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• Mayo-Perlegen LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) Collaboration

  We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62E-6). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70E-5). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07E-6; P=2.96E-5) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility. Note: The following instruments were used: 1)clinical assessments form and manual; 2) sibling screening form and manual; 3) unrelated control screening and manual; and 4) risk factors questionnaire and manual. All cases underwent #1, as did sibling controls screening positive (see below). Unrelated controls were not examined. All siblings underwent #2. All unrelated controls underwent #3. All subjects (cases, sibling controls, and unrelated controls) underwent #4. Any publications using the data are to cite the original American Journal of Human Genetics article (Maraganore et al., 2005). Investigators using the data collection instruments are to acknowledge Drs. Maraganore and Rocca, and cite grants ES-10751 and NS-33978.

  Study phs000048

• Genomic Characterization of Head and Neck Squamous Cell Carcinoma Cell Lines

  Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer by incidence worldwide(1). Various chemical carcinogens (tobacco, alcohol and betel nut), human papillomavirus (HPV) infection, and genetic predisposition contribute to the etiology of HNSCC, and to the complex genetic alterations in tumor subsets that differ in prognosis and response to therapies (2). Recently, a comprehensive landscape of genomic and transcriptomic alterations in HNSCC tumors has emerged from The Cancer Genome Atlas (TCGA) Network (3). TCGA revealed novel and previously recognized gene and chromosomal region copy number alterations (CNAs), mutations, and expression clusters, and defined their frequency, co-occurrence, and relationship to common and rare subtypes of HPV(-) and (+) tumors that vary in prognosis. To identify cell line models for determining the functional role and therapeutic importance of these alterations, we are performing whole exome and RNA sequencing and bioinformatic analysis of an expanded panel of 15 HPV(-) and 11 HPV(+) HNSCC cell lines and primary oral keratinocytes. We find that the recurrent genomic alterations in cell lines are remarkably consistent with those found in more aggressive tumors, from which cell lines have traditionally been most readily adapted to culture (4). Genome-wide correlation of CN (copy number) with expression identified a suite of potential drivers or modifier genes that differ by HPV status, and are of potential biologic and therapeutic relevance. Further, our findings elucidate and validate genomic alterations underpinning numerous discoveries made with these widely-used and recently derived HNSCC lines, and provide a roadmap for their potential use as models for future studies of tumor subtypes with worse prognosis. References Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. Van Waes C, Musbahi O. Genomics and advances towards precision medicine for head and neck squamous cell carcinoma. Laryngoscope Investig Otolaryngol. 2017;2(5):310-9. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-82. White JS, Weissfeld JL, Ragin CC, Rossie KM, Martin CL, Shuster M, et al. The influence of clinical and demographic risk factors on the establishment of head and neck squamous cell carcinoma cell lines. Oral Oncol. 2007;43(7):701-12.

  Study phs001581

• National Institute of Arthritis and Musculoskeletal and Skin Diseases and Istanbul Faculty of Medicine Genome-wide Association Study of Behçet's Disease (Turkish)

