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• Loss of IFN-gamma Signaling in Tumor Cells Associates with Primary Resistance to Anti-CTLA-4 Therapy

  Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here we demonstrate that, based upon exome sequencing data, patients identified as non-responders to anti-CTLA-4 (ipilimumab) harbor a much higher genomic defects in the IFN-γ pathway genes than melanoma patients who had clinical response to ipilimumab therapy.

  Study phs001257

• Tracing the molecular route to progression in miRNA biogenesis-defective thyroid lesions

  Alterations in the DICER1 and DGCR8 microprocessor genes confer risk to the development of benign and malignant thyroid lesions. The involvement of 2 miRNA biogenesis genes in benign and malignant thyroid tumors highlights the key role of miRNAs in the thyroid gland. We traced the progression from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions by performing a multiomic characterization of these lesions aiming to uncover unique features characterizing either form for potential use as biomarkers. This multiomic characterization included whole exome sequencing (WES) (N=18), miRNA profiling (N=38), spatial transcriptomics (N=2) and/or methylome (N=281).

  Study EGAS50000001577

• Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations

  Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here, we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3,908 controls in the Chinese population, followed by two independent replicate samples including 2,142 cases and 4,697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 X 10-10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 X 10-9) and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 X 10-8).

  Study EGAS00001003040

• THE GENOMIC LANDSCAPE OF ACTINIC KERATOSIS

  Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (CSCC). Identifying the specific genomic alterations driving progression from normal skin-AK-invasive CSCC is challenging due to the massive ultraviolet radiation-induced mutational burden characteristic at all stages of this progression. Here, we report the largest AK whole exome sequencing study to date and perform mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AK, from both immunosuppressed and immunocompetent patients, that there are significant similarities to CSCC in terms of mutational burden, copy number alterations, mutational signatures and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in CSCC. We identify the azathioprine mutational signature in all AK from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. CSCC differ from AK in having higher levels of intra-sample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGF-β signaling significantly more mutated in CSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGF-β signaling may represent an important event in AK-CSCC progression.

  Dataset EGAD00001006894

• Family Investigation of Nephropathy and Diabetes (FIND) Study

  The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic kidney disease. Study subjects were recruited from eleven centers and in many ethnic groups throughout the United States. A genome-wide association study (GWAS) was conducted with the Affymetrix 6.0 chip. Subjects (index cases) with diabetes and kidney disease were initially recruited, and their parents and siblings were invited to participate. Genetic material from these participants was used to genotype markers throughout the genome. For association-based testing, a case-control design was implemented with study subjects selected primarily from the index cases of the families. Unrelated controls were selected from families where a case was not already selected. Several study sites also contributed non-FIND subjects, both cases and controls (consent forms for the release of FIND and non-FIND subjects/samples are included in this dbGaP release). Cases were selected if they met study criteria for diabetic nephropathy or met inclusion criteria based on elevated serum creatinine levels and abnormal urine protein excretion. Similarly, controls were long-term diabetics with otherwise normal kidney function. See inclusion/exclusion criteria section for a detailed description for the FIND study as a whole and this GWAS. The goal of the FIND study is to identify genes that influence susceptibility to diabetic kidney disease, leading to a better understanding of how kidney disease develops. In the long run, this may lead to improved treatment and prevention of diabetic kidney disease.

  Study phs000333

• Early Methamphetamine Abstinence: fMRI and Brain Function

  This study included two groups of subjects, methamphetamine-dependent and healthy control participants, with the purpose of characterizing brain structure and cognition during the first month of abstinence from methamphetamine. Participants were able to participate in one or both phases of the study. Methamphetamine abusers were held as inpatients and abstained from methamphetamine use during the entirety of the study. Phase I covered the 1st week of abstinence and Phase II covered the next 3-4 weeks of abstinence. Control subjects participated as outpatients at timeframes which corresponded to the assessments taken of methamphetamine users. The following outlines the procedures in more detail. After initial telephone screening, in-person screening and recruitment procedures took place at the UCLA Neuropsychiatric Institute. Each methamphetamine abuser subject entered the study after completing an interview and questionnaires on drug use history, and providing a positive urine test for methamphetamine. The evaluation included a psychiatric diagnostic interview according to the Structured Clinical Inventory for DSM-IV (SCID-IV), a medical history and physical examination, blood tests [including a complete chemistry panel, hepatic panel, and tests for hepatitis-C and HIV]. Urine samples were also taken for drug screening of illicit drugs, and to test for pregnancy (female subjects). The methamphetamine abusers were then admitted to the General Clinical Research Center (CRC) and participated on a residential basis, where they were administered daily questionnaires about drug craving, withdrawal and mood. The current study makes available phenotype and genotype data, and interested investigators may contact the principal investigator regarding potential sharing of fMRI data.

