henhaobio
Sign in

bioRxivGeneticsPreprint

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

Paola Giusti‐RodrígueziD, Patrick F. SullivaniD

PDFDOI
Structured summary available · Jump to summary ↓

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 non-coding 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, Alzheimers 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.

Abstract summary

Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract · CC BY-ND 4.0

Hi-C maps of adult and fetal cortex, with matched RNA-seq, ATAC-seq and ChIP-seq, connect 938 GWAS loci for brain traits to 8,595 candidate genes.

Most GWAS signals for psychiatric and cognitive traits sit in non-coding sequence within blocks of correlated variants, so the gene they act on is rarely obvious. Chromatin contact maps from the relevant tissue, here adult and fetal cortex, give a physical basis for assigning those loci to genes instead of defaulting to the nearest one.

Key results

  1. ShownChromatin contacts assign significant association signals for ten brain traits to target genes, with a sizeable fraction of those genes implicated more than once.

    938 significant loci across psychiatric, neurological and cognitive traits were connected to 8,595 genes, 42.1% of which were implicated more than once. · Abstract

  2. ClaimedThe work delivers high-resolution three-dimensional genome maps of cortex at two developmental stages together with matched regulatory annotation.

    Hi-C on adult and fetal brain cortex with concomitant RNA-seq, ATAC-seq and ChIP-seq for H3K27ac, H3K4me3 and CTCF; quality and information content are described as established by extensive analyses but no metrics are reported here. · Abstract

  3. SuggestedAssigning genes by physical proximity captures only part of the signal, and gene-set analyses built on the functional genomic data point to a broader set of biological processes for schizophrenia and related traits.

    Stated as a conclusion from comparing proximity-based with interaction-based gene assignment; no overlap counts, enrichment statistics or named pathways are given in this text. · Abstract

Methods, data and reproducibility

Hi-C was generated from adult and fetal brain cortex alongside RNA-seq, ATAC-seq and ChIP-seq for H3K27ac, H3K4me3 and CTCF, and the resulting chromatin interactions were used to link significant GWAS loci for psychiatric, neurological and cognitive traits to genes, which were then compared with proximity-based assignment and used for gene set analyses.

  • Hi-C from adult and fetal brain cortex with matched RNA-seq, ATAC-seq and ChIP-seq (H3K27ac, H3K4me3, CTCF)
  • GWAS loci: schizophrenia, bipolar disorder, major depression, ADHD, autism spectrum disorder, anorexia nervosa, alcohol dependence, Alzheimer's disease, intelligence, educational attainment · human · n = 938 significant loci
Methods & tools
Hi-C, RNA-seq, ATAC-seq, ChIP-seq
Limitations (2)
  • Quality and salience of the new contact maps are asserted rather than quantified: no resolution, sequencing depth, replicate structure or benchmark values appear in the available text. · noted in this summary
  • Gene assignments rest on chromatin contacts in bulk cortex tissue and are not validated experimentally or against an independent set of causal genes here. · noted in this summary

Read this if you turn non-coding GWAS signals for brain traits into gene lists and want cortex chromatin contacts rather than nearest-gene assignment.

Citations
72

Reproducibility ledger

Nobody has reported trying to reproduce this paper yet. Did you replicate an experiment or run the code? Your report saves the next lab a week.

Sign in to file a reproducibility report.

Related papers

Similarity Map
SelectedSame fieldCross-field
THISUlianov '26Mangnier '22Kim '25Sey '20Gusev '18Kouakou '21
63% semantic matchBioinformatics
Kirill A. Ulianov, Diana Zagirova, Anna D. Kononkova+15 more·bioRxiv·May 28, 2026