Search Results - EGA European Genome-Phenome Archive

Whole Genome Sequences of 18th century African descended individuals from Charleston, South Carolina.

This study presents Whole Genome Sequencing results from the Anson Street African Burial Ground Project, which is a community-based initiative aimed at understanding the histories of 37 Ancestors in Charleston, South Carolina. Here we report fastq files for all 37 Ancestors. DNA was extracted at the University of Tennessee-Knoxville following Dabney et al. 2013, and dual index libraries prepared using a modified NEBNext Ultra II kit with partial USER enzyme digestion. Libraries were then enriched for human genomic DNA (MyBaits) and sequenced on Illumina Platforms.

Dataset EGAD00001009643

IG-MYC ALL - DNA and RNA sequencing

The dataset is composed by the raw RNA sequencing (n=6), targeted DNA sequencing (n=18) and whole exome sequencing (n=17) from 19 patients with IG-MYC-rearrangements.

Dataset EGAD00001008705

16S sequencing data of mucosal biopsies

This is the dataset of 16S data from mucosal biopsies.

Dataset EGAD00001008215

Subset of EGAS00001005112 (The INFORM Precision Medicine Study for High-Risk Pediatric Malignancies, 17 exomes) which is used in EGAS00001005243 (Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B)

Part of the project: The INFORM Precision Medicine Study for High-Risk Pediatric Malignancies resulted in the publication of this study: Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B. This dataset contains the subset of 17 patient exome sequencing data.

Dataset EGAD00001007864

Peruvian Genome Project

Through the Peruvian Genome Project we generate and analyze the high coverage genomes of 150 individuals where the majority have >90% Native American ancestry and explore questions at the interface of evolutionary genetics, history, anthropology, and medicine. This is the most extensive sampling of high-coverage Native American and mestizo whole genomes to date. Reference: https://doi.org/10.1073/pnas.1720798115

Dataset EGAD00001007082

Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Isolated memory and naïve T cells were activated using anti-CD3, anti-CD28 or both in combination. As a control we cultured cells in the same conditions but without the stimuli. We carried Chipmentation using the H3K27ac antibody on 200,000 cross-linked cells. 1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ .

Dataset EGAD00001006611

AVENIO Expanded ctDNA panel sequence alignments (BAMs) from plasma DNA of BC, CRC and NSCLC patients

The AVENIO ctDNA Expanded Kit is a next-generation sequencing (NGS) liquid biopsy assay with a 77 gene panel (192 kb) containing genes in U.S. National Comprehensive Cancer Network (NCCN) Guidelines and emerging cancer biomarkers. This pan-cancer assay was applied to 48 plasma samples from patients with breast, colorectal and non-small cell lung cancer. After sequencing 150bp paired-end, reads were aligned to the hg38 genome with the AVENIO Oncology Analysis Software (version 2.0). These files are the deduplicated alignments generated by the analysis software used for subsequent variant, indel and CNV calling.

Dataset EGAD00001006301

V2 panel bait design test

This study comprises of three different datasets. 1) 57 samples from the 1243 canapps cell line study,2) 91 FFPE normal samples and 3) 87 samples from the SCORT WS2 dataset. The aim is to sequence these 235 samples in order to test the new V2 Colorectal bait design.

Dataset EGAD00001003242

Whole-exome sequencing of 20 samples of actinic keratosis (10s) and cutaneous squamous cell carcinoma (10s)

Whole-exome sequencing of 20 samples of actinic keratosis (10) and cutaneous squamous cell carcinoma (10) was performed to investigate a potential relationship between DNA methylation-based subtypes and genetic mutation patterns. 7 samples were shown to belong to the stem cell-like subclass (4 AK and 2 SCC), 12 - to the keratinocyte-like subtype (6 AK and 6 SCC) and one SCC sample is unclassified (was not included in the methylation analysis). Exome regions were captured using Agilent Low Input Exome-Seq Human v5 kit and sequenced on Illumina Hiseq4000 with paired-end 100-nucleotide reads.

Dataset EGAD00001003765

Detection of clinically relevant genetic and transcriptomic landscape in DLBCL uniformly treated by R-CHOP

Recent studies using next-generation sequencing strategies have described the landscape of genetic alterations in diffuse large B-cell lymphoma (DLBCL). However, little is known about the clinical relevance of recurrent mutations and copy number alterations and their transcriptional footprints. This study examines the frequency, interaction and clinical impact of recurrent genetic aberrations in DLBCL using high-resolution technologies in a large population-based cohort.