  IntroductionBehçet's disease (BD) is a genetically complex multisystem disease of unknown etiology, characterized by recurrent inflammatory attacks affecting orogenital mucosa, eyes, skin, joints, blood vessels, and less frequently, the central nervous system and gastrointestinal tract. Family studies suggest a genetically complex contribution to BD. With the exception of HLA-B51, which explains less than 20% of the genetic risk, the identities of alleles that are responsible for the complex inheritance of this disease have remained unclear. AimTo identify genes that contribute to BD susceptibility. MethodsA genome-wide association study was undertaken with 311,459 informative and high quality SNPs in a collection of 1215 BD patients and 1278 healthy controls from Turkey using a beadchip microarray assay (Infinium SNP genotype assay, Illumina). HLA-B types were determined with a reverse sequence-specific oligonucleotide method (One Lambda). Regions with evidence for association were fine-mapped using Sequenom iPLEX gold assays. Disease-associated SNPs were genotyped in additional ethnically matched case/control collections from diverse genetic backgrounds, including a total of 2430 cases and 2660 controls, using TaqMan SNP genotype assays. Association data were combined in a meta-analysis of all the collections. ResultsWe confirmed the known association with HLA-B51 and found evidence for a second, independent susceptibility locus in the Class I region of the MHC. In addition, we identified one SNP with genome-wide evidence for disease association (P < 5.0 x 10-8) within the gene encoding the immunoregulatory cytokine, interleukin-10 (IL10). A meta-analysis of the data from all the collections established associations with the IL10 variant (rs1518111, P = 3.54 x 10-18, odds ratio 1.45 with 95% confidence interval 1.34 to 1.58) and with a variant located between the interleukin-23 receptor (IL23R) and interleukin 12 receptor β2 (IL12RB2) genes (rs924080, P = 6.69 x 10-9, odds ratio 1.28 with 95% confidence interval 1.18 to 1.39). The disease-associated IL10 variant was associated with diminished mRNA expression and low protein production by cells obtained from healthy blood donors. ConclusionsThese data suggest that genetically encoded low production of IL-10 increases risk of BD and suggest novel interventional targets in the IL-10 and IL-23 pathways. Note: The submitted data are the genotypes of the 311,459 SNPs in 1215 cases and 1278 controls.

  Study phs000272

• Genetic Causes of Congenital Anosmia

  The Genetic Causes of Congenital Anosmia study was designed to provide a list of candidate genes that are potentially causal for isolated congenital anosmia (ICA), a rare inherited disorder where individuals lack a sense of smell from birth in the absence of a known genetic syndrome (i.e. Kallman's syndrome). This study includes 193 participants from 18-87 years of age, divided into two cohorts: family and non-family. Genetic data from the family cohort was analyzed in a case-control family design to generate a list of 162 candidate genes for ICA. A targeted search for variants in this list of genes was then conducted in the non-family cohort to create a prioritized list of genes for further study. Ten unrelated families were recruited for the family cohort for a total of 52 participants, 25 of which had anosmia. The non-family cohort consisted of 141 anosmic individuals. 3 additional normosmic participants from incomplete families were collected, one of whom has a participating family member in the non-family cohort, and so has data provided here. Data collection was conducted remotely, resulting in 146 participants recruited from the United States, and 48 recruited internationally from ten different countries. Participants were interviewed for their anosmia status and to confirm that they had no known genetic syndromes. Participants also completed the University of Pennsylvania Brief Smell Identification Test (BSIT; Doty et al., 1984) to confirm their anosmic/normosmic status and provided a saliva sample for whole exome sequencing (WES). Participants who had family members with anosmia provided pedigree information via interview. Data submitted to dbGap include whole exome sequences from 194 individuals (163 anosmic) conducted with Illumina HiSeq2500 and Illumina NovaSeq next generation sequencing technologies. Family pedigree information for the 10 participating families and all participants in the non-family cohort who have non-participating anosmic family members was also included. Our goal was to provide a resource for further research into the genetics of isolated congenital anosmia and to aide in the understanding of this disorder, as well as human olfaction, in general. The WES data provided could be further analyzed for polygenic interactions, additional non-targeted analysis on the non-family cohort, or combined into databases of other anosmic populations for further gene targeting or selection.

  Study phs003328

• Acute Respiratory Distress Network (ARDSNet) Studies 06 and 08 Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo for the Treatment of Acute Lung Injury (ALTA) (ARDSNet-ALTA-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ALTA include Plasma, DNA, Urine, and BAL. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives This clinical trial was designed to test the hypothesis that an aerosolized beta-2-agonist, albuterol, would improve clinical outcomes in participants with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Background In participants with acute lung injury and acute respiratory distress syndrome (ALI/ARDS), inflammation of the pulmonary circulation increases vascular permeability. Fluid leaks from blood vessels into the pulmonary interstitium and alveoli. Recovery from this form of acute respiratory failure requires that the pulmonary edema resolve. The resolution of alveolar edema is driven by active transport of sodium and chloride ions from the luminal space across both type I and type II alveolar epithelial cells, creating an osmotic gradient for the reabsorption of water. In the ex vivo human lung, the rate of alveolar fluid clearance can be doubled by treatment with a cyclic AMP beta-2 adrenergic receptor agonist. On the basis of the preclinical observations that treatment with beta-2-agonists could reduce pulmonary edema and accelerate the rate of alveolar fluid clearance, the ALTA study was designed and undertaken with the hypothesis that treatment of participants with ALI/ARDS with beta-agonist therapy would accelerate the resolution of alveolar edema and improve clinical outcomes. Participants There were 282 participants. Design Study staff conducted a multicenter, randomized, placebo-controlled clinical trial in which participants were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. Conclusions Ventilator-free days were not significantly different between the albuterol and placebo groups. The results suggest that aerosolized albuterol does not improve clinical outcomes in participants with ALI. Routine use of beta-2 agonist therapy in mechanically ventilated participants with ALI cannot be recommended (Matthay, et al., 2011, PMID: 21562125).

