The purpose of this dataset is to facilitate development of technical implementations for rare disease data integration, analysis, discovery, and federated access. This synthetic dataset includes clinical and genomic data from 6 rare disease cases. It consists of 18 whole genomes (6 index cases with their parents) which have genetic background based on public human data sequenced in the context of the Illumina Platinum initiative (Eberle, MA et al. (2017)) and made available by the HapMap project (https://www.genome.gov/10001688/international-hapmap-project). In each of the cases, real causative variants correlating with the phenotypic data provided were spiked-in. The cases included in this synthetic dataset correspond to the following type of disorders: CASE 1- Congenital myasthenic syndrome (Autosomal Dominant -de novo variant) CASE 2- Macular dystrophy (Autosomal Dominant) CASE 3- Muscular dystrophy (Autosomal Recessive-compound heterozygous variants) CASE 4- Mitochondrial disorder (Autosomal Recessive-consanguineous case - homozygous variant) CASE 5- Breast cancer (Autosomal Dominant) CASE 6- Similar as case 1 for patient matchmaking tests: Congenital myasthenic syndrome (Autosomal Dominant-de novo variant) For each case you will be able to download the following data: clinical information (phenopackets per individual and pedigree per family), raw genomic data (FASTQ and BAMs) and processed genomic data (vcfs). When using the data, the following should be acknowledged: the RD-Connect GPAP (https://platform.rd-connect.eu/), EC H2020 project EJP-RD (grant # 825575), EC H2020 project B1MG (grant # 951724) and Generalitat de Catalunya VEIS project (grant # 001-P-001647).
Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens. In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Original description of the study: From ELLIPSE (linked to the PRACTICAL consortium), we contributed ~78,000 SNPs to the OncoArray. A large fraction of the content was derived from the GWAS meta-analyses in European ancestry populations (overall and aggressive disease; ~27K SNPs). We also selected just over 10,000 SNPs from the meta-analyses in the non-European populations, with a majority of these SNPs coming from the analysis of overall prostate cancer in African ancestry populations as well as from the multiethnic meta-analysis. A substantial fraction of SNPs (~28,000) were also selected for fine-mapping of 53 loci not included in the common fine-mapping regions (tagging at r2>0.9 across ±500kb regions). We also selected a few thousand SNPs related with PSA levels and/or disease survival as well as SNPs from candidate lists provided by study collaborators, as well as from meta-analyses of exome SNP chip data from the Multiethnic Cohort and UK studies. The Contributing Studies: Aarhus: Hospital-based, Retrospective, Observational. Source of cases: Patients treated for prostate adenocarcinoma at Department of Urology, Aarhus University Hospital, Skejby (Aarhus, Denmark). Source of controls: Age-matched males treated for myocardial infarction or undergoing coronary angioplasty, but with no prostate cancer diagnosis based on information retrieved from the Danish Cancer Register and the Danish Cause of Death Register. AHS: Nested case-control study within prospective cohort. Source of cases: linkage to cancer registries in study states. Source of controls: matched controls from cohort ATBC: Prospective, nested case-control. Source of cases: Finnish male smokers aged 50-69 years at baseline. Source of controls: Finnish male smokers aged 50-69 years at baseline BioVu: Cases identified in a biobank linked to electronic health records. Source of cases: A total of 214 cases were identified in the VUMC de-identified electronic health records database (the Synthetic Derivative) and shipped to USC for genotyping in April 2014. The following criteria were used to identify cases: Age 18 or greater; male; African Americans (Black) only. Note that African ancestry is not self-identified, it is administratively or third-party assigned (which has been shown to be highly correlated with genetic ancestry for African Americans in BioVU; see references). Source of controls: Controls were identified in the de-identified electronic health record. Unfortunately, they were not age matched to the cases, and therefore cannot be used for this study. Canary PASS: Prospective, Multi-site, Observational Active Surveillance Study. Source of cases: clinic based from Beth Israel Deaconness Medical Center, Eastern Virginia Medical School, University of California at San Francisco, University of Texas Health Sciences Center San Antonio, University of Washington, VA Puget Sound. Source of controls: N/A CCI: Case series, Hospital-based. Source of cases: Cases identified through clinics at the Cross Cancer Institute. Source of controls: N/A CerePP French Prostate Cancer Case-Control Study (ProGene): Case-Control, Prospective, Observational, Hospital-based. Source of cases: Patients, treated in French departments of Urology, who had histologically confirmed prostate cancer. Source of controls: Controls were recruited as participating in a systematic health screening program and found unaffected (normal digital rectal examination and total PSA < 4 ng/ml, or negative biopsy if PSA > 4 ng/ml). COH: hospital-based cases and controls from outside. Source of cases: Consented prostate cancer cases at City of Hope. Source of controls: Consented unaffected males that were part of other studies where they consented to have their DNA used for other research studies. COSM: Population-based cohort. Source of cases: General population. Source of controls: General population CPCS1: Case-control - Denmark. Source of cases: Hospital referrals. Source of controls: Copenhagen General Population Study CPCS2: Source of cases: Hospital referrals. Source of controls: Copenhagen General Population Study CPDR: Retrospective cohort. Source of cases: Walter Reed National Military Medical Center. Source of controls: Walter Reed National Military Medical Center ACS_CPS-II: Nested case-control derived from a prospective cohort study. Source of cases: Identified through self-report on follow-up questionnaires and verified through medical records or cancer registries, identified through cancer registries or the National Death Index (with prostate cancer