Dataset EGAD00001003783

The British Autozygosity Populations BioResource (2018-06-06)

This data set contains whole exome sequences of individuals with self-stated parental relatedness from the East London Genes & Health cohort. Rare frequency functional variants in these healthy individuals will be studied with respect to the genetic health of the participants and loss-of-function analysis of human genes. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-06-06.

Dataset EGAD00001004150

Adeno-associated virus in the liver: natural history and consequences in tumor development

Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterize the natural history of AAV infection in the liver and its consequence in tumor development. In silico analyses using viral capture data explored viral variants and new clonal insertions. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.

Dataset EGAD00001004484

Chordoma Sequencing Project Whole Genome

This is a continuation of the Chordoma Sequencing Project. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. RNA Sequencing/Methylation and SNP6 and an additional sequencing of three cancer cell lines will be added to this work.

Dataset EGAD00001000721

Whole-genome plasma DNA sequencing in CRC patients under anti-EGFR therapy

In this study we performed whole genome sequencing of plasma DNA (plasma-Seq) of 19 plasma-DNA samples from a total of 10 patients treated with anti-EGFR therapy. We demonstrated that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. We also showed that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy.

Dataset EGAD00001000748

Whole genome sequence of third generation family member (SFHS)

Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.These data can only be used for the investigation of the genetic causes of the reported clinical phenotypes in these patients

Dataset EGAD00001001454

ENU-LS-411N-TripleTherapy

BRAF V600E colorectal cancers do not respond to the only currently FDA approved targeted therapy for CRC. There is currently a trial underway in the UK recruiting V600E CRC patients for treatment with a triple therapy combination of Cetuximab, Trametinib and Dabrafenib. We have mutagenized a pool of V600E CRC cell lines and treated with this triple therapy to select out drug resistant clones. We will now sequence these drug resistant clones with the aim of identifying common point mutations engendering resistance to this new therapy.

Dataset EGAD00001002051

Identification of drug resistance genes in cancer cell lines by insertional mutagenesis

Our aim is to identify genes involved in resistance to anti-cancer therapies. In order to do this we have taken advantage of a lentiviral vector (LV)-based insertional mutagen to mutagenize cancer cell lines. LV-transduced cell lines were then treated with anti-cancer therapies and the emergence of resistant clones scored. DNA from pools of resistant clones was collected, subjected to custom capture by baits designed against the LV sequence, and then sequenced to identify the LV-genomic junction. We hope that the identification of recurrently targeted genes in resistant cell population will allow us to identify genes that mediate drug resistance.

Dataset EGAD00001002207

Genomic Evolution of Breast Cancer Metastasis and Relapse

Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

Dataset EGAD00001002697

A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family

Purpose: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases.Methods: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers, identified a mutation in the MAGEB4 gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on mRNA and protein levels were tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain.Results: The novel single base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein or the ability to homo / heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners. Conclusion: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein.

Study EGAS00001002272

ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation.

Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors1. However, the consequences of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins1–3 devoid of key chromatin interaction domains. Here we demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma tumor harboring an ATRX IFF revealed that H3K27me3 occupies a subset of REST target genes that are transcriptionally silenced, and are sensitive to EZH2 inhibition in our cell-based assays. Thus, our study greatly advances our understanding of indolent neuroblastoma and identifies EZH2 inhibition as a potential therapy for patients with ATRX mutant disease. Further, these studies may be applicable to other ATRX mutant pediatric malignancies, particularly those carrying similar structural alterations of ATRX.

Study EGAS00001002507

Whole Genome Sequencing of clonal expansions of single healthy somatic cells (human, female)