  Study phs001198

• Study on the Genetics of Alcoholism (COGA): Smoke Screen and Exome Sequencing

  This is a family study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This project has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results are included on a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3.

  Study phs001208

• Nanopore sequencing enables allelic phasing of FLG loss-of-function variants, intragenic copy number variation and methylation status in atopic dermatitis and ichthyosis vulgaris

  Loss-of-function (LoF) variants in the FLG gene are associated with ichthyosis vulgaris (IV) and atopic dermatitis (AD). IV and AD patients with two FLG LoF variants are reported to have a more severe disease course. However, subsets of compound heterozygous patients display phenotypic heterogeneity despite a prediction of a severe phenotype from their genotype. The underlying genetic mechanism of this phenotypic variability is unknown. One possibility is that two LoF FLG variants could be located in cis (on the same allele), thus altering the predicted gene dosage. To investigate the allelic contribution of compound heterozygous FLG LoF mutations to IV phenotypic variability, we employ long reads from Oxford Nanopore Technologies, utilising two methodologies to phase the entire coding region of FLG into parental alleles: an amplicon-sequencing approach and an adaptive-sampling strategy. We investigated the allelic phasing of FLG LoF variants and intragenic-repeat copy-number variations (CNV) of 21 subjects with known compound heterozygous genotypes and mixed IV severity. Our results suggest that IV severity is not linked to the presence of cis variants in our IV patient cohort. Nanopore reads enabled detection and accurate phasing of CNVs and LoF variants into parental alleles, providing a framework for future in-depth genetic analysis. These results highlight the usefulness of utilising long reads for interrogating the FLG gene and other highly repetitive genes for genetic stratification related to clinical phenotypes.

  Study EGAS50000000166

• NINDS Family-Based Whole-Genome Sequencing to Find Modifiers of Age of Onset in Huntington's Disease

  The goal of our studies is to identify genetic modifiers of neurodegeneration in Huntington's disease (HD). HD is caused by expansion of CAG repeats in the huntingtin (Htt) gene, with longer stretches often leading to more rapid disease onset and progression. Yet, for a given number of repeats, the age of symptom onset can be variable, differing by up to decades. Thus, the age of onset of motor symptoms in HD is only partly explained by the length of the CAG expansion. Available evidence suggests that genetic modifiers contribute to the variation in HD onset. Identifying genetic modifiers is important because they may provide critical insights into HD pathogenesis and reveal key pathways that could be targeted by novel HD therapeutics. This is important since there are no disease-modifying therapies for HD, and mHtt is an unattractive small-molecule drug target. We recruited 21 HD families with varying characteristics of disease progression and age of onset and obtained medical histories, clinical records and DNA samples that were subjected to whole-genome sequencing (WGS). These WGS data describe families of 104 subjects, including HD patients and their unaffected family members. These individuals were selected based on individual clinical histories and family structures that best fit our criteria for expressing potential genetic modifiers. We are testing the hypothesis that novel, rare genetic variants contribute to HD and those genetic modifiers can be identified by WGS.

  Study phs001071

• Whole Genome Sequencing Analysis in a Family of Discordant Twins With Non-Syndromic Microtia and Hemifacial Microsomia: Identification of Novel Candidate Genes and Variants

  This research is a non-NIH effort to discover the pathogenesis of non-syndromic microtia and to detect potential candidate genes. Microtia (OMIM 600674, 612290, 251800) is a spectrum of congenital anomalies and facial abnormalities, 90% of the cases followed by hearing loss. Two types of the disease are described in terms of connection to the affected syndromes: anomalies (syndromic) and only clinical manifestation (non-syndromic) associated with other symptoms. Though the exact pathogenesis of microtia remains unknown, pathogenic genes of majority of the microtia syndromic types have been identified. However, the genetic mutation of the non-syndromic microtia has not been confirmed. In this study, whole genome sequencing (WGS) was utilized to screen mutations in monozygotic discordant twins of congenital microtia-atresia and their family members. One of the twins, along with her grandfather, was discordant for microtia-atresia. By bioinformatic analysis of the WGS data from monozygotic twins with microtia and their non-microtia relatives, we proposed that among 28 identified potential genes, 4 of them (CNOT1, ODAD4, TBX15, and GIPC3) could be more responsible for non-syndromic microtia development and phenotypic features. Interested investigators may request to access the DNA genomic sequencing data of the study participants via dbGaP authorized access. In addition to raw genomic sequencing data, datasets of germline mutations and candidate gene mutations may also be available for investigators to request.

  Study phs003216