3613 results for "*geneti*"

in 74.46 milliseconds.

• DNA Methylation Analysis of Prostate Cancer Cell Lines and Tissues Using Next Generation Sequencing

  Aberrant DNA methylation changes are known to occur during prostate cancer progression beginning with precursor lesions. Utilizing fifty nanograms of genomic DNA in Methylplex-Next Generation Sequencing (M-NGS) we mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2). Peaks were located from mapped reads obtained in each sequencing run using a Hidden Markov Model (HMM)-based algorithm previously used for Chip-Seq data analysis(http://www.sph.umich.edu/csg/qin/HPeak). The total methylation events in intergenic/intronic regions between benign adjacent and cancer tissues were comparable. Promoter CGI methylation gradually increased from -12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues and approximately 20% of all CpG islands (CGIs) (68,508) were methylated in tissues. We observed distinct patterns in promoter methylation around transcription start sites, where methylation occurred directly on the CGIs, flanking regions and on CGI sparse promoters. Among the 6,691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer specific and several previously studied targets were among them. A novel cancer specific DMR in WFDC2 promoter showed 77% methylation in cancer (17/22), 100% methylation in transformed prostate cell lines (6/6), none in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested a role for DNA methylation in alternate transcription start site utilization. While methylated promoters containing CGIs had mutually exclusive H3K4me3 modification, the histone mark was absent in CGI sparse promoters. Finally, we observed difference in methylation of LINE-1 elements between transcription factor ERG positive and negative cancers. The comprehensive methylome map presented here will further our understanding of epigenetic regulation of the prostate cancer genome. Overall Design: We mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). For replicate analysis in cell lines, a total of 4 runs were completed for PrEC prostate normal cell line, and 5 runs were completed for LNCaP prostate cancer cell line. For tissue samples, 2 benign prostate samples were sequenced twice on Illumina next generation sequencing platform to access overall repeatability of M-NGS.

  Study phs000597

• Exome Sequencing of Esophageal Adenocarcinoma

  The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. When coupled to the five-year survival rate of only 15% for this disease, identification of new therapeutic targets for EAC is of great importance. Here, we analyze the mutational spectra identified from the whole genome sequencing of 16 EACs and complete exome sequencing of 149 EAC tumors and matched germline samples. We identify a novel mutation signature marked by high prevalence of A to C transversions at AA*(N) trinucleotides. Notably, the development of EAC is preceded by pathologic intestinal metaplasia of the lower esophagus, Barrett's esophagus, itself a response to injury from gastric-esophageal reflux disease (GERD). Thus, we hypothesize to represent these AA*(N) mutations to a novel signature of GERD-induced mutagenesis. Analysis of the exome data identified 26 genes subject to statistically significant recurrent mutation. Of these 26 genes, only TP53, CDKN2A, SMAD4, and PIK3CA had been previously implicated in EAC. Novel mutations include those targeting chromatin modifying factors and novel candidate contributors to EAC: SPG20, TLR4, ELMO1 and DOCK2. Of these, ELMO1 and DOCK2 are notably direct dimerization partners that act to activate Rac1 to enhance cellular invasiveness, thus generating new hypotheses about the potential for the Rac1 pathway to be a novel target for therapy of EAC. "Reprinted from 'Unraveling the mutational complexity of esophageal adenocarcinoma', with permission from Nature Genetics."

  Study phs000598

• Filtering and Annotation of Variants That Are Rare (FAVR)

  The project developed a suite of new methods (FAVR) designed to assist the shortlisting of genetic variants under a rare variant-phenotype/disease model. The methods were designed to work with commonly used massively parallel sequencing analysis pipelines, such as the GATK or ANNOVAR, and have been made publically available as a suite of software tools (https://github.com/bjpop/favr). The FAVR methods use signatures in comparator sequence alignment files to facilitate the filtering of mapping artifacts and common genetic variants, and annotation of genetic variants based on evidence of co-occurrence in individuals. As relevant, FAVR methods can also be used to filter out artifacts derived from imbalanced paired-end sequencing. Pope et al., BMC Bioinformatics, accepted Dec 2012.

