunio, Tiina; Agartz, Ingrid; Melle, Ingrid; Djurovic, Srdjan; Strengman, Eric; Jürgens, Gesche; Glenthøj, Birte; Terenius, Lars; Hougaard, David M; Ørntoft, Torben; Wiuf, Carsten; Didriksen, Michael; Hollegaard, Mads V; Nordentoft, Merete; van Winkel, Ruud; Kenis, Gunter; Abramova, Lilia; Kaleda, Vasily; Arrojo, Manuel; Sanjuán, Julio; Arango, Celso; Sperling, Swetlana; Rossner, Moritz; Ribolsi, Michele; Magni, Valentina; Siracusano, Alberto; Christiansen, Claus; Kiemeney, Lambertus A; Veldink, Jan; van den Berg, Leonard; Ingason, Andres; Muglia, Pierandrea; Murray, Robin; Nöthen, Markus M; Sigurdsson, Engilbert; Petursson, Hannes; Thorsteinsdottir, Unnur; Kong, Augustine; Rubino, I Alex; De Hert, Marc; Réthelyi, János M; Bitter, István; Jönsson, Erik G; Golimbet, Vera; Carracedo, Angel; Ehrenreich, Hannelore; Craddock, Nick; Owen, Michael J; O'Donovan, Michael C; Ruggeri, Mirella; Tosato, Sarah; Peltonen, Leena; Ophoff, Roel A; Collier, David A; St Clair, David; Rietschel, Marcella; Cichon, Sven; Stefansson, Hreinn; Rujescu, Dan; Stefansson, Kari; deCODE Genetics, IS-101 Reykjavik, Iceland. (Oxford University Press, 2011-10-15)
      Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).
    • Common variants conferring risk of schizophrenia.

      Stefansson, Hreinn; Ophoff, Roel A; Steinberg, Stacy; Andreassen, Ole A; Cichon, Sven; Rujescu, Dan; Werge, Thomas; Pietiläinen, Olli P H; Mors, Ole; Mortensen, Preben B; Sigurdsson, Engilbert; Gustafsson, Omar; Nyegaard, Mette; Tuulio-Henriksson, Annamari; Ingason, Andres; Hansen, Thomas; Suvisaari, Jaana; Lonnqvist, Jouko; Paunio, Tiina; Børglum, Anders D; Hartmann, Annette; Fink-Jensen, Anders; Nordentoft, Merete; Hougaard, David; Norgaard-Pedersen, Bent; Böttcher, Yvonne; Olesen, Jes; Breuer, René; Möller, Hans-Jürgen; Giegling, Ina; Rasmussen, Henrik B; Timm, Sally; Mattheisen, Manuel; Bitter, István; Réthelyi, János M; Magnusdottir, Brynja B; Sigmundsson, Thordur; Olason, Pall; Masson, Gisli; Gulcher, Jeffrey R; Haraldsson, Magnus; Fossdal, Ragnheidur; Thorgeirsson, Thorgeir E; Thorsteinsdottir, Unnur; Ruggeri, Mirella; Tosato, Sarah; Franke, Barbara; Strengman, Eric; Kiemeney, Lambertus A; Melle, Ingrid; Djurovic, Srdjan; Abramova, Lilia; Kaleda, Vasily; Sanjuan, Julio; de Frutos, Rosa; Bramon, Elvira; Vassos, Evangelos; Fraser, Gillian; Ettinger, Ulrich; Picchioni, Marco; Walker, Nicholas; Toulopoulou, Timi; Need, Anna C; Ge, Dongliang; Yoon, Joeng Lim; Shianna, Kevin V; Freimer, Nelson B; Cantor, Rita M; Murray, Robin; Kong, Augustine; Golimbet, Vera; Carracedo, Angel; Arango, Celso; Costas, Javier; Jönsson, Erik G; Terenius, Lars; Agartz, Ingrid; Petursson, Hannes; Nöthen, Markus M; Rietschel, Marcella; Matthews, Paul M; Muglia, Pierandrea; Peltonen, Leena; St Clair, David; Goldstein, David B; Stefansson, Kari; Collier, David A; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland. (Nature Publishing Group, 2009-08-06)
      Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
    • A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2.

