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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：
10045419
负责人：
Michael Gandal
金额：
$ 69万
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/10045419
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 genomic profiles improved insight male middle age 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.

项目总结/文摘