Expanded chromatin accessibility mapping explains genetic variation associated with complex traits in liver.

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Genome-wide association studies (GWAS) identify genetic loci for complex traits.
• Chromatin accessibility studies aim to find regulatory elements influencing gene expression.
• Genetic variants affecting chromatin accessibility (caQTLs) can explain GWAS signals.

Purpose of the Study:

• To investigate chromatin accessibility in human liver using ATAC-seq.
• To identify caQTLs and their colocalization with GWAS signals for liver-relevant traits.
• To assess the proportion of complex trait signals with proposed molecular mechanisms.

Main Methods:

• Assay for transposase-accessible chromatin with sequencing (ATAC-seq) on 189 human liver samples.
• Identification of accessible chromatin regions and caQTLs.
• Integration of liver caQTLs, eQTLs, and blood lipid GWAS data.

Main Results:

• Over 2 million accessible chromatin regions and over 14,000 caQTLs identified.
• 157 loci showed colocalization between caQTLs, eQTLs, and GWAS signals.
• Approximately 20% of blood lipid GWAS signals lacked a statistically supported mechanism.

Conclusions:

• Integrating multi-omic QTL data enhances understanding of GWAS signals.
• caQTLs provide mechanistic hypotheses for complex trait associations.
• Further experimental approaches are needed to fully elucidate complex trait mechanisms.