  Study phs000601

• Rare Genetic Steroid Disease Consortium (GSD) Apparent Mineralocorticoid Excess (AME) Syndrome Natural History Clinical Protocol

  The objective of this project is to observe the natural history of apparent mineralocorticoid excess (AME). AME is a rare monogenic hypertensive disease first described by the Principal Investigator, Dr. Maria I. New, in 1977 [1], for which the first mutation in the causative HSD11B2 gene was reported by her group in 1995. [2] Little is known about the progression of this rare hypertensive disorder, which is defined by the presence of hypertension in conjunction with low renin, low to absent levels of the mineralocorticoid aldosterone, elevated urinary cortisol/cortisone metabolite ratio 5β-tetrahydrocortisol (THF) + allo-THF/ tetrahydrocortisone (THE) (i.e., THF+αTHF/THE) and the presence of mutations in the HSD11B2 gene on both alleles. The range of symptoms reflecting progressive end-organ damage is wide in the small number of affected individuals studied to date. It is important to develop accurate information on the longitudinal pattern of progression (natural history) of AME not only because it may improve the care of affected individuals, but also because it may serve as a platform for understanding the role of mineralocorticoid excess in other forms of low-renin hypertension, which constitute 40% of all forms of hypertension. In this study, we will recruit as widely as possible through the Rare Diseases Clinical Research Network (RDCRN) to identify individuals with the triad of low renin, low aldosterone, and elevated urinary THF+αTHF/THE and confirm their disorder as AME by molecular genetic testing of the HSD11B2 gene. We will gather clinical and biochemical data yearly for the duration of the grant. We will describe phenotype and genotype at diagnosis and follow the progression or regression of symptoms over time under standard treatment, with rigorous review of end organs potentially damaged by chronic hypertension. Finally, we will study the natural history of the carriers of HSD11B2 mutations, i.e., the heterozygote relatives of the probands, in order to ascertain evidence of existing or developing hypertension and resulting end-organ damage. This will be the first rigorous study of AME heterozygotes. The participant accrual for AME-affected patients and the carriers of HSD11B2 mutations will be at least two years, but as long as seven years.

  Study phs000603

• Mapping Genes for Mammographic Density

  We recruited 1,521 women from the Old Order Amish (OOA) population of Lancaster County, Pennsylvania, with the primary goal of identifying genetic factors that influence mammographic density. All women were between the ages of 40 and 88 years, with a mean of 54 years. Additional study design details, including eligibility criteria, are described elsewhere (Douglas et al., 2008). The present-day OOA of Lancaster County are the descendants of approximately 550 individuals from central Western Europe who immigrated to the U.S. in the early eighteenth century. All living individuals derive from a single, 14-generation pedigree (Lee et al., 2010). Although the OOA are a genetically closed founder population, allele frequencies and LD profiles are remarkably similar between the OOA and U.S. participants in the International HapMap project (HapMap CEU) for common SNPs (MAF>/=5%) (Van Hout et al., 2010). We recently completed genome-wide linkage and association analyses of mammographic density, including dense and non-dense areas of the breast and the ratio of dense to total area of the breast. Summary-level data from our GWAS are available here and through the Marker of DEnsity (MODE) Consortium.

  Study phs000604

• Genomic Analysis of Pediatric Low Grade Gliomas

  Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from mutations or duplications in the BRAF kinase in specific subclasses, few genetic driver events are known. Diffuse PLGGs compose a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. These tumors are particularly poorly understood. We performed high-resolution copy-number analysis of 44 diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gains, was observed in 28% of diffuse astrocytoma WHO grade II (DA2) and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene MYB on 6q23.3. Whole genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Two truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth when expressed in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. "Reprinted from www.pnas.org/cgi/doi/10.1073/pnas.1300252110 with permission from PNAS."

