Functional dissection of complex and molecular trait variants at single nucleotide resolution

Area of Science:

• Human Genetics
• Molecular Biology
• Genomics

Background:

• Identifying causal variants for complex traits and diseases is challenging.
• Many variants are in non-coding regions, affecting gene regulation.
• Understanding how single nucleotide alterations impact phenotypes is limited.

Purpose of the Study:

• To systematically characterize the function of trait-associated variants.
• To investigate the mechanisms by which variants modulate transcriptional processes.
• To provide insights into the regulatory grammar underlying disease risk.

Main Methods:

• Massively Parallel Reporter Assay (MPRA) was used to measure the activity of 221,412 trait-associated variants in 5 cell types.
• Saturation mutagenesis was employed to dissect the mechanisms of 136 variants.
• Orthogonal measures were used to validate variant function.

Main Results:

• MPRA precisely identified 12,025 regulatory variants.
• Only 69% of variants' effects were explained by known transcription factor (TF) binding motifs.
• Mechanisms for 91% of variants without canonical mechanisms were assigned, revealing prevalent epistasis.

Conclusions:

• This study provides a comprehensive functional characterization of likely causal common variants.
• Novel insights into gene regulation and disease risk mechanisms were gained.
• The findings advance our understanding of the regulatory grammar governing human traits and diseases.