Daily Archives: February 5, 2022

Several years ago, in a lab meeting, one of Nikolaus Schultzs postdoctoral fellows posed a question: Do you think its possible to predict, based on the genomic profile of an individual tumor, which organs it might metastasize to?

And just like that, a research project was born.

Dr. Schultz is a computational oncologist in the Department of Epidemiology and Biostatistics at Memorial Sloan Kettering Cancer Center. He also serves as Head of Knowledge Systems in the Marie-Jose and Henry R. Kravis Center for Molecular Oncology. In these dual roles, he has gained a wealth of experience sequencing the DNA in patients tumors and using this information to help physicians guide treatment.

MSK computational oncologists Francisco Sanchez-Vega and Nikolaus Schultz

Every person with advanced cancer who is treated at MSK undergoes genetic sequencing of their tumor with MSK-IMPACT, a tool that looks for mutations in 400-plus cancer-associated genes. Since sequencing started in 2014, MSK has compiled genetic tumor profiles from more than 50,000 patients. This vast repository represents a goldmine for biologists interested in asking questions about the relationships between tumor mutations and cancer progression.

Dr. Schultz and Francisco Sanchez-Vega the curious postdoc who originally posed the question about metastasis and who is now an Assistant Attending Computational Oncologist at MSK realized that they could use computational techniques to search this mountain of data for clues. Specifically, they could ask whether particular mutations (or groups of mutations) correlate with the spread of cancer to particular organs, across many different types of cancer.

That was six years ago. Now, in a paper published February 3, 2022, in the journal Cell, Drs. Schultz and Sanchez-Vega and their team, including postdoctoral researchers Bastien Nguyen and Christopher Fong, and 71 other MSK scientists present the results of their investigation.

To the question of whether its possible to look at an individual tumor and, based on its genomic profile alone, predict its precise future metastatic trajectory, the answer is clearly no.

VIDEO | 01:38

Learn about metastasis, which is the spreading of cancer from its original location to a new location. Memorial Sloan Kettering researchers are making advances in understanding the three stages of metastasis.

While we found some gene mutations to be slightly more common in tumor samples with specific metastatic transitions, we found no single gene that, when mutated, will predict with absolute certainty whether or not a tumor will metastasize to a particular organ, Dr. Schultz says.

The study was revealing in other ways: At a very high level, what the data are telling us is that metastatic disease is genomically different from primary disease, Dr. Schultz says.

For example, in many cancer types, metastatic tumors have more of what geneticists call DNA copy-number changes compared with primary tumors. A DNA copy-number change is when a particular segment of DNA is present in greater or fewer than the normal number of copies. These copy-number changes, when observed in primary tumors, were an indicator of metastatic potential, Dr. Schultz points out.

In addition, he notes, some cancer-driving mutations were detected at different frequencies in metastases compared with primary tumors across a variety of cancer types.

Dr. Schultz likens the extensive dataset his team has curated to The Cancer Genome Atlas (TCGA) project, in which he was also involved. An important goal of TCGA was to assemble a valuable dataset and get it out into the world so that others could mine it, he says.

To help researchers mine these new data for insights, the team is making them publicly available through the cBioPortal for Cancer Genomics as MSK-MET (Memorial Sloan Kettering Metastatic Events and Tropisms).

The dataset includes information on genetic changes and clinical outcomes from 25,000 patients across 50 different cancer types.

Because no single mutation or set of mutations stood out as reliable predictors of metastatic behavior across tumor types, the new study may add support to an emerging framework in cancer science that views metastasis the cause of 90% of cancer deaths as not primarily driven by genetic mutations. Rather, epigenetic changes that occur in cancer cells as a consequence of their interactions with normal cells in the surrounding environment could be more to blame. (Epigenetic changes are ones that alter what genes are turned on or off in a cell without altering the DNA sequence as a mutation would.) These changes may underlie the ability of metastatic cells to adapt to otherwise hostile tissue environments.

To the question of whether its possible to look at an individual tumor and, based on its genomic profile alone, predict its precise future metastatic trajectory, the answer is clearly no.

Recent discoveries from other investigators at MSK including Joan Massagu, Karuna Ganesh, Charles Sawyers, Kat Hadjantonakis, and Dana Peer have pointed to a kind of epigenetically driven identity switching that enables cancer cells to assume more developmentally primitive states and thereby grow in new parts of the body.

