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Principal Investigator: Stephan Sanders
Organization: UNIVERSITY OF OXFORD
Fiscal Year: 2024
Award: $439,038
Funding agency: National Institute of Mental Health
ABSTRACT
Functional genomic analyses of the developing human brain have revealed highly dynamic spatiotemporal
patterns of gene expression and epigenetic changes during prenatal and early postnatal development and
across brain regions. Disruptions of these developmentally dynamic processes have been implicated by
numerous complementary analyses in the etiology of multiple neurodevelopmental and neuropsychiatric
disorders. Expression quantitative trait loci (eQTLs), along with splicing quantitative trait loci (sQTLs) and
structural variant quantitative trait loci (svQTLs), are genomic variants that differ between individuals, with
these differences correlating with functional changes to gene expression or splicing behavior. Many of these
QTLs show specificity to tissues, brain regions, developmental stages, or cell types, and a proportion overlap
with known genetic risk factors of human disorders. Here, we propose to pursue three integrated Aims,
including whole-genome sequencing and both bulk tissue and single-nuclei RNA sequencing, to identify
genomic variants, eQTL/sQTL/svQTLs, and patterns of gene expression and co-expression in two regions of
the human brain across mid-fetal development through to adolescence. In addition, we will apply novel and
newly developed computational tools to associate these QTLs with specific cell types and loci or genes
implicated in neuropsychiatric disorders. By so doing we will augment, and dramatically expand upon, earlier
efforts to understand QTLs and their roles in neural development, function, and neuropsychiatric disorders.
Terms: <12-20 years old><21+ years old><AD dementia><ASD><Adolescence><Adult><Adult Human><Affect><Age of Onset><Allele Frequency><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Autism><Autistic Disorder><Behavior><Biological><Bipolar Affective Psychosis><Bipolar Disorder><Body Tissues><Brain><Brain Nervous System><Brain region><Causality><Cell Body><Cell Nucleus><Cells><Chromatin><Code><Coding System><Communities><Complement><Complement Proteins><Computational toolkit><Copy Number Polymorphism><Corpus Striatum><Corpus striatum structure><DNA><Data><Data Bases><Data Set><Databases><Deoxyribonucleic Acid><Developing fetus><Development><Disease><Disorder><Early Infantile Autism><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Exhibits><Expression Signature><Fetal Development><Functional RNA><GWA study><GWAS><Gene Expression><Gene Expression Profile><Gene Frequency><Gene Splicing><Gene variant><Generations><Genes><Genetic><Genetic predisposing factor><Genotype><Human><Human Genome><Individual><Infantile Autism><Kanner's Syndrome><Link><Manic-Depressive Psychosis><Methods><Modern Man><Neural Development><Neurobiology><Neurodevelopmental Disorder><Neurological Development Disorder><Neurosciences><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleus><Pattern><Prefrontal Cortex><Prevalence><Primary Senile Degenerative Dementia><Process><Property><Proteins><QTL><Quantitative Trait Loci><RNA Seq><RNA Splicing><RNA sequencing><RNAseq><Regulatory Element><Research Resources><Resources><Risk><Risk-associated variant><Role><Sampling><Schizophrenia><Schizophrenic Disorders><Single Base Polymorphism><Single Nucleotide Polymorphism><Single-Nucleus Sequencing><Source><Specificity><Spliced Genes><Splicing><Striate Body><Striatum><System><Tissues><Untranslated RNA><Validation><Variant><Variation><adolescence (12-20)><adulthood><allele variant><allelic frequency><allelic variant><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><biologic><bipolar affective disorder><bipolar disease><bipolar illness><bipolar mood disorder><brain cell><brain tissue><causation><cell type><cohort><complementation><computational toolbox><computational tools><computational toolset><computerized tools><copy number variant><copy number variation><data base><data integration><dementia praecox><developmental><disease causation><disease risk><disorder risk><entire genome><epigenetic biomarker><epigenetic marker><epigenetically><experiment><experimental research><experimental study><experiments><fetal><full genome><functional genomics><gene expression pattern><gene expression signature><gene locus><genetic locus><genetic risk factor><genetic variant><genome sequencing><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data-set><genomic dataset><genomic location><genomic locus><genomic variant><genomic variation><global gene expression><global transcription profile><histone modification><human whole genome><indel><inherited factor><insertion-deletion><insertion-deletion mutation><insertion/deletion><insertion/deletion mutation><insight><manic depressive disorder><manic depressive illness><neurobiological><neurodevelopment><neurodevelopmental disease><neuropsychiatric disease><neuropsychiatric disorder><next generation><noncoding><novel><post-natal development><postnatal development><prenatal><primary degenerative dementia><rare allele><rare mutation><rare variant><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sNuc-Seq><schizophrenic><senile dementia of the Alzheimer type><sex><single nucleotide variant><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><spatiotemporal><striatal><trait><transcriptional profile><transcriptional signature><transcriptome><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><unborn><validations><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>