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Publications

Journal Article Ahead of print

PubMed: 42816628 DOI: 10.1038/s41586-026-11078-2

Population-scale immune multiome atlas reveals regulatory disease mechanisms.

Nature

Authors: Masahiro Kanai, Toni M Delorey, Jarno Honkanen, Rodosthenis S Rodosthenous, Julianna Juvila, Shane Murphy, Isabella Teixeira-Soldano, Hee Seung Hwang, Juha Karjalainen, Jussi Halonen, Georgia Panagiotaropoulou, Yuanxiang Zhang, Cristin McCabe, Eric Chen, Kosaku Nanki, Toshimi Yoshida, Kai Liu, Marla Glean, Nitya Mehrotra, Emily P Finan, Daniel Chafamo, Yixiao Zhu, Mikko Arvas, Sanni Ruotsalainen, Zhili Zheng, Yoshihiko Tomofuji, Daiki Tokuyasu, Shinichi Namba, Kyuto Sonehara, Yukinori Okada, Mary Pat Reeve, Mitja Kurki, Caroline B M Porter, Orr Ashenberg, Wei Zhou, Kimmo Pitkänen, Jukka Partanen, Aarno Palotie, Daniel B Graham, Mark J Daly, Ramnik J Xavier

Affiliations

  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Blood Service Biobank, Finnish Red Cross Blood Service, Vantaa, Finland.
  • Program in Infectious Disease and Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland.
  • Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
  • Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), The University of Osaka, Suita, Japan.
  • Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), The University of Osaka, Suita, Japan.
  • Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Program in Infectious Disease and Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

Most disease-associated genetic variants lie in non-coding regions 1,2, yet mechanistic insights are limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation. Single-cell molecular quantitative trait locus (QTL) mapping 3,4 connects variants to gene regulation but lacks the power and simultaneous measurements to trace mechanisms from chromatin to expression 5. Here we show that population-scale simultaneous profiling of chromatin accessibility and gene expression across immune cells reveals regulatory architectures connecting variants to disease. From paired single-nucleus assay for transposase-accessible chromatin-sequencing (snATAC-seq) and single-nucleus RNA-sequencing (snRNA-seq) analysis of 10 million peripheral blood mononuclear cells in 1,108 Finnish individuals 6, we identify 51,083 cis-expression QTLs for 20,829 genes, 338,100 cis-chromatin accessibility QTLs for 210,584 peaks, 119,094 putative causal variants and 593,765 peak-gene links. Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, with massively parallel reporter assays 7 validating 10,428 fine-mapped molecular QTLs. At evolutionarily constrained genes, we identify multilayered regulatory buffering, in which chromatin accessibility changes occur with normal effect sizes, but transmission to expression is attenuated through weaker, more numerous enhancer-gene links. This reconciles why disease variants preferentially target constrained genes despite apparent expression QTL depletion 8-11. Analysis using a massively parallel reporter assay 7 confirms that this buffering acts downstream of the regulatory element, with constraint operating at the chromatin-to-expression interface rather than on intrinsic cis-regulatory activity. Our atlas provides testable hypotheses for over half of immune disease associations, illustrated by cascades at autoimmune loci (TICAM1 and RHOH) and Finnish-enriched variants (TNRC18 and IL21R).

MeSH

Cells, Genes, Chromatin