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• Expression profiles and genetic makeup of metastases of a cancer of unknown primary.

  Study EGAS00001004059

• Characterization of a novel MEF2D-BCL9 fusion positive acute lymphoblastic leukemia cell line RNA-Seq derived

  Study EGAS00001006803

• Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer

  Study EGAS00001004055

• NPY methylated ctDNA is a promising biomarker for treatment response monitoring in metastatic colorectal cancer

  Study EGAS00001006820

• Transcriptome analyses of a large cohort of adult B cell acute lymphoblastic leukemia samples

  Study EGAS00001007217

• 20200819_EGA_Qld_Melanoma.biomarkers

  A study looking at Germline and Somatic biomarkers using WES data only

  Dataset EGAD00001006374

• ELLIPSE Prostate Cancer Meta-Analysis and Genotyping

  The ELLIPSE Consortium is an international effort to discover risk loci for prostate cancer. It includes the meta-analysis of existing GWAS data as well as novel GWAS, exome, and iCOGS genotyping. The GWAS meta-analysis includes the following cases and controls from studies of European ancestry: UK GWAS stage 1 (Illumina Infinium HumanHap 550 Array: 1854 cases and 1894 controls), UK GWAS stage 2 (Illumina iSELECT: 3706 cases and 3884 controls), CAPS1 (Affymetrix GeneChip 500K: 474 cases and 482 controls), CAPS2 (Affymetrix GeneChip 5.0K: 1458 cases and 512 controls), BPC3 (Illumina Human610 Illumina: 2068 cases and 3011 controls), PEGASUS (HumanOmni2.5: 4600 cases and 2941 controls). The OMNI 2.5M genotyping was conducted for 977 prostate cancer cases from UKGPCS. The Exome SNP array genotyping was conducted for 4741 subjects from UKGPCS. The iCOGs genotyping was conducted for 10366 subjects which includes the Multiethnic Cohort (n=1648) and UKGPCS (n=8718). Below is a description of each study that contributed to the meta-analysis of men of European ancestry. Information about the studies that contributed to the multiethnic meta-analysis can be found on the associated study page and also in Conti et al (Nature Genetics, PMID:33398198).   UK GWAS Stage 1 (UK1) and Stage 2 (UK2): The UK Genetic Prostate Cancer Study (UKGPCS) was first established in 1993 and is the largest prostate cancer study of its kind in the UK, involving nearly 189 hospitals. We are based at The Institute of Cancer Research in Sutton, Surrey, and collaborate with the Royal Marsden NHS Foundation Trust. Our aim is to find genetic changes which are associated with prostate cancer risk. Our target is to recruit 26,000 gentlemen into the UKGPCS by 2017. Men are eligible to take part if they fit into at least one of the following groups: They have been diagnosed with prostate cancer at 60 years of age or under (up to their 61st birthday). They have been diagnosed with prostate cancer and a first, second or third degree relative where at least one of these men were diagnosed with prostate cancer at 65 years of age or under. They are affected and have 3 or more cases of prostate cancer on one side of their family. They are a prostate cancer patient at the Royal Marsden NHS Foundation Trust. We have to date recruited around 16,000 men on whom we have germline DNA and clinical data at diagnosis. The UK GWAS is based on genotyping of 541,129 SNPs in 1,854 individuals with clinically detected (non-PSA-screened) prostate cancer (cases) and 1,894 controls. 43,671 SNPs showing strong evidence of association in stage 1 were followed up by genotyping a further 3,268 cases and 3,366 controls from UK and Melbourne in stage2. CAPS1 and CAPS2: The CAPS (Cancer of the Prostate in Sweden) study represents a large Swedish population-based cancer study, comprising 3,161 cases and 2,149 controls, recruited between 2001 and 2003. Biopsy confirmed prostate cancer cases were identified and recruited from four out of six regional cancer registries in Sweden, diagnosed between July 2001 and October 2003. Clinical data including TNM stage, Gleason grade and PSA levels at time for diagnosis were retrieved through record linkage to the National Prostate Cancer Registry. Control subjects, who were recruited concurrently with case subjects, were randomly selected from the Swedish Population Registry and matched according to the expected age distribution of cases (groups of 5-year intervals) and geographic region. Whole blood was collected from all individuals for extraction of genomic DNA. A GWAS was conducted in two parts. In the first phase (CAPS1) 498 cases and 502 controls were genotyped, in the second phase 1,483 cases and 519 controls were genotyped. Genotyping was performed using the GeneChip Human Mapping 500K (CAPS1) and 5.0K (CAPS2) Array Set from Affymetrix (Santa Clara, CA). The National Cancer Institute Breast and Prostate Cancer Cohort Consortium, BPC3: BPC3 was a consortium of prospective cohort studies investigating genetic and gene-environmental risk factors for breast and prostate cancer. Each study selected cases and controls for this study as described below. The clinical criteria defining advanced prostate cancer (Gleason = 8 or stage C/D) were either obtained from medical records or cancer registries. The Gleason score source was either surgical specimens (radical prostatectomy or autopsy) or the diagnostic biopsy (needle biopsy or TURP). When multiple Gleason scores were available the surgical value was used. PLCO was removed from the analysis as the samples were included in the Pegasus GWAS described below. In total 2,473 advanced prostate cancer cases and 3,534 controls were included in the analysis following QC. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: ATBC was a randomized, placebo-controlled primary prevention trial to investigate whether α-tocopherol or ß-carotene supplementation reduced the incidence of lung or other cancers in male smokers. Between 1985 and 1988, 29,133 men ages 50 to 69 years were enrolled in the trial from Finland and randomized to supplementation (50 mg α-tocopherol, 20mg ß-carotene, or both) or placebo. Men with a prior history of cancer, other than non-melanoma skin cancer or carcinoma in situ, were excluded from participating. Incident cancer cases are identified through linkage with the Finnish Cancer Registry, which has ~100% ascertainment of cancer cases nationwide. Cases included 249 men diagnosed with advanced prostate cancer (Gleason = 8 or stage C/D) from 1985 to 2003 with DNA available. Controls were 1,271 men selected previously for a GWAS of lung cancer in ATBC without a diagnosis of prostate cancer. CPSII, Cancer Prevention Study II: CPSII is a cohort study started in 1982 to investigate the relationship between dietary, lifestyle and other etiologic factors and cancer mortality. Approximately 1.2 million men and women enrolled in the study from 50 states in the U.S. In 1992, a subset of these participants (n= ~184,000) were enrolled in the CPSII Nutrition Cohort to examine the relationship between dietary and other exposures and cancer incidence. Blood samples were drawn from approximately 39,376 members of the Nutritional Cohort from 1998 to 2001, and buccal cells were collected from 69,467 members from 2001 to 2002. Cancer cases are identified by self-report through follow-up questionnaires followed by verification through medical records and/or linkage to state cancer registries as well as death certificates. A total of 660 advanced prostate cancer cases (Gleason = 8 or stage III/IV) with a source of DNA were identified for this study. Controls were 660 men matched on ethnicity, date of birth, sample collection date and DNA type. EPIC, European Prospective Investigation into Cancer and Nutrition: EPIC is a prospective study designed to investigate both genetic and non-genetic risk factors for different forms of cancer. Study participants were almost all white Europeans. Approximately 500,000 individuals (150,000 men) in EPIC were recruited between 1992 and 2000, from 23 centers in 10 European countries. Overall approximately 400,000 subjects also provided a blood sample at recruitment. The methods of recruitment and details of the study design are described in detail elsewhere. In brief, study participants completed an extensive questionnaire on both dietary and nondietary data at recruitment. The present study includes subjects from advanced prostate cancer cases (Gleason = 8 or stage