Exploring the ramifications of these and other findings will be the focus of MSKs new Marie-Jose and Henry R. Kravis Cancer Ecosystems Project, which launches today.

Currently, genetic sequencing of tumors with MSK-IMPACT can inform whether or not a specific patient should receive a specific drug based on a single genomic alteration. For example, if someone is found to have a mutation in the BRAF gene, they might be a good candidate for a targeted drug called vemurafenib.

But Dr. Schultz points out that there is potentially much more information to be found in the mass of sequencing data and associated patient clinical data that could inform treatment decisions.

When properly mined, this data could tell us a lot more about prognosis of these patients, whether or not their tumors will metastasize, maybe even to what tissues, he says. This information might determine how these patients get monitored in the future. We can learn about what treatments they might be more sensitive to or less sensitive to. I think that theres enormous potential for personalized medicine that goes beyond the single biomarker, and therefore justification to keep sequencing more patients with broader sequencing panels to increase our power to make new discoveries.

Key Takeaways

See the article here:
The Mystery of Metastasis: Can a Tumors Genetic Mutations Predict Whether and Where Cancer Will Spread? - On Cancer - Memorial Sloan Kettering

DUBLIN, Feb. 1, 2022 /PRNewswire/ -- The "Cell & Gene Therapy Market - Global Outlook & Forecast 2022-2027" report has been added to ResearchAndMarkets.com's offering.

The cell and gene therapy market size was valued at USD 4.99 billion in 2021 and is expected to reach USD 36.92 billion by 2027, growing at a CAGR of 39.62 % during the forecast period

In the cell and gene therapy field, gene therapy gathered the pace last from 2 decades because of the discovery of several genes responsible for mutation in various diseases. The advancement in the cell & gene therapy field and innovative technologies give the new era for biological therapeutics. Also, PRIME Designation and marketing authorization for products provide a new opportunity for the manufacturer's financing and revenue generation.

KEY HIGHLIGHTS

As per the American Society of Cell + Gene Therapy report in 2021, increasing the number of cellular and gene therapy products, application rate and products in clinical trials drive the market growth.

As per the Dive Biopharma report 2021, biotech companies who actively engaged in regenerative medicines and therapies reported USD 14 billion funding only in six months of 2021 which was reported to be USD 19.9 billion for the overall year.

CELL AND GENE THERAPY MARKET SEGMENTATION

Increasing application of gene therapies in diseases diagnosis and rapidly growing new drugs applications will give new market space in upcoming years. In 2020, around USD 2.3 billion funding was reported only from private companies for gene therapies. By 2025, the FDA is expected to approve 10?20 products each year, driving the global cell and gene therapy manufacturing market.

In 2020, Medicine in Development Report 2020, around 176 products were reported in cancer therapies in development procedures.

GEOGRAPHICAL OUTLOOK

North America: High economic status and high expenditure on healthcare services drive the cell and gene therapy market in North America. National Health Institutes, industries, academic institutes, and hospitals are the significant contributors of sponsorship and financial funding for cell and gene therapy products.

Europe: The increasing funding for cell and gene therapy drives the cell and gene therapy market growth consistently in Europe. Around USD 2.6 billion financings were reported in Europe for CGTs in 2020, which increased by 103% compared to previous years. In the cell therapy segment, USD 1.8 billion and in gene therapy, USD 2.3 billion funding accounted in 2020, which increased by 196% and 111% growth respectively

VENDOR LANDSCAPE

The key players in the cell and gene therapy market are Gilead Sciences, Novartis, Smith Nephew, Amgen, Organogenesis, Roche (Spark Therapeutics), Dendreon, Vericel, and Bristol-Myers Squibb Company.

An increasing number of mergers and acquisitions gives new potential to market growth. Gilead Sciences acquired Kite Pharma in 2020. Also, Novartis acquired Avexis in 2018, and Smith & Nephew acquired Osiris Therapeutics.