HSC73_clone: Bone marrow mononuclear cells from the healthy 73 years old female were thawed and labeled with Alexa-Fluor 488-conjugated anti-CD34 (581, Biolegend), Alexa-Fluor 700-conjugated anti-CD38 (HIT2, eBioscience), a cocktail of APC-conjugated lineage antibodies consisting of anti-CD4 (RPA-T4), anti-CD8 (RPA-T8), anti-CD11b (ICRF44), anti-CD20 (2H7), anti-CD56 (B159, all BD Biosciences), anti-CD14 (61D3), anti-CD19 (HIB19) and anti-CD235a (HIR2, all eBiocience) and 1 micro-gram/ml propidium iodide (Sigma). Using a BD FACSAria cell sorter, single Lin-CD34+CD38-PI- cells were individually sorted into low-adhesion 96-well tissue culture plates (Corning) containing 100micro-litre of StemSpan Serum-Free Expansion Medium (Stemcell technologies) supplemented with 100ng/ml of human SCF and FLT-3L, 50ng/ml of human TPO, 20ng/ml of human IL-3, IL-6 and G-CSF (all cytokines from Peprotech) and 50U/ml of penicillin and 50μg/ml of streptomycin (Sigma). Cells were incubated at 37 degrees C in a humidified atmosphere with 5% CO2 in air. After 5 days in culture, another 100micro litres of cytokine-containing medium were added. 13 days after seeding, clones B6 and G2 had expanded to approx. 105 cells and were selected for whole genome sequencing (2x101bp, paired-end, Illumina HiSeq2500) after tagmentation-based library preparation (see Extended Experimental Procedures) for clone B6 and standard library preparation for clone G2. For germline-control ~106 unsorted bone marrow mononuclear cells from the same donor were used for sequencing. An average of 30-fold sequence coverage for each the clones and the matching control were obtained.L4clone: A progenitor cell clone was raised from a peripheral blood sample of the 39 year old healthy female. Frozen peripheral blood mononuclear cells (PBMCs) were isolated from 2 ml heparinised peripheral blood via Ficoll Paque density centrifugation. A methylcellulose assay was performed as described earlier (Weisse et al., 2012). In brief, non-adherent mononuclear cells were incubated in the presence of the recombinant human cytokines IL-3, IL-5 and GM-CSF (R&D systems) over 14 days to induce colony formation. Colonies were detected under an inverted light microscope, and plucked by a pipette when colonies had approximately 10,000 cells/CFU. Each colony was washed three times in PBS and finally frozen as a cell pellet in -80 degrees C. Genomic DNA was isolated using the QIAamp DNA micro kit according to the instructions of the manufacturer (Qiagen, Hilden, Germany). Whole genome sequencing (2x101bp, paired-end, Illumina HiSeq2500) was performed for colony 4 after tagmentation-based library preparation and resulted in 15-fold sequence coverage for each the colony and the matching whole blood.

