Population-Scale Multiome Immune Cell Atlas Reveals Complex Disease Drivers
Researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital, and international partner institutions released a population-scale multiome immune cell atlas on November 25, 2025, detailing single-cell chromatin accessibility and gene expression across 10 million peripheral blood mononuclear cells from 1,108 Finnish individuals. The preprint study, which has not been peer-reviewed, connects genetic variants to gene regulation to help explain complex disease drivers.
Single-Cell Profiling of Finnish Cohort
The research team generated paired single-nucleus ATAC-seq and RNA-seq profiles to map molecular quantitative trait loci. According to the study findings, the analysis identified 51,083 cis-eQTLs for 20,829 genes and 338,100 cis-caQTLs for 210,584 peaks. Investigators also mapped 119,094 fine-mapped variants and 496,488 enhancer–gene links across the cohort.
Most genetic variants associated with complex diseases reside in non-coding regions. Prior studies lacked the necessary sample sizes to detect variants at disease-relevant genes while simultaneously measuring multiple regulatory layers to trace complete mechanisms from chromatin state to gene expression.
Regulatory Cascades and Disease Relevance
Systematic classification of regulatory mechanisms revealed a distinct hierarchy where mechanistic cascades predict disease relevance. Variants exhibiting complete chromatin-to-expression cascades showed twice the disease colocalization of chromatin-only effects.
When examining evolutionarily constrained genes, the researchers observed multi-layered regulatory buffering. Chromatin accessibility changes occurred with normal effect sizes, but the transmission to gene expression was attenuated through systematically weaker enhancer–gene links. This dynamic helps reconcile why disease variants preferentially target these genes despite apparent eQTL depletion.
Base Editing Validation at Finnish-Enriched Loci
To test their findings experimentally, the researchers incorporated base editing to validate causal variants and mechanisms at Finnish-enriched disease loci such as TNRC18. The resulting resource provides testable mechanistic hypotheses for over half of immune disease associations.
The study authors acknowledged support from funding sources including the Klarman Cell Observatory and discretionary funds from the Department of Molecular Biology at Massachusetts General Hospital awarded to Ramnik J. Xavier, alongside support from the Masason Foundation for Masahiro Kanai. Sample collection relied on blood donors and staff at the Finnish Red Cross Blood Service, alongside participants and investigators of the FinnGen study, which is funded by Business Finland and industry partners including AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, and Bayer.