mapping-alzheimer-s-disease-variants-to-their-target-genes-using

Mapping Alzheimer's Disease Variants to Their Target Genes Using Computational Analysis of Chromatin Configuration

Genome-wide association studies (GWAS) have successfully identified hundreds of genomic loci that are associated with human traits and disease. However, ...

University of North Carolina

The PsychENCODE project.

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies. 

Advancing the understanding of autism disease mechanisms through genetics.

Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.

Chromosome conformation elucidates regulatory relationships in developing human brain.

Non-coding regions comprise most of the human genome and harbor a significant fraction of risk alleles for neuropsychiatric diseases, yet their functions remain poorly defined. We created a high-resolution map of non-coding elements involved in human cortical neurogenesis by contrasting chromatin accessibility and gene expression in the germinal zone and cortical plate of the developing cerebral cortex. We link distal regulatory elements (DREs) to their cognate gene(s) together with chromatin interaction data and show that target genes of human-gained enhancers (HGEs) regulate cortical neurogenesis and are enriched in outer radial glia, a cell type linked to human cortical evolution. We experimentally validate the regulatory effects of predicted enhancers for FGFR2 and EOMES. We observe that common genetic variants associated with educational attainment, risk for neuropsychiatric disease, and intracranial volume are enriched within regulatory elements involved in cortical neurogenesis, demonstrating the importance of this early developmental process for adult human cognitive function.

The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis.

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.

Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including , , , , and ) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Integrative functional genomic analysis of human brain development and neuropsychiatric risks.

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Comprehensive functional genomic resource and integrative model for the human brain.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Identification of common genetic risk variants for autism spectrum disorder.

Recent advances in our understanding of the genetic architecture of schizophrenia have shed light on the schizophrenia etiology. While common variation is one of the major genetic contributors, the majority of common variation reside in non-coding genome, posing a significant challenge in understanding the functional impact of this class of genetic variation. Functional genomic datasets that range from expression quantitative trait loci (eQTL) to chromatin interactions are critical to identify the potential target genes and functional consequences of non-coding variation. In this review, we discuss how three-dimensional chromatin landscape, identified by a technique called Hi-C, has facilitated the identification of potential target genes impacting schizophrenia risk. We outline key steps for Hi-C driven gene mapping, and compare Hi-C defined schizophrenia risk genes defined across developmental epochs and cell types, which offer rich insights into the temporal window and cellular etiology of schizophrenia. In contrast with a neurodevelopmental hypothesis in schizophrenia, Hi-C defined schizophrenia risk genes are postnatally enriched, suggesting that postnatal development is also important for schizophrenia pathogenesis. Moreover, Hi-C defined schizophrenia risk genes are highly expressed in excitatory neurons, highlighting excitatory neurons as a central cell type for schizophrenia. Further characterization of Hi-C defined schizophrenia risk genes demonstrated enrichment for genes that harbor loss-of-function variation in neurodevelopmental disorders, suggesting a shared genetic etiology between schizophrenia and neurodevelopmental disorders. Collectively, moving the search space from risk variants to the target genes lays a foundation to understand the neurobiological basis of schizophrenia.

The three-dimensional landscape of the genome in human brain tissue unveils regulatory mechanisms leading to schizophrenia risk.

Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We leverage chromatin interaction profiles in human fetal and adult cortex to assign three classes of human-evolved elements to putative target genes. We find that human-evolved elements involving DNA sequence changes and those involving epigenetic changes are associated with human-specific gene regulation via effects on different classes of genes representing distinct biological pathways. However, both types of human-evolved elements converge on specific cell types and laminae involved in cerebral cortical expansion. Moreover, human evolved elements interact with neurodevelopmental disease risk genes, and genes with a high level of evolutionary constraint, highlighting a relationship between brain evolution and vulnerability to disorders affecting cognition and behavior. These results provide novel insights into gene regulatory mechanisms driving the evolution of human cognition and mechanisms of vulnerability to neuropsychiatric conditions.

Human evolved regulatory elements modulate genes involved in cortical expansion and neurodevelopmental disease susceptibility.

The core diagnostic criteria for autism comprise two symptom domains - social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, though this hypothesis has not yet been tested using molecular genetics. We test this using a genome-wide association study ( = 51,564) of a non-social trait related to autism, systemising, defined as the drive to analyse and build systems. We demonstrate that systemising is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemising. Supporting this, polygenic scores for systemising are significantly and positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism.

Article	Year
The PsychENCODE project. Nature neuroscience\| PubMed ID: 26605881	2015
Advancing the understanding of autism disease mechanisms through genetics. Nature medicine\| PubMed ID: 27050589	2016
Chromosome conformation elucidates regulatory relationships in developing human brain. Nature\| PubMed ID: 27760116	2016
The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis. Cell\| PubMed ID: 29307494	2018
Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nature genetics\| PubMed ID: 29632383	2018
Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature genetics\| PubMed ID: 30478444	2019
Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science (New York, N.Y.)\| PubMed ID: 30545854	2018
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science (New York, N.Y.)\| PubMed ID: 30545856	2018
Comprehensive functional genomic resource and integrative model for the human brain. Science (New York, N.Y.)\| PubMed ID: 30545857	2018
A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment. Nature neuroscience\| PubMed ID: 30692689	2019
Identification of common genetic risk variants for autism spectrum disorder. Nature genetics\| PubMed ID: 30804558	2019
The three-dimensional landscape of the genome in human brain tissue unveils regulatory mechanisms leading to schizophrenia risk. Schizophrenia research\| PubMed ID: 30894290	2019
Human evolved regulatory elements modulate genes involved in cortical expansion and neurodevelopmental disease susceptibility. Nature communications\| PubMed ID: 31160561	2019
Social and non-social autism symptoms and trait domains are genetically dissociable. Communications biology\| PubMed ID: 31508503	2019

Hyejung Won

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