MAJOR GROWTH FACTORS

KEY VENDORS

OTHER PROMINENT VENDORS

UPCOMING VENDORS

Key Topics Covered:

1 Research Methodology

2 Research Objectives

3 Research Process

4 Scope & Coverage4.1 Market Definition4.2 Base Year4.3 Scope of The Study

5 Report Assumptions & Caveats5.1 Key Caveats5.2 Currency Conversion5.3 Market Derivation

6 Market at a Glance

7 Introduction7.1 Overview7.1.1 Cell & Gene Therapy Approved Products 2020-20217.2 Cell & Gene Therapy Phase-III Products7.3 Road Map of Cell & Gene Therapy

8 Market Opportunities & Trends8.1 Rising Number of Mergers & Acquisitions8.2 Expansion of CGT Manufacturing Plants8.3 Expanding Applications for Cell & Gene Therapies8.4 Growing Demand for Car T-Cell Therapies

9 Market Growth Enablers9.1 New Product Approvals & Increasing Pipeline of Products9.2 Prime Designation & Funding Support For CGT9.3 Rising Use of CGT Products for Disease Care9.4 Increasing Use of CGT Products for Disease Treatment

10 Market Restraints10.1 High Cost of Cell & Gene Therapies10.2 Ethical Issues Regarding Genetical Material10.3 Stringent Regulation for CGT Approvals

11 Market Landscape11.1 Market Overview11.2 Market Size & Forecast11.3 Five Forces Analysis

12 Therapy12.1 Market Snapshot & Growth Engine12.2 Market Overview12.3 Gene Therapy12.4 Cell Therapy

13 Application13.1 Market Snapshot & Growth Engine13.2 Market Overview13.3 Oncology13.4 Genetic Disorders13.5 Dermatology13.6 Musculoskeletal Diseases13.7 Other Diseases

14 End-User14.1 Market Snapshot & Growth Engine14.2 Market Overview14.3 Hospitals14.4 Cancer Care Centers14.5 Wound Care Centers14.6 Other End-Users

15 Geography15.1 Market Snapshot & Growth Engine15.2 Geographic Overview15.2.1 Global Cell & Gene Therapy Market by Geography

For more information about this report visit https://www.researchandmarkets.com/r/z7gm5

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

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SOURCE Research and Markets

Here is the original post:
Global Cell & Gene Therapy Market Research Report 2022: Expanding Application for Cell & Gene Therapies & Growing Demand for CAR T- Cell...

The authors would like to thank the participants of the individual studies contributing to the BCAC, GECCO, CORECT, CCFR, INTEGRAL-ILCCO, PRACTICAL, Finngen, BioBank Japan, Asia Colorectal Cancer Consortium, ICBP, DIAGRAM, CARDIoGRAMplusC4D, and MEGASTROKE consortia and the Genetic Epidemiology Research on Adult Health, UK Biobank, and the Korean National Cancer Center CRC Study 2. The authors would also like to acknowledge the investigators of these consortia and studies for generating the data used for this analysis. The authors would like to acknowledge the following investigators of the OncoArray and GAME-ON1KG INTEGRAL-ILCCO analyses: Maria Teresa Landi, Victoria Stevens, Ying Wang, Demetrios Albanes, Neil Caporaso, Paul Brennan, Christopher I Amos, Sanjay Shete, Rayjean J Hung, Heike Bickebller, Angela Risch, Richard Houlston, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, H-Erich Wichmann, David Christiani, Gadi Rennert, Susanne Arnold, John K. Field, Loic Le Marchand, Olle Melander, Hans Brunnstrm, Geoffrey Liu, Angeline Andrew, Lambertus A Kiemeney, Hongbing Shen, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, M Dawn Teare, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich. Cancer consortia-specific funding and acknowledgments is presented in S1 Text.