      Thiele, Ines; Hyduke, Daniel R; Steeb, Benjamin; Fankam, Guy; Allen, Douglas K; Bazzani, Susanna; Charusanti, Pep; Chen, Feng-Chi; Fleming, Ronan M T; Hsiung, Chao A; De Keersmaecker, Sigrid C J; Liao, Yu-Chieh; Marchal, Kathleen; Mo, Monica L; Özdemir, Emre; Raghunathan, Anu; Reed, Jennifer L; Shin, Sook-il; Sigurbjörnsdóttir, Sara; Steinmann, Jonas; Sudarsan, Suresh; Swainston, Neil; Thijs, Inge M; Zengler, Karsten; Palsson, Bernhard O; Adkins, Joshua N; Bumann, Dirk; [ 1 ] Univ Basel, Biozentrum, Basel, Switzerland [ 2 ] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland [ 3 ] Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland [ 4 ] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA [ 5 ] USDA ARS, Plant Genet Res Unit, Donald Danforth Plant Sci Ctr, St Louis, MO USA [ 6 ] Tech Univ Carolo Wilhelmina Braunschweig, Inst Bioinformat & Biochem, Braunschweig, Germany [ 7 ] Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan, Taiwan [ 8 ] Univ Iceland, Inst Sci, IS-107 Reykjavik, Iceland [ 9 ] Katholieke Univ Leuven, Ctr Microbial & Plant Genet, Dept Microbial & Mol Syst, Louvain, Belgium [ 10 ] Ecole Polytech Fed Lausanne, Lab Computat Syst Biotechnol, Swiss Inst Bioinformat, Lausanne, Switzerland [ 11 ] Mt Sinai Sch Med, Dept Infect Dis, New York, NY USA [ 12 ] Univ Wisconsin, Dept Chem & Biol Engn, Madison, WI USA [ 13 ] Univ Iceland, Fac Life & Environm Sci, Reykjavik, Iceland [ 14 ] Tech Univ Dortmund, Dept Biochem & Chem Engn, Dortmund, Germany [ 15 ] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England [ 16 ] Univ Manchester, Manchester Ctr Integrat Syst Biol, Manchester Interdisciplinary Bioctr, Manchester, Lancs, England [ 17 ] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA (BioMed Central Ltd, 2011)
      Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. Salmonella enterica subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem.
    • A community-driven global reconstruction of human metabolism.