  Study phs000614

• Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

  Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM). Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

  Study phs000605

• Neurodevelopmental Genomics: Trajectories of Complex Phenotypes

  This study is a collaboration between the Center for Applied Genomics (CAG) at Children's Hospital of Philadelphia (CHOP) and the Brain Behavior Laboratory at the University of Pennsylvania (Penn). The cohort consists of youths aged 8-21 years who consulted the CHOP network and volunteered to participate in genomic studies of complex pediatric disorders. All participants underwent clinical assessment, including a neuropsychiatric structured interview and review of electronic medical records. They were also administered a neuroscience based computerized neurocognitive battery (CNB) and a subsample underwent neuroimaging. These are described separately below. Clinical Testing: GOASSESS, a computerized, structured screener developed from a modified version of the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS, Kaufman et al. 1997, PMID: 9204677). Components of the interview include a timeline of life events, demographics and medical history, Global Assessment of Functioning, and Interviewer Observations. A psychopathology symptom and criterion-related assessment of mood disorders (depression, mania/hypomania), anxiety disorders (overanxious/generalized-, separation-, social-anxiety, specific phobia, panic disorder, agoraphobia, obsessive compulsive disorder, post-traumatic stress disorder), behavioral disorders (attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder), psychosis spectrum (psychosis and prodromal symptoms), eating disorders, suicidal thinking and behavior, and treatment history. This is also based on K-SADS. An abbreviated Family Interview for Genetics Studies (FIGS) to assess major domains of psychopathology in the proband's first-degree relatives. Computerized Neurocognitive Battery: The CNB, developed for large-scale studies, yields measures of accuracy and speed for domains of executive-control functions (abstraction, attention, working memory), episodic memory (verbal, facial, spatial), complex cognitive processing (language reasoning, nonverbal reasoning, spatial processing), social cognition (emotion identification, emotion intensity differentiation, age differentiation) and sensorimotor and motor speed. The following neurobehavioral domains were assessed: Penn Conditional Exclusion Test is a measure of abstraction and concept formation. Participants decide which of 4 objects does not belong with the other 3, based on one of three sorting principles, which change. Feedback is used. Attention: The Penn Continuous Performance Test. Participants respond to a set of 7-segment displays whenever they form a digit or letter. Working Memory: The Letter N-back Test displays sequences of uppercase letters with a stimulus duration of 500 ms (ISI 2,500 ms.) In the 0-back condition, participants respond to a single target (i.e., X). In the 1-back condition they respond if the letter is identical to that preceding it. In the 2-back condition, they respond if the letter is identical to that presented two trials back. Verbal Memory: The Penn Word Memory Test presents 20 target words that are then mixed with 20 distracters equated for frequency, length, concreteness and low imageability. A 20 min delayed recall procedure is also administered. Face Memory: The Penn Face Memory Test presents 20 digitized faces that are then mixed with 20 distracters equated for age, gender and ethnicity. The procedure is repeated at 20 min delay. Spatial Memory: The Visual Object Learning Test uses Euclidean shapes as stimuli with the same paradigm as the word and face. Language and Analogical Reasoning: The Penn Verbal Reasoning consists of verbal analogy problems. Spatial Processing: Penn Line Orientation Test presents two lines at an angle, and participants click on a button that makes one line rotate until it has the same angle as the other. Emotion Processing: Facial displays of 4 emotions (Happy, Sad, Anger, Fear) and Neutral faces, 8 each, are presented and the subject identifies the emotion in a multiple-choice format. The facial stimuli are balanced for gender, age, and ethnicity. Sensory-motor Processing Speed: The task requires moving the mouse and clicking on a green square that disappears after the click. The square gets increasingly small and appears in unpredictable locations. Neuroimaging Protocol: Studies were performed at Penn using a Siemens Trio (Erlangen, Germany) 3T scanner equipped with 40mT/m gradients and 200 mT/m/s slew-rates. RF transmission utilized a quadrature body-coil, and reception a 12-channel head coil optimized for parallel imaging. Total image acquisition time was about 45 min. Structural Imaging: The T1-weighted protocol utilized a 3D, inversion-recovery, and magnetization-prepared rapid acquisition gradient echo. Relevant imaging procedures include: Structural magnetic imaging Diffusion tensor imaging ASL perfusion BOLD fMRI Neuroimaging tasks: Fractal N-Back Task of Spatial Working Memory Face Emotion Identification Task Neuroimages: The current data release includes over 9700 MRI images that may be downloaded through Authorized Access.