  Study phs003743

• Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis (CleanUP IPF-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives To investigate whether the addition of antimicrobial treatments improves outcomes compared to usual care alone among patients with idiopathic pulmonary fibrosis. Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Lung dysbiosis, characterized by increased bacterial load and/or loss of diversity, has been reported in patients with IPF and may contribute to hospitalization and death. Clinical trials investigating other chronic disorders suggest that antimicrobial therapy favorably alters the lung microbial community. The CleanUP IPF study was initiated to determine if an antimicrobial treatment reduces respiratory hospitalization or death among patients with IPF. Participants A total of 513 participants were enrolled. 254 participants were randomized to receive antimicrobials, of those 128 were randomized to receive co-trimoxazole and 126 were randomized to receive doxycycline. 259 participants were randomized to receive usual care alone. Design CleanUP IPF was a randomized, unblinded, multicenter study. Patients were randomized to receive antimicrobials in addition to usual care or usual care alone. Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily) or doxycycline (100 mg once daily if body weight Data collected included diffusion capacity of lungs for carbon monoxide (DLCO), forced vital capacity (FVC), and occurrence of severe adverse events. Several questionnaires were administered to assess quality of life, including the impacts of shortness of breath, fatigue, and chronic cough on participants. The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. The study was terminated early due to futility. Conclusions Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. Martinez FJ, Yow E, Flaherty KR, et al. Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. JAMA. 2021;325(18):1841-1851. doi:10.1001/jama.2021.4956

  Study phs004314

• METABRIC: Data from Pereira et al (2016), The somatic mutation profiles of 2433 breast cancers refine their genomic and transcriptomic landscapes. Nat Comms 7.

  The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2433 primary breast tumours that have copy number aberration (CNA), gene expression, and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters, and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intratumour heterogeneity using mutant allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intratumour heterogeneity are in general associated with worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intratumour heterogeneity. These results emphasise the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

  Study EGAS00001001753

• WES of adult intellectual disabilities with co-morbid psychiatric disorders (2019-08-07)

  ost adults with intellectual disabilities (ID) do not undergo genetic diagnostic investigation as part of their clinical care and have 'missed the boat' with regard to the WES and WGS genetic testing that is now being provided for children with ID. There is a dramatically increased risk of psychistric disorders in adults with ID, e.g. the risk of psychoses is 10X higher than in the general population. It remains an open question as to how much of adult ID is genetic in origin and how similar the genetic forms of adult ID are to those being diagnosed in children, in part due to survivor bias. There is also the opportunity to identify adults with treatable forms of ID, of which over 80 have been described, thus improving their clinical management. Furthermore, analysis of medical records of adults with genetic forms of ID can help to characterise the 'natural history' of individual disorders, resulting in more accurate prognoses for diagnosed children and identifying opportunities for improved management and possibly therapeutic intervention (e.g. optimal anti-epileptic therapy). Here we propose to exome sequence (to ~50X coverage) 200 adults with ID and co-morbid psychiatric disorders. This cohort has previously been assayed with chromosomal microarrays (Wolfe et al 2017 EJHG, 25, 66-72) identifying a diagnostic yield of ~11% which is comparable to the CNV diagnostic yield in various child ID cohorts (10-15%). The authors observed no substantive biases in diagnostic yield between different psychiatric diagnostic classes. The WES data will be analysed using the diagnostic workflows developed in the DDD study to ensure comparability between child and adult ID datasets. This study is intended as a pilot study to demonstrate the value of WES in adults with ID. 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 2019-08-07.

