K. B. TRANG

Genome Biology 2025 · joint first author · junctions 2 · 3 · 5

Where 16 autoimmune diseases’ risk concentrates, and one gene worth drugging

Sixteen autoimmune diseases, one question: which cells carry the inherited risk? We built 3D chromatin maps (accessible chromatin plus promoter contacts) in 57 human cell types, nine of them immune types profiled for the first time, and asked where each disease’s heritability concentrates.

Regulatory elements contacted by a gene promoter captured more heritability than one-dimensional annotations. Regulatory T cells showed the strongest enrichment for type 1 diabetes. The maps linked risk variants to 5,488 candidate genes.

One candidate, FDFT1, encodes an enzyme of cholesterol synthesis. Its inhibitor lapaquistat altered T-cell secretion of TNF, IL-17A, IL-10 and IL-21: a pharmacological hypothesis for further preclinical testing.

My contribution: led the heritability partitioning and variant-to-gene integration across 57 cell types and 16 diseases; first-author manuscript.

  1. 16 autoimmune diseasesGWAS
  2. 57 cell typesopen chromatin + promoter contacts
  3. Treg for type 1 diabetesstrongest heritability enrichment
  4. 5,488 geneslinked to risk variants
  5. FDFT1 → lapaquistatT-cell cytokines shift
Each box is a different kind of thing, counted in its own units.

Figures

Heritability of 16 autoimmune diseases partitioned across cis-regulatory elements of 57 cell types (S-LDSC); regulatory T cells lead for type 1 diabetes.
Figure 1. Heritability of 16 autoimmune diseases partitioned across cis-regulatory elements of 57 cell types (S-LDSC); regulatory T cells lead for type 1 diabetes. Genome Biology 2025 · CC BY
Variant-to-gene maps: SNP–gene pairs shared across, or unique to, cell types and traits.
Figure 2. Variant-to-gene maps: SNP–gene pairs shared across, or unique to, cell types and traits. Genome Biology 2025 · CC BY
3D-chromatin variant-to-gene links compared with eQTL resources, and the effector genes shared across autoimmune traits.
Figure 3. 3D-chromatin variant-to-gene links compared with eQTL resources, and the effector genes shared across autoimmune traits. Genome Biology 2025 · CC BY
The FDFT1 locus: chromatin contacts link multiple sclerosis, rheumatoid arthritis and lupus variants to FDFT1, expressed in immune cells.
Figure 4. The FDFT1 locus: chromatin contacts link multiple sclerosis, rheumatoid arthritis and lupus variants to FDFT1, expressed in immune cells. Genome Biology 2025 · CC BY
Lapaquistat, an FDFT1 inhibitor, shifts T-cell cytokines (TNF, IL-10, IL-17A, IL-21) in human tonsil organoids.
Figure 5. Lapaquistat, an FDFT1 inhibitor, shifts T-cell cytokines (TNF, IL-10, IL-17A, IL-21) in human tonsil organoids. Genome Biology 2025 · CC BY

Trang KB, Sharma P, Cook L, et al. 3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility. Genome Biol. 2025;26:414. PubMed →

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