  Study phs000607

• The National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN)

  The NINDS Stroke Genetics Network (SiGN) is a large international collaboration designed to detect genetic variants that predispose to subtypes of ischemic stroke. The study implements a genome wide association study (GWAS) methodology with all stroke cases undergoing phenotypic and stroke-subtype classification using the same web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating Research Centers (GRC's). SiGN includes ischemic stroke cases from 24 GRC's, 13 from the US and 11 from Europe. Each GRC has access to well-characterized ischemic stroke cases in which extensive phenotype data and high-quality DNA was available. Genome-wide data was available for many cases and for those without, new genome-wide genotyping, including exome chip genotyping of rare variants, was done through the Center for Inherited Diseases Research (CIDR). To maximize power for subtype analyses, genotyping resources were allocated almost exclusively to cases. With few exceptions, controls were drawn from studies with publicly available genome-wide data.

  Study phs000615

• CIP: Obesity-Diabetes Familial Risk, Viva La Familia Study

  The VIVA LA FAMILIA Study was designed to identify genetic variants influencing childhood obesity and its comorbidities in the Hispanic population. Family recruitment and phenotyping were conducted in 2000-2005 in Houston, TX. All enrolled children (n=1030) and parents gave written informed consent or assent. The protocol was approved by the Institutional Review Boards for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals and for Texas Biomedical Research Institute. The VIVA LA FAMILIA study design and methodology have been described in detail (Butte NF, 2006). Each family was ascertained on an obese proband, defined as a BMI > 95th percentile, between the ages 4-19 y. The cross-sectional, longitudinal study design consisted of baseline measurements, with a one-year. GWAS was performed using the Illumina HumanOmni1 v1.0 BeadChips on 815 children from 263 Hispanic families and HumanOmni 2.5-8v1 on an additional 43 children. Exome sequencing is being performed on 822 children using NimbleGen capture, followed by Illumina DNA sequencing. Butte NF, Cai G, Cole SA, Comuzzie AG. Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in Hispanic population. Am J Clin Nutr 2006;84(3):646-54. PMID: 16960181

  Study phs000616

• PGRN-Leducq: Identification of the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

  The goal of this study was to search for genetic variants that could be responsible for modifying the risk of drug-induced long QT syndrome (diLQTS). diLQTS is a relatively common adverse drug event and has been a leading cause for drug relabeling and withdrawal from the market. Our hypothesis, that variants in genes which regulate electrical properties in the heart modify the risk of diLQTS, was tested by genotyping patients of European descent at 1424 single nucleotide polymorphisms (SNPs) in 18 candidate genes. We found that the SNP KCNE1 D85N was highly predictive of diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5-22.9).