  Dataset EGAD00001005236

• Djerroudi et al., E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma

  Invasive lobular breast carcinoma (ILC) shows specific stromal features, T lymphocyte infiltration (TIL) being associated with poor prognosis. Here, we reveal the involved mechanism by performing single cell RNA sequencing, combined immunohistochemistry, deconvolution of bulk RNA sequencing from large retrospective ILC series, and functional assays using primary cells. We show that ILC accumulate FAP+ inflammatory cancer-associated fibroblasts (iCAF) through a previously undescribed mechanism mediated by E-cadherin/CDH1 on CAF plasticity. Indeed, CDH1 inactivation in ILC cancer cells prevents differentiation of iCAF into myofibroblastic CAF (myCAF), leading to iCAF accumulation. In turn, iCAF increase TIL infiltration and shape their spatial organization in ILC. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape by lack of retention and activation of ITGAE-expressing resident memory CD8+ T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, iCAF and CD8+ TRM, revealing why and how TILs have a poor prognosis in ILC patients, a mechanism extrapolated to other CDH1-mutated cancer types.

  Study EGAS50000000761

• CIDR: NINDS High Throughput Genotyping Resource Access for Structural Hindbrain Disorders

  Recessive forms for many structural brain disorders (SBDs), including cerebellar hypoplasia (CBH), corpus callosum hypoplasia (CCH), cobblestone lissencephaly (COB), classical lissencephaly (LIS), microcephaly (MIC), and pontocerebellar hypoplasia (PCH), have been described. Patients usually present to the clinic with neurodevelopmental disorders (NDDs), including autism, epilepsy, intellectual disability, and cerebral palsy. Subsequent brain MRI usually leads to the diagnosis of an SBD. While a handful of genes that cause these diseases have been identified, most patients do not have mutations in these genes, suggesting that there is still much work to be done in identifying the genetic causes of these disorders. We have recruited a cohort of families with inherited SBDs, most from families with documented parental consanguinity with more than one affected member. Current approaches utilizing exome sequencing of SBD affected members still leave most cases unsolved, in part because there are too many possible variants to consider. Linkage analysis will allow us to extract all the useful genetic information from the family, taking advantage of each genetically informative meiosis in each family. We propose to analyze up to 100 SBD families for 500 samples per year for 4 years, through the CIDR SNP Genotyping Service, in parallel with already-funded exome sequencing of affects, leveraging off an already funded Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) effort to identify new causes of SBDs. Understanding the pathogenetic mechanisms underlying recessive pediatric SBDs will lead to better diagnostic and therapeutic opportunities for patients, and may shed light on complex NDDs. Ultimately, this work will identify new genetic disease loci to provide insight into pediatric SBD, with the hope to mitigate the impact of SBD worldwide.Public Health Significance: NDDs affect approximately 4-­6% of the general population, most notably children, and are evident in disorders, such as intellectual disability, epilepsy, and autism, with estimated yearly costs of $51.2B for intellectual disability, $11.5B for cerebral palsy, and $2.5B for visual impairment, making up >5% of total health care costs. Recessive NDDs impose enormous personal, social, and economic costs because of the early onset and the lifetime of medical dependence that often ensues. Genetic testing is critical to the diagnosis and treatment of these diseases. Many of the diseases under study have no treatment or cure. Structural brain diseases (SBDs) underlie a large percentage of these diseases, and are defined loosely as any condition in which defects in the structure or volume of a key brain component. SBDs are divided into major categories based upon the anatomical brain location. The major types involve the anatomical structures of the developing neural tube, forebrain, hindbrain, cerebral cortex, and those affecting overall brain size. For the purposes of this application, we have excluded SBDs resulting from environmental causes (i.e. prematurity-­induced), those below the brainstem, or those unlikely to be due to a germline or de novo mutation (i.e. focal SBDs or simplex disease).

  Study phs002621