III/IV) matched to controls based on study center, length of follow-up, age at enrollment (± 6 months), fasting and time of day of blood collection (± 1 hour). The advanced prostate cancer subjects were from 8 of the 10 participating countries: Denmark, Germany, Greece, Italy, the Netherlands, Spain, Sweden and the United Kingdom (UK). France and Norway were not included in the current study because these cohorts only included female subjects. All participants gave written consent for the research and approval for the study was obtained from the ethical review board from all local institutions in the regions where participants had been recruited for the EPIC study. HPFS, Health Professionals Follow-up Study: HPFS began in 1986 and is an ongoing prospective cohort study of 51,529 United States male dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians 40 to 75 years of age. The baseline questionnaire provided information on age, marital status, height and weight, ancestry, medications, smoking history, disease history, physical activity, and diet. At baseline the cohort was 97% white, 2% Asian American, and 1% African American. The median follow-up through 2005 was 10.5 years (range 2-19 years). Self-reported prostate cancer diagnoses were confirmed by obtaining medical and/or pathology records. Prostate cancer deaths are either reported by family members in response to follow-up questionnaires, discovered by the postal system, or the National Death Index. Questionnaires are sent every two years to surviving men to update exposure and medical history. In 1993 and 1994, a blood specimen was collected from 18,018 men without a prior diagnosis of cancer. Prostate cancer cases are matched to controls on birth year (+/-1) and ethnicity. Controls are selected from those who are cancer-free at the time of the case’s diagnosis, and had a prostate-specific antigen test after the date of blood draw.   MEC, Multiethnic Cohort: The Multiethnic Cohort Study is a population-based prospective cohort study that was initiated between 1993 and 1996 and includes subjects from various ethnic groups - African Americans and Latinos primarily from Californian (great Los Angeles area) and Native Hawaiians, Japanese-Americans, and European Americans primarily from Hawaii. State drivers’ license files were the primary sources used to identify study subjects in Hawaii and California. Additionally, in Hawaii, state voter’s registration files were used, and, in California, Health Care Financing Administration (HCFA) files were used to identify additional African American men. All participants (n=215,251) returned a 26-page self-administered baseline questionnaire that obtained general demographic, medical and risk factor information. In the cohort, incident cancer cases are identified annually through cohort linkage to population-based cancer Surveillance, Epidemiology, and End Results (SEER) registries in Hawaii and Los Angeles County as well as to the California State cancer registry. Information on stage and grade of disease are also obtained through the SEER registries. Blood sample collection in the MEC began in 1994 and targeted incident prostate cancer cases and a random sample of study participants to serve as controls for genetic analyses. PHS, Physicians Health Study:PHS was a randomized trial of aspirin and ß carotene for cardiovascular disease and cancer among 22,071 U.S. male physicians ages 40-84 years at randomization; none had a cancer diagnosis at baseline. The original trial ended, but the men are followed. From 1982 to 1984, blood samples were collected from 14,916 physicians before randomization. Participants are sent yearly questionnaires to ascertain endpoints. Whenever a physician reports cancer, we request permission to obtain the medical records, and cancers are confirmed by pathology report. We obtain death certificates and pertinent medical records for all deaths. Follow-up for nonfatal outcomes in PHS is over 97% complete, and for mortality, over 99%. PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial:PLCO is a multicenter, randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer. Between 1993 and 2001, over 150,000 men and women ages 55-74 years were recruited from ten centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, D.C.). Men randomized to the screening arm underwent prostate cancer screening with prostate-specific antigen (PSA) annually for six years and digital rectal exam annually for four years. Blood specimens were collected from participants randomized to the screening arm of the trial, and buccal cell specimens were obtained from participants randomized to the control arm. Cases included 754 men diagnosed with advanced prostate cancer (Gleason = 8 or stage III/IV) from either arm of the trial. Of these cases, 317 were genotyped previously as part of Cancer Genetic Markers of Susceptibility (CGEMS), a GWAS for prostate cancer. Controls included 1,491 men without a diagnosis of prostate cancer from the screening arm of the PLCO trial. All subjects provided informed consent to participate in genetic etiology studies of cancer and other traits. This study was approved by the institutional review boards at the ten centers and the National Cancer Institute. PLCO was removed from the meta-analysis of the BPC3 studies as a consequence of PEGASUS below. PEGASUS, Prostate cancer Genome-wide Association Study of Uncommon Susceptibility loci: Pegasus is a genome-wide association nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. PLCO is a multicenter, randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer. Between 1993 and 2001, over 150,000 men and women ages 55-74 years were recruited from ten centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, D.C.). Men randomized to the screening arm underwent prostate cancer screening with prostate-specific antigen annually for six years and digital rectal exam annually for four years. Blood specimens were collected from participants randomized to the screening arm of the trial, and buccal cell specimens were obtained from participants randomized to the control arm. Cases included 4,598 men of European ancestry diagnosed with prostate cancer from either arm of the trial and controls included 2,941 men of European ancestry without a diagnosis of cancer from the screening arm, matched on age and year of randomization. All subjects provided informed consent, and the study approved by the institutional review board at the National Cancer Institute. Funding:This work was supported by the GAME-ON U19 initiative for prostate cancer (ELLIPSE): U19 CA148537. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233, U01-CA98710, U01-CA98216, and U01-CA98758, and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). The ATBC study and PEGASUS 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 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. CAPS: The Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden was supported by the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant: K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant: 09-0677), the Hedlund Foundation, the Söderberg Foundation, the Enqvist Foundation, ALF funds from the Stockholm County Council. Stiftelsen Johanna Hagstrand och Sigfrid Linnér’s Minne, Karlsson’s Fund for urological and surgical research. We thank and acknowledge all of the participants in the Stockholm-1 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 skillful work with the databases. KI Biobank is acknowledged for handling the samples and for DNA extraction. Hans Wallinder at Aleris Medilab and Sven Gustafsson at Karolinska University Laboratory are thanked for their good cooperation in providing historical laboratory results. UKGPCS would like to acknowledge the NCRN nurses and Consultants for their work in the UKGPCS study. We thank all the patients who took part in this study. This work was supported by Cancer Research UK (grants: C5047/A7357, C1287/A10118, C1287/A5260, C5047/A3354, C5047/A10692, C16913/A6135 and C16913/A6835). We would also like to thank the following for funding support: Prostate Research Campaign UK (now Prostate Cancer UK), The Institute of Cancer Research and The Everyman Campaign, 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. The MEC was supported by NIH grants CA63464, CA54281 and CA098758. 

