Search Results - EGA European Genome-Phenome Archive

A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on NCIC CTG Trial MA.27 Evaluating Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine.

Source of Patients The source of the patients for this genome-wide case control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma and DCIS in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been ER and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. Case Definition for Musculoskeletal Adverse Events Cases were defined to have had at least one of the following six MSAE): 1. pain - joint, 2. pain - muscle, 3. pain - bone, 4. arthritis, 5. joint - function, 6. musculoskeletal - other. Cases were required to have at least grade 3 toxicity, according to the NCI Common Terminology Criteria for Adverse Events v3.0, or go off treatment for any grade of the six MSAEs; and were required to have had an MSAE within the first two years (i.e., a MSAE occurring after 2 years was not be considered a case). Subjects were excluded from the case group who met the case definition while on celecoxib or in the three months after stopping celecoxib but subjects were allowed to be cases if they developed their first MSAE more than three months after stopping celecoxib. Study Design The design was a nested matched case-control study with two controls selected for each case. Random matching from the potential control group (i.e., risk-set sampling such that controls had at least the same length of followup as the timing of the case event) was done by matching the case on the following factors: 1. treatment arm (exemestane vs. anastrozole, blinded), 2. prior adjuvant chemotherapy (yes vs. no), 3. age at start of treatment (+/- 5 years), 4. Celecoxib allocation (yes vs. no). Attempts were made to exactly match each case with two controls according to the above criteria. If, however, controls could not be exactly matched, "close" matching was used to define a distance between each case and all potential controls in an optimal matching algorithm. Race is a potential confounding factor, and 94% of the MA.27 population is Caucasian, 3% are Black, 1% Asian, 1% American Indian, and 1% are of unknown race. Because there are so few non-Caucasian participants, was restricted to only Caucasians. Following identification of cases and controls, the list was sent to the CALGB Pathology Coordinating Office (PCO) at Ohio State University Medical Center for plating of the samples. Other patient factors that might influence the association of SNP genotypes with a MSAE, either as confounding factors or as effect modifiers, were included as investigational covariates. These include 1. body mass index (BMI), 2. bisphosphonate use, 3. fractures in past 10 years, 4. baseline ECOG performance status, 5. prior hormone replacement therapy, 6. prior adjuvant radiotherapy, and 7. prior taxane treatment. An Honest Broker Process was utilized to ensure patient confidentiality. Genotype Assays and Quality Control A GWAS was performed with the Illumina Human610-Quad at the RIKEN Center for Genomic Medicine. The DNA for all of the samples were adjusted to a concentration of 50 to 100 ng/µL in a final volume of 50 µL. The 96-well plates were designed to have a unique distribution pattern with x duplicates per plate to evaluate genotype concordance. Samples with <98% call rate were removed from analyses. SNPs with ambiguous call will be excluded using the following criteria: 1. low signal intensity of each allele, 2. low cluster separation score, 3. SNP call rate <0.98, 4. SNPs with Hardy Weinberg Equilibrium p-value <0.001 were excluded. X-chromosome SNPs were used to validate female sex and quality control measures were examined across the different submitting centers. For all pairs of subjects, the percentage of matching genotypes were computed to screen for unexpected duplicate samples. All SNPs found to be associated with MSAE were subjected to visual inspection of the cluster plots to verify that the genotype clustering was adequate.

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National Cancer Institute (NCI) TARGET: Therapeutically Applicable Research to Generate Effective Treatments

