Integration of single cell omics with biobank data discovers allele-specific trans effects of SREBF1 on adipocyte expression of nearly 100 genes

Background: Given the high global prevalence of obesity and lack of mechanistic, cell-type level knowledge of regulatory genes predisposing obesity, it would be critical to improve our understanding of how gene expression profiles are regulated in trans in adipocytes, the main cell-type in subcutaneous adipose tissue (SAT), and how that relates to obesity. Methods: We utilize single nucleus RNA-sequencing data sets from human SAT biopsies to elucidate the heritability of cardiometabolic disease risk in SAT cell-types and identify transcription factor (TF) encoding genes present in multiple functional pathways of the SAT cell-type marker genes. We integrate genome-wide association study (GWAS) data with expression quantitative trait locus (eQTL) data and conduct polygenic risk analyses for abdominal obesity and type 2 diabetes (T2D) to test if a cis regulatory GWAS variant for a key TF encoding gene, SREBF1 , harbors allele-specific trans effects on adipocyte marker genes and their polygenic risk. Results: We show that the heritability of epigenetic sites around SAT adipocyte marker genes is enriched for abdominal obesity, and that these cell-type markers are also enriched for central pathways of adipocyte function. Next, we discover SREBF1 as the most frequent TF in these adipocyte pathways and identify rs8079321, an abdominal obesity and T2D GWAS variant, regulating the bulk SAT SREBF1 expression in cis . We further discover and verify in an independent SAT snRNA-seq cohort, that the GWAS risk allele of rs8079321 affects the adipocyte expression of SREBF1 in cis and 89 SAT adipocyte marker genes in trans . Finally, we demonstrate that this trans effect extends to the polygenic risk by showing that the partitioned abdominal obesity and T2D polygenic risk scores of the 89 trans genes differ by the risk allele of rs8079321 in the UK Biobank, indicating widespread cell-type level cis -mediated trans effects on highly common CMDs. Conclusions: We discover that the SAT master TF, SREBF1, trans regulates the adipocyte expression profiles of nearly one hundred adipocyte marker genes in an allele-specific way, a finding that indicates that human trans -eQTL genes can be identified by integrating single cell omics with biobank data.