  Study phs001120

• Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS)

  This pharmacogenomic study focused on the response of patients with MDD to an 8-week course of treatment with citalopram or escitalopram. Briefly, clinical assessments and research assessments were performed at each study visit as summarized in Table 1. Many patients continued on antidepressant medication after the 8 week study. Table 1: Study timeline and patient contacts. Week Consent/Med Hx Write Rx SI Qx SCID HRS-D17 QIDSC16 CGI-I 0 SC RC RC SC SC SC 4 RC RC SC SC RC 8 RC RC SC SC RC HRS-D17=Hamilton Rating Scale for Depression, QIDS-C16=Quick Inventory of Depressive Symptomatology, CGI-I=Clinical Global Impression-Improvement, SCID=Structured Clinical Interview for DSM-IV, SC=Study Coordinator, RC=Research Clinician. Enrollment and baseline assessment. Upon initial intake, the Study Coordinator (SC) obtained informed consent as well as clinical and demographic information, including history of bone marrow or liver transplant or blood transfusion within the previous 6 weeks, and prior history of treatment during the current major depressive episode. The SC completed the Structured Clinical Interview for DSM-IV (SCID), the HRS-D17 (17-item Hamilton Rating Scale for Depression) and the QIDS-C16 (Quick Inventory of Depressive Symptomatology) and reviewed the inclusion/exclusion criteria. After review with the Research Clinician (RC) and when appropriate, after a negative pregnancy test, the SC invited the subject to participate in the study if entry criteria were met. If the subject agreed, he/she received treatment according to the study protocol. Treatment schedule. Participants selected for inclusion in the study were seen at weeks 0, 4, and 8. The appropriate treatment antidepressant (citalopram or escitalopram) was determined following discussion between the patient and RC concerning medical, financial, and insurance considerations. The study medication citalopram was given in tablet or liquid form, depending on the patient's need. A fixed-flexible dose schedule was employed with the possibility of a dose escalation. In particular, the initial dose of citalopram was 20 mg and escitalopram was 10 mg. This dose was increased to 40 mg and 20 mg, respectively, after 4 weeks if the subject had a score of >/= 6 on the QIDS-C16 and the RC concluded that the subject could tolerate the increase. If necessary, dose was reduced at the discretion of the RC. The importance of medication compliance was discussed with the subject, and subjects were asked to bring in the medication at each visit for the purpose of counting remaining pills to assess compliance. Participants may have had an abbreviated course of therapy if they were clearly intolerant of the drug or failed to respond to a 40 mg dose of citalopram or a 20 mg dose of escitalopram. They then received standard treatment from a primary physician or psychiatrist with different medications and/or therapeutic modalities (e.g. psychotherapy). Special attention was given to subjects with suicidal ideation. Those subjects were offered additional appointments as needed to ensure their safety. Participants were also contacted by telephone at week 1 and week 2 by the Clinical Nurse Specialist (CNS) or other study personnel to ensure medication compliance and patient safety. The CNS was supervised by the study psychiatrist and principal investigator and deferred to the physician's judgment as needed. The SC was trained to notify the RC at the time of the clinical visits or the phone interviews if the subject endorsed any suicidal ideation or plans. For those subjects who were unable to attend the follow-up visits as scheduled, the patient was contacted by phone to complete the HRS-D17/QIDS-C16. The participant was also asked to return to the clinic to complete a final blood draw for the study. Adjunctive and concurrent medications. Adjunctive treatments were those used to manage transient associated symptoms (e.g., insomnia) or transient or longer-term medication side effects (e.g., sexual dysfunction). Adjunctive treatments that were not used to treat depression were allowed during the study. However, drugs in the exclusion criteria for this study were not used as adjunctive therapies. Subjects were allowed to participate in the study while receiving concurrent medications for general medical conditions as long as there was no contraindication to use while taking citalopram or escitalopram. Drug efficacy phenotype evaluation. The change in QIDS-C16 score and change in HRS-D17 score were used as the major research outcome measures to assess drug response. At each clinical research visit, the RC also completed the Clinician Global Impression of Improvement (CGI-I) scale. For the primary genome-wide association analyses, dichotomous outcome variables, remission and response, were defined based on the QIDS-C16 last visit score. Remission was defined as a QIDS-C16 score of 5 or less, while response was defined as at least a 50% reduction in the QIDS-C16 score from baseline. Specimen collection. Specimen collections were obtained by the General Clinical Research Center (GCRC) at St. Mary's Hospital (SMH). Subjects had blood drawn on an outpatient basis at GCRC-SMH on three separate occasions - baseline (0), week 4 and week 8 visits. Prior to sample collection, date and time of last dose of study medication was gathered at the 4 and 8 week visits. For those patients who were unable to complete the regularly scheduled visits, a dismissal blood draw was requested. GCRC then shipped samples to Mayo Clinic's Biospecimens Accessioning and Processing Lab. Genotyping and biomarker assays. DNA from 529 patients was genotyped by the RIKEN Center for Genomic Medicine (Yokohama, Japan) using Illumina Human610-Quad BeadChips (Illumina, San Diego, CA). The study also included the determination of plasma drug levels at weeks 4 and 8, and metabolite levels at baseline and weeks 4 and 8 for a subset of subjects. The primary genome-wide association study based on these data, which includes a summary of the protocol, subject description, selection of subjects for genetic analyses, and definitions of clinical outcomes, was published in the Pharmacogenomics Journal (Ji et al., 2012).