  Study phs000617

• Genome-Wide Association Study of Hypertriglyceridemia in Mexicans

  Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are highly common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. This study is a research collaboration between investigators at the University of California, Los Angeles (UCLA) and Instituto Nacional de Ciencias Médicas y Nutrición (INCMN), Mexico City, to perform a two-stage genome-wide association study (GWAS) for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (Weissglas-Volkov et al. 2013, PMID: 23505323). This study was funded by an RO1 grant from NIH/NHLBI (PI Paivi Pajukanta; PI of the subaward Teresa Tusie-Luna). In stage 1 of the GWAS, we tested all GWAS SNPs from the Illumina Infinium Human610-Quad platform that passed quality control for association in ~2,200 hypertriglyceridemia cases and controls. In stage 2, we genotyped the ~1,200 positive signals of stage 1 in additional ~2,200 hypertriglyceridemia cases and controls, and performed a combined analysis of the two stages to identify genome-wide significant variants. The subjects were recruited at the INCMN. The DNA isolation and clinical laboratory measurements of the case-control study samples were performed at INCMN using standardized procedures. Genotyping and statistical analyses of the data were performed at UCLA. A summary of this GWAS can be found in Weissglas-Volkov et al. 2013 Journal of Medical Genetics, PMID: 23505323. Briefly, using the two-stage GWAS design, we identified a novel Mexican-specific genome-wide significant locus for serum TG levels close to the Niemann-Pick type C1 protein (NPC1) gene (Weissglas-Volkov et al. 2013, PMID: 23505323). Of the European lipid GWAS loci, three TG loci (APOA5, GCKR, and LPL) and four HDL-C loci (ABCA1, CETP, LIPC and LOC55908) resulted in genome-wide significant signals in Mexicans. Furthermore, our cross-ethnic mapping narrowed three European TG GWAS loci, APOA5, MLXIPL, and CILP2 that exhibited long range LD and a large number of candidate SNPs in the European GWAS scan. In the apolipoprotein A1C3A4A5 gene cluster region, the cross-ethnic fine mapping and LD comparisons reduced the number of candidate variants to one SNP, rs964184. We also found that although 52% of the associations from European lipid GWAS meta-analysis could be generalized to Mexicans, in 82% of the European GWAS loci, a different variant other than the European lead SNP provided the statistically strongest evidence of association in the Mexican scan (Weissglas-Volkov et al. 2013, PMID: 23505323). Taken together, our Mexican GWAS for lipids identified a novel Mexican-specific locus for high serum TGs; restricted three European GWAS loci; and investigated which European lipid GWAS variants extend to the Mexican population (Weissglas-Volkov et al. 2013, PMID: 23505323). This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to serum lipid levels in Mexicans. In addition to de-identified genome wide genotypic data, a selected list of de-identified phenotypic data related to hypertriglyceridemia and related metabolic traits are also available in dbGaP.

  Study phs000618

• DNA Methylation Analysis of Peripheral Blood Cells from Siblings Discordant for ASD

  Autism is a common disorder whose causes are poorly understood. Both genetic and environmental influences are thought to act together causing autism. Epigenetics is an area that bridges genetic and environmental influencing and commonly is studied by examining dynamic methylation changes to the DNA. We have screened a total of 78 autistic boys and their fathers by this method in 807 genes and find 116 methylation changes that together can correctly identify nearly 80% of the affected boys from their fathers. We propose to confirm these exciting data in a much larger set of genes in 1,200 autistic boys and their families, including unaffected brothers. These data not only could provide new insight into the causes of autism but could also result in a screening test for autism.

  Study phs000619

• FaceBase Study of Facial Shape in Tanzania: CIDR

  The goals of this project are to identify loci that underlie major genetic determinants of orofacial shape, by means of a GWAS in a cohort of normal African children (from Tanzania) from whom we have collected 3D digitized facial morphometric scans, and a subsequent replication study of normal children from the same population. These studies are part of the NIDCR FaceBase initiative (https://www.facebase.org/). In addition to dbGaP, all study genotype and phenotype data (including primary facial scans and landmarks) will be available for data-sharing with qualified investigators via the NIDCR FaceBase Hub (www.facebase.org/), following approval by the NIDCR FaceBase Data Access Committee.

  Study phs000622

• Rare Mendelian Disease in Old Order Amish and Mennonite Patients

  The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

  Study phs000623

• The Lung Genomics Research Consortium (LGRC)

  Chronic lung diseases represent a broad spectrum of chronic fibrosing/inflammatory lung conditions that are for the most part poorly responsive to treatment and often fatal. COPD/emphysema is the fourth leading cause of death in the United States and the incidence and rate of death from pulmonary fibrosis is increasing each year. Although progress has been made in interpretation of the clinical, radiological, and pathological features of chronic lung disorders, and progress in determining the pathobiology continues, the causes, biologic mechanisms, and therapeutic options remain obscure. Moreover, predicting individuals or populations at risk for developing any of these complex diseases, at present, is not possible. To address this challenge, we plan to create a genetic, molecular, and quantitative clinical phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. The composite genetic, genomic, and epigenetic signature combined with quantitative clinical phenotypes has the potential to characterize the dynamic biological state of a complex disease and complement existing diagnostic approaches that are reliant on traditional clinical measures of disease. In the proposed project, we plan to extend the scope and impact of the NHLBI Lung Tissue Research Consortium (LTRC) biorepository by creating the Lung Genomics Research Consortium (LGRC), a comprehensive genetic, molecular, and quantitative clinical phenotyping warehouse. Our overall hypothesis is that a genetic, molecular, and quantitative clinical phenotyping warehouse combined with a rich clinical database will enable the lung research community to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. We plan to pursue this hypothesis through the following aims. Specific Aim 1: Establish a genetic, genomic, and epigenetic molecular library to complement the existing clinical database in the LTRC. Specific Aim 2: Develop a quantitative clinical phenotyping platform using existing LTRC data, as well as an enhanced data set including novel quantitative CT and histology imaging analyses. Specific Aim 3: Establish a publicly-accessible database that would integrate the genetic, molecular, and quantitative phenotyping data with the existing clinical data in the LTRC and provide query and data exploration tools that are easily accessible to the lung research community. These discoveries will enable clinicians to Identify individuals at risk of developing chronic lung diseases; Diagnose these conditions earlier; Identify novel mechanisms that cause these diseases; Reclassify disease entities into categories more representative of molecular and cellular pathogenic mechanisms regardless of traditional disease categories; develop personalized approaches to treatment.