Dataset EGAD00001000666

Genetic Causes of Growth Disorders

Description of the disorder: A very common disorder presenting to pediatricians/pediatric endocrinologists is childhood growth failure. Sometimes the cause is evident, for example, growth hormone deficiency. In other children, the etiology remains unknown despite extensive evaluation, resulting in the unhelpful diagnosis of severe idiopathic short stature (SISS). These conditions are quite heterogeneous, including children with isolated growth failure and others who also have other abnormalities such as developmental delay or a constellation of congenital anomalies (syndromic short stature). Sometimes, the disorder appears to primarily affect the growth plate, which drives skeletal growth and thereby determines overall body proportions, whereas in other children, the disorder affects skeletal and non-skeletal tissues equally. Some cases of SISS have a polygenic inheritance while others appear to follow a Mendelian inheritance model, recessive, dominant or X-linked. Very recently, genome-wide analysis for copy number variants (CNVs) and whole-exome sequencing have begun to identify some of the molecular etiologies of these disorders.1 Identifying the molecular etiology of growth disorders has clinical and scientific value. Clinically, identifying a molecular cause prevents extensive further testing and may direct anticipatory care for associated medical problems. For example, we recently studied aggrecan (ACAN) gene mutations in families with autosomal dominant short stature and accelerated skeletal maturation. These mutations affect both growth plate cartilage, causing linear growth failure, and also articular cartilage, causing osteochondritis dissecans and early-onset osteoarthritis.1 Etiological classification of idiopathic growth failure allows more precise characterization of prognosis and response to treatment, which are currently highly imprecise because of the locus heterogeneity. In some cases, finding the genetic etiology points to a novel treatment approach that targets the specific molecular pathway involved. The proposed project is central to the main focus of our group, the Section on Growth and Development, NICHD. Our primary goal is to investigate cellular and molecular mechanisms governing childhood growth and to gain insight into the many human genetic disorders causing childhood growth failure. The proposed project is well suited for the intramural program because it takes advantage of Clinical Center expertise to phenotype subjects with SISS. Study subjects: We will study subjects with SISS and nuclear family members. SISS will be defined by height SDS < -2.5 for age without evident cause after routine evaluation including: growth hormone axis evaluation; thyroid function testing; celiac disease screening; urinalysis; CBC; chemistry; karyotype (girls, for Turner syndrome); and testing for single gene defects based on the clinical evaluation (for example, SHOX or Noonan-associated genes). Candidate families will include isolated growth disorders and growth disorders that are accompanied by congenital anomalies, developmental delay, or other syndromic short stature. Strong preference will be given to subjects with a severe phenotype and a pedigree that indicates a Mendelian inheritance. Multiple independent families with the same phenotype will have priority. The pool of applicants for recruitment is large, and we receive many inquiries by emails and phone consultations from pediatric endocrinologists for advice regarding diagnosis and management of unusual growth disorders, including familial disease. Often these families are seeking further evaluation and are willing to participate in a research study. From this pool, we will be selecting pedigrees with very favorable Mendelian characteristics, for example de novo dominant occurrences where two normal parents have a child with SISS, and the child grows up to be an adult who passes this phenotype on to multiple grandchildren in the next generation. Subjects and family members will be brought to the NIH Clinical Center (NIHCC) for outpatient evaluation. Participants will be evaluated by pediatric endocrinology fellows (as part of our training program) and by senior staff to establish the clinical findings and construct a pedigree. Subjects will receive additional biochemical and imaging studies at the Clinical Center to complete the phenotyping and assign affected status. The growth abnormality will be evaluated by assessing body proportions, relative organ size, and skeletal imaging as indicated. Associated clinical abnormalities beyond altered growth will be characterized with the help of other Clinical Center subspecialists. Subjects and family members will be evaluated by SNP microarray and whole-exome sequencing. We anticipate 4-5 persons for each of 16-20 families, for a total of 72-90 whole-exome sequences. Half of the families will be recruited and studied within the first year and half in the second year. We will use freshly collected peripheral blood as the DNA source for SNP array and NextGen Sequencing. Analytic approach: The candidate genes will be chosen based on 1) inheritance state consistency, 2) population frequency in the ESP and UDP databases, and 3) predictions of deleteriousness. We will use VarSifter and the B road Institute Integrated Genome Viewer to filter and visualize these data. The genetic model will be dependent on the family's pedigree. For a simple trio, we will explore variants using genetic models including autosomal recessive, de novo (dominant), compound heterozygous, deletion/point mutation recessive, and X-linked (male only). The candidate variants will be identified using Boolean logic sets in VarSifter following intramural NHGRI/UDP methods. We will also use SNP microarray data to identify copy number variations, complete/single copy deletions, duplications, non-paternity, consanguinity for homozygosity mapping, uniparental isodisomy, mosaicism, and segregation patterns (bed file generation for use in VarSifter filter work). After a list of candidate sequence variants has been generated, annotation will include using the Exome Variant Server, Polyphen-2, MutationTaster, Sift, and CADD predictions of deleteriousness. Biological laboratory data will be included to prioritize candidate variants. Our group has expertise in the molecular mechanisms regulating both skeletal growth2,3 and growth of other tissues4,5, which may be helpful in this phase of the analysis. The most promising candidate mutations will be confirmed by Sanger sequencing and studied functionally, in vitro and/or in vivo. For mutations that affect skeletal growth, we will use experimental systems related to growth plate cartilage. For in vitro studies, we have experience transfecting chondrocyte cell lines, such as ATDC5, and primary chondrocytes. We will determine whether the mutation alters protein and/or cell function. In vivo studies can be used to explore pathophysiology. We have recently successfully used a new approach, the CAS9/CRISPR system to knockout multiple loci in mice (unpublished), which can be used again in the future to create mouse models efficiently. 1J Clin Endocrinol Metab, 2014 (PMID: 24762113) 2J Mol Endocrinol, 2014 (PMID: 24740736) 3Hum Mol Genet, 2012 (PMID: 22914739) 4Proc Natl Acad Sci U S A, 2013 (PMID: 23530192) 5Endocr Rev, 2011 (PMID: 21441345)

Study phs001617

ALS Compute

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of brain and spinal cord motor neurons. Half of ALS patients display cognitive symptoms of frontotemporal dementia (FTD); reciprocally, about 40% of FTD patients show motor neuron deficits, and approximately 15% develop overt ALS. The clinical overlap between ALS and FTD means that the two conditions are thought to represent a disease spectrum (ALS/FTD). In recent years, the identification of several genetic causes of ALS/FTD has contributed significantly to our understanding of disease pathogenesis. Unfortunately, one-third of the underlying genetic causes of familial cases and ~90% of sporadic cases of ALS/FTD remain unexplained. As such, there is a dire need to identify additional genetic factors contributing to ALS/FTD. Such studies require huge cohorts of harmonized whole genome sequencing (WGS) data sets from cases and controls. Currently, there are several major ongoing sequencing efforts for ALS patients. Numerous centers lead to inefficiency, especially in terms of overall costs. At a minimum, this includes the cost of high-performance computing, the storage of large data files, and the duplication of effort between groups. This lack of data harmonization between groups precludes sharing of genetic information and weakens collaborative efforts. The cost and logistics are also a barrier to attracting talented investigators to the ALS/FTD field. To overcome this unmet need, we have founded the ALS Compute project. We are centralizing the storage of ALS/FTD WGS data from every significant sequencing effort in the United States and beyond within a single Cloud environment. This approach will facilitate data harmonization and improve accessibility to the data. To accomplish this, we have made the data and the computational infrastructure available via the Terra platform hosted by NHGRI's Genomic Data Science Analysis, Visualization, and Informatics Lab-Space (AnVIL). This will allow researchers worldwide to access this wealth of data, develop new theories of the disease, and yield breakthroughs in our understanding of ALS/FTD.