  Study phs000670

• CIDR: Collaborative Study on the Genetics of Alcoholism Case Control Study

  This is a case-control study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This sample has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results are included on a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3 (See Porjesz et al., 2005; Porjesz and Rangaswamy, 2007 for reviews). A brief description of COGA is in Edenberg, H. J. (2002) The Collaborative Study on the Genetics of Alcoholism: an update. Alcohol Res Health 26, 214-218., Bierut, LJ, NL Saccone, JP Rice, A Goate, T Foroud, HJ Edenberg, L Almasy, PM Conneally, R Crowe, V Hesselbrock, T-K Li, JI Nurnberger, Jr, B Porjesz, MA Schuckit, J Tischfield, H Begleiter, and T Reich (2002) Defining alcohol-related phenotypes in humans: The Collaborative Study on the Genetics of Alcoholism. Alcohol Res Health 26, 208-213. Edenberg HJ and Foroud T (2006) The genetics of alcoholism: identifying specific genes through family studies. Addiction Biology 11, 386-396. This case-control sample of biologically unrelated individuals was drawn from COGA subjects. All cases meet DSM-IV criteria for alcohol dependence. Controls are individuals who have consumed alcohol, but did not meet any definition of alcohol dependence or alcohol abuse, nor did they meet any DSM-IIIR or DSM-IV definition of abuse or dependence for other drugs (except nicotine). All cases and controls have undergone identical clinical assessments. Many individuals in this case-control sample have not previously been genotyped. The Collaborative Study on the Genetics of Alcoholism (COGA) has four Co-Principal Investigators: B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut. COGA includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-Investigators are: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice); University of California at San Diego (M. Schuckit); Howard University (R. Taylor); Rutgers University (J. Tischfield); Southwest Foundation (L. Almasy). Q. Max Guo serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Institute on Alcohol Abuse and Alcoholism, the NIH GEI (U01HG004438),and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). COGA has over 250 publications listed at www.niaaagenetics.org

  Study phs000125

• Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer's disease and Longitudinal follow-up of Genotype-Phenotype Associations in Alzheimer's disease and Neuroimaging component of Genotype-Phenotype Associations in Alzheimer's disease

  GenADA is a multi-site collaborative study, involving GlaxoSmithKline Inc and nine medical centres in Canada, to develop a dataset containing 1000 Alzheimer's disease patients and 1000 ethnically-matched controls in order to associate DNA sequence (allelic) variations in candidate genes with Alzheimer's disease phenotypes. The study consists of both retrospective and prospective components, that is, patients with an existing diagnosis of Alzheimer's disease as well as newly diagnosed patients were enrolled in the study. Thus, clinical data was retrospectively or prospectively obtained on Day 1 of entry into GenADA. Where possible, biological relatives with Alzheimer's (up to third degree relationship such as cousins) and unaffected siblings of AD cases were also recruited. Note that recruitment numbers for biological relatives were lower than expected and genotypic data has not been submitted to dbGap for these subjects. The purpose of this study is: To identify DNA sequence variations (genotype) in candidate genes that are associated with the clinical symptoms and behavioural features of Alzheimer's disease (phenotype), which differ between study participants with and without the disease. To identify other genotype-phenotype associations in cognitively impaired study participants such as age of onset, family history, rate of cognitive decline, patterns of behavioural/psychiatric non-cognitive symptoms factors, response to treatment co-morbid conditions, and risks/exposure. The final subject recruitment for this study included 875 Alzheimer's disease patients, 850 ethnically-matched controls, and 37 family members. GenADA LONG is a longitudinal assessment to the original GenADA study. Eligible subjects were recruited from five of the nine memory clinics that participated in the GenADA study. Mild to moderate AD participants, a matched subset of controls, and biological related siblings (both affected and unaffected) or other blood relatives affected with AD, were initially examined a minimum of 12 months from recruitment into the original GenADA study, then at two further intervals of 12 and 18 months after time of entry into GenADA LONG. This enables an evaluation of the disease progression in AD patients and a determination of whether controls show evidence of cognitive decline. The overall goal of this extension study is to identify genetic differences and environmental influences that modulate the age of onset of the disease, the course of the disease, and/or biomarkers for neurodegenerative processes. Three of the five memory clinics that participated in the GenADA LONG study recruited eligible patients into GenADA Imaging. A concurrent neuroimaging sub-study was conducted at three of the five memory clinics participating in GenADA LONG. Eligible AD cases with mild to moderate AD, who were recruited into the original GenADA study and participated in the GenADA LONG extension study, were enrolled. Additionally, controls that showed signs of cognitive decline, as part of the assessment in GenADA LONG, were imaged at baseline, 12 and 18 month scanning intervals. The objective of this study is to find genes that: affect changes in AD brain volume measure by magnetic resonance in order to investigate how well change in brain volume predicts other key clinical measures in AD, such as neurodegenerative scales; that correlate changes in brain volume for other genotype-phenotype associations in cognitively impaired study participants; and that correlate with other clinically applicable magnetic resonance measures of pathology that can be conducted at the same time as structural volume measures, and are complementary to the volume measures. The ultimate aim of this research is to obtain a better understanding and definition of Alzheimer's Disease in order to develop new improved medicines.

  Study phs000219

• Bogalusa Heart Study (BHS-BioLINCC)

  Objectives: To investigate the early natural history of cardiovascular disease in a cohort of children and young adults in a biracial, semirural community.Background: The Bogalusa Heart Study has been a long-term epidemiologic study. The investigators have identified and followed black and white participants for nearly 40 years, and have described the incidence and prevalence of biologic and behavioral cardiovascular disease risk factors from childhood through adulthood. Their participation has enabled the study to not only document differences between males and females, but also between blacks and whites. The results from the Bogalusa Heart Study have clearly documented that the genesis of atherosclerosis has its basis in childhood, and that prevention can and must begin at the early ages.The Bogalusa Heart Study had been funded over the years by the Specialized Centers of Research (SCOR) Program. The SCOR program was initiated by NHLBI in 1970 to expedite the development and application of new knowledge essential for improved diagnosis, treatment, and prevention of arteriosclerosis, hypertension, pulmonary disease, and thrombosis. In 1984 a Demonstration and Education Component was added to the parent SCOR of the Bogalusa Heart Study in order to translate the experience gained in epidemiological studies into an intervention study designed to retard the development of cardiovascular risk factors in children. Beginning in 1997, the study was supported by the cooperative agreement mechanism. Participants: The Bogalusa dataset includes 11,796 participants that attended at least one of seven cross-sectional pediatric exams and/or the 1995-96 adult examination. Subjects ranged in age from 3 to 20 years at the pediatric exams and 20-37 at the time of the adult exam. Approximately 6,000 have more than one examination constituting a dynamic cohort. Design: The initial survey in 1973-1974 was restricted to children ages 2 1/2 to 14. A physical examination was conducted and information was collected on anthropometric data, hemoglobin, blood pressure, serum lipids, and health history. Over 3,500 children participated. The second cross-sectional survey of 1976-1977 and subsequent surveys expanded the eligible population to include all children ages 5-17 years. The second survey of over 4,000 children also included information on salt intake, smoking, health beliefs, and attitudes, and for girls ages 8-17, menstrual history and oral contraceptive use. The third survey of over 3,500 participants in 1978-1979 also collected anthropometric measurements on skinfold thickness and two measurements of heart rate. The fourth survey of over 3,300 participants in 1981-1982 added data on alcohol use, Type A behavior, peer networks and dieting habits.The Bogalusa Heart Study continued to use a cross-sectional and longitudinal design with the general cross-sectional survey of approximately 3,700 Bogalusa children ages five to seventeen in 1988-1989 in the sixth screen and additional longitudinal studies to recall children in defined subgroups for more intensive evaluation. Half of the 12,000 participants screened since 1973 had been studied three or more times. The Post High School Study examined young adults ages 21 through 30 who previously were examined as children ages five through fourteen in the first Bogalusa Heart Study screening in 1973-1974. The population included approximately 4,603 young adults originally screened and any other children or adolescents examined for the first time in any subsequent surveys. The cardiovascular phenotypes include obesity, blood pressure, lipids, lipoproteins, apoproteins, homocysteine, glucose-insulin, fibrinogen, plasminogen activator inhibitor-1 and von Willebrand Factor. Environmental risk factors consist of sociodemographic characteristics, tobacco and alcohol use, oral contraception, physical activity, cognitive and physical function, and quality of sleep and diet. Subclinical morbidity includes echo-Doppler measurements of cardiac-carotid structure and function.

