Liver single-nucleus multiome profiling reveals cell-type mechanisms for cardiometabolic traits

Area of Science:

• Genomics and Molecular Biology
• Cardiovascular and Metabolic Research
• Hepatology

Background:

• The liver is crucial for cardiometabolic health, regulating key physiological processes.
• Genome-wide association studies (GWASs) have linked numerous genetic variants to cardiometabolic traits, but their liver-specific molecular functions are largely unknown.
• Understanding cell-type-specific gene regulation in the liver is essential for deciphering complex cardiometabolic diseases.

Purpose of the Study:

• To create a high-resolution map of the hepatic regulatory landscape at the single-nucleus level.
• To identify cell-type-specific genetic regulatory elements and their association with cardiometabolic traits.
• To uncover molecular mechanisms underlying cardiometabolic diseases that are obscured in bulk tissue analyses.

Main Methods:

• Multiome sequencing (gene expression and chromatin accessibility) was performed on 68,398 nuclei from six primary liver cell types.
• Quantitative trait loci (QTLs), including chromatin accessibility QTLs (caQTLs) and expression QTLs (eQTLs), were mapped within specific liver cell types.
• Cell-type-specific QTLs were integrated with GWAS data to identify genetic associations with cardiometabolic traits.

Main Results:

• 306,706 accessible chromatin regions were identified, with 70,884 unique to single-nucleus analysis, particularly in less abundant cell types.
• 1,885 caQTLs and 67 eQTLs were detected, revealing cell-type-specific gene regulation.
• Integration with GWAS data identified specific cell types, genes, and regulatory elements involved in liver enzyme and cholesterol levels.
• Non-hepatocyte cell-type analyses uncovered mechanisms like an eQTL for ADAMTS12 in liver sinusoidal endothelial cells, potentially linked to liver fibrosis.
• Cell-type prediction for bulk liver caQTLs colocalized with GWAS signals enhanced mechanistic insights into complex trait associations.

Conclusions:

• Single-nucleus multiome sequencing provides unprecedented resolution of the liver's regulatory landscape.
• This approach reveals cell-type-specific mechanisms underlying cardiometabolic traits, including those missed by bulk analyses.
• The findings advance the understanding of genetic contributions to cardiometabolic diseases by highlighting specific cellular contexts and molecular players.