Tissue-specific enhancer–gene maps from multimodal single-cell data identify causal disease alleles

Saori Sakaue, Kathryn Weinand, Shakson Isaac, Kushal Dey, Karthik Jagadeesh, Masahiro Kanai, Gerald F M Watts, Zhu Zhu, Michael B. Brenner, Andrew McDavid, Laura T. Donlin, Kevin Wei, Alkes L. Price, Soumya Raychaudhuri*, Accelerating Medicines Partnership® RA/SLE Program and Network

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Translating genome-wide association study (GWAS) loci into causal variants and genes requires accurate cell-type-specific enhancer–gene maps from disease-relevant tissues. Building enhancer–gene maps is essential but challenging with current experimental methods in primary human tissues. Here we developed a nonparametric statistical method, SCENT (single-cell enhancer target gene mapping), that models association between enhancer chromatin accessibility and gene expression in single-cell or nucleus multimodal RNA sequencing and ATAC sequencing data. We applied SCENT to 9 multimodal datasets including >120,000 single cells or nuclei and created 23 cell-type-specific enhancer–gene maps. These maps were highly enriched for causal variants in expression quantitative loci and GWAS for 1,143 diseases and traits. We identified likely causal genes for both common and rare diseases and linked somatic mutation hotspots to target genes. We demonstrate that application of SCENT to multimodal data from disease-relevant human tissue enables the scalable construction of accurate cell-type-specific enhancer–gene maps, essential for defining noncoding variant function.
Original languageEnglish
Pages (from-to)615-626
Number of pages31
JournalNature Genetics
Volume56
Issue number4
DOIs
Publication statusPublished - 9 Apr 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

ASJC Scopus subject areas

  • Genetics

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