as the primary cause of death). Source of controls: Cohort participants who were cancer-free at the time of diagnosis of the matched case, also matched on age (±6 mo) and date of biospecimen donation (±6 mo). EPIC: Case-control - Germany, Greece, Italy, Netherlands, Spain, Sweden, UK. Source of cases: Identified through record linkage with population-based cancer registries in Italy, the Netherlands, Spain, Sweden and UK. In Germany and Greece, follow-up is active and achieved through checks of insurance records and cancer and pathology registries as well as via self-reported questionnaires; self-reported incident cancers are verified through medical records. Source of controls: Cohort participants without a diagnosis of cancer EPICAP: Case-control, Population-based, ages less than 75 years at diagnosis, Hérault, France. Source of cases: Prostate cancer cases in all public hospitals and private urology clinics of département of Hérault in France. Cases validation by the Hérault Cancer Registry. Source of controls: Population-based controls, frequency age matched (5-year groups). Quotas by socio-economic status (SES) in order to obtain a distribution by SES among controls identical to the SES distribution among general population men, conditionally to age. ERSPC: Population-based randomized trial. Source of cases: Men with PrCa from screening arm ERSPC Rotterdam. Source of controls: Men without PrCa from screening arm ERSPC Rotterdam ESTHER: Case-control, Prospective, Observational, Population-based. Source of cases: Prostate cancer cases in all hospitals in the state of Saarland, from 2001-2003. Source of controls: Random sample of participants from routine health check-up in Saarland, in 2000-2002 FHCRC: Population-based, case-control, ages 35-74 years at diagnosis, King County, WA, USA. Source of cases: Identified through the Seattle-Puget Sound SEER cancer registry. Source of controls: Randomly selected, age-frequency matched residents from the same county as cases Gene-PARE: Hospital-based. Source of cases: Patients that received radiotherapy for treatment of prostate cancer. Source of controls: n/a Hamburg-Zagreb: Hospital-based, Prospective. Source of cases: Prostate cancer cases seen at the Department of Oncology, University Hospital Center Zagreb, Croatia. Source of controls: Population-based (Croatia), healthy men, older than 50, with no medical record of cancer, and no family history of cancer (1st & 2nd degree relatives) HPFS: Nested case-control. Source of cases: Participants of the HPFS cohort. Source of controls: Participants of the HPFS cohort IMPACT: Observational. Source of cases: Carriers and non-carriers (with a known mutation in the family) of the BRCA1 and BRCA2 genes, aged between 40 and 69, who are undergoing prostate screening with annual PSA testing. This cohort has been diagnosed with prostate cancer during the study. Source of controls: Carriers and non-carriers (with a known mutation in the family) of the BRCA1 and BRCA2 genes, aged between 40 and 69, who are undergoing prostate screening with annual PSA testing. This cohort has not been diagnosed with prostate cancer during the study. IPO-Porto: Hospital-based. Source of cases: Early onset and/or familial prostate cancer. Source of controls: Blood donors Karuprostate: Case-control, Retrospective, Population-based. Source of cases: From FWI (Guadeloupe): 237 consecutive incident patients with histologically confirmed prostate cancer attending public and private urology clinics; From Democratic Republic of Congo: 148 consecutive incident patients with histologically confirmed prostate cancer attending the University Clinic of Kinshasa. Source of controls: From FWI (Guadeloupe): 277 controls recruited from men participating in a free systematic health screening program open to the general population; From Democratic Republic of Congo: 134 controls recruited from subjects attending the University Clinic of Kinshasa KULEUVEN: Hospital-based, Prospective, Observational. Source of cases: Prostate cancer cases recruited at the University Hospital Leuven. Source of controls: Healthy males with no history of prostate cancer recruited at the University Hospitals, Leuven. LAAPC: Subjects were participants in a population-based case-control study of aggressive prostate cancer conducted in Los Angeles County. Cases were identified through the Los Angeles County Cancer Surveillance Program rapid case ascertainment system. Eligible cases included African American, Hispanic, and non-Hispanic White men diagnosed with a first primary prostate cancer between January 1, 1999 and December 31, 2003. Eligible cases also had (a) prostatectomy with documented tumor extension outside the prostate, (b) metastatic prostate cancer in sites other than prostate, (c) needle biopsy of the prostate with Gleason grade ≥8, or (d) needle biopsy with Gleason grade 7 and tumor in more than two thirds of the biopsy cores. Eligible controls were men never diagnosed with prostate cancer, living in the same neighborhood as a case, and were frequency matched to cases on age (± 5 y) and race/ethnicity. Controls were identified by a neighborhood walk algorithm, which proceeds through an obligatory sequence of adjacent houses or residential units beginning at a specific residence that has a specific geographic relationship to the residence where the case lived at diagnosis. Malaysia: Case-control. Source of cases: Patients attended the outpatient urology or uro-onco clinic at University Malaya Medical Center. Source of controls: Population-based, age matched (5-year groups), ascertained through electoral register, Subang Jaya, Selangor, Malaysia MCC-Spain: Case-control. Source of cases: Identified through the urology departments of the participating hospitals. Source of controls: Population-based, frequency age and region matched, ascertained through the rosters of the primary health care centers MCCS: Nested case-control, Melbourne, Victoria. Source of cases: Identified by linkage to the Victorian Cancer Registry. Source of controls: Cohort participants without a diagnosis of cancer MD Anderson: Participants in this study were identified from epidemiological prostate cancer studies conducted at the University of Texas MD Anderson Cancer Center in the Houston Metropolitan area. Cases were accrued in the Houston Medical Center and