Population-level and mechanistic dissection of 17q21 structural variant association with psychiatric traits

17q21 结构变异与精神特征关联的群体水平和机制剖析

基本信息

批准号：
10201458
负责人：
Michael Gandal
金额：
$ 63.2万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10201458
关键词：
11 year old 17q21 3-Dimensional ATAC-seq Adolescent Adult Alleles Biological Brain British Cell Line Cells Chromatin Chromosome 17 Clinical Code Cognitive Cohort Studies Communities Complex Copy Number Polymorphism Data Set Development Diagnostic Disease Dissection European Female Future Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Risk Genetic Variation Genetic study Genomics Genotype Haplotypes Heritability Human Human Genome Individual Linkage Disequilibrium Measures Mediating Medical Mental disorders Molecular Nerve Degeneration Nervous system structure Neurobiology Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurotic Disorders Outcome Pattern Performance Phenotype Population Post-Traumatic Stress Disorders Psychiatric Diagnosis Psychiatry Recurrence Regulation Research Risk Sampling Schizophrenia Science Structure Surface Therapeutic Intervention Tissue-Specific Gene Expression Variant Walkers Work autism spectrum disorder biobank brain volume cell growth clinical Diagnosis cohort disorder risk endophenotype fetal functional genomics genetic variant genome wide association study improved insight male middle age multi-ethnic nerve stem cell neurobiological mechanism neuroimaging phenome protective effect psychiatric symptom public health relevance repository sex single-cell RNA sequencing trait transcriptome transcriptome sequencing volunteer

项目摘要

PROJECT SUMMARY/ABSTRACT Large-scale genetic studies have made tremendous progress identifying the heritable basis for many neurodevelopmental, psychiatric disorders. However, connecting common genotypes to phenotypes -- and their underlying biological mechanisms -- in the nervous system is often complicated by complex patterns of linkage disequilibrium (LD) as well as the long-range action of genomic regulation. Common genetic variation within the 17q21.31 locus shows strong, highly pleiotropic genome-wide associations with several brain-related phenotypes including neuroticism, PTSD, brain volume, educational attainment, as well as multiple neurodegenerative disorders, among others. This locus, however, is among the most complex in the human genome, as it is known to harbor at least 8 common, complex structural haplotypes, including a ~900 kb inversion (“H2”) under positive selection and present in ~20% of Europeans. Consequently, the specific haplotypes mediating these brain relevant trait-associations -- and the biological mechanisms through which this risk is conferred -- remain unknown. This proposal leverages recently developed 17q21.31 haplotype-specific SNP imputation panels to fully elucidate the “phenome-wide” impact of these common structural haplotypes on a wide range of neurodevelopmental, psychiatric, cognitive, and neuroimaging phenotypes. In Aim 1, we interrogate haplotype-specific neurodevelopmental trajectories in the iPSYCH case-cohort, comprising ~90k Danish individuals with clinical and psychiatric diagnoses from nationwide medical registers. In Aim 2, we characterize haplotype-specific associations with neuroimaging, psychiatric symptom, and cognitive phenotypes among up to ~500k British 40-70 year old volunteers in the UK Biobank and in the ABCD Study, a community sample of ~10k 9-11 year olds in the US. In Aim 3, we interrogate the molecular impact of haplotypes on gene expression and coexpression patterns in human brain across development. Finally, we perform single-cell RNA-seq and ATAC-seq on primary human neural progenitor cell lines ascertained for distinct haplotypes, enabling direct assessment of the allelic impact on developmental cell growth, gene expression, and chromatin accessibility. Altogether, proposed studies will characterize the “phenome-wide” impact of common 17q21.31 complex structural variation in the population and deconstruct the specific neurobiological mechanisms underlying these broad associations with neurodevelopmental and psychiatric traits.

项目概要/摘要大规模的遗传学研究已经取得了巨大的进展，确定了许多疾病的遗传基础。然而，将常见的基因型与表型及其相关的联系起来。潜在的生物机制——神经系统通常因复杂的连接模式而变得复杂不平衡（LD）以及基因组调控中常见的遗传变异的长期作用。 17q21.31 位点显示出与多种大脑相关的强、高度多效性全基因组关联表型包括神经质、创伤后应激障碍、脑容量、教育程度以及多种然而，神经退行性疾病是人类最复杂的基因座之一。基因组，已知至少有 8 个常见的、复杂的结构单倍型，包括约 900 kb 的倒位（“H2”）在正选择下存在于约 20% 的欧洲人中，即特定的单倍型。调节这些与大脑相关的特征关联——以及这种风险发生的生物机制该提案利用了最近开发的 17q21.31 单倍型特异性 SNP。插补小组充分阐明这些常见结构单倍型对广泛的“表型范围”的影响在目标 1 中，我们询问一系列神经发育、精神病学、认知和神经影像表型。 iPSYCH 病例队列中的单倍型特异性神经发育轨迹，包括约 9 万丹麦人在目标 2 中，我们对来自全国医疗登记册的具有临床和精神科诊断的个人进行了描述。单倍型特异性与神经影像学、精神症状和认知表型之间的关联英国生物银行和 ABCD 研究中约 50 万英国 40-70 岁志愿者的社区样本在目标 3 中，我们探究了美国约 10,000 名 9-11 岁儿童的基因表达的分子影响。最后，我们进行单细胞 RNA 测序并进行研究。 ATAC-seq 对原代人神经祖细胞系确定了不同的单倍型，从而能够直接评估等位基因对发育细胞生长、基因表达和染色质可及性的影响。总而言之，拟议的研究将描述常见 17q21.31 复合体的“全表型”影响人群的结构变异并解构这些变异背后的特定神经生物学机制与神经发育和精神特征的广泛关联。