The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative seeks to accelerate research in novel marker and drug development, along with understanding the molecular basis of pediatric malignancy, through identification of genomic changes associated with the following childhood cancers: Acute Lymphoblastic Leukemia (ALL) - A fast-growing type of blood cancer in which too many immature white blood cells are found in the blood and bone marrow. Acute Myeloid Leukemia (AML), including AML Induction Failure cases (AML-IF) - Another type of blood cancer marked by too many myeloblasts, an alternate type of immature white blood cell, are found in the blood and bone marrow. Upon diagnosis, AML patients without high-risk genetic markers undergo standard chemotherapy regimen, called the primary induction phase, to eliminate most cancer cells and induce a remission state. Clear Cell Sarcoma of the Kidney (CCSK) - A rare type of kidney cancer, in which the inside of the cells looks clear when viewed under a microscope. Clear cell sarcoma can spread from the kidney to other organs, most commonly the bone, but also including the lungs, brain, and soft tissues of the body. Neuroblastoma (NBL) - Cancer of cells of the sympathetic nervous system. Cancer Model Systems (MDLS), including PPTP - MDLS includes acute leukemia cell lines and xenografts with matched primary and/or relapsed tumor information, NBL cell lines and xenografts with matched controls, kidney tumor cell lines, normal brain tissues, and embryonic stem cell lines that were sequenced for some TARGET disease projects. Osteosarcoma (OS) - A cancer of the bone that primarily affects children and adolescents. Rhabdoid Tumor (RT) - A rare, fast-growing cancer that usually forms in the kidney or central nervous system (the brain and spinal cord) but can also form in soft tissues in other areas of the body. Rhabdoid tumors tend to spread quickly, are hard to treat, and have a poor prognosis. Wilms' Tumor (WT) - A cancer of cells in the kidney that can spread to the liver, lung and lymph nodes. More information can be found about each TARGET subproject by following the links on the top of this page. Together these cancers account for the majority of the more than 10,000 childhood cancer cases diagnosed in the United States each year. TARGET has employed a set of advanced and complementary genome analysis technologies, including large scale 2nd and 3rd generation genome sequencing, to strategically characterize alterations in both gene expression and in genomic structure (such as deletions and amplification) that are involved in childhood cancers. The goal of this coordinated effort has been to create a comprehensive genomic and transcriptomic profile of each cancer. Integrated analysis of the TARGET data has identified those genes that are either altered in their expression level or mapped to the chromosome regions of deletion/amplification/translocation, as these genes represent strong candidates for therapeutic targeting. To learn more about the TARGET project, which is now completed, visit the website at https://www.cancer.gov/ccg/research/genome-sequencing/target. TARGET data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the TARGET Publication Pages at the GDC (Please see the "Supplemental Links" section of any TARGET publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original TARGET research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data - gene expression, copy number variation, epigenetics, targeted sequencing), as well as higher level data generated by the GDC. Please see the TARGET Use and Publication Guidelines for updated details on the sharing of any TARGET substudy data, including how to cite TARGET.

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National Cancer Institute Cancer Genome Characterization Initiative (CGCI)

The Office of Cancer Genomics at the National Cancer Institute sponsored a series of studies as part of the Cancer Genome Characterization Initiative (CGCI) to assess novel emerging sequencing technologies in cancer. The CGCI program included comprehensive characterization of the genetic aberrations found in different pediatric and/or adult tumors. CGCI characterized a number of B-cell non-Hodgkin lymphomas (including diffuse large B-cell lymphoma (DLBCL) from patients with and without HIV+ infection, follicular lymphoma (FL), as well as adult and pediatric Burkitt lymphomas), and additional HIV-associated tumors (including DLBCL, lung, and cervical cancers). All data from these projects is available at the NCI Genomic Data Commons. Individual project descriptions are available by disease on the substudy pages (links are included at the top of this page). Brief summaries are as follows: Non-Hodgkin Lymphoma (NHL) - CGCI investigators probed genomic alterations more deeply than had previously been possible by using state-of-the-art RNA sequencing (mRNA-seq) and whole genome shotgun sequencing (WGS) coupled with leading edge bioinformatics, data management and analysis approaches. The project sequenced tumor DNA and/or RNA from 117 NHL tumor samples and 10 cell lines. This included the genomes or exomes of 1 Follicular Lymphoma (FL) and 13 diffuse large B-cell lymphoma (DLBCL) cases, all with matched constitutional DNA sequenced to comparable depths, RNA-sequencing (mRNA-seq) of 92 DLBCL, 12 FL and 8 B-cell NHL cases with other histologies and 10 DLBCL-derived cell lines. The DLBCL cases and cell-lines are from the two major subtypes of DLBCL: germinal center B-cell (GCB) and activated B-cell (ABC). HIV+ Tumor Molecular Characterization Project (HTMCP) - This project was a joint effort of the Office of Cancer Genomics (OCG) and the Office of HIV and AIDS Malignancy (OHAM). Its goals were to characterize HIV-associated cancers (obtained from HIV-infected patients) and compare them to the same types of cancers from patients without HIV infection. Investigators performed 30X genome sequencing of 100 cases of paired tumor and germline DNA, along with transcriptome sequencing in each of 3 types of HIV+ tumors (DLBCL, lung and cervical cancers). These platforms allow discovery of mutations both in coding and non-coding genomic regions, gene expression and genomic alterations (including translocations, insertions and deletions). Comparing tumors of cancer patients both with and without HIV-infection provides insight into the potential function of this virus in certain cancers. Burkitt Lymphoma Genome Sequencing Project (BLGSP) - This project was a collaborative effort between the National Cancer Institute and the Foundation for Burkitt Lymphoma Research to develop a databank of the many alterations found in Burkitt lymphoma (BL), an uncommon type of Non-Hodgkin lymphoma that occurs most often in children and young adults. The goal of the BLGSP was to explore potential genetic changes in patients with BL that could lead to better prevention, detection and treatment of the cancer. The project characterized the alterations of the tumors' genomes (with matched normal as control) and transcriptomes by sequencing the DNA and RNA of each case. Using the data generated, the ultimate goals of the project was to discover the molecular changes that are present in BL patients and then determine how those changes correlate with treatment regimen and outcome. CGCI data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the CGCI Publication Pages at the GDC (Please see the "Supplemental Links" section of any CGCI publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original CGCI research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data), as well as higher level data generated by the GDC. Please see the CGCI Use and Publication Guidelines for updated details on the sharing of any CGCI substudy data, including how to cite CGCI.To learn more about the CGCI studies, please visit the CGCI Program website.

