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Novel approaches to identify tandem repeat expansions in neurodegenerative disease

识别神经退行性疾病串联重复扩增的新方法

基本信息

批准号：
10440935
负责人：
Paul Nils Valdmanis
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440935
关键词：
African American Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyotrophic Lateral Sclerosis Back Base Sequence Biological Models Biology Cells Complement DNA Data Data Set Dementia Disease Ethnic group General Population Genes Genetic Genetic Risk Genome Goals Haplotypes Hispanic Human Human Genome Individual Introns Lead Length Maps Methods Minisatellite Repeats Molecular NID gene Neurodegenerative Disorders Not Hispanic or Latino Nucleic Acid Regulatory Sequences Nucleotides Outcome Pathogenesis Pathogenicity Patients Play Population Positioning Attribute Property RNA-Binding Proteins Reporting Role Sampling Site Structure Tandem Repeat Sequences Techniques Testing Validation Variant WD Repeat Work causal variant cohort experimental study genome wide association study genome-wide global health insight multi-ethnic multiple omics nervous system disorder neurogenetics novel novel strategies novel therapeutics promoter risk variant sex whole genome

项目摘要

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and has a high global health burden. While several AD genetic risk loci have been identified, the causal variant at these genome- wide association study (GWAS) sites is still unknown despite intensive sequencing efforts. Importantly, however, most genome-wide sequencing methods fail to accurately resolve tandem repeats, over 40 of which are key drivers of neurological disorders. We hypothesize that a substantial fraction of genetic contributions to AD come from variable number tandem repeats (VNTRs) that often contain internal repeat units 20 nucleotides or more and that until now have not been systematically assessed genome-wide. We have surmounted critical sequencing barriers by establishing state-of-the-art long-read sequencing techniques to amplify and characterize the exact nucleotide sequence across tandem repeats. We recently reported the identification of a tandem repeat in WDR7 that is associated with Amyotrophic Lateral Sclerosis (ALS). Using the pipeline that we established for tandem repeat length estimation and validation, we propose to characterize human-specific tandem repeat expansions in AD. Our exciting preliminary analysis reveals many examples of repeats with increased or decreased length in AD. Several of these significantly differentially expanded repeats are in GWAS loci previously implicated in AD. Remarkably, the lead SNP at these loci is associated with stepwise changes in repeat length in individuals heterozygous or homozygous for the risk allele, suggesting that VNTRs may even play a causal role at these loci. We also identify rare instances of massive expansions, and/or internal sequence differences that depend on disease state. Our goal is to assess tandem repeats prone to expansion to estimate VNTR length genome- wide in AD to identify the contribution of novel repeat expansions in disease. We leverage large cohorts of whole genome sequence data from the Alzheimer’s Disease Sequencing Project. The thousands of genomes available means we can detect VNTR expansions in Hispanic, African American and Non- Hispanic White individuals as well as sex-specific effects of VNTR expansions. We will then perform targeted long-read sequencing of AD DNA samples to resolve the complete sequence of tandem repeats and define the consequence of internal sequence variation to AD. Finally, we will work to establish mechanisms of pathogenesis of novel tandem repeat expansions in AD. Our proposed studies will establish a novel paradigm to interrogate the mechanism of repeat expansion and will reveal insight into novel genetic factors that cause or modulate risk for AD.

阿尔茨海默病（AD）是最常见的神经退行性疾病之一，具有很高的全球发病率