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

• 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
• 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

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.

项目摘要/摘要 大规模的基因研究取得了巨大的进展，确定了许多人的遗传基础 神经发育和精神障碍。然而，将常见的基因类型与表型联系起来--以及它们的 神经系统中潜在的生物机制通常因复杂的连接模式而变得复杂 不平衡(LD)以及基因组调控的长期作用。个体内常见的遗传变异 17q21.31基因座显示出强烈的、高度多效性的全基因组与几个与脑相关的关联 表型包括神经质、创伤后应激障碍、脑容量、教育程度以及多个 神经退行性疾病等。然而，这个基因是人类最复杂的基因之一 基因组，已知至少含有8种常见的、复杂的结构单倍型，包括一个~900kb的倒位 (“H2”)在正选择下，存在于约20%的欧洲人中。因此，特定的单倍型 调节这些与大脑相关的特征-关联-以及这种风险所通过的生物机制 授予--仍不为人所知。该建议利用了最近开发的17q21.31单倍型特定SNP 充分阐明这些常见结构单倍型对广泛的 一系列神经发育、精神、认知和神经成像表型。在目标1中，我们审问 IPSYCH病例队列中单倍型特有的神经发育轨迹，包括约90K丹麦人 来自全国医疗登记簿的有临床和精神疾病诊断的个人。在目标2中，我们描述了 UP患者单倍型特异性与神经影像、精神症状和认知表型的相关性 到英国生物库和ABCD研究中的~50万名40-70岁的英国志愿者，一个社区样本 美国约有10000名9-11岁的儿童。在目标3中，我们询问了单倍型对基因表达的分子影响 以及人类大脑在发育过程中的共表达模式。最后，我们进行了单细胞rna-seq和 人类原代神经前体细胞系上的ATAC-SEQ被确定为不同的单倍型，使直接 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。 总之，拟议的研究将表征常见的17q21.31复合体的“表观范围”的影响 种群的结构变异并解构其背后的特定神经生物学机制 与神经发育和精神病学特征有着广泛的联系。