http://practical.icr.ac.uk/

Rosalind A. Eeles1,2, Christopher A. Haiman3, Zsofia Kote-Jarai1, Fredrick R. Schumacher4,5, Sara Benlloch6,1, Ali Amin Al Olama6,7, Kenneth Muir8,9, Sonja I. Berndt10, David V. Conti3, Fredrik Wiklund11, Stephen Chanock10, Ying Wang12, Victoria L. Stevens12, Catherine M. Tangen13, Jyotsna Batra14,15, Judith A. Clements14,15, APCB BioResource (Australian Prostate Cancer BioResource)14,15, Henrik Grnberg11, Nora Pashayan16,17, Johanna Schleutker18,19, Demetrius Albanes10, Stephanie Weinstein10, Alicja Wolk20, Catharine M. L. West21, Lorelei A. Mucci22, Graldine Cancel-Tassin23,24, Stella Koutros10, Karina Dalsgaard Srensen25,26, Eli Marie Grindedal27, David E. Neal28,29,30, Freddie C. Hamdy31,32, Jenny L. Donovan33, Ruth C. Travis34, Robert J. Hamilton35,36, Sue Ann Ingles37, Barry S. Rosenstein38,39, Yong-Jie Lu40, Graham G. Giles41,42,43, Adam S. Kibel44, Ana Vega45,46,47, Manolis Kogevinas48,49,50,51, Kathryn L. Penney52, Jong Y. Park53, Janet L. Stanford54,55, Cezary Cybulski56, Brge G. Nordestgaard57,58, Sune F. Nielsen57,58, Hermann Brenner59,60,61, Christiane Maier62, Jeri Kim63, Esther M. John64, Manuel R. Teixeira65,66,67, Susan L. Neuhausen68, Kim De Ruyck69, Azad Razack70, Lisa F. Newcomb54,71, Davor Lessel72, Radka Kaneva73, Nawaid Usmani74,75, Frank Claessens76, Paul A. Townsend77,78, Jose Esteban Castelao79, Monique J. Roobol80, Florence Menegaux81, Kay-Tee Khaw82, Lisa Cannon-Albright83,84, Hardev Pandha78, Stephen N. Thibodeau85, David J. Hunter86, Peter Kraft87, William J. Blot88,89, Elio Riboli90

1 The Institute of Cancer Research, London, SM2 5NG, UK

2 Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK

3 Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA

4 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 441067219, USA

5 Seidman Cancer Center, University Hospitals, Cleveland, OH 44106, USA

6 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK

7 University of Cambridge, Department of Clinical Neurosciences, Stroke Research Group, R3, Box 83, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK

8 Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

9 Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK

10 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA

11 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden

12 Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA

13 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

14 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane QLD 4059, Australia

15 Translational Research Institute, Brisbane, Queensland 4102, Australia

16 Department of Applied Health Research, University College London, London, WC1E 7HB, UK

17 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK

18Institute of Biomedicine, University of Turku, Finland

19 Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, PO Box 52, 20521 Turku, Finland

20 Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden

21 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, M13 9PL UK

22 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA

23 CeRePP, Tenon Hospital, F-75020 Paris, France

24 Sorbonne Universite, GRC n5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France

25 Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200 Aarhus N, Denmark

26 Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N

27 Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway

28 Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK

29 University of Cambridge, Department of Oncology, Box 279, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK

30 Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK

31 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX1 2JD, UK

32 Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK

33 Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2PS, UK

34 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK

35 Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto ON M5G 2M9, Canada

36 Dept. of Surgery (Urology), University of Toronto, Canada

37 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA

38 Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Box 1236, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA

39 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 100295674, USA

40 Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

41 Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia

42 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia

43 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria 3168, Australia

44 Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA

45 Fundacin Pblica Galega Medicina Xenmica, Santiago de Compostela, 15706, Spain

46 Instituto de Investigacin Sanitaria de Santiago de Compostela, Santiago De Compostela, 15706, Spain

47 Centro de Investigacin en Red de Enfermedades Raras (CIBERER), Spain

48 ISGlobal, Barcelona, Spain

49 IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

50 CIBER Epidemiologa y Salud Pblica (CIBERESP), 28029 Madrid, Spain

51 Universitat Pompeu Fabra (UPF), Barcelona, Spain

52 Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital/Harvard Medical School, Boston, MA 02115, USA

53 Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA

54 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 981091024, USA

55 Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98195, USA

56 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70115 Szczecin, Poland

57 Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark

58 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200 Copenhagen, Denmark

59 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany

60 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany

61 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany

62 Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076 Tuebingen, Germany

63 The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1515 Holcombe Blvd., Houston, TX 77030, USA

64 Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304 USA

65 Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), 4200072 Porto, Portugal

66 Biomedical Sciences Institute (ICBAS), University of Porto, 4050313 Porto, Portugal

67 Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), 4200072 Porto, Portugal

68 Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, 626-256-HOPE (4673)

69 Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Proeftuinstraat 86, B-9000 Gent

70 Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia

71 Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA 98195, USA

72 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany

73 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria

74 Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2

75 Division of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2

76 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Belgium

77 Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, Univeristy of Manchester, M13 9WL

78 The University of Surrey, Guildford, Surrey, GU2 7XH, UK

79 Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigacin Biomdica Galicia Sur (IISGS), 36204, Vigo (Pontevedra), Spain

80 Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands

81 "Exposome and Heredity", CESP (UMR 1018), Facult de Mdecine, Universit Paris-Saclay, Inserm, Gustave Roussy, Villejuif