were not restricted with respect to Gleason score, stage or PSA. Controls were identified via random-digit-dialing or among hospital visitors and they were frequency matched to cases on age and race. Lifestyle, demographic, and family history data were collected using a standardized questionnaire. MDACC_AS: A prospective cohort study. Source of cases: Men with clinically organ-confined prostate cancer meeting eligibility criteria for a prospective cohort study of active surveillance at MD Anderson Cancer Center. Source of controls: N/A MEC: The Multiethnic Cohort (MEC) is comprised of over 215,000 men and women recruited from Hawaii and the Los Angeles area between 1993 and 1996. Between 1995 and 2006, over 65,000 blood samples were collected from participants for genetic analyses. To identify incident cancer cases, the MEC was cross-linked with the population-based Surveillance, Epidemiology and End Results (SEER) registries in California and Hawaii, and unaffected cohort participants with blood samples were selected as controls MIAMI (WFPCS): Prostate cancer cases and controls were recruited from the Departments of Urology and Internal Medicine of the Wake Forest University School of Medicine using sequential patient populations as described previously (PMID:15342424). All study subjects received a detailed description of the study protocol and signed their informed consent, as approved by the medical center's Institutional Review Board. The general eligibility criteria were (i) able to comprehend informed consent and (ii) without previously diagnosed cancer. The exclusion criteria were (i) clinical diagnosis of autoimmune diseases; (ii) chronic inflammatory conditions; and (iii) infections within the past 6 weeks. Blood samples were collected from all subjects. MOFFITT: Hospital-based. Source of cases: clinic based from Moffitt Cancer Center. Source of controls: Moffitt Cancer Center affiliated Lifetime cancer screening center NMHS: Case-control, clinic based, Nashville TN. Source of cases: All urology clinics in Nashville, TN. Source of controls: Men without prostate cancer at prostate biopsy. PCaP: The North Carolina-Louisiana Prostate Cancer Project (PCaP) is a multidisciplinary population-based case-only study designed to address racial differences in prostate cancer through a comprehensive evaluation of social, individual and tumor level influences on prostate cancer aggressiveness. PCaP enrolled approximately equal numbers of African Americans and Caucasian Americans with newly-diagnosed prostate cancer from North Carolina (42 counties) and Louisiana (30 parishes) identified through state tumor registries. African American PCaP subjects with DNA, who agreed to future use of specimens for research, participated in OncoArray analysis. PCMUS: Case-control - Sofia, Bulgaria. Source of cases: Patients of Clinic of Urology, Alexandrovska University Hospital, Sofia, Bulgaria, PrCa histopathologically confirmed. Source of controls: 72 patients with verified BPH and PSA<3,5; 78 healthy controls from the MMC Biobank, no history of PrCa PHS: Nested case-control. Source of cases: Participants of the PHS1 trial/cohort. Source of controls: Participants of the PHS1 trial/cohort PLCO: Nested case-control. Source of cases: Men with a confirmed diagnosis of prostate cancer from the PLCO Cancer Screening Trial. Source of controls: Controls were men enrolled in the PLCO Cancer Screening Trial without a diagnosis of cancer at the time of case ascertainment. Poland: Case-control. Source of cases: men with unselected prostate cancer, diagnosed in north-western Poland at the University Hospital in Szczecin. Source of controls: cancer-free men from the same population, taken from the healthy adult patients of family doctors in the Szczecin region PROCAP: Population-based, Retrospective, Observational. Source of cases: Cases were ascertained from the National Prostate Cancer Register of Sweden Follow-Up Study, a retrospective nationwide cohort study of patients with localized prostate cancer. Source of controls: Controls were selected among men referred for PSA testing in laboratories in Stockholm County, Sweden, between 2010 and 2012. PROGReSS: Hospital-based, Prospective, Observational. Source of cases: Prostate cancer cases from the Hospital Clínico Universitario de Santiago de Compostela, Galicia, Spain. Source of controls: Cancer-free men from the same population ProMPT: A study to collect samples and data from subjects with and without prostate cancer. Retrospective, Experimental. Source of cases: Subjects attending outpatient clinics in hospitals. Source of controls: Subjects attending outpatient clinics in hospitals ProtecT: Trial of treatment. Samples taken from subjects invited for PSA testing from the community at nine centers across United Kingdom. Source of cases: Subjects who have a proven diagnosis of prostate cancer following testing. Source of controls: Identified through invitation of subjects in the community. PROtEuS: Case-control, population-based. Source of cases: All new histologically-confirmed cases, aged less or equal to 75 years, diagnosed between 2005 and 2009, actively ascertained across Montreal French hospitals. Source of controls: Randomly selected from the Provincial electoral list of French-speaking men between 2005 and 2009, from the same area of residence as cases and frequency-matched on age. QLD: Case-control. Source of cases: A longitudinal cohort study (Prostate Cancer Supportive Care and Patient Outcomes Project: ProsCan) conducted in Queensland, through which men newly diagnosed with prostate cancer from 26 private practices and 10 public hospitals were directly referred to ProsCan at the time of diagnosis by their treating clinician (age range 43-88 years). All cases had histopathologically confirmed prostate cancer, following presentation with an abnormal serum PSA and/or lower urinary tract symptoms. Source of controls: Controls comprised healthy male blood donors with no personal history of prostate cancer, recruited through (i) the Australian Red Cross Blood Services in Brisbane (age range 19-76 years) and (ii) the Australian Electoral Commission (AEC) (age and post-code/ area matched to ProsCan, age range 54-90 years). RAPPER: Multi-centre, hospital based blood sample collection study in patients enrolled in clinical trials with