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Genetics Core

遗传学核心

基本信息

批准号：
10450020
负责人：
Rosa Rademakers
金额：
$ 54.54万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450020
关键词：
Aging Alzheimer&apos s Disease American Bioinformatics Blood C9ORF72 Classification Clinical Communities Copy Number Polymorphism Custom DNA Data Data Set Dideoxy Chain Termination DNA Sequencing Disease Disease model Distant Early Diagnosis Enrollment Ethnic Origin Etiology Family Frontotemporal Lobar Degenerations Functional disorder Funding Future Gene Mutation Generations Genes Genetic Genetic Enhancement Genetic Risk Genetic study Genomics Genotype Goals Guidelines Heterogeneity Image Immune System Diseases Immune system Individual Knowledge Laboratories MAPT gene Manuals Measures Medical Genetics Molecular Genetics Mutation Analysis Natural History Nerve Degeneration Neurodegenerative Disorders PGRN gene Participant Pathologic Pathology Pathway interactions Patient Recruitments Patients Phenotype Population Progressive Supranuclear Palsy Protocols documentation Publishing Research Research Personnel Resources Risk SCA2 protein Sample Size Sampling Single Nucleotide Polymorphism Site Statistical Data Interpretation Testing Trinucleotide Repeat Expansion U-Series Cooperative Agreements United States National Institutes of Health Validation Variant Work accurate diagnosis causal variant clinical subtypes cohort cost design experimental study follow-up gene discovery genetic analysis genetic association genetic risk factor genome analysis genome sequencing genome wide association study genome-wide genomic data improved kindred medical schools member mutation screening mutational status neurodegenerative dementia novel patient stratification polygenic risk score programs protein TDP-43 tau Proteins tau mutation variant of unknown significance whole genome

项目摘要

ABSTRACT – ARTFL LEFFTDS Longitudinal FTLD: GENETICS CORE The overarching goal of the Genetics Core is the accurate and timely generation, annotation, interpretation and sharing of state-of-the art genetic data on all frontotemporal lobar degeneration (FTLD) patients and blood relatives enrolled in ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) to support FTLD research within and outside of the ALLFTD Program. Genetic characterization of this unique cohort is critically important to test hypotheses and interpret research findings obtained in the other ALLFTD Cores and Projects and will be invaluable to future FTLD gene discovery efforts within the larger research community. The work proposed in this Core is highly complementary and non-overlapping with currently ongoing NIH-funded FTLD sequencing efforts, which will be leveraged to enhance the genetic characterization of our participant cohorts. More than 1,100 unique individuals have been enrolled in ARTFL and LEFFTDS since their inception in 2014 and an additional 1,600 unique individuals are expected to be enrolled as part of the ALLFTD protocol. Consequently, DNA of at least 2,700 individuals will be available for genetic studies, making this an unprecedented resource. Most notably, on all 2,700 subjects, the Genetics Core will: generate genome-wide single nucleotide variant (SNP) data; perform targeted mutation screening of ~300 neurodegenerative disease genes; determine presence or absence of causal mutations in known disease genes; and integrate genetic data in the form of polygenic risk scores (PGRS) for downstream analyses in the Projects. These important goals are achieved through the following Specific Aims: 1) Perform genetic analyses to determine ethnicity and relatedness between ALLFTD participants. Genotyping using the Infinium Omni2.5Exome-8 Kit will be performed in all newly ascertained ALLFTD participants (n=1,600) and combined with previously obtained genotype data (n=1,100) to determine the ethnicity and relatedness between ALLFTD participants, to call copy-number variants (CNVs) and to calculate PGRS; 2) Perform targeted mutation analysis in ALLFTD participants. We will follow an efficient, step-wise, approach to genetically characterize ALLFTD participants, including C9orf72 and ATXN2 repeat expansion testing, targeted gene sequencing of ~300 neurodegenerative disease genes with sequence validation and manual curation of observed variants using American College of Medical Genetics and Genomics guidelines, and whole-genome sequencing and analysis of newly ascertained genetically unexplained familial FTLD patients; and 3) Generate PGRS for ALLFTD participants. Distinct datasets from published genome-wide association studies will be used to generate PGRS in study participants for use in the Projects, including PGRS for individual neurodegenerative diseases and PGRS that reflect related pathologies such as immunological disorders. As our sample size increases we will further derive PGRS from genomic data generated as part of ALLFTD, especially for FTLD clinical subtypes.

ARTFL LEFFTDS纵向FTLD：遗传学核心遗传学核心的首要目标是准确和及时地生成、注释、全额颞叶变性最新遗传数据的解释和共享 (FTLD)参加ARTFL LEFFTDS纵向FTLD(ALLFTD)的患者和血亲支持ALLFTD项目内外的FTLD研究。这是一种遗传特征独特的队列对于检验假设和解释在另一个队列中获得的研究结果是至关重要的 ALLFTD的核心和项目，对于未来在更大范围内发现FTLD基因的努力将是无价的研究社区。本核心建议的工作具有很强的互补性，与目前正在进行由NIH资助的FTLD测序工作，这将被用来增强基因我们的参与者队列的特征。已有1100多名独特的个人在ARTFL注册和LEFFTDS自2014年成立以来，预计还将有1,600个独特的个体作为ALLFTD协议的一部分登记。因此，至少2700人的DNA将可用于基因研究，使其成为一种前所未有的资源。最值得注意的是，在所有2700个主题中，遗传学核心将：生成全基因组单核苷酸变异(SNP)数据；执行有针对性的突变筛查 ~300个神经退行性疾病基因；确定已知疾病中是否存在因果突变基因；并以多基因风险分数(PGR)的形式整合遗传数据，用于在项目。这些重要目标是通过以下具体目标实现的：1)执行遗传分析以确定ALLFTD参与者之间的种族和亲属关系。使用基因分型技术 Infinium Omni2.5Exome-8试剂盒将在所有新确定的ALLFTD参与者(n=1,600)中进行结合以前获得的基因数据(n=1,100)来确定种族和亲属关系在ALLFTD参与者之间，调用拷贝数变体(CNV)并计算PGR；2)执行 ALLFTD参与者的靶向突变分析。我们将遵循高效、循序渐进的方法 ALLFTD参与者的基因特征，包括C9orf72和ATXN2重复扩增测试，有针对性对约300个神经退行性疾病基因进行基因测序，并进行序列验证和手动管理使用美国医学遗传学和基因组学指南和全基因组观察到的变异对新发现的遗传原因不明的家族性FTLD患者进行测序和分析；以及3)生成为ALLFTD参与者提供的PGRS。来自已发表的全基因组关联研究的不同数据集将是用于在研究参与者中生成用于项目的PGR，包括针对个人的PGR 神经退行性疾病和反映相关病理的PGR，如免疫紊乱。AS 我们的样本量增加了，我们将进一步从作为ALLFTD一部分产生的基因组数据中获得PGR，尤其是FTLD临床亚型。