Using three-dimensional regulatory chromatin interactions from adult and fetal cortex to interpret genetic results for psychiatric disorders and cognitive traits

Abstract

Genome-wide association studies have identified hundreds of genetic associations for complex psychiatric disorders and cognitive traits. However, interpretation of most of these findings is complicated by the presence of many significant and highly correlated genetic variants located in noncoding regions. Here, we address this issue by creating a high-resolution map of the three-dimensional (3D) genome organization by applying Hi-C to adult and fetal brain cortex with concomitant RNA-seq, open chromatin (ATAC-seq), and ChIP-seq data (H3K27ac, H3K4me3, and CTCF). Extensive analyses established the quality, information content, and salience of these new Hi-C data. We used these data to connect 938 significant genetic loci for schizophrenia, intelligence, ADHD, alcohol dependence, Page 2 Alzheimer's disease, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depression, and educational attainment to 8,595 genes (with 42.1% of these genes implicated more than once). We show that assigning genes to traits based on proximity provides a limited view of the complexity of GWAS findings and that gene set analyses based on functional genomic data provide an expanded view of the biological processes involved in the etiology of schizophrenia and other complex brain traits.URLs 1000 Genomes Selection Browser,

Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits

“…To explore the biological interpretations of TWAS and GWAS-significant genes, we performed enrichment analysis in promoter-related chromatin interactions of four types of brain neurons 97 (iPSC-induced excitatory neurons, iPSC-derived hippocampal DG-like neurons, iPSC-induced lower motor neurons, and primary astrocytes), and also in high confident interactions of adult and fetal cortex 98 (Method). The raw p-values of Wilcoxon rank test for enrichment were summarized in Supplementary Table 15.…”

“…The enrichment was tested separately in four cell types, including induced pluripotent stem cells (iPSC)-induced excitatory neurons, iPSC-derived hippocampal DG-like neurons, iPSC-induced lower motor neurons, and primary astrocytes. For the high confident interactions of adult and fetal cortex, the enrichment of each gene was measured as the sum of –log 10 (P-value) of all significant interactions overlapping the gene 98 . The drug-target lookups were conducted using the drug-gene associations reported in Wang, et al 99 .…”

Genetic overlap between psychotic experiences in the community across age and with psychiatric disorders

“…Many of the overlapping genes we report were identified based only on chromatin interactions. The chromatin interaction data had a high resolution (10kb) resulting in more mapped genes, and included enhancer-promoter and promoter-promoter interactions only (73), therefore providing strong hypotheses for variant-gene associations. For psychotic experiences and depression, functional consequences on genes were annotated to variants clumped at lower than conventional genome-wide significance levels.…”

Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD

“…Using FUMA SNP2GENE, SNPs are mapped to genes based on physical position (positional mapping of deleterious coding SNPs (CADD score≥12.37) and eQTL associations (we used 13 brain tissue types from the GTEx.v8 project). Moreover, SNPs are mapped to genes based on 3D chromatin interactions (chromatin interaction mapping; Hi-C data of 2 tissue types: adult and foetal cortex (42)). Chromatin interaction mapping can involve long-range interactions.…”