prospective collection of radiotherapy toxicity data. Source of cases: Prostate cancer patients enrolled in radiotherapy trials: CHHiP, RT01, Dose Escalation, RADICALS, Pelvic IMRT, PIVOTAL. Source of controls: N/A SABOR: Prostate Cancer Screening Cohort. Source of cases: Men >45 yrs of age participating in annual PSA screening. Source of controls: Males participating in annual PSA prostate cancer risk evaluations (funded by NCI biomarkers discovery and validation grant), recruited through University of Texas Health Science Center at San Antonio and affiliated sites or through study advertisements, enrolment open to the community SCCS: Case-control in cohort, Southeastern USA. Prospective, Observational, Population-based. Source of cases: SCCS entry population. Source of controls: SCCS entry population SCPCS: Population-based, Retrospective, Observational. Source of cases: South Carolina Central Cancer Registry. Source of controls: Health Care Financing Administration beneficiary file SEARCH: Case-control - East Anglia, UK. Source of cases: Men < 70 years of age registered with prostate cancer at the population-based cancer registry, Eastern Cancer Registration and Information Centre, East Anglia, UK. Source of controls: Men attending general practice in East Anglia with no known prostate cancer diagnosis, frequency matched to cases by age and geographic region SNP_Prostate_Ghent: Hospital-based, Retrospective, Observational. Source of cases: Men treated with IMRT as primary or postoperative treatment for prostate cancer at the Ghent University Hospital between 2000 and 2010. Source of controls: Employees of the University hospital and members of social activity clubs, without a history of any cancer. SPAG: Hospital-based, Retrospective, Observational. Source of cases: Guernsey. Source of controls: Guernsey STHM2: Population-based, Retrospective, Observational. Source of cases: Cases were selected among men referred for PSA testing in laboratories in Stockholm County, Sweden, between 2010 and 2012. Source of controls: Controls were selected among men referred for PSA testing in laboratories in Stockholm County, Sweden, between 2010 and 2012. PCPT: Case-control from a randomized clinical trial. Source of cases: Randomized clinical trial. Source of controls: Randomized clinical trial SELECT: Case-cohort from a randomized clinical trial. Source of cases: Randomized clinical trial. Source of controls: Randomized clinical trial TAMPERE: Case-control - Finland, Retrospective, Observational, Population-based. Source of cases: Identified through linkage to the Finnish Cancer Registry and patient records; and the Finnish arm of the ERSPC study. Source of controls: Cohort participants without a diagnosis of cancer UGANDA: Uganda Prostate Cancer Study: Uganda is a case-control study of prostate cancer in Kampala Uganda that was initiated in 2011. Men with prostate cancer were enrolled from the Urology unit at Mulago Hospital and men without prostate cancer (i.e. controls) were enrolled from other clinics (i.e. surgery) at the hospital. UKGPCS: ICR, UK. Source of cases: Cases identified through clinics at the Royal Marsden hospital and nationwide NCRN hospitals. Source of controls: Ken Muir's control- 2000 ULM: Case-control - Germany. Source of cases: familial cases (n=162): identified through questionnaires for family history by collaborating urologists all over Germany; sporadic cases (n=308): prostatectomy series performed in the Clinic of Urology Ulm between 2012 and 2014. Source of controls: age-matched controls (n=188): age-matched men without prostate cancer and negative family history collected in hospitals of Ulm WUGS/WUPCS: Cases Series, USA. Source of cases: Identified through clinics at Washington University in St. Louis. Source of controls: Men diagnosed and managed with prostate cancer in University based clinic. Acknowledgement Statements: Aarhus: This study was supported by the Danish Strategic Research Council (now Innovation Fund Denmark) and the Danish Cancer Society. The Danish Cancer Biobank (DCB) is acknowledged for biological material. AHS: This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01CP010119). ATBC: This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, and HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. BioVu: The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding and by the National Center for Research Resources, Grant UL1 RR024975-01 (which is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06). Canary PASS: PASS was supported by Canary Foundation and the National Cancer Institute's Early Detection Research Network (U01 CA086402) CCI: This work was awarded by Prostate Cancer Canada and is proudly funded by the Movember Foundation - Grant # D2013-36.The CCI group would like to thank David Murray, Razmik Mirzayans, and April Scott for their contribution to this work. CerePP French Prostate Cancer Case-Control Study (ProGene): None reported COH: SLN is partially supported by the Morris and Horowitz Families Endowed Professorship COSM: The Swedish Research Council, the Swedish Cancer Foundation CPCS1 & CPCS2: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, DenmarkCPCS1 would like to thank the participants and staff of the Copenhagen General Population Study for their important contributions. CPDR: Uniformed Services University for the Health Sciences HU0001-10-2-0002 (PI: David G. McLeod, MD) CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. CPS-II thanks the participants and Study Management Group for their invaluable contributions to this research. We would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. EPIC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); the Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation, Greek Ministry of Health; Greek Ministry of Education (Greece); the Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); the Statistics Netherlands (The Netherlands); the Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Spanish Ministry of Health ISCIII RETIC (RD06/0020), Red de Centros RCESP, C03/09 (Spain); the Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten, Fundacion Federico SA (Sweden); the Cancer Research UK, Medical Research Council (United Kingdom). EPICAP: The EPICAP study was supported by grants from Ligue Nationale Contre le Cancer, Ligue départementale