  Study phs004173

• How to use EGA Webin?

  EGA Webin EGA Webin serves as a platform for registering metadata for array based submissions, large scale sequence submission as well as for legacy EGA submission accounts (ega-box-XXXX). For large scale submitters of sequence data you have also the option to submit metadata via XMLS programmatic submission, while new submitters are advised to utilise the Submitter Portal for their submissions. You can request a legacy EGA submission account (ega-box-XXXX) by populating this form. Please, allow two business days for our Helpdesk team to contact you after populating this form. WEBIN actions: Register metadata for a sequence submission Register study, samples, experiments, runs, DAC, policy and dataset/s after file upload. Register components for your array-based metadata submission Register study, samples, DAC or policy before uploading files. Edit existing submission metadata Change or update previously submitted metadata. Register metadata for a sequence submission Ensure that all sequence files have been encrypted before uploading them to your submission account using the EgaCryptor. Go to the EGA Webin and log in using your submission account name (ega-box-XXX) and password. Register components of your metadata submission Study Samples Data Access Committee (DAC) Data access policy Dataset For array-base submissions: Study, Samples, Data Access Committee (DAC) and Data access policy may all be registered BEFORE file upload and dataset registration through the array-base template. Register your Study Go to the “Studies (Projects)” box Click on “Register Study” and fill in the information related to your study. Click on “Submit”, this will save the information and generate an EGA study ID. To use the study accession number in a publication, the study has to be previously released on the EGA website, we suggest the following format: "Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGASXXXXXXXXXXX.Further information about EGA can be found on https://ega-archive.org and “The European Genome-phenome Archive in 202 "(10.1093/nar/gkab1059)" Register your Samples Go to the “Samples” box Click on “Register Samples” Select “Download spreadsheet to register samples” and customise your template, there is a default EGA template (EGA default checklist) but more attributes can be added if required. For the EGA default checklist, there are mandatory,recommended and optional attributes. As well custom fields which can be added if required. Mandatory attributes Field Name Description tax_id Taxonomy ID of the organism as in the NCBI Taxonomy database. Entries in the NCBI Taxonomy database have integer taxon IDs. See our tips for sample taxonomy here scientific_name Scientific name of the organism as in the NCBI Taxonomy database. Scientific names typically follow the binomial nomenclature. For example, the scientific name for humans is Homo sapiens. sample_alias Unique name of the sample. If not selected system will auto generate an unique alias sample_title Title of the sample sample_description Description of the sample phenotype *** Where possible, please use the Experimental Factor Ontology (EFO) to describe your phenotypes. Recommended attributes Field Name Description subject_id Identifier for the subject where the sample has been derived from gender * Sex Optional attributes Field Name Description sex sex of the organism from which the sample was obtained disease_site Affected organ sample type Affected organ donor_id ** Identifier of the donor where the sample has been derived from *Gender should be described as 'male', 'female' or 'unknown'. If 'unknown' due to a known sex chromosome aneuploidy, please create a user defined attribute called 'Sex chromosome karyotype' and add the appropriate value, for example, 'XXY'. **Donor id (Subject id) should be a de-identified subject handle. If unknown, please add 'unknown' to the field. ***Phenotypes should, where possible, be an Experimental Factor Ontology accession. If a term cannot be found to describe your phenotype please use free text. All sample phenotypes considered important for further analysis of the data should be provided (for example, tumour type), additional phenotype attributes can be created by defining your own attributes; use the notion 'phenotype2', 'phenotype3', etc. After you have customised the fields for the sample submission, download the template and fill in the information. Example of the sample template: Finally upload the sample template to get the EGA accession IDs for the samples. Register your Data Access Committee (DAC) Further information on the role of your DAC Go to the “Data Access” box Click on “Register Dacs” Input the information about the DAC and register at least one main DAC contact. Register your Data Access Policy Your Data Access Policy provides the terms and conditions of data use, this is also referred to as the Data Access Agreement (DAA). Completion of a DAA by the applicant/s should form part of the application process to the Data Access Committee (DAC). Go to the “Data Access” box Click on “Register Policies” Select the DAC to which this policy will be linked to and fill in the policy information. Submitting your Runs and Analyses This section is only for sequence data submission, for array-based submission it can be skipped. Please refer to our Submitting array based metadata Runs Registration Go to the “Raw Reads (Experiments and Runs)” box Click on “Submit Reads” Select “Download spreadsheet template for Read submission” Select the template corresponding to your submission type For the templates you have the option to customise the optional fields. To check their description click on “Show Description “ Download the template and fill in the required information. Example of the runs template: We recommend that Fastq, BAM, and CRAM read files are submitted using Webin-CLI When using this interface instead of Webin-CLI, raw sequences must be uploaded in one of the supported data formats before they can be submitted. The files can be uploaded using FTP or Aspera. The study and the sequenced samples must be pre-registered before the raw reads are submitted. Please note that each individual study and sample should be registered only once. You will be asked to provide information about the sequencing libraries and instruments. Submitting your Dataset This section is only for sequence data submissions, for array based submissions it can be skipped. Please refer to our Submitting array based metadata The dataset describes the data files, defined by the run (EGARXXXXXXXXXXX) and analysis (EGAZXXXXXXXXXXX) accessions that make up the dataset and links the collection of data files to a specified Data Access Committee and Data Access Policy. As a result, you must have registered your Reads and experiments, Data Access Committee (DAC) and Data access policy before submitting your Dataset. Please consider the number of datasets that your submission consists of, for example, a case control study is likely to consist of at least two datasets. In addition, we suggest that multiple datasets should be described for studies using the same samples but different sequence technologies. Please contact EGA Helpdesk for further assistance. Go to the “Data Access” box Click on “Register Dataset” Select the Data Access Committee (DAC) and Data access policy Register your dataset After submitting your dataset you should contact the EGA Helpdesk to provide a release date for your dataset. Datasets are automatically held (i.e. not released) unless they are affiliated to a study that has already been released. Edit/update existing submission metadata Go to the “Report” section of the object you would like to edit. Locate the object and click on the arrow under action. An option menu will be displayed. Objects can be edited through their XML or with the WEBIN menu. After an object has been edited, changes would be available on the website until the submission is released again. Please contact the EGA Helpdesk if you require further assistance.