  Study phs000624

• Targeted Sequencing of GWAS Loci in Cleft Lip and Palate

  Nonsyndromic cleft lip and palate (NSCL/P) is a complex disorder caused by both genetic and environmental factors and has been the focus of an extensive effort to identify genetic risk factors. A number of candidate gene studies have been performed but have not been widely replicated. To date, four independent genome wide association studies have been performed as well as a meta-analysis. Together these studies have identified many loci associated with NSCL/P. The goal of this project is to use targeted sequencing to further characterize these regions and to progress from the association signals identified by GWAS to the identification of causative genes and/or variants. This study is part of the GWASeq project, a collaboration of five disease studies, which will sequence genomic regions from GWAS to characterize the genetic variation underlying these diseases and to compare study design and methods for the follow-up of GWAS studies by sequencing. The goal of this study is to sequence 1000+ NSCL/P case-parent trios from China and the Philippines and 400 trios of European ancestry. Targeted sequencing was performed on intervals ranging between 60kb to 1Mb surrounding 13 genes/loci previously associated with NSCL/P including: IRF6, MAFB, ARHGAP29, 8q24, PAX7, VAX1, NTN1, NOG, FOXE1, MSX1, BMP4, FGFR2, PTCH1.

  Study phs000625

• CD4+ cell transcriptional profiling by RNA sequencing

  We use next generation sequencing to investigate the different transcriptomes of closely related CD4+ T-cells from healthy human donors to elucidate the genetic programs that underlie their specialized immune functions. Six cell types were included: Regulatory T-cells (CD25hiCD127low/neg with >95% FOXP3+ purity), regulatory T-cells activated using PMA/ionomycin, CD25-CD45RA+ ('naive' helper T-cells), CD25-CD45RO+ ('memory' helper T-cells), activated Th17 cells (>98% IL17A+ purity) and activated IL17-CD4+ T-cells (called 'ThPI'). Poly-T capture beads were used to isolate mRNA from total RNA, and fragment sizes of ~200 were sequenced from both ends on Illumina's genome analyzer. We confirm many of the canonical signature genes of T-cell populations, but also discover new genes whose expression is limited to specific CD4 T-cell lineages, including long non-coding RNAs. Additionally, we find that genes encoded at loci linked to multiple human autoimmune diseases are enriched for preferential expression upon T-cell activation, suggesting that an aberrant response to T-cell activation is fundamental to pathogenesis.

  Study phs000626

• University of North Carolina at Chapel Hill (UNC) Hepatocellular Carcinoma Study by Exome Sequencing (HCCSES)

  Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4 (7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma.

  Study phs000627

• Genetic Epidemiology of Lung Cancer Consortium GWAS of Familial Lung Cancer

  Familial lung cancer cases were collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) recruitment sites: University of Cincinnati, Karmanos Cancer Institute at Wayne State University, Louisiana State University Health Sciences Center-New Orleans, Mayo Clinic, and Medical College of Ohio. Familial cases for this study came from three sources: 1) one case each from families (at least 3 affected lung cancer cases in the family) included in the linkage analysis; 2) one case from linkage-eligible families (at least 3 affected lung cancer cases in the family) but where there were insufficient biospecimens available to make them informative for linkage analysis; and 3) one case from families not eligible for the linkage study with a family history of at least one first or second degree relative affected with lung cancer. Unrelated controls were selected from 1) among the spouses of family members, thus matching on socio-economic status (SES) and ethnicity (typically) of the cases or 2) from case-control studies of lung cancer conducted in the same location in which the linkage families were collected and matched on age, sex, and race. All cases and controls self-reported as European American. Biospecimens used for normal DNA extraction included blood, saliva or mouthwash. Some samples underwent whole genome amplication.

