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: 10732393
• 负责人: Michael Gandal
• 金额: $ 61.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732393
• 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; Education; 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; 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; 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 大规模的遗传研究已经取得了巨大的进展，确定了许多遗传基础， 神经发育和精神疾病然而，将常见的基因型与表型联系起来， 神经系统中的潜在生物学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。常见的遗传变异 17q21.31基因座显示出强的，高度多效性的全基因组关联，与几个脑相关的 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 神经退行性疾病等。然而，这个基因座是人类中最复杂的基因座之一， 基因组，因为它是已知的港口至少8个共同的，复杂的结构单倍型，包括一个约900 kb的倒位 （“H2”），并且存在于约20%的欧洲人中。因此，特定的单体型 介导这些大脑相关的特质协会-以及这种风险的生物机制， 授予--仍然未知。该提议利用最近开发的17q21.31单倍型特异性SNP 插补面板，以充分阐明“全表型”的影响，这些共同的结构单倍型对广泛的 一系列神经发育、精神、认知和神经影像表型。在目标1中，我们询问 iPSYCH病例队列中的单倍型特异性神经发育轨迹，包括约90 k丹麦人 从全国医疗登记处获得临床和精神病诊断的个人。在目标2中，我们描述 up患者单倍型特异性与神经影像学、精神症状和认知表型相关性 在英国生物银行和ABCD研究中，约50万名40-70岁的英国志愿者， 约10 k 9-11岁的美国人。在目标3中，我们探讨了单倍型对基因表达的分子影响 和人类大脑发育过程中的共表达模式。最后，我们进行单细胞RNA-seq， ATAC-seq对原代人神经祖细胞系确定不同的单倍型，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。 总而言之，拟议的研究将表征常见17q21.31复合体的“全表型”影响。 人口结构的变化，并解构这些具体的神经生物学机制 与神经发育和精神特征的广泛关联。

项目成果

Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain.

• DOI: 10.1038/s41588-023-01560-2
• 发表时间: 2023-12
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Bhattacharya, Arjun;Vo, Daniel D.;Jops, Connor;Kim, Minsoo;Wen, Cindy;Hervoso, Jonatan L.;Pasaniuc, Bogdan;Gandal, Michael J.
• 通讯作者: Gandal, Michael J.

Neuron-specific transcriptomic signatures indicate neuroinflammation and altered neuronal activity in ASD temporal cortex.

• DOI: 10.1073/pnas.2206758120
• 发表时间: 2023-03-07
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility.

• DOI: 10.1016/j.xgen.2023.100326
• 发表时间: 2023-07-12
• 期刊: CELL GENOMICS
• 作者: Wu, Yeda;Goleva, Slavina B.;Breidenbach, Lindsay B.;Kim, Minsoo;Macgregor, Stuart;Gandal, Michael J.;Davis, Lea K.;Wray, Naomi R.
• 通讯作者: Wray, Naomi R.

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications.

• DOI: 10.1038/s41588-023-01563-z
• 发表时间: 2023-12
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Levey, Daniel F.;Galimberti, Marco;Deak, Joseph D.;Wendt, Frank R.;Bhattacharya, Arjun;Koller, Dora;Harrington, Kelly M.;Quaden, Rachel;Johnson, Emma C.;Gupta, Priya;Biradar, Mahantesh;Lam, Max;Cooke, Megan;Rajagopal, Veera M.;Empke, Stefany L. L.;Zhou, Hang;Nunez, Yaira Z.;Kranzler, Henry R.;Edenberg, Howard J.;Agrawal, Arpana;Smoller, Jordan W.;Lencz, Todd;Hougaard, David M.;Borglum, Anders D.;Demontis, Ditte;Gaziano, J. Michael;Gandal, Michael J.;Polimanti, Renato;Stein, Murray B.;Gelernter, Joel
• 通讯作者: Gelernter, Joel

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia.

• DOI: 10.1038/s41593-021-00847-z
• 发表时间: 2021-06
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Kim M;Haney JR;Zhang P;Hernandez LM;Wang LK;Perez-Cano L;Loohuis LMO;de la Torre-Ubieta L;Gandal MJ
• 通讯作者: Gandal MJ