  Documentation submission/metadata/submission/EGA_webin

• How to upload GPG files

  Uploading files Users that holds an ega-box-XXX account can upload files using either INBOX or FTP. Users who have a Submitter role associated with their email will only be able to upload files using INBOX. Before uploading your files please make sure that any files that will be uploaded to EGA do not use special characters in their naming convention such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &. This can cause issues with the archiving process, leading to problems for end users. The EGA is a shared, public service with limited storage. In order to manage the available resources, we enforce a limit of 10Tb per submission account at any one time. Please do not exceed this limit. INBOX FTP The FTP is only compatible with files encrypted using the EGACryptor tool Before uploading Once your submission files have been prepared using the EGAryptor, the resulting encrypted files and associated md5sum files can be uploaded to your submission account using Aspera or FTP. The EGA is a shared, public service with limited resources. In order to manage the available resources, EGA submission boxes should not exceed 8Tb in size, and cannot exceed 12Tb. If you are approaching this limit please contact contact EGA Helpdesk so that we can advise on how to register the associated metadata and trigger the archiving of files, so that you can continue with your submission. If we note that your submission account increases above 10Tb on a consistent base your password will be changed until metadata is associated. Aspera Download Aspera Using Aspera FTP FTP windows FTP Linux / Unix FTP client (Filezilla) FTP and TLS Troubleshooting Troubleshooting Aspera Download Aspera is a commercial file transfer protocol that may provide faster transfer speeds than ftp especially over longer distances. The Aspera ascp command line client. Please select Aspera Connect. The ascp command line client is distributed as part of the aspera connect highperformance transfer browser plugin and is free to use, without registration. The minimum required version of the IBM Aspera Cli is V4. Further instructions. Using the Aspera ascp command line program The location of the ascp program in the filesystem: Mac: on the desktop go cd /Applications/Aspera\ Connect.app/Contents/Resources/ there you'll see the command line utilities where you're going to use ascp. Windows: the downloaded files are a bit hidden. For instance, in Windows 7 the ascp.exe is located in the users home directory in: AppData\Local\Programs\Aspera\Aspera Connect\bin\ascp.exe Linux: should be in your user's home directory, cd /home/username/.aspera/connect/bin/ there you'll see the command line utilities where you're going to use ascp. Your command should look similar to this: ascp -P33001 -O33001 -QT -l300M -L- /path/file ega-box-N@fasp.ega.ebi.ac.uk:/path If you wish to upload several files without being requested the password, please use the below command : ASPERA_SCP_PASS=ega-box-password ascp -P33001 -O33001 -QT -l300M /path/file ega-box-N@fasp.ega.ebi.ac.uk:/path/ Explanation of parameters l300M option sets the upload speed limit to 30MB/s. You may wish to lower this value to increase the reliability of the transfer. L option is for printing logs out while transferring files to upload can be a file mask (e.g. '/homes/submitter/*.srf) or a list of files. ega-box-N is your submission account login. Add k2 switch for transfer restarts Check the command line transfer usage for more configuration details. Using FTP to upload your prepared files Use your preferred ftp client. For example, lftp is a popular choice for Linux and Mac users. Use binary mode for file transfers. Use ftp.ega.ebi.ac.uk as the target host. Login with your ega-box username and password. Upload files to your private ega-box upload area. Depending on your network setting you might wish to start FTP in passive or active mode. Using default FTP command line client in Windows Start the command line interpreter: press WinR, type cmd, hit enter Enter ftp ftp.ega.ebi.ac.uk Enter your submission username Enter your submission password Type binary to enter binary mode for transfer To see a list of available ftp commands type help. Type ls command to check the content of your submission account. Type prompt to switch off confirmation for each file uploaded. Use mput command to upload files: mput *.bam* Use bye command to exit the ftp client. Use exit command to exit the command line interpreter. Using default FTP command line client in Linux / Unix Open a terminal and type ftp ftp.ega.ebi.ac.uk Enter your submission username Enter your submission password Type binary to enter binary mode for transfer To see a list of available ftp commands type help. Type ls command to check the content of your submission account. Type prompt to switch off confirmation for each file uploaded. Use mput command to upload files: mput *.bam* Use bye command to exit the ftp client. Using FTP client FileZilla We recommend the use of FileZilla, a free FTP client . FileZilla is open source software distributed free of charge under the terms of the GNU General Public License. Use the following connection details (File - Site Manager) and add yoursubmission account username and password: Using FTP client FileZilla Select the files you wish to upload and then select upload: Using FTP client Filezilla Using LFTP with TLS We recommend the following to force the use of a secure connection. lftp > set ftp:ssl-force yes We also recommend setting the following for not encrypting the bulk data itself for performance reasons (theauthentication will still be encrypted): lftp > ftp:ssl-protect-data no In order to verify the certificate,the recommended way would be to use the CA certificates from your machine. To do that use this command in lftp adjusting the path to your ca-certificates location. lftp > ssl:ca-file "/etc/ssl/certs/ca-certificates.crt" If that is not possible or certificates are old and you can't update them, you can download the certificates needed from Quo Vadis Digital Repository The two certificates to download in PEM format are: QuoVadis Root CA2 G3 QuoVadis EV SSL ICA G3 Then you can concatenate them in a file one after the other and save it as lftp-certificates.pem Once this is done you have to point the ssl:ca-file variable to the path lftp > set ssl:ca-file "/path/to/lftp-certificates.pem" Also note that you can save this configuration at ~/.lftp/rc Another option is to download the certificates and add them to the ca-certificates of your machine. For example: In RHEL7 and cenots and others box the process to add the certificates globally is: Download the two certificates (in PEM or DER format, doesn't matter) and save them to "/etc/pki/ca-trust/source/anchors/" Run "update-ca-trust extract" Another less secure option is to turn off certificate verification with the following command: lftp > set ssl:verify-certificate false Troubleshooting If you are having problems with Aspera connection timeouts, it can be down to either one of the following. Transfers cannot start the connection fails instantly. Ensure that TCP traffic on port 33001 is allowed (open) for outbound connections through your computer's firewall and network's firewall. The connection is made, transfers are started, but 0 bytes (0%) are uploaded for each file. Ensure that UDP traffic on port 33001 is allowed (open) for outbound connections through your computer's firewall and network's firewal