du Val de Marne; Fondation de France; Agence Nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES). The EPICAP study group would like to thank all urologists, Antoinette Anger and Hasina Randrianasolo (study monitors), Anne-Laure Astolfi, Coline Bernard, Oriane Noyer, Marie-Hélène De Campo, Sandrine Margaroline, Louise N'Diaye, and Sabine Perrier-Bonnet (Clinical Research nurses). ERSPC: This study was supported by the DutchCancerSociety (KWF94-869,98-1657,2002-277,2006-3518, 2010-4800), The Netherlands Organisation for Health Research and Development (ZonMW-002822820, 22000106, 50-50110-98-311, 62300035), The Dutch Cancer Research Foundation (SWOP), and an unconditional grant from Beckman-Coulter-HybritechInc. ESTHER: The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. The ESTHER group would like to thank Hartwig Ziegler, Sonja Wolf, Volker Hermann, Heiko Müller, Karina Dieffenbach, Katja Butterbach for valuable contributions to the study. FHCRC: The FHCRC studies were supported by grants R01-CA056678, R01-CA082664, and R01-CA092579 from the US National Cancer Institute, National Institutes of Health, with additional support from the Fred Hutchinson Cancer Research Center. FHCRC would like to thank all the men who participated in these studies. Gene-PARE: The Gene-PARE study was supported by grants 1R01CA134444 from the U.S. National Institutes of Health, PC074201 and W81XWH-15-1-0680 from the Prostate Cancer Research Program of the Department of Defense and RSGT-05-200-01-CCE from the American Cancer Society. Hamburg-Zagreb: None reported HPFS: The Health Professionals Follow-up Study was supported by grants UM1CA167552, CA133891, CA141298, and P01CA055075. HPFS are grateful to the participants and staff of the Physicians' Health Study and Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. IMPACT: The IMPACT study was funded by The Ronald and Rita McAulay Foundation, CR-UK Project grant (C5047/A1232), Cancer Australia, AICR Netherlands A10-0227, Cancer Australia and Cancer Council Tasmania, NIHR, EU Framework 6, Cancer Councils of Victoria and South Australia, and Philanthropic donation to Northshore University Health System. We acknowledge support from the National Institute for Health Research (NIHR) to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Foundation NHS Trust. IMPACT acknowledges the IMPACT study steering committee, collaborating centres, and participants. IPO-Porto: The IPO-Porto study was funded by Fundaçäo para a Ciência e a Tecnologia (FCT; UID/DTP/00776/2013 and PTDC/DTP-PIC/1308/2014) and by IPO-Porto Research Center (CI-IPOP-16-2012 and CI-IPOP-24-2015). MC and MPS are research fellows from Liga Portuguesa Contra o Cancro, Núcleo Regional do Norte. SM is a research fellow from FCT (SFRH/BD/71397/2010). IPO-Porto would like to express our gratitude to all patients and families who have participated in this study. Karuprostate: The Karuprostate study was supported by the the Frech National Health Directorate and by the Association pour la Recherche sur les Tumeurs de la ProstateKarusprostate thanks Séverine Ferdinand. KULEUVEN: F.C. and S.J. are holders of grants from FWO Vlaanderen (G.0684.12N and G.0830.13N), the Belgian federal government (National Cancer Plan KPC_29_023), and a Concerted Research Action of the KU Leuven (GOA/15/017). TVDB is holder of a doctoral fellowship of the FWO. LAAPC: This study was funded by grant R01CA84979 (to S.A. Ingles) from the National Cancer Institute, National Institutes of Health. Malaysia: The study was funded by the University Malaya High Impact Research Grant (HIR/MOHE/MED/35). Malaysia thanks all associates in the Urology Unit, University of Malaya, Cancer Research Initiatives Foundation (CARIF) and the Malaysian Men's Health Initiative (MMHI). MCCS: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553, and 504711, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MCC-Spain: The study was partially funded by the Accion Transversal del Cancer, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI09/00773-Cantabria, PI11/01889-FEDER, PI12/00265, PI12/01270, and PI12/00715), by the Fundación Marqués de Valdecilla (API 10/09), by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489. Samples: Biological samples were stored at the Parc de Salut MAR Biobank (MARBiobanc; Barcelona) which is supported by Instituto de Salud Carlos III FEDER (RD09/0076/00036). Also sample collection was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncologia de Catalunya (XBTC). MCC-Spain acknowledges the contribution from Esther Gracia-Lavedan in preparing the data. We thank all the subjects who participated in the study and all MCC-Spain collaborators. MD Anderson: Prostate Cancer Case-Control Studies at MD Anderson (MDA) supported by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. MDACC_AS: None reported MEC: Funding provided by NIH grant U19CA148537 and grant U01CA164973. MIAMI (WFPCS): ACS MOFFITT: The Moffitt group was supported by the US National Cancer Institute (R01CA128813, PI: J.Y. Park). NMHS: Funding for the Nashville Men's Health Study (NMHS) was provided by the National Institutes of Health Grant numbers: RO1CA121060. PCaP only data: The North Carolina - Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. For HCaP-NC follow-up data: The Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study is carried out as a collaborative study supported by the American Cancer Society award RSGT-08-008-01-CPHPS. For studies using both PCaP and HCaP-NC follow-up data please use: The North Carolina - Louisiana Prostate Cancer Project (PCaP) and the Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study are carried out as collaborative studies supported by the Department of Defense contract DAMD 17-03-2-0052 and the American Cancer Society award RSGT-08-008-01-CPHPS, respectively. For any PCaP data, please include: The authors thank the staff, advisory committees and research subjects participating in the PCaP study for their important contributions. For studies using PCaP DNA/genotyping data, please include: We would like to acknowledge the UNC BioSpecimen Facility and LSUHSC Pathology Lab for our DNA extractions, blood processing, storage and sample disbursement (https://genome.unc.edu/bsp). For studies using PCaP tissue, please include: We would like to acknowledge the RPCI Department