Exploring the role of genetic structural variation in neuropsychiatric diseases

探索遗传结构变异在神经精神疾病中的作用

• 批准号: 10470859
• 负责人: Maxwell Aaron Sherman
• 金额: $ 4.68万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470859
• 关键词: Adult; Age; Autopsy; Base Pairing; Biological; Biology; Bipolar Disorder; Case-Control Studies; Catalogs; Cell Fraction; Chromosomal Rearrangement; Collection; Communities; Computer software; Copy Number Polymorphism; Data; Data Sources; Databases; Diagnosis; Disease; Embryonic Development; Epilepsy; Event; Foundations; Frequencies; Future; Genetic; Genetic Risk; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Hematopoiesis; Heritability; Human; Individual; Maps; Measures; Medical; Mental disorders; Methodology; Methods; Minority; Modeling; Mosaicism; Mutation; Nucleotides; Phase; Play; Population; Populations at Risk; Property; Research; Research Personnel; Resources; Risk; Role; Schizophrenia; Severity of illness; Siblings; Structure; Testing; Training; United States; United States National Institutes of Health; Variant; Work; age related; autism spectrum disorder; base; biobank; brain tissue; career; case control; cohort; comorbidity; computerized tools; detection method; disorder risk; economic cost; genetic architecture; genetic variant; genome-wide; human disease; improved; individuals with autism spectrum disorder; loss of function mutation; member; neuropsychiatric disorder; neuropsychiatry; open source; proband; psychiatric genomics; risk variant; sex; societal costs; tool; whole genome

Project Summary Neuropsychiatric conditions such as Autism Spectrum Disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BP) are among the most common long-term diseases in US adults. Genetics play an important role in these conditions, and structural variants (SVs) – chromosomal rearrangements impacting at least 50 base pairs of the genome – contribute particularly to the genetic risk of these diseases. Yet only a small minority of SVs present in the human population has been accounted for in current studies. The goal of this project is to more fully explore the role of SVs in neuropsychiatric conditions. This work leverages the recent creation of two key data sources: 1) extensive catalogues of human structural variation by the 1000 Genomes Project, Genome Aggregation Database, and other projects and 2) the collection of genotyping data in large neuropsychiatric case-control studies by the Psychiatric Genomics Consortium among others. The statistical genetic principles of haplotype phasing and imputation provide the framework to integrate these two resources. I will develop phase-based and imputation-based methods to detect post-zygotic mosaic copy number variations (CNVs) and population polymorphic SVs in genotyping intensity data. By applying these methods in neuropsychiatric case-control cohorts, I will: (i) identify post- zygotic mosaic copy number variants (CNVs) in individuals with ASD; (ii) identify polymorphic SVs in individuals with ASD, SCZ, and BP; and (iii) determine mosaic CNVs and polymorphic SVs that increase risk for neuropsychiatric disorders. Successful completion of these aims will result in a more complete understanding of the role of SVs in neuropsychiatric conditions; indeed, the SVs I will investigate in this project account for much of the genetic diversity in the human population. Furthermore, the computational tools I will develop will be applicable to study other human diseases. These tools will be made publicly available to the research community. Characterizing the role of SVs in neuropsychiatric and other medical conditions will contribute to our understanding of the genetic architectures of these diseases. Long-term, this may help detect at-risk populations, contribute to diagnosis, and ultimately aid in treatment.

项目摘要 神经精神疾病，如自闭症谱系障碍（ASD）、精神分裂症（SCZ）和双相情感障碍 糖尿病（BP）是美国成年人最常见的长期疾病之一。遗传学在以下方面发挥着重要作用： 这些条件和结构变异（SV）-影响至少50个碱基的染色体重排 对基因组-特别有助于这些疾病的遗传风险。然而，只有一小部分 在当前研究中已考虑了人群中存在的SV。该项目的目标是 更全面地探讨SV在神经精神疾病中的作用。 这项工作利用了最近创建的两个关键数据源：1）人类结构的广泛目录 1000个基因组计划、基因组聚合数据库和其他项目的变异，以及2） 精神病学基因组学在大型神经精神病病例对照研究中收集基因分型数据 财团等。单倍型定相和插补的统计遗传学原理提供了 整合这两种资源。我将开发基于阶段和基于估算的方法， 在基因分型中检测合子后嵌合拷贝数变异（CNVs）和群体多态性SV 强度数据。通过将这些方法应用于神经精神病病例对照队列，我将：（i）确定后， ASD个体中合子嵌合拷贝数变异（CNVs）;（ii） ASD、SCZ和BP个体;和（iii）确定增加风险的嵌合CNV和多态SV 治疗神经精神疾病 成功完成这些目标将使我们更全面地了解志愿人员在以下方面的作用： 神经精神疾病;事实上，我将在这个项目中调查的SV占了大部分遗传性疾病的比例。 人类的多样性。此外，我将开发的计算工具将适用于 研究其他人类疾病。这些工具将向研究界公开提供。 描述SV在神经精神和其他医学疾病中的作用将有助于我们的研究。 了解这些疾病的遗传结构。长期而言，这可能有助于检测风险 有助于诊断，并最终帮助治疗。

项目成果

Paving the path toward genomic privacy with secure imputation.

通过安全插补为基因组隐私铺平道路。

• DOI: 10.1016/j.cels.2021.09.006
• 发表时间: 2021
• 期刊: Cell systems
• 影响因子: 9.3
• 作者: Sherman,MaxwellA

Genome-wide mapping of somatic mutation rates uncovers drivers of cancer.

• DOI: 10.1038/s41587-022-01353-8
• 发表时间: 2022-11
• 期刊: NATURE BIOTECHNOLOGY
• 影响因子: 46.9
• 作者: Sherman, Maxwell A.;Yaari, Adam U.;Priebe, Oliver;Dietlein, Felix;Loh, Po-Ru;Berger, Bonnie
• 通讯作者: Berger, Bonnie