  Documentation submission/data/uploading-files/ftp

• Determining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)

  CHD is the leading cause of death in the United States. One of the most common ways to prevent CHD is to take an anti-platelet agent, which lessens platelet aggregation. Two of the most common anti-platelet agents are aspirin and clopidogrel. However, up to 25% to 30% of people do not respond to these medications. Evidence indicates that treatment response may be related to genetics. The purpose of this study is to determine specific gene variants that predict response to aspirin and clopidogrel therapy. This study is part of a larger group of studies called the Pharmacogenomics Research Network (PGRN). Participants are from the Old Order Amish of Lancaster, Pennsylvania. They are well suited for genetic studies because they are a homogenous, closed, founder population. Participants received 300 mg of clopidogrel on the first day, then 75 mg of clopidogrel per day for the next 6 days. On the last day of clopidogrel treatment, participants took a single dose of 324 mg aspirin. Participants underwent platelet function tests before and after clopidogrel alone, and then again after taking clopidogrel plus aspirin. Using the gene variation profiles across the genome, researchers analyzed which variants correspond to treatment response.

  Study phs000391

• The Role of CTCF in the Organization of the Centromeric 11p15 Imprinted Domain Interactome

  Beckwith-Wiedemann Syndrome (BWS) is the most common human imprinting disorder and comprises a spectrum of overgrowth phenotypes. While approximately 35% of BWS cases are caused by isolated loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15, only around 5% of patients develop BWS due to structural alterations to the IC2 domain. In this study, we identify a BWS-causing 7.6 kB familial deletion within the IC2 domain by performing Whole Genome Sequencing (WGS) on patient-derived human fibroblasts. Using a chromatin conformation capture technique, Capture C, on 3 control fibroblast samples, 3 BWS LOM fibroblast samples, and the single familial deletion sample, we investigate how the domain interactome changes in BWS patients. We find that high-strength interactions occur within the IC2 domain between the 5&#8217; end of KCNQ1, KCNQ1 intron 2, and the 5&#8217; end of CDKN1C in the control profile that are largely abrogated in the BWS samples, but some lower frequency contacts between the imprinting control region (ICR), KCNQ1 intron 2, and the 5&#8217; end of CDKN1C are unaffected. We conclude that the strong KCNQ1-CDKN1C interactions are important in maintaining the domain imprint.

  Study phs002408

• Joslin Study on the Genetics of Type 2 Diabetes

  Between 1993 and 2003, families were recruited in the Joslin Study on the Genetics of Type 2 Diabetes for the presence of an autosomal dominant mode of inheritance of diabetes. Recruiting and screening of families occurred through probands who were receiving medical care at the Joslin Clinic (Boston, MA). Screening of families included 1) a proband and at least one sibling with type 2 diabetes, 2) diabetes occurring in at least three generations, 3) diabetes inherited on one side of the prospective family. Probands had to have a diabetes diagnosis between the age range from 10 to 60 years. Demographic data, clinical data, and family history were collected from participating family members, along with blood and urine samples. This study includes genetic and phenotypic data from one family examined in Simeone, Wilkerson, et. al. (NPJ Genomic Medicine 2022, PMID: 35869090). Genotype data for 14 family members and whole genome sequencing data for 6 individuals were generated with the goal of identifying a potential genetic cause of disease in this family. To de-identify this family and protect confidentiality, information on sex in phenotype data and variants identified in X, Y, and MT chromosomes have been removed in compliance with IRB guidelines.

  Study phs002959

• Whole Genome Profiling to Detect Schizophrenia Methylation Markers

  Schizophrenia (SCZ) is a devastating psychiatric disorder. The aim of this study was to detect DNA methylation (5meC) profiles in whole blood associated with SCZ. The sample consisted of schizophrenia cases and controls selected from national population registers in Sweden. We employed MBD protein-based enrichment of the methylated DNA fraction, followed by single end sequencing (50 bp reads) on the SOLiD platform. To improve methylome-wide coverage we used an existing protocol variant, which increases the relative number of fragments from CpG poor regions. To analyze the data, we used an analysis pipeline described elsewhere7, that was designed specifically for MBD-seq and included alignment, quality control (QC) of reads and samples, coverage calculations for the 26,752,702 autosomal CpGs in the reference genome using a non-parametric estimate of the fragment size distribution, an in silico experiment to identify CpGs in loci with alignment problems, a 2-stage adaptive algorithm to combine data from correlated adjacent CpG sites in "blocks", principal component analysis (PCA), association testing, bioinformatics annotation and network analysis. After QC, 1459 subjects with on average 32.4 million high quality reads remained. Association testing was performed on 4.3 million high quality blocks after regressing out possible assay related technical artifacts, sex/age, and unmeasured confounders through the PCA components.

  Study phs000608

• Genome-Wide Assessment of DNA Methylation in Systemic Lupus Erythematosus-Related Autoantibodies

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can have debilitating effects on multiple organ systems. In SLE, the pivotal immunologic disturbance is the formation of autoantibodies directed against nuclear and cellular antigens. These autoantibodies are associated with specific organ manifestations. Our previous work has shown that certain single nucleotide polymorphisms (SNPs) are associated with the production of SLE-related autoantibodies. However, these genetic associations do not completely explain autoantibody development in SLE. Therefore, we examined whether epigenetic factors such as DNA methylation may be associated with the development of SLE-related autoantibodies. In this study, we examined whether differential DNA methylation is associated with anti-dsDNA, anti-SSA/Ro, anti-Smith, and anti-RNP autoantibodies. Using the Illumina HumanMethylation450 Beadchip, over 450,000 DNA methylation sites were characterized in 325 female SLE cases of European descent. Using a multivariable regression analyses, the methylation status of 16 CpG sites in 11 genes was found to be associated with the SLE-related autoantibodies under study. This study shows that epigenetic factors are associated with autoimmune disease phenotypes, and epigenetic studies are a complementary method to genetic association studies for understanding the biologic mechanisms contributing to autoimmune disease.

