Genetics Core

摘要- 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的生成，注释， 解释和分享所有额颞叶变性的最新遗传数据 在ARTFL LEFFTDS纵向FTLD（ALLFTD）中入组的FTLD患者和血亲， 支持在ALLFTD计划内外的FTLD研究。基因特征 一个独特的队列对于检验假设和解释另一个队列中获得的研究结果至关重要。 ALLFTD核心和项目，将是宝贵的未来FTLD基因发现的努力，在更大的 研究社区。本核心建议的工作与下列工作具有高度互补性和不重叠性： 目前正在进行的NIH资助的FTLD测序工作，这将被用来增强遗传 我们的参与者队列的特征。超过1，100名独特的个人已在ARTFL注册 和LEFFTDS自2014年成立以来，预计将有1，600名独特的个人 作为ALLFTD方案的一部分入组。因此，至少2,700人的DNA将可用于 基因研究，使其成为前所未有的资源。最值得注意的是，在所有2,700名受试者中， 核心将：生成全基因组单核苷酸变异（SNP）数据; ~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;并以多基因风险评分（PGRS）的形式整合遗传数据，用于下游分析。 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受试者之间的种族和相关性。基因分型使用 Infinium Omni2.5Exome-8 Kit将在所有新确定的ALLFTD受试者（n= 1，600）中进行， 结合先前获得的基因型数据（n= 1，100），以确定种族和相关性 在ALLFTD受试者之间，调用拷贝数变体（CNV）并计算PGRS; 2）进行 ALLFTD受试者的靶向突变分析。我们将采取有效、循序渐进的方法， 对ALLFTD受试者进行基因表征，包括C9 orf 72和ATXN 2重复扩增试验， 对约300个神经退行性疾病基因进行基因测序，并进行序列验证和人工管理， 使用美国医学遗传学和基因组学学会指南观察变异， 对新确定的遗传原因不明的家族性FTLD患者进行测序和分析;以及 ALLFTD受试者的PGRS。来自已发表的全基因组关联研究的不同数据集将被 用于生成研究参与者的PGRS，以用于项目，包括个人PGRS 神经退行性疾病和反映相关病理的PGRS，如免疫紊乱。作为 我们的样本量增加，我们将进一步从作为ALLFTD的一部分产生的基因组数据中获得PGRS， 特别是对于FTLD临床亚型。

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.