3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

Abstract Background Insight into the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but this alone does not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. Results Here, we generate 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrate this data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. The majority of variants implicated by these cis-regulatory architectures are trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, leading to enrichment of similar biological networks. While this suggests a high level of genetic diversity and complexity that converges at the level of target gene and cell type, some trait-specific pathways representing potential areas for disease-specific intervention were identified. We pharmacologically validate squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach and supported by prior eQTL data in multiple sclerosis and systemic lupus erythematosus, as a novel immunomodulatory drug target controlling T cell inflammatory cytokine production and aiding B cell antibody production in a human lymphoid organoid model. Conclusions These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types. Graphical Abstract

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Publication Details

Journal
Genome biology
Published
2025-12-08
DOI
https://doi.org/10.1186/s13059-025-03880-4
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
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article

3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

Megan K. Levings, Klaus H. Kaestner, Alessandra Chesi, Suzanna Rachimi et al.
Genome biology
Genetic Associations and Epidemiology
article

3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility

Megan K. Levings, Klaus H. Kaestner, Alessandra Chesi, Suzanna Rachimi, Kurt D. Hankenson, Ashley Jermusyk, Prabhat Sharma, Matthew C. Pahl, Emylette Cruz Cabrera, Laufey T. Ámundadóttir, Kevin M. Brown, Paul M. Titchenell, Patrick Seale, Andrew D. Wells, Chun Su, Bao Khanh Trang, Babette S. Zemel, Zachary Mount, Laura E. Cook, James A. Pippin, Struan F.A. Grant, Rajan M. Thomas, Neil Romberg, Yadav Wagley, Jason W. Hoskins, Joan M. O’Brien, Wenli Yang, Nikhil N Kulkarni, Stewart A. Anderson, Mai Xu
article en

Abstract

Abstract Background Insight into the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but this alone does not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. Results Here, we generate 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrate this data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. The majority of variants implicated by these cis-regulatory architectures are trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, leading to enrichment of similar biological networks. While this suggests a high level of genetic diversity and complexity that converges at the level of target gene and cell type, some trait-specific pathways representing potential areas for disease-specific intervention were identified. We pharmacologically validate squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach and supported by prior eQTL data in multiple sclerosis and systemic lupus erythematosus, as a novel immunomodulatory drug target controlling T cell inflammatory cytokine production and aiding B cell antibody production in a human lymphoid organoid model. Conclusions These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types. Graphical Abstract

Genome biologyVol. 26(1)
Children's Hospital of Philadelphia (US), University of British Columbia (CA), Penn Presbyterian Medical Center (US), The University of Melbourne (AU), University of Michigan (US), Peter Doherty Institute (AU), Michigan Medicine (US), Ann Arbor VA Medical Center (US), Penn Center for AIDS Research (US), National Cancer Institute (US), BC Children's Hospital (CA), Division of Cancer Epidemiology and Genetics, University of Pennsylvania (US)
Openalex Percentile: Top 59%
Genetic Associations and Epidemiology
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