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National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) Consortium Glaucoma Genome-Wide Association Study

This is a case-control study of primary open angle glaucoma (POAG). POAG is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. For this study we have formed a collaborative consortium contributing 2170 POAG cases and 2347 controls with a unified definition of POAG (the NEIGHBOR consortium: NEI Glaucoma Human genetic collaBORation). The case definition has also been harmonized with an additional 976 cases and 1140 controls from the NHGRI supported GENEVA (gene-environment) study of glaucoma (GLAUGEN) (NIH/NHGRI U01HG004728, Pasquale PI). Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases, the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. Cases and controls were also drawn from two clinical trial populations: Advanced Glaucoma Intervention Study (AGIS, NEI U10EY006827, D. Gaasterland PI) and Collaborative Initial Glaucoma Treatment Study (CIGTS, NEI U10 EY009149, P. Lichter PI). The NEIGHBOR consortium has two Co-Principal Investigators: J. Wiggs (Harvard, MEEI), and M. Hauser (Duke). The consortium includes eleven different centers where data collection and analysis take place. The eleven sites and investigators are: Harvard Medical School (Massachusetts Eye and Ear Infirmary) (J. Wiggs, L. Pasquale); Duke University Medical Center (M. Hauser, E. Hauser, R. Allingham, S. Schmidt); University of Michigan (J. Richards, S. Moroi, P. Lichter); University of Miami (M. Pericak-Vance, R. Lee, D. Budenz); Vanderbilt University (J. Haines); University of California San Diego (K. Zhang, R. Weinreb; T. Gaasterland); University of Pittsburgh (J. Schuman, G. Wollstein); University of West Virginia (A. Realini, J. Charlton, S. Zareparsi); Johns Hopkins University (D. Friedman, D. Zack); Stanford University (D. Vollrath, K. Singh), Eye Doctors of Washington (D. Gaasterland). Hemin Chin serves as the NEI Staff Collaborator. This national collaborative study is supported by multiple NIH grants: NEI R01 EY015543 (Allingham); NEI U10 EY006827 (D. Gaasterland); NHLBI R01 HL073389 (E. Hauser); NEI R01 EY13315 (M. Hauser); NEI U10 EY009149 (Lichter); NEI R01 EY015473 (Pasquale); NEI U10 EY012118 (Pericak-Vance); NEI R03 EY015682 (Realini); NEI R01 EY011671 (Richards); NEI R01 EY09580 (Richards); NEI R01 EY013178 (Schuman); NEI R01 EY015872 (Wiggs); NEI R01 EY009847 (Wiggs); NEI R01 EY010886 (Wiggs); NEI R01 EY144428 (Zhang); NEI R01 EY144448 (Zhang); NEI R01 EY18660 (Zhang). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Eye Institute (X01HG005259).