of Urology Tissue Microarray and Immunoanalysis Core for our tissue processing, storage and sample disbursement. For studies using HCaP-NC follow-up data, please use: The Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study is carried out as a collaborative study supported by the American Cancer Society award RSGT-08-008-01-CPHPS. The authors thank the staff, advisory committees and research subjects participating in the HCaP-NC study for their important contributions. For studies that use both PCaP and HCaP-NC, please use: The authors thank the staff, advisory committees and research subjects participating in the PCaP and HCaP-NC studies for their important contributions. PCMUS: The PCMUS study was supported by the Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2-2009; DFNI-B01/28/2012) with additional support from the Science Fund of Medical University - Sofia (contract 51/2009; 8I/2009; 28/2010). PHS: The Physicians' Health Study was supported by grants CA34944, CA40360, CA097193, HL26490, and HL34595. PHS members are grateful to the participants and staff of the Physicians' Health Study and Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. PLCO: This PLCO study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIHPLCO thanks Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention at the National Cancer Institute, the screening center investigators and staff of the PLCO Cancer Screening Trial for their contributions to the PLCO Cancer Screening Trial. We thank Mr. Thomas Riley, Mr. Craig Williams, Mr. Matthew Moore, and Ms. Shannon Merkle at Information Management Services, Inc., for their management of the data and Ms. Barbara O'Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial. We also thank the PLCO study participants for their contributions to making this study possible. Poland: None reported PROCAP: PROCAP was supported by the Swedish Cancer Foundation (08-708, 09-0677). PROCAP thanks and acknowledges all of the participants in the PROCAP study. We thank Carin Cavalli-Björkman and Ami Rönnberg Karlsson for their dedicated work in the collection of data. Michael Broms is acknowledged for his skilful work with the databases. KI Biobank is acknowledged for handling the samples and for DNA extraction. We acknowledge The NPCR steering group: Pär Stattin (chair), Anders Widmark, Stefan Karlsson, Magnus Törnblom, Jan Adolfsson, Anna Bill-Axelson, Ove Andrén, David Robinson, Bill Pettersson, Jonas Hugosson, Jan-Erik Damber, Ola Bratt, Göran Ahlgren, Lars Egevad, and Roy Ehrnström. PROGReSS: The PROGReSS study is founded by grants from the Spanish Ministry of Health (INT15/00070; INT16/00154; FIS PI10/00164, FIS PI13/02030; FIS PI16/00046); the Spanish Ministry of Economy and Competitiveness (PTA2014-10228-I), and Fondo Europeo de Desarrollo Regional (FEDER 2007-2013). ProMPT: Founded by CRUK, NIHR, MRC, Cambride Biomedical Research Centre ProtecT: Founded by NIHR. ProtecT and ProMPT would like to acknowledge the support of The University of Cambridge, Cancer Research UK. Cancer Research UK grants (C8197/A10123) and (C8197/A10865) supported the genotyping team. We would also like to acknowledge the support of the National Institute for Health Research which funds the Cambridge Bio-medical Research Centre, Cambridge, UK. We would also like to acknowledge the support of the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant code G0500966/75466) which has funded tissue and urine collections in Cambridge. We are grateful to staff at the Welcome Trust Clinical Research Facility, Addenbrooke's Clinical Research Centre, Cambridge, UK for their help in conducting the ProtecT study. We also acknowledge the support of the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository. The UK Department of Health funded the ProtecT study through the NIHR Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by Department of Health, England; Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466, and The NCRI, UK. The epidemiological data for ProtecT were generated though funding from the Southwest National Health Service Research and Development. DNA extraction in ProtecT was supported by USA Dept of Defense award W81XWH-04-1-0280, Yorkshire Cancer Research and Cancer Research UK. The authors would like to acknowledge the contribution of all members of the ProtecT study research group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health of England. The bio-repository from ProtecT is supported by the NCRI (ProMPT) Prostate Cancer Collaborative and the Cambridge BMRC grant from NIHR. We thank the National Institute for Health Research, Hutchison Whampoa Limited, the Human Research Tissue Bank (Addenbrooke's Hospital), and Cancer Research UK. PROtEuS: PROtEuS was supported financially through grants from the Canadian Cancer Society (13149, 19500, 19864, 19865) and the Cancer Research Society, in partnership with the Ministère de l'enseignement supérieur, de la recherche, de la science et de la technologie du Québec, and the Fonds de la recherche du Québec - Santé.PROtEuS would like to thank its collaborators and research personnel, and the urologists involved in subjects recruitment. We also wish to acknowledge the special contribution made by Ann Hsing and Anand Chokkalingam to the conception of the genetic component of PROtEuS. QLD: The QLD research is supported by The National Health and Medical Research Council (NHMRC) Australia Project Grants (390130, 1009458) and NHMRC Career Development Fellowship and Cancer Australia PdCCRS funding to J Batra. The QLD team would like to acknowledge and sincerely thank the urologists, pathologists, data managers and patient participants who have generously and altruistically supported the QLD cohort. RAPPER: RAPPER is funded by Cancer Research UK (C1094/A11728; C1094/A18504) and Experimental Cancer Medicine Centre funding (C1467/A7286). The RAPPER group thank Rebecca Elliott for project management. SABOR: The SABOR research is supported by NIH/NCI Early Detection Research Network, grant U01 CA0866402-12. Also supported by the Cancer Center Support Grant to the Cancer Therapy and Research Center from the National Cancer Institute (US) P30 CA054174. SCCS: SCCS is funded by NIH grant R01 CA092447, and SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SCPCS: SCPCS is funded by CDC grant S1135-19/19, and SCPCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). SEARCH: SEARCH is funded by a program grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SNP_Prostate_Ghent: The study was supported by the National Cancer Plan, financed by the Federal Office of Health and Social Affairs, Belgium. SPAG: Wessex Medical ResearchHope for Guernsey, MUG, HSSD, MSG, Roger Allsopp STHM2: STHM2 was supported by grants from The Strategic Research Programme on Cancer (StratCan), Karolinska Institutet; the Linné Centre for Breast and Prostate Cancer (CRISP, number 70867901), Karolinska Institutet; The Swedish Research Council (number K2010-70X-20430-04-3) and The Swedish Cancer Society (numbers 11-0287 and 11-0624); Stiftelsen Johanna Hagstrand och Sigfrid Linnérs minne; Swedish Council for Working Life and Social Research (FAS), number 2012-0073STHM2 acknowledges the Karolinska University Laboratory, Aleris Medilab, Unilabs and the Regional Prostate Cancer Registry for performing analyses and help to retrieve data. Carin Cavalli-Björkman and Britt-Marie Hune for their enthusiastic work as research nurses. Astrid Björklund for skilful data management. We wish to thank the BBMRI.se biobank facility at Karolinska Institutet for biobank services. PCPT & SELECT are funded by Public Health Service grants U10CA37429 and 5UM1CA182883 from the National Cancer Institute. SWOG and SELECT thank the site investigators and staff and, most importantly, the participants who donated their time to this trial. TAMPERE: The Tampere (Finland) study was supported by the Academy of Finland (251074), The Finnish Cancer Organisations, Sigrid Juselius Foundation, and the Competitive Research Funding of the Tampere University Hospital (X51003). The PSA screening samples were collected by the Finnish part of ERSPC (European Study of Screening for Prostate Cancer). TAMPERE would like to thank Riina Liikanen, Liisa Maeaettaenen and Kirsi Talala for their work on samples and databases. UGANDA: None reported UKGPCS: UKGPCS would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. UKGPCS should also like to acknowledge the NCRN nurses, data managers, and consultants for their work in the UKGPCS study. UKGPCS would like to thank all urologists and other persons involved in the planning, coordination, and data collection of the study. ULM: The Ulm group received funds from the German Cancer Aid (Deutsche Krebshilfe). WUGS/WUPCS: WUGS would like to thank the following for funding support: The Anthony DeNovi Fund, the Donald C. McGraw Foundation, and the St. Louis Men's Group Against Cancer.
Each tumor sample was cut into three pieces, yielding two end-pieces for cryovials and a middle portion placed in 10% buffered formalin. End pieces were homogenized manually and with a paddle blender (Stomacher). All paraffin-embedded blocks, including formalin-fixed tumor samples and molecular-fixed fallopian tubes, were sectioned and stained with hematoxylin and eosin prior to expert histopathological review to confirm the presence of high grade serous carcinoma. Homogenized end pieces were then flash frozen, and RNA was extracted using the miRNeasy Mini kit. Nanodrop was used to assess quality (260/280) and quantity. Total RNA samples were also QC checked using the Caliper HT RNA HiSens assay. Samples ranging from 60-255ng RNA were re-arrayed into a 96-well plate. 5'-RACE PCR was carried out as described in "The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer" (Zhang et al.). Briefly, this involved first round and nested PCR with TRB (TCR beta chain) and IGH (immunoglobulin heavy chain) gene-specific primers. The indexed libraries were sequenced on the Illumina HiSeq platform with paired-end 250bp reads using v2 chemistry reagents.
This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP). The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.
The goal of this study was to determine whether screening children (2-16 yrs) in pediatric waiting rooms for genetic risk of type 1 diabetes (T1D) could be applied to diverse (by geography, genetic ancestry) communities, and for those at "high genetic risk," if barriers prevent subsequent screening for presence of islet autoantibodies. A total of 3,818 children were recruited from eight general pediatric and specialty clinics across Virginia. Clinical Research Coordinators were stationed at each clinic and obtained informed consent/assent, a brief medical history, and a saliva sample for DNA extraction and determination of their genetic risk using a T1D Genetic Risk Score (T1D GRS). Children were present in the clinic for a "healthy" visit, although children with and without a history of T1D were recruited into the study. Age, sex, self-reported ancestry/race, T1D history, and other medical history information was obtained. DNA was extracted from the saliva samples and genotyping with a T1D-focused array using 74 SNPs (including 26 SNPs in the HLA region) provided data to generate a T1D GRS for each individual. Of the 3,818 children recruited, there was a slight excess of males (1,959, 51.3%), a majority of white and Hispanic/Latino ancestry (82.8%), and 91 (2.4%) with prevalent T1D. A total of 542 (14.2%) had "high T1D genetic risk" (T1D GRS > 5). Although the T1D GRS included non-HLA genetic variants, 80% of those with "high genetic risk" would have been classified using only those SNPs in the HLA region alone. Of children with "high genetic risk" and without pre-existing T1D (n=494), 7.0% (34/494) consented for islet autoantibody screening. Among children with pre-existing T1D (n=91), 52% (n=48) also had a "high genetic risk." The HLA-focused T1D GRS was not significantly associated with age at onset of T1D. Of those at high genetic risk that consented for autoantibody testing (n=34) and completed the blood collection (n=28), two (2/28, 7.1%) tested positive for multiple autoantibodies and were at significant risk of developing T1D. Follow up of 55% of parents/guardians identified 2 (of 2,096, 0.095%) participants who developed T1D, one at "high genetic risk" and one with a first-degree relative with T1D. A major factor in obtaining islet autoantibody testing was concern over SARS-Cov-2 exposure and an independent non-scheduled blood collection.Individual-level data at each SNP (genotyped and imputed) for T1D genetic risk and affiliated data are provided in dbGaP.