      Thiele, Ines; Swainston, Neil; Fleming, Ronan M T; Hoppe, Andreas; Sahoo, Swagatika; Aurich, Maike K; Haraldsdottir, Hulda; Mo, Monica L; Rolfsson, Ottar; Stobbe, Miranda D; Thorleifsson, Stefan G; Agren, Rasmus; Bölling, Christian; Bordel, Sergio; Chavali, Arvind K; Dobson, Paul; Dunn, Warwick B; Endler, Lukas; Hala, David; Hucka, Michael; Hull, Duncan; Jameson, Daniel; Jamshidi, Neema; Jonsson, Jon J; Juty, Nick; Keating, Sarah; Nookaew, Intawat; Le Novère, Nicolas; Malys, Naglis; Mazein, Alexander; Papin, Jason A; Price, Nathan D; Selkov, Evgeni; Sigurdsson, Martin I; Simeonidis, Evangelos; Sonnenschein, Nikolaus; Smallbone, Kieran; Sorokin, Anatoly; van Beek, Johannes H G M; Weichart, Dieter; Goryanin, Igor; Nielsen, Jens; Westerhoff, Hans V; Kell, Douglas B; Mendes, Pedro; Palsson, Bernhard Ø; Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland, Univ Manchester, Manchester Inst Biotechnol, Manchester Ctr Integrat Syst Biol, Manchester, Lancs, England, Univ Manchester, Sch Comp Sci, Manchester, Lancs, England, Univ Iceland, Dept Biochem & Mol Biol, Reykjavik, Iceland, Charite, Computat Syst Biochem Grp, D-13353 Berlin, Germany, Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA, Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinform, NL-1105 AZ Amsterdam, Netherlands, Netherlands Bioinformat Ctr, Nijmegen, Netherlands, Chalmers, Dept Chem & Biol Engn, S-41296 Gothenburg, Sweden, Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA, Univ Sheffield, Dept Chem & Biol Engn, Sheffield, S Yorkshire, England, Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, CADET, Manchester, Lancs, England, Univ Vienna, Inst Theoret Chem, Vienna, Austria, Univ N Texas, Dept Biol, Denton, TX 76203 USA, CALTECH, Comp & Math Sci Dept, Pasadena, CA 91125 USA, European Bioinformat Inst, European Mol Biol Lab, Hinxton, England, Babraham Inst, Cambridge, England, Univ Manchester, Fac Life Sci, Manchester, Lancs, England, Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England, Univ Edinburgh, Sch Informat, Edinburgh, Midlothian, Scotland, Inst Syst Biol, Seattle, WA USA, Genome Designs Inc, Walnut Creek, CA USA, Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg, Univ Bremen, Sch Sci & Engn, D-28359 Bremen, Germany, Univ Manchester, Sch Math, Manchester, Lancs, England, Russian Acad Sci, Inst Cell Biophys, Pushchino 142292, Moscow Region, Russia, Vrije Univ Amsterdam, Dept Mol Cell Physiol, Amsterdam, Netherlands, Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Med Gen, Amsterdam, Netherlands, Netherlands Consortium Syst Biol, Amsterdam, Netherlands, Univ Manchester, Sch Dent, Manchester, Lancs, England, Okinawa Inst Sci & Technol, Okinawa, Japan, Univ Manchester, Sch Chem Engn & Analyt Sci, Manchester, Lancs, England, Univ Amsterdam, Fac Sci, Swammerdam Inst Life Sci, Amsterdam, Netherlands, Univ Manchester, Sch Chem, Manchester, Lancs, England, Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA USA (Nature Publishing Group, 2013-05)
      Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including ∼2× more reactions and ∼1.7× more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type-specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/.
    • A compendium of inborn errors of metabolism mapped onto the human metabolic network.

      Sahoo, Swagatika; Franzson, Leifur; Jonsson, Jon J; Thiele, Ines; Center for Systems Biology, University of Iceland, Iceland. (RSC publishing, 2012)
      Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitine (AC) and fatty acid oxidation (FAO) metabolism. Using literary data, we reconstructed an AC/FAO module consisting of 352 reactions and 139 metabolites. When this module was combined with the human metabolic reconstruction, the synthesis of 39 acylcarnitines and 22 amino acids, which are routinely measured, was captured and 235 distinct IEMs could be mapped. We collected phenotypic and clinical features for each IEM enabling comprehensive classification. We found that carbohydrate, amino acid, and lipid metabolism were most affected by the IEMs, while the brain was the most commonly affected organ. Furthermore, we analyzed the IEMs in the context of metabolic network topology to gain insight into common features between metabolically connected IEMs. While many known examples were identified, we discovered some surprising IEM pairs that shared reactions as well as clinical features but not necessarily causal genes. Moreover, we could also re-confirm that acetyl-CoA acts as a central metabolite. This network based analysis leads to further insight of hot spots in human metabolism with respect to IEMs. The presented comprehensive knowledge base of IEMs will provide a valuable tool in studying metabolic changes involved in inherited metabolic diseases.
    • Consensus and conflict cards for metabolic pathway databases.

      Stobbe, Miranda D; Swertz, Morris A; Thiele, Ines; Rengaw, Trebor; van Kampen, Antoine H C; Moerland, Perry D; [ 1 ] Univ Amsterdam, Acad Med Ctr, Bioinformat Lab, NL-1100 DE Amsterdam, Netherlands [ 2 ] Univ Amsterdam, Swammerdam Inst Life Sci, NL-1098 XH Amsterdam, Netherlands [ 3 ] Univ Luxembourg, Luxembourg Ctr Syst Biomed, L-4362 Esch Sur Alzette, Luxembourg [ 4 ] Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9700 RB Groningen, Netherlands [ 5 ] Univ Groningen, NL-9700 RB Groningen, Netherlands [ 6 ] Netherlands Bioinformat Ctr, NL-6525 GA Nijmegen, Netherlands [ 7 ] Univ Amsterdam, Netherlands Consortium Syst Biol, NL-1090 GE Amsterdam, Netherlands (BioMed Central, 2013)
      The metabolic network of H. sapiens and many other organisms is described in multiple pathway databases. The level of agreement between these descriptions, however, has proven to be low. We can use these different descriptions to our advantage by identifying conflicting information and combining their knowledge into a single, more accurate, and more complete description. This task is, however, far from trivial.
    • Contextualization procedure and modeling of monocyte specific TLR signaling.