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National Eye Institute (NEI) Ocular Hypertension Treatment Study (OHTS)

The Ocular Hypertension Treatment Study (OHTS) is an National Eye Institute-sponsored multi-center, randomized, prospective treatment trial designed to determine whether lowering intraocular pressure (IOP) in individuals with ocular hypertension delays or prevents the development of primary open angle glaucoma (POAG). A total of 1,636 individuals with ocular hypertension between 40 and 80 years old were enrolled in the study. In addition to ocular hypertension, subjects in the OHTS were required to have normal optic nerve appearance as determined by the OHTS Optic Disc Reading Center and normal and reliable visual field tests at the time of enrollment by the OHTS Visual Field Reading Center. OHTS subjects were randomly assigned to either an observational group which received close observation or a topical medication group which received medication as needed to achieve a 20% reduction in IOP from their baseline levels. Subjects then were examined at regular intervals for optic disc cupping or visual field defects. Other clinical measures were also obtained from OHTS subjects including central corneal thickness (CCT) and intraocular pressure. The primary outcome monitored for the OHTS was the development of glaucoma in one or both eyes as defined by reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG by the masked OHTS Endpoint Committee. The OHTS study design has been reported in detail (Gordon, 1999; PMID: 10326953). The OHTS confirmed that ocular hypertension is a risk factor for developing POAG and showed that lowering IOP reduced the risk for developing POAG (Kass, 2002; PMID: 12049574). The OHTS also demonstrated that thin CCT is a significant risk factor for the development of POAG (Gordon, 2002; PMID: 12049575). Blood samples were also collected from 1,077 OHTS participants for an ancillary genetics study. DNA was prepared from these samples and used in a genome-wide association scan (GWAS) designed to identify genetic factors that control the magnitude of quantitative features of glaucoma (baseline IOP, baseline cup-to-disc ratio, and CCT). Genotypes from the GWAS and these clinical data (IOP, cup-to-disc ratio, and CCT) have been provided to dbGaP.

Study phs000240

Foregut Microbiome in Development of Esophageal Adenocarcinoma

The distal esophagus is an important anatomical area where gastric acid reflux can cause reflux esophagitis (RE), Barrett's esophagus (BE) (intestinal metaplasia), and esophageal adenocarcinoma (EA). The incidence of EA has increased 6-fold in the U.S. since the 1970s, parallel to a significant increase in the prevalence of gastroesophageal reflux diseases (GERD). Although specific host factors might predispose one to disease risk, such a rapid increase in incidence must be predominantly environmental. The cause remains unknown. Our hypothesis is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in the GERD sequence. We will conduct a case control study to characterize the microbiome in every stage of the GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA. Specific Aim 1. To conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence, by a 16S rRNA gene survey. We will analyze samples of the foregut microbiome at three anatomic loci: mouth, distal esophagus, and gastric corpus. Changes of the microbiota in the distal esophagus will be correlated with the phenotypes. Spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Specific Aim 2. To define distal esophageal metagenome and demonstrate its association with GERD sequence, by shotgun metagenomic analysis. We will first classify samples of the metagenome into metagenotypes by between-sample k-mer distance and correlate the metagenotypes with the four phenotypes. Subsequent detailed analyses will include pathway-disease and gene-disease associations. DNA viruses and fungi, if identified, also will be correlated with the phenotypes. A significant association between the foregut microbiome composition and GERD sequence, if demonstrated, will be the first step for eventually testing the causal hypothesis that an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microbial ecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiome through use of antibiotics, probiotics, or prebiotics. Causative therapy for GERD could prevent its progression and reverse the current trend of increasing incidence of EA.

