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Polygenic risk scores (PRS) identify at-risk individuals for many common diseases. A discussion of strengths and limitations is carried out in this review. PRS complement traditional genetic testing and have shown utility in establishing a proper diagnosis and guiding primary and secondary prevention.

ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex.

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region.

The three-dimensional landscape of cortical chromatin accessibility in Alzheimer's disease.

To characterize the dysregulation of chromatin accessibility in Alzheimer's disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer-promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome).

Common variants contribute to intrinsic human brain functional networks.

The human brain forms functional networks of correlated activity, which have been linked with both cognitive and clinical outcomes. However, the genetic variants affecting brain function are largely unknown. Here, we used resting-state functional magnetic resonance images from 47,276 individuals to discover and validate common genetic variants influencing intrinsic brain activity.

Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 10-10-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography.

Common genetic variation influencing human white matter microstructure.

Brain regions communicate with each other through tracts of myelinated axons, commonly referred to as white matter. We identified common genetic variants influencing white matter microstructure using diffusion magnetic resonance imaging of 43,802 individuals. Genome-wide association analysis identified 109 associated loci, 30 of which were detected by tract-specific functional principal components analysis.

Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons.

The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability.

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder.

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons.

CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder.

Identification of common genetic risk variants for autism spectrum disorder.

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.

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

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.

The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease.

Alzheimer's disease (AD) affects half the US population over the age of 85 and is universally fatal following an average course of 10 years of progressive cognitive disability. Genetic and genome-wide association studies (GWAS) have identified about 33 risk factor genes for common, late-onset AD (LOAD), but these risk loci fail to account for the majority of affected cases and can neither provide clinically meaningful prediction of development of AD nor offer actionable mechanisms. This cohort study generated large-scale matched multi-Omics data in AD and control brains for exploring novel molecular underpinnings of AD.

Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas.

An atlas of chromatin accessibility in the adult human brain.

Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date.

Brain Cell Type Specific Gene Expression and Co-expression Network Architectures.

Elucidating brain cell type specific gene expression patterns is critical towards a better understanding of how cell-cell communications may influence brain functions and dysfunctions. We set out to compare and contrast five human and murine cell type-specific transcriptome-wide RNA expression data sets that were generated within the past several years. We defined three measures of brain cell type-relative expression including specificity, enrichment, and absolute expression and identified corresponding consensus brain cell "signatures," which were well conserved across data sets.

Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls.

Transcription at enhancers is a widespread phenomenon which produces so-called enhancer RNA (eRNA) and occurs in an activity-dependent manner. However, the role of eRNA and its utility in exploring disease-associated changes in enhancer function, and the downstream coding transcripts that they regulate, is not well established. We used transcriptomic and epigenomic data to interrogate the relationship of eRNA transcription to disease status and how genetic variants alter enhancer transcriptional activity in the human brain.

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression.

Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach.

Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci.

Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease.

The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice.

Background: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.

Methods: This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro.

Schizophrenia risk variants affecting microRNA function and site-specific regulation of NT5C2 by miR-206.

Despite the identification of numerous schizophrenia-associated genetic variants, few have been examined functionally to identify and characterize the causal variants. To mitigate this, we aimed at identifying functional variants affecting miRNA function. Using data from a large-scale genome-wide association study of schizophrenia, we looked for schizophrenia risk variants altering either miRNA binding sites, miRNA genes, promoters for miRNA genes, or variants that were expression quantitative trait loci (eQTLs) for miRNA genes.