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Modeling the contribution of common variants to schizophrenia risk

模拟常见变异对精神分裂症风险的贡献

基本信息

批准号：
9768547
负责人：
Kristen Jennifer Brennand
金额：
$ 75.1万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768547
关键词：
Affect Alleles American Astrocytes Autopsy Biological Assay Brain CISH gene Cell model Childhood Schizophrenia Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Computer Simulation Copy Number Polymorphism Data Data Set Disease Enhancers FDA approved FURIN gene Future Gene Expression Genes Genetic Engineering Genetic screening method Genetic study Genotype Human Individual Intervention K-Series Research Career Programs Mediating Messenger RNA Modeling Molecular Mutation Network-based Neurodevelopmental Disorder Neurons Nuclear Pore Complex Nucleic Acid Regulatory Sequences Pathway interactions Pattern Pharmaceutical Preparations Prefrontal Cortex Proteins Psychotic Disorders Quantitative Trait Loci RNA Splicing Research Risk Risk Factors Role Schizophrenia Single Nucleotide Polymorphism Synapses Testing Variant Work astrocyte progenitor base case control causal variant cell type cohort disorder risk excitatory neuron exome sequencing genome wide association study improved induced pluripotent stem cell insight novel novel therapeutics risk variant standard care synaptic function transcriptome sequencing

项目摘要

PROJECT SUMMARY Schizophrenia (SZ) is a common and debilitating neurodevelopmental disorder that affects nearly three million Americans. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Genome wide association studies (GWAS) indicate that SZ risk reflects both highly penetrant rare copy number variants as well as common single nucleotide polymorphisms with small effect sizes. By overlapping GWAS and post-mortem expression analyses, common variants with expression quantitative trait loci (eQTL) that may contribute to altered gene expression and liability in SZ have been identified; however, demonstrating which risk loci are the causal contributors to disease risk remains an intractable problem. Consequently, we propose to apply a human induced pluripotent stem cell (hiPSC)-based approach to manipulate the genotype and/or expression levels of putative causal SZ risk variants, focusing largely on genes implicated in synaptic formation, maturation and function. Through isogenic comparisons, we propose to examine the molecular and functional effects of perturbing five putative causal eQTLs and ten SZ GWAS- associated genes, testing the impact on cis-gene expression, global network expression patterns and synaptic function. Our hope is that this work may identify novel therapeutic points of intervention in order to improve the disease course in individuals with SZ.

项目总结