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Genome-Wide Association Study of Celiac Disease

Celiac disease (gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity and mortality. It is caused by sensitivity to the dietary protein gluten, resulting in a chronic enteropathy in the small intestine. Celiac disease is now recognized to be a common disease, with reports that the disease frequency is 1:133 in the United States, similar to European estimates. There is recent evidence to suggest that the incidence of the disease is rising. Occult disease is frequently present with minimal classic symptoms or signs. The ratio of symptomatic to asymptomatic celiac disease is estimated to be 1:7. Some complications of celiac disease include lymphoma, osteoporosis, anemia, miscarriages, seizures, vitamin deficiencies, and co-occurrence of other autoimmune diseases. The only treatment is a gluten-free diet, so that recurrence of symptoms and complications may occur after minor dietary indiscretions. Identifying the underlying genetic causes of celiac disease may allow us to identify susceptible individuals, as well as advance new ways to prevent the disease and to treat it once it occurs. Several genome-wide linkage studies and one genome-wide association study of celiac disease have been conducted. Other than the common locus at HLA, few putative celiac disease loci have been replicated between studies, suggesting that the disease is heterogeneous and complex. A portion of the genetic predisposition can be attributed to HLA, but the etiology is likely due to a number of rare, high penetrant genes (as would be identified in linkage analysis) and to more common, low penetrant genes (as would be identified in association studies). The objective of this study is to identify new loci that increase risk to develop celiac disease. We will capitalize on existing North American resources, including three large collections of celiac cases and controls (Aim 1) and an independent set of celiac cases and their families (Aim 3). We propose a comprehensive multi-stage approach, with the following specific aims. In Aim 1, we will conduct a genome-wide association (GWA) study of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). The GWA will include1900 disease cases and 3400 matched controls, genotyped using the Illumina Human 610-quad chip. Statistical analyses will be performed to test for associations with celiac disease. In Aim 2, we will conduct a combined analysis of our GWA dataset from Aim 1 and a previous GWA dataset to identify additional low-penetrance loci. In Aim 3, we will attempt to replicate significant findings from the GWA study in two independent sample sets. At the conclusion of this study, we expect to have validated a number of SNPs and CNPs from regions in the genome that alter the risk of developing celiac disease. These SNPs may prove useful at both the clinical and research level. The data from the study will be shared with the scientific community.

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A Genome-Wide Association Study in Participants Experiencing Breast Cancer Events in High-Risk Postmenopausal Women Receiving Selective Estrogen Receptor Modulators on NSABP Trials P-1 and P-2. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

The primary aim of this study is to identify genes related to the occurrence of breast events, defined as occurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), in women at high risk of developing breast cancer who have received a Selective Estrogen Receptor Modulator (SERM - tamoxifen or raloxifene) on the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 or P-2 trials. Cases and controls were selected from the tamoxifen arm in the P-1 and from the tamixifen and raloxifene arms in the P-2 trial. For the P-1 trial, cases and controls were required to be 50 years of age or older at time of entry. Cases were females who experienced an invasive breast cancer or DCIS on P-1 or P-2. Controls were females who did not experience an invasive breast cancer or DCIS. A nested matched case-control design was used, with matching on the following factors: 1) trial and treatment arm (P-1 tamoxifen, P-2 tamoxifen, P-2 raloxifene); 2) age at trial entry (when controls could not be exactly matched on age, we incremented the age of matching by +/- 1 year, in sequence until a match was obtained without exceeding +/- 5 years); 5-year predicted breast cancer risk based on the Gail model ( <2.00%, 2.01-3.00, 3.01-5.00, >5.01), 3) history of lobular carcinoma in situ (yes vs. no); 4) history of atypical hyperplasia in breast (yes vs. no); 5) time on study (controls must be on study at least as long as the time to diagnosis of the breast event for the case). Because 94.2% of the participants on P-1 and P-2 treated with tamoxifen or raloxifene were Caucasian, this study was restricted to only Caucasians. Two cases and two controls were randomly chosen as duplicates for quality control of genotype concordance. The DNA samples were plated into 96-well plates, with cases and controls randomly distributed across the plates. A Caucasian parent-child CEPH trio from the HapMap project was included to check for Mendelian transmission of alleles. Genotypes were determined by the RIKEN Center for Genomic Medicine with the Illumina Human610-Quad.

