Multiple causal variants underlie genetic associations in humans

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Genetic associations often reside in noncoding regions with high linkage disequilibrium (LD).
• A single causal variant is typically assumed to explain these associations.
• Understanding the functional impact of variants in LD is crucial for interpreting genetic association studies.

Purpose of the Study:

• To functionally evaluate genetic variants within high LD regions for independent cis-expression quantitative trait loci (eQTLs).
• To investigate the prevalence of multiple causal variants underlying genetic associations.
• To identify the regulatory mechanisms and chromatin features associated with these variants.

Main Methods:

• Application of a massively parallel reporter assay (MPRA) to assess the regulatory activity of genetic variants.
• Analysis of variants in high, local LD to detect independent cis-eQTLs.
• Integration of MPRA data with eQTL and complex trait colocalization data across 114 human traits and diseases.

Main Results:

• 17.7% of tested eQTLs demonstrated more than one major allelic effect in tight LD.
• Detected regulatory variants were enriched for activating chromatin structures.
• Variants showed specific enrichment for allelic transcription factor binding.
• Identified causal variant sets that explain how genetic signals arise from multiple linked variants.

Conclusions:

• Genetic associations in LD can be driven by multiple independent causal variants, challenging the single-variant assumption.
• MPRA is a powerful tool for dissecting complex regulatory architectures in the genome.
• These findings have implications for understanding the genetic basis of human traits and diseases.