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：
10400959
负责人：
Michael Gandal
金额：
$ 62.45万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400959
关键词：
11 year old 17q21 3-Dimensional ATAC-seq Adolescent Adult Alleles Area 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 Nervous system structure Neurobiology Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurotic Disorders Outcome Pattern Performance Persons Phenotype Population Post-Traumatic Stress Disorders Psychiatric Diagnosis Psychiatry Recurrence Regulation Research Risk Sampling Schizophrenia Science Surface Syndrome 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

11 year old 17q21 3-Dimensional ATAC-seq Adolescent Adult Alleles Area 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 Nervous system structure Neurobiology Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurotic Disorders Outcome Pattern Performance Persons Phenotype Population Post-Traumatic Stress Disorders Psychiatric Diagnosis Psychiatry Recurrence Regulation Research Risk Sampling Schizophrenia Science Surface Syndrome 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

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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.

项目摘要/摘要大规模的遗传研究取得了巨大的进步，以确定许多人的可遗传基础神经发育，精神疾病。但是，将共同基因型与表型联系起来 - 及其基本的生物学机制 - 在神经系统中，复杂的链接模式通常会复杂化基因组调节的二动作（LD）以及远距离作用。常见的遗传变异 17q21.31基因座显示与几个与大脑有关表型包括神经质，PTSD，大脑体积，教育程度以及多个神经退行性疾病等。但是，这个基因座是人类最复杂的地方之一众所周知，基因组至少具有8种常见的复杂结构单倍型，包括约900 kb的倒置（“ H2”）在肯定的选择下，占欧洲人的约20％。因此，特定的单倍型调解这些大脑相关的性状交往 - 以及这种风险的生物学机制会议 - 仍然未知。该提案利用最近开发了17q21.31单倍型特异性SNP 插补面板，以完全阐明这些常见结构单倍型对宽阔的“全现”影响神经发育，精神病，认知和神经影像型表型。在AIM 1中，我们讯问单倍型特异性的神经发育轨迹在ipsypy case-ohort中，完成了〜90k丹麦在AIM 2中，我们表征了来自国家医学记录的临床和精神诊断的人。与神经影像学，精神病症状和认知表型的单倍型特定关联到英国生物库和ABCD研究中，到约500万英国40-70岁的志愿者〜美国10K 9-11岁的孩子。在AIM 3中，我们询问单倍型对基因表达的分子影响和人类大脑的共表达模式跨发育。最后，我们执行单细胞RNA-seq和对原代人神经祖细胞系的ATAC-SEQ确定了不同的单倍型，使直接评估等位基因对发育细胞生长，基因表达和染色质的可及性的影响。总共提出的研究将表征共同17q21.31复合物的“全现”影响人群的结构变化并解构了这些特定的神经生物学机制与神经发育和精神病特征的广泛联系。