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The Primary Open-Angle Glaucoma Genes and Environment (GLAUGEN) Study

Background Information: Primary open-angle glaucoma (POAG) is an age-related, intraocular pressure (IOP)-dependent progressive optic neuropathy that ultimately leads to irreversible blindness. Vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. Despite the fact that a positive family history of disease is an important risk factor for POAG, conventional linkage and candidate gene approaches have revealed less than 5% of the genetic component of the disease. Furthermore, there is no consensus on environment risk factors for POAG. Elevated IOP is the only modifiable risk factor for POAG; yet, lowering IOP slows, but does not halt the disease process. Study Objectives: The overall goal of our research is to elucidate the pathogenesis of POAG so that cost-effective disease detection and primary prevention strategies can be implemented. The primary aim of the Glaucoma Gene Environment Initiative (GLAUGEN), funded by the Human Genome Research Institute (NHGRI), is to discover genetic loci associated with POAG. The secondary aim of GLAUGEN, funded by NHGRI and the National Eye Institute, is to discover gene environment interactions in POAG. Methods and study populations: For this study, we have assembled cases and controls from three studies: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS) and the Genetic Etiologies of POAG (GEP) project based at Massachusetts Eye and Ear Infirmary (MEEI). This case-control group includes 1057 unrelated cases and 1272 controls. Members of the NHS and HPFS also have repeated environmental exposure data collected prior to a diagnosis of POAG. NHS - The Nurses Health Study started in 1976 under the direction of Dr. Frank E. Speizer. With funding from the NIH, registered nurses from 11 US states were invited to complete a detailed questionnaire regarding lifestyle and health biennially. Initially, 121,000 women responded to the baseline questionnaire. Currently, Dr. Susan Hankinson serves as the program director for the NHS. HPFS - The Health Professionals Follow-up Study began in 1986 under the direction of Drs. Walter Willett and Meir Stampfer. Under the auspices of the NIH, they enlisted 51,529 male health professionals from throughout the US to complete similarly designed biennial questionnaires. Beginning in 1990, questions regarding ocular health were added to biennial questionaires completed by health professionals participating in the NHS and HPFS. This allowed us to formulate (PI: S. Hankinson; NEI) and maintain (PI: L. Pasquale; NEI) a cohort at risk for POAG derived from the respective general cohorts who were under ophthalmic care. We then developed a definition of POAG that allowed us to identify cases from a population that was geographically dispersed. The centerpiece of this definition is the presence of reproducible visual field loss consistent with nerve fiber layer (NFL) dropout (the NFL contains the axons that comprise the optic nerve) on reliable tests. Reproducible visual field loss occurred in the context of anterior segment findings that did not suggest a secondary cause of elevated IOP and posterior segment findings that did not suggest a secondary cause of visual field loss. We selected controls from the cohort at risk for POAG on the basis of age, gender and time period when cases were identified. GEP - The Genetic Etiologies of POAG was initiated in 1996 with funding from the National Eye Institute under the direction of Dr. Janey Wiggs. The purpose of this work was to discover novel genetic loci associated with POAG. In the GEP, cases were derived predominantly from the Glaucoma Service at MEEI. The majority of cases had an examination by a glaucoma specialist and met the definition for POAG used in NHS and HPFS. Cases with only one reliable visual field consistent with NFL dropout were included if there was a cup-disc ratio of 0.7 or more. The majority of controls were patients who presented to the MEEI comprehensive ophthalmology service for routine eye examination or from spouses of MEEI patients with secondary forms of glaucoma. Other controls were identified from regional glaucoma screenings held throughout Massachusetts. Members of GEP have detailed ocular phenotype data but limited information on environmental exposures. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to primary open-angle glaucoma through large-scale genome-wide association studies of three well-characterized cohorts of cases and controls, some in matched pairs. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington.

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Towards a Genomic Understanding of Myeloma

This project was designed to describe genetic abnormalities in primary samples from patients with multiple myeloma by next generation sequencing. We generated sequence data from multiple myeloma (MM) patients analyzing DNA both from tumor cells (purified from bone marrow using CD138 selection as a marker of plasma cells) and from normal peripheral blood cells (either whole blood or Ficoll-purified mononuclear cells). Using massively parallel sequencing technology (Illumina GA-2 or HiSeq)), we performed whole-genome sequencing (WGS) and/or whole-exome sequencing (WES). The initial set currently deposited contains data from 38 MM patients (23 patients surveyed by WGS and 16 patients by WES, with one patient analyzed by both approaches). Genomes were sampled to high depth, obtaining an average of 33X coverage and 104X coverage for WGS and WES tumors, respectively. The normal samples had similar coverage. Our goal is to help researchers understand the complex genetic landscape of multiple myeloma and provide a resource for the generation of biological hypotheses.

Study phs000348

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