Functional dissection of complex 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.
• Most disease-associated variants are in non-coding regions with poorly understood regulatory functions.

Purpose of the Study:

• To systematically characterize the function of trait-associated variants.
• To understand how genetic variants modulate gene regulation and impact human phenotypes.

Main Methods:

• Utilized a massively parallel reporter assay (MPRA) to test 221,412 fine-mapped variants across 5 cell types.
• Employed saturation mutagenesis to investigate variant mechanisms and identify affected transcription factors.
• Analyzed regulatory epistasis and variants on the same haplotype.

Main Results:

• Identified 13,121 high-precision regulatory variants.
• Found that only 69% of variants could be explained by known transcription factor binding motifs.
• Determined affected transcription factors for 91% of variants investigated via saturation mutagenesis.
• Detected regulatory epistasis in 11% of tested variants.

Conclusions:

• Provides a comprehensive functional catalog of common variants underlying complex human traits.
• Offers new insights into the regulatory grammar governing gene expression and disease risk.
• Highlights the importance of non-coding variants and complex regulatory interactions in human genetics.