82 Clinical Gerontology Unit, University of Cambridge, Cambridge, CB2 2QQ, UK

83 Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA

84 George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA

85 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA

86 Nuffield Department of Population Health, University of Oxford, United Kingdom

87 Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

88 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN 37232 USA

89 International Epidemiology Institute, Rockville, MD 20850, USA

90 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, SW7 2AZ, UK

Rainer Malik 1, Ganesh Chauhan 2, Matthew Traylor 3, Muralidharan Sargurupremraj 4,5, Yukinori Okada 6,7,8, Aniket Mishra 4,5, Loes Rutten-Jacobs 3, Anne-Katrin Giese 9, Sander W van der Laan 10, Solveig Gretarsdottir 11, Christopher D Anderson 12,13,14,14, Michael Chong 15, Hieab HH Adams 16,17, Tetsuro Ago 18, Peter Almgren 19, Philippe Amouyel 20,21, Hakan Ay 22,13, Traci M Bartz 23, Oscar R Benavente 24, Steve Bevan 25, Giorgio B Boncoraglio 26, Robert D Brown, Jr. 27, Adam S Butterworth 28,29, Caty Carrera 30,31, Cara L Carty 32,33, Daniel I Chasman 34,35, Wei-Min Chen 36, John W Cole 37, Adolfo Correa 38, Ioana Cotlarciuc 39, Carlos Cruchaga 40,41, John Danesh 28,42,43,44, Paul IW de Bakker 45,46, Anita L DeStefano 47,48, Marcel den Hoed 49, Qing Duan 50, Stefan T Engelter 51,52, Guido J Falcone 53,54, Rebecca F Gottesman 55, Raji P Grewal 56, Vilmundur Gudnason 57,58, Stefan Gustafsson 59, Jeffrey Haessler 60, Tamara B Harris 61, Ahamad Hassan 62, Aki S Havulinna 63,64, Susan R Heckbert 65, Elizabeth G Holliday 66,67, George Howard 68, Fang-Chi Hsu 69, Hyacinth I Hyacinth 70, M Arfan Ikram 16, Erik Ingelsson 71,72, Marguerite R Irvin 73, Xueqiu Jian 74, Jordi Jimnez-Conde 75, Julie A Johnson 76,77, J Wouter Jukema 78, Masahiro Kanai 6,7,79, Keith L Keene 80,81, Brett M Kissela 82, Dawn O Kleindorfer 82, Charles Kooperberg 60, Michiaki Kubo 83, Leslie A Lange 84, Carl D Langefeld 85, Claudia Langenberg 86, Lenore J Launer 87, Jin-Moo Lee 88, Robin Lemmens 89,90, Didier Leys 91, Cathryn M Lewis 92,93, Wei-Yu Lin 28,94, Arne G Lindgren 95,96, Erik Lorentzen 97, Patrik K Magnusson 98, Jane Maguire 99, Ani Manichaikul 36, Patrick F McArdle 100, James F Meschia 101, Braxton D Mitchell 100,102, Thomas H Mosley 103,104, Michael A Nalls 105,106, Toshiharu Ninomiya 107, Martin J ODonnell 15,108, Bruce M Psaty 109,110,111,112, Sara L Pulit 113,45, Kristiina Rannikme 114,115, Alexander P Reiner 65,116, Kathryn M Rexrode 117, Kenneth Rice 118, Stephen S Rich 36, Paul M Ridker 34,35, Natalia S Rost 9,13, Peter M Rothwell 119, Jerome I Rotter 120,121, Tatjana Rundek 122, Ralph L Sacco 122, Saori Sakaue 7,123, Michele M Sale 124, Veikko Salomaa 63, Bishwa R Sapkota 125, Reinhold Schmidt 126, Carsten O Schmidt 127, Ulf Schminke 128, Pankaj Sharma 39, Agnieszka Slowik 129, Cathie LM Sudlow 114,115, Christian Tanislav 130, Turgut Tatlisumak 131,132, Kent D Taylor 120,121, Vincent NS Thijs 133,134, Gudmar Thorleifsson 11, Unnur Thorsteinsdottir 11, Steffen Tiedt 1, Stella Trompet 135, Christophe Tzourio 5,136,137, Cornelia M van Duijn 138,139, Matthew Walters 140, Nicholas J Wareham 86, Sylvia Wassertheil-Smoller 141, James G Wilson 