  Study phs000629

• ARDSnet and the iSPAAR Consortium: Genomic Basis of Susceptibility and Outcomes in Patients with the Acute Respiratory Distress Syndrome (ARDS)

  Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000631 ARDSnet iSPAAR Consortium. phs000334 ESP_LungGO_ALI phs000686 ALI_GeneticRisk

  Study phs000631

• NHLBI GO-ESP: Family Studies (Hematological Cancers)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Two major goals in the study of human malignancies are (i) to understand the genetic basis that underlies the predisposition of certain individuals to develop cancer and (ii) to identify the full spectrum of acquired mutations that occur in human cancers. There has been some progress in both of these areas with respect to hematologic malignancies but much remains to be discovered. As a result of recent advantages in sequencing technologies it is now feasible to sequence multiple individual whole exomes at reasonable cost. Such technologies provide a unique opportunity to transform our understanding of the biological basis of human cancer and to identify inherited genetic variants that predispose individuals to the development of hematologic malignancies. Myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute leukemia are clonal disorders of hematopoieis. Our study involves performing whole exome sequencing of individuals with these disorders for the purpose of identifying (i) novel inherited genetic variants associated with the risk of developing of MPN/MDS/acute leukemia and (ii) novel acquired mutations associated with the development of MPN/MDS/acute leukemia.

  Study phs000632

• National Cancer Institute (NCI) Genome Wide Association Study (GWAS) of Lung Cancer in Never Smokers