Study phs003184

The Familial Intracranial Aneurysm Linkage Study (FIA)

Our long-term objective is to identify susceptibility genes that are related to the formation of intracranial aneurysms (IA). Rupture of IAs occurs in 16,000 to 17,000 persons in the U.S. annually and nearly half of affected persons are dead within the first 30 days. An additional 6,000 to 7,000 persons with unruptured IAs are identified each year. Accumulated evidence indicates that a genetic component plays an important role in the development of IAs, but specific loci affecting the risk of IA have not been identified. The primary hypothesis of this study is that there are specific human chromosomal regions that are associated with an increased risk of IAs. Specific Aims of are: Recruitment of 400 (475) families with multiple individuals who have an IA through 23 (25) referral centers throughout North America, Australia, and New Zealand that represent 35 (40) recruitment sites. Ascertainment of interviews and blood samples from all affected family members as well as their first-degree relatives. White blood cells from living persons with an IA will be cryopreserved at Coriell Institute for Medical Research for future immortalization of cells lines as indicated. Identification of unruptured IAs by obtaining MRAs in selected asymptomatic siblings (of affected individuals). Completion of a 10 cM genome series in persons with IAs as well as the spouses and children of persons with an IA who are deceased. We will perform finer mapping of chromosomal regions with suggestive evidence of linkage in the genome screen. Performance of a nonparametric (allele sharing) linkage analysis, including relevant environmental factors such as smoking, to identify chromosomal regions linked to IA. Reconstruction of the genotypes of deceased affected family members will be performed. Identification of individuals who are genetically at high risk for the development of IAs would enable targeted and effective screening/prevention/treatment strategies to reduce the substantial mortality and morbidity associated with this devastating type of stroke. Only a multidisciplinary, collaborative effort to identify, accrue, and genotype FIA families will be successful in identifying sufficient high-risk families to characterize the genetic underpinnings of IA.

Study phs000293

Asian Indian Diabetic Heart Study (AIDHS) /Sikh Diabetes Study (SDS)

The Punjabi Sikh population is a well-defined, carefully collected homogeneous sample from northern India and the US. It has unique characteristics, which are ideal for genetic studies. Sikhs are strictly a non-smoking population and about 50% of participants are life-long vegetarians. All subjects included in the genome-wide association studies (GWAS) were recruited from one geographical location. Our population demonstrates a strong familial clustering of type 2 diabetes and related cardio-metabolic disorders that may be genetic and we believe that the contribution of alleles at specific loci are likely to be unique to Punjabi Asians compared to Europeans. Our group first showed that the association of a common variant at rs9939609 in the FTO (fat mass and obesity) gene in South Asians was independent of BMI (PMID:18598350) in contrast to Europeans where the association of same variant with T2D is mediated through obesity (PMID:17434869). These findings were later confirmed in an independent sample of South Indians (PMID:19005641), Pakistanis (PMID:21294771), and even East and South Asians in a large meta-analyses study comprising 96,551 individuals (PMID: 22109280). Earlier reported association of MTNR1B with fasting glucose concentrations and type 2 diabetes in European GWAS could not be confirmed in our Sikh cohort. On the other hand, our study revealed, for the first time, a significant protective association of another less common variant in MTNR1B with fasting glucose levels that was modulated by obesity. Ours was the first report that suggested that the low CETP activity was associated with higher CAD risk (PMID:22143414) in South Asians and that the genetic effects are significantly modulated by environmental factors (alcohol consumption). Our recent GWAS on type 2 diabetes has identified a novel locus at chromosome 13q12 in the SGCG gene (p=1.82x10-8) associated with type 2 diabetes (PMID:23300278) in Punjabi Sikhs. From these findings, we are optimistic that our resource will provide new insights to gene functions in the diabetic pathway and better help researchers to understand and translate these insights to novel therapeutic treatment and early prevention to T2D that may be important beyond Indians.

Study phs000583

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