142, Kerri L Wiggins 109, Qiong Yang 47, Salim Yusuf 15, Najaf Amin 16, Hugo S Aparicio 185,48, Donna K Arnett 186, John Attia 187, Alexa S Beiser 47,48, Claudine Berr 188, Julie E Buring 34,35, Mariana Bustamante 189, Valeria Caso 190, Yu-Ching Cheng 191, Seung Hoan Choi 192,48, Ayesha Chowhan 185,48, Natalia Cullell 31, Jean-Franois Dartigues 193,194, Hossein Delavaran 95,96, Pilar Delgado 195, Marcus Drr 196,197, Gunnar Engstrm 19, Ian Ford 198, Wander S Gurpreet 199, Anders Hamsten 200,201, Laura Heitsch 202, Atsushi Hozawa 203, Laura Ibanez 204, Andreea Ilinca 95,96, Martin Ingelsson 205, Motoki Iwasaki 206, Rebecca D Jackson 207, Katarina Jood 208, Pekka Jousilahti 63, Sara Kaffashian 4,5, Lalit Kalra 209, Masahiro Kamouchi 210, Takanari Kitazono 211, Olafur Kjartansson 212, Manja Kloss 213, Peter J Koudstaal 214, Jerzy Krupinski 215, Daniel L Labovitz 216, Cathy C Laurie 118, Christopher R Levi 217, Linxin Li 218, Lars Lind 219, Cecilia M Lindgren 220,221, Vasileios Lioutas 222,48, Yong Mei Liu 223, Oscar L Lopez 224, Hirata Makoto 225, Nicolas Martinez-Majander 172, Koichi Matsuda 225, Naoko Minegishi 203, Joan Montaner 226, Andrew P Morris 227,228, Elena Muio 31, Martina Mller-Nurasyid 229,230,231, Bo Norrving 95,96, Soichi Ogishima 203, Eugenio A Parati 232, Leema Reddy Peddareddygari 56, Nancy L Pedersen 98,233, Joanna Pera 129, Markus Perola 63,234, Alessandro Pezzini 235, Silvana Pileggi 236, Raquel Rabionet 237, Iolanda Riba-Llena 30, Marta Ribass 238, Jose R Romero 185,48, Jaume Roquer 239,240, Anthony G Rudd 241,242, Antti-Pekka Sarin 243,244, Ralhan Sarju 199, Chloe Sarnowski 47,48, Makoto Sasaki 245, Claudia L Satizabal 185,48, Mamoru Satoh 245, Naveed Sattar 246, Norie Sawada 206, Gerli Sibolt 172, sgeir Sigurdsson 247, Albert Smith 248, Kenji Sobue 245, Carolina Soriano-Trraga 240, Tara Stanne 249, O Colin Stine 250, David J Stott 251, Konstantin Strauch 229,252, Takako Takai 203, Hideo Tanaka 253,254, Kozo Tanno 245, Alexander Teumer 255, Liisa Tomppo 172, Nuria P Torres-Aguila 31, Emmanuel Touze 256,257, Shoichiro Tsugane 206, Andre G Uitterlinden 258, Einar M Valdimarsson 259, Sven J van der Lee 16, Henry Vlzke 255, Kenji Wakai 253, David Weir 260, Stephen R Williams 261, Charles DA Wolfe 241,242, Quenna Wong 118, Huichun Xu 191, Taiki Yamaji 206, Dharambir K Sanghera 125,169,170, Olle Melander 19, Christina Jern 171, Daniel Strbian 172,173, Israel Fernandez-Cadenas 31,30, W T Longstreth, Jr 174,65, Arndt Rolfs 175, Jun Hata 107, Daniel Woo 82, Jonathan Rosand 12,13,14, Guillaume Pare 15, Jemma C Hopewell 176, Danish Saleheen 177, Kari Stefansson 11,178, Bradford B Worrall 179, Steven J Kittner 37, Sudha Seshadri 180,48, Myriam Fornage 74,181, Hugh S Markus 3, Joanna MM Howson 28, Yoichiro Kamatani 6,182, Stephanie Debette 4,5, Martin Dichgans 1,183,184.

1 Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany

2 Centre for Brain Research, Indian Institute of Science, Bangalore, India

3 Stroke Research Group, Division of Clinical Neurosciences, University of Cambridge, UK

4 INSERM U1219 Bordeaux Population Health Research Center, Bordeaux, France

5 University of Bordeaux, Bordeaux, France

6 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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