  A genomewide study of lung cancer in never smokers Abstract and specific aims In the United States, lung cancer incidence and mortality rates have been steadily declining over the past decade, following decline in the prevalence of tobacco smoking. However, lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined. Although tobacco smoke is the predominant risk factor for development of lung cancer, some patients develop the disease without a history of tobacco smoking. About 10 - 15% of all lung cancers occur in lilfetime never smokers. This figure will increase as the proportion of never smokers increases in the population. Even at present rates, lung cancer in never smokers, if considered a separate disease, is 6th to 8th top cause of cancer death. The growing number of never smokers in the USA and other countries emphasizes the importance of understanding the epidemiology and biology underlying lung cancer in this group. Genetic polymorphisms associated with the risk of lung cancer in never smokers are expected to overlap with those associated with the risk of lung cancer in ever smokers only partially. Epidemiological, molecular and clinical data suggest that molecular mechanisms of LC may differ in smokers and non-smokers, implying that lung cancer in never smokers is a different disease compared to the lung cancer in smokers. One can expect that there should be stronger genetic component in the control lung cancer in never smokers because effects of the genetic factors in never smokers are unmasked by the lack of tobacco smoke exposure. The genetic epidemiology of lung cancer in never smokers has not been well explored, largely because of difficulties in accruing the needed sample size for association studies. We propose a multicenter (total 14 sites from the US and Europe) genomewide association study of lung cancer in never smokers with the following specific aims: Aim 1: To identify candidate SNPs influencing risk for lung cancer in never smokers using Discovery sample. In the Discovery phase we will genotype 1256 Caucasian cases and 1365 age- and gender-matched never smoker controls using the Illumina Human660W-Quad platform. In addition, we will include in the analysis 284 cases and 175 matched controls already genotyped on the 610Quad platform. In this phase we will only include the study sites that have collected blood specimens (MDACC, Mayo Clinic, Karmanos Cancer Institute, The University of Liverpool Cancer research Centre, Institute of Cancer Research in Sutton, and Lunenfeld Research Institute in Toronto, Canada). All the samples will be sent to the independent lab for genotyping, to reduce site-specific technical artifacts. The final sample will consist of 1540 cases and 1540 controls matched by study site. Aim 2: To perform the second phase (validation) analysis of significant SNPs identified in aim 1 using an independent set of cases and controls. SNPs associated with risk at the significance level of 0.01 or below in the discovery set will be included in the replication phase. The proposed threshold guarantees an adequate power to retain SNPs with the typical effect size of 1.3. We plan to carry 6000-7000 SNPs for validation. The independent replication set will include 800 cases and 800 controls, mostly from sites that collected tissue (Mayo Clinic, Karmanos Cancer Institute, UT Southwestern) or buccal specimens (UCLA), but also blood samples (Imperial College London, University of Pennsylvana, German Cancer Research Center, Heidelberg, National Research Center for Environment and Health, Neuherberg, Carmel Medical Center, Haifa). We will then perform a joint analysis to test the significance of the SNPs identified in the first stage using a stringent critical p-value of 10-7. There will be 2340 cases and 2340 controls in the joint set. Based on our experience with GWAS in smokers and assuming that genetic component in lung cancer risk in never smokers can be higher than genetic component in smokers, we expect to identify about 5-10 candidate regions associated with lung cancer risk in never smokers. Aim 3: To identify and explore pathways associated with the risk of lung cancer in never smokers. Results of the number of studies on the molecular mechanisms and drug response suggest that lung cancer in never smokers is a different disease and different pathways will be associated with lung cancer risk in non-smokers and smokers. To identify pathways and molecular functions associated with lung cancer risk in never smokers we will apply Ingenuity and DAVID bioinformatics tools. We will use at least 300 top candidate genes identified in joint and discovery analysis. The reason why we select rather large number of candidate genes for functional annotation is two-fold: 1. Both algorithms are looking for enrichment of pathways and function by most significant genes and they produce statistically robust results only when number of genes is relatively high. 2. Despite the fact that this study will be largest possible for never smokers we still are underpowered to detect SNPs with relatively small effect size. But though those SNPs will not reach genome wide level of significance they will tend to be on the top of the list. In other words genes from the gray zone (significant on individual level and non-significant for genome wide level) are expected to be enriched by true discoveries. True discoveries are likely to be associated with limited number of pathways / functions while false positives are expected to be uniformly distributed across functions and pathways. Therefore significant clustering of the gene to a given function will suggest that that those genes are true discoveries. This is the first GWAS aiming at identifying the genetic control of susceptibility to lung cancer in Caucasian never smokers. We will combine the available resources from the multiple sites to achieve the sample size sufficient for this study. The study will identify genetic architecture of the predisposition to the lung cancer in never smokers.

  Study phs000634

• Whole Exome Sequencing for Familial Intracranial Aneurysm (FIA I-II) Study

  The goal of this study is to identify the genes underlying the risk of intracranial aneurysm (IA). The FIA Study initially recruited families appropriate for linkage analysis. Therefore, the recruitment focus was not only on probands with a family history of IA but also required that biological samples be obtained for at least two affected family members. Family members underwent detailed interviews for medical, social and family history, and provided blood samples for DNA extraction. Over 400 multiplex IA families were recruited and enrolled. The whole exome sequencing project aims to identify novel and rare (in the general population) genetic variants that are enriched in seven extended multiplex families with a strong familial aggregation of intracranial aneurysms.

  Study phs000636

• Genome-Wide Association Study of Relapse of Childhood Acute Lymphoblastic Leukemia

  Using risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the last 40 years. However, a substantial portion of patients experience relapse, many of whom have no known risk factors. Taking a genome-wide approach, we sought to evaluate the relationships between germline SNP genotypes and the risk of relapse in 2,535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We examine prognostic value of selected SNPs in the context of known relapse risk factors (molecular subtypes, minimal residual disease, age and leukocyte count at diagnosis). Associations of relapse-related SNPs with pharmacokinetic and pharmacodynamics of antileukemic drugs offer plausible mechanism by which they are linked to treatment outcome. Finally, we aim to identify SNPs that are related to both genetic ancestry and relapse which are likely to contribute to racial disparities in ALL survival.

  Study phs000638