  Study phs000947

• RNASeq of Plasmacytoid Dendritic Cells in Head and Neck Squamous Cell Cancer Patients

  Plasmacytoid dendritic cells (pDC) are a subset of dendritic cells with unique immunophenotypic properties and functions. While their role in antiviral immunity through production of type I interferons is well-established, their contributions to anti-tumor immunity are less clear. While some evidence demonstrates that pDC in the tumor microenvironment (TME) may drive CD4+ T cell to become Foxp3+ T regulatory cells, little is understood about the relationship of pDC with cytotoxic CD8+ T cell, the key player in antitumor immune responses. In this study, we perform comprehensive immunophenotyping and functional analysis of pDC from the TME and draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC) and identify a novel pDC subset characterized by expression of the TNF receptor superfamily member CD134 (OX40). We show that OX40 expression is expressed on intratumoral pDC in both humans and mice in a tumor-model specific fashion and that this subset of pDC enhances tumor associated-antigen (TAA)-specific CD8+ T cell responses. Through transcriptomic profiling of OX40-expressing pDC from the TME, we further characterize gene signatures unique to this pDC subset that support its role as an important immunostimulatory immune population in the TME.

  Study phs001824

• Pathways Study

  The Pathways Study (NCI R01 CA105274, PI: Kushi), is a prospective cohort study of a diverse population of recently diagnosed breast cancer survivors in KPNC. The aims are to examine the effect on recurrence and survival of 1) lifestyle factors such as diet, physical activity, and use of complementary and alternative therapies and 2) molecular factors such as biomarkers of inflammation and tumor DNA methylation profiles. Recruitment into the cohort was from January 2006 to May 2013. Baseline data collection was by in-person interview (on average two months post-diagnosis), with follow-up via mailed or phone questionnaires at 6, 24, and 72 months and outcomes and comorbidities at 12, 24, 48, 72, and 96 months post-enrollment. The Pathways Study is now funded through May 2021 as a cancer cohort infrastructure grant (U01 CA195565, MPI: Kushi/Ambrosone). The Pathways baseline interview consists of interviewer- and self-administered questionnaires. Interviewer-administered questionnaires collected information including demographics, family health history, pregnancy health history, menstrual history, history of breast care screening procedures, smoking history, hormone use, medication history, and vitamin and mineral use. Self-administered questionnaires collected information on diet, physical activity, CAM use, lymphedema, and psychosocial and quality of life measures.

  Study phs001534

• Identification and Targeting of Inflammatory Macrophage-Fibroblast Crosstalk in Rheumatoid Arthritis

  Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, redirecting them into a state is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions. Reprinted from Kuo, Ding et al., Science Translational Medicine 2019, PMID: 31068444, with permission from American Association for the Advancement of Science.

  Study phs001340

• GATA2 Deficiency

  The aim of this study is to identify somatic mutations that contribute to the progression of GATA2 Deficiency patients from bone marrow failure to myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). We investigated somatic mutations in &gt;100 patients by whole exome and myeloid malignancy targeted array sequencing to identify acquired mutations associated with myeloid malignancies. MDS was the most common diagnosis (~45%), followed by GATA2 Bone Marrow Immunodeficiency Disorder (G2BMID) (~35%). Approximately ten percent of our cohort were unaffected "carrier" family members with no disease manifestations. In contrast, about ten percent had progressed to a proliferative leukemia. There were no correlations with GATA2 mutation, patient age or gender and disease progression or survival. Somatic Recurrent somatic mutations were uncommon in cancer associated genes, and virtually absent in asymptomatic patients. However, mutations in the cohesin gene STAG2 and chromatin remodeling gene ASXL1 were detected in ~20% of patients. Patients with ASXL1 mutations had a lower survival. ASXL1 mutations were ~10-times more prevalent in female patients than males. Other recurrent mutations were in the DNMT3A, BCOR, and SETBP1 genes. There was a conspicuous absence of the most commonly mutated genes associated with myeloid malignancies, including TET2, RUNX, IDH1/2 and splicing factor genes.&nbsp;

  Study phs002311

• Genetic analysis of Hirschsprung disease

  Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5,000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and Congenital Central Hypoventilation syndrome (CCHS). Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described. The goal of the research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families using whole genome mapping and sequencing studies with functional follow-up of candidate genes and variants. We intend to ascertain the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Clinical information is collected to allow investigation of possible genotype - phenotype correlations. The subject population consists of individuals diagnosed with HSCR and their unaffected relatives. Individuals/families are ascertained through support groups, web-based listings of research studies and genetic testing services, an educational study website, and referrals from genetic counselors and physicians. Blood, or tissue, samples are requested from affected individuals and their unaffected relatives.

  Study phs000497

• Creatine in Huntington's Disease (HD) (CREST-E)

  This is a multi-center, randomized, double-blind, placebo-controlled trial of creatine monohydrate involving 553 ambulatory subjects with HD who are not requiring skilled care or institutionalization. Eligible subjects were randomized to receive up to 40 grams daily of creatine monohydrate or matching placebo. Randomization will be followed by a Titration Phase, a Maintenance Phase, an Optional Extended Maintenance Phase, and Washout. During the Titration Phase, which may last up to six months, study drug will be initially escalated in 5-gram increments starting at 5 g/day until the 40 g/day target dose is reached. Should subjects be unable to reach or stay at the maximum dose during the Titration Phase, they will remain on the highest tolerated dose (HTD) for which they have no significant side effects. During the Maintenance Phase, subjects will be followed prospectively and systematically. Subjects completing 36 months of follow-up on study drug will be eligible to continue in the study for an additional twelve months of follow-up in the Extended Maintenance Phase. The primary measure of efficacy is the annualized rate of change in TFC. The primary hypothesis of the study is that chronic treatment of early-stage HD subjects with creatine monohydrate will slow the progressive functional decline of HD.

  Study phs001488

• Single Cell and Tissue Level Functional Genomics Analysis of Astrocyte-Related Mechanisms in Taupathy

  This data is the first part of a larger single cell and tissue level functional genomics analysis of dementias with tau pathology. &nbsp;Cellular resolution will clarify the role of glial genes and pathways in neurodegenerative disease. This includes understanding the role of microglia and astrocytes in neurodegenerative disorders characterized by Tau protein pathology. To achieve a refined view of microglial neuroinflammatory signaling in tau-associated neurodegeneration, we performed a functional genomic analysis that integrated time-course gene expression data from mouse models expressing human mutant MAPT (the tau gene) with single nuclear sequencing data obtained from patients with frontotemporal dementia with Tau protein pathology (Pick&#8217;s disease). This included microglia-specific gene expression data obtained from single nuclear sequencing of postmortem frozen precentral gyrus samples collected from 16 total individuals, including 8 subjects with clinical diagnosis of behavior variant frontotemporal dementia and neuropathological diagnosis of Pick&#8217;s disease (Tau protein pathology) and controls (n=8). Our findings present detailed molecular profiles of disease-associated microglial transitions over the course of tau-associated neurodegeneration. Furthermore, we demonstrate overlap between microglia profiles obtained from precentral gyrus of patients with Pick&#8217;s disease with those up-regulated during the neurodegenerative stage in mice expressing human MAPT mutations.

  Study phs002197