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These cookies do not store information that directly identifies you.You can set your browser to block or delete cookies. Please note that if you disable strictly necessary cookies, parts of the website may not function properly.Published on February 6, 2019
The study 'Bladder Cancer Organoids as a Functional System to Model Different Disease Stages and Therapy Response' reports the genomic characterization at the single allele level upon Whole Exome Sequencing of Bladder Cancer (BLCa) Patient Tumor (PT) samples obtained from 18 patients and corresponding Patient Derived Organoids (PDOs), implementing the SPICE pipeline (Ciani Y et al). Our cohort included 21 PTs and 22 PDOs. In this study, we generated a unique biobank resource of BLCa organoids that encompasses a broad spectrum of disease stages. We demonstrated that PDOs retain cancer heterogeneity and mutational burden. Furthermore, we observed that BLCa PDO can have different morphologies which may reflect tumor-specific features. Indeed, a solid morphology may be associated with more advanced tumors, as supported by the high PDO genomic burden and high primary tumor stage. Moreover, with our drug screening pipeline, we demonstrated the clinical relevance and feasibility of using a BLCa PDO-based drug assay for comparing the standard of care (SOC) drugs with compounds not currently in use for BLCa. Response to SOC was highly heterogeneous with approximately 50% of non-muscle invasive bladder cancer and 33% of muscle invasive bladder cancer PDOs showing no or minimal response. The most effective targeted therapy was lapatinib. We used an integrative analysis of drug response profiles with matched PDO genomic analysis to determine enrichment thresholds for candidate markers of therapy resistance and sensitivity. Importantly, by assessing the clinical history of longitudinally sampled cases, the clonal evolution of the disease could be determined and matched with PDO drug response profiles.
The GOLDN study was initiated to assess how genetic factors interact with environmental (diet and drug) interventions to influence blood levels of triglycerides and other atherogenic lipid species and inflammation markers (registered at clinicaltrials.gov, number NCT00083369). The study recruited Caucasian participants primarily from three-generational pedigrees from two NHLBI Family Heart Study (FHS) field centers (Minneapolis, MN and Salt Lake City, UT). Only families with at least two siblings were recruited and only participants who did not take lipid-lowering agents (pharmaceuticals or nutraceuticals) for at least 4 weeks prior to the initial visit were included. The diet intervention followed the protocol of Patsch et al. (1992). The whipping cream (83% fat) meal had 700 Calories/m2 body surface area (2.93 mJ/m2 body surface area): 3% of calories were derived from protein (instant nonfat dry milk) and 14% from carbohydrate (sugar). The ratio of polyunsaturated to saturated fat was 0.06 and the cholesterol content of the average meal was 240 mg. The mixture was blended with ice and flavorings. Blood samples were drawn immediately before (fasting) and at 3.5 and 6 hours after consuming the high-fat meal. The diet intervention was administered at baseline as well as after a 3-week treatment with 160 mg micronized fenofibrate. Participants were given the option to complete one or both (diet and drug) interventions. Of all participants, 1079 had phenotypic data and provided appropriate consent, and underwent whole genome sequencing through the Trans-Omics for Precision Medicine (TOPMed) program. Comprehensive phenotypic and pedigree data for GOLDN study participants are available through dbGaP phs000741.
We propose to undertake, at the McDonnell Genome Institute of Washington University, a collaborative exome sequencing project of ~10,000 samples from a large Finnish population cohort, FINRISK, a participating component of the Sequencing Initiative Suomi (SISu) consortium. Together these sequenced samples will provide a unique resource for identification of infrequent or rare variants with a large impact on cardiovascular and metabolic disorders as well as on a wide range of heritable, disease-related quantitative phenotypes. Our collaborative group has already shown, in exome sequencing studies of smaller Finnish samples, that numerous loss of function variants are dramatically more frequent in Finland compared to other European populations, and that such variants demonstrate strong associations to several disease-related traits. Finland is the largest population isolate in Europe and the enrichment of these variants reflects its rapid growth from a severe population bottleneck about 100 generations ago. Northern and Eastern parts of Finland experienced additional, more recent bottlenecks, and therefore the enrichment of particular high-impact variants in these regions is even more extreme (Stoll et al., 2013, PMID: 23912948). We therefore propose to focus exome sequencing efforts on about 10,000 members of FINRISK who are specifically drawn from these sub-isolate regions. As a very wide range of phenotypes are available from this cohort (including cardiovascular and metabolic disease outcomes obtained from national registries) we hypothesize that the proposed exome sequencing will identify numerous new disease-related associations. Within the National Biobanks of Finland (www.nationalbiobanks.fi) we have DNA and tissue samples from over 200,000 individuals of whom 50,000 have GWAS data; these samples provide an exceptional resource for both imputation from the sequencing studies proposed here, as well as for replication of associations.