      Aurich, Maike K; Thiele, Ines; [ 1 ] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland (Public Library Science, 2012)
      Innate immunity is the first line of defense against invasion of pathogens. Toll-like receptor (TLR) signaling is involved in a variety of human diseases extending far beyond immune system-related diseases, affecting a number of different tissues and cell-types. Computational models often do not account for cell-type specific differences in signaling networks. Investigation of these differences and its phenotypic implications could increase understanding of cell signaling and processes such as inflammation. The wealth of knowledge for TLR signaling has been recently summarized in a stoichiometric signaling network applicable for constraint-based modeling and analysis (COBRA). COBRA methods have been applied to investigate tissue-specific metabolism using omics data integration. Comparable approaches have not been conducted using signaling networks. In this study, we present ihsTLRv2, an updated TLR signaling network accounting for the association of 314 genes with 558 network reactions. We present a mapping procedure for transcriptomic data onto signaling networks and demonstrate the generation of a monocyte-specific TLR network. The generated monocyte network is characterized through expression of a specific set of isozymes rather than reduction of pathway contents. While further tailoring the network to a specific stimulation condition, we observed that the quantitative changes in gene expression due to LPS stimulation affected the tightly connected set of genes. Differential expression influenced about one third of the entire TLR signaling network, in particular, NF-κB activation. Thus, a cell-type and condition-specific signaling network can provide functional insight into signaling cascades. Furthermore, we demonstrate the energy dependence of TLR signaling pathways in monocytes.
    • Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene.

      Luo, X-J; Li, M; Huang, L; Steinberg, S; Mattheisen, M; Liang, G; Donohoe, G; Shi, Y; Chen, C; Yue, W; Alkelai, A; Lerer, B; Li, Z; Yi, Q; Rietschel, M; Cichon, S; Collier, D A; Tosato, S; Suvisaari, J; Rujescu, Dan; Golimbet, V; Silagadze, T; Durmishi, N; Milovancevic, M P; Stefansson, H; Schulze, T G; Nöthen, M M; Chen, C; Lyne, R; Morris, D W; Gill, M; Corvin, A; Zhang, D; Dong, Q; Moyzis, R K; Stefansson, K; Sigurdsson, E; Hu, F; Su, B; Gan, L; College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China [2] Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA. 2Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. 31] Nanchang University, Nanchang, China [2] Gannan Medical University, Ganzhou, China [3] Jiangxi Provincial People's Hospital, Nanchang, China. 4deCODE Genetics, Reykjavik, Iceland. 5Department of Biomedicine, Aarhus University, Aarhus C, Denmark. 6College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China. 7Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland. 8Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. 9Department of Psychology and Social Behavior, University of California, Irvine, CA, USA. 101] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China. 11Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 12Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, China. 13Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany. 14Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany. 151] Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK [2] Eli Lilly and Co. Ltd, Erl Wood Manor, Surrey, UK. 16Section of Psychiatry, University of Verona, Verona, Italy. 17Mental Health and Substance Abuse Services, National Institute for Health and Welfare THL, Helsinki, Finland. 181] Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany. 19Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia. 20Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia. 21Department of Child and Adolescent Psychiatry, University of Skopje, Skopje, Macedonia. 22Medical Faculty, University of Belgrade, Belgrade, Serbia. 23Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Goettingen, Germany. 24State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China. 25Department of Biological Chemistry, University of California, Irvine, CA, USA. 261] deCODE Genetics, Reykjavik, Iceland [2] School of Medicine, University of Iceland, Reykjavik, Iceland. 271] School of Medicine, University of Iceland, Reykjavik, Iceland [2] Department of Psychiatry, National University Hospital, Reykjavik, Iceland. 28Affiliated Eye Hospital of Nanchang University, Nanchang, China. 29State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. (Nature Publishing Group, 2014-07)
      Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.