Read mismapping from segmental duplications drives spurious trans associations

Area of Science:

• Genetics
• Genomics
• Bioinformatics

Background:

• Heritable variation in gene regulation influences disease risk and evolution.
• Trans-acting quantitative trait loci (trans-QTLs) are key sources of this variation.
• Identifying trans-QTLs is challenging due to false positives from RNA and DNA read mismapping.

Purpose of the Study:

• To identify categories of RNA and DNA mismapping artifacts leading to false-positive trans-QTLs.
• To develop a method for detecting spurious trans-QTLs using long-range genotypic disequilibrium.
• To estimate the proportion of artifactual QTLs in the Genotype-Tissue Expression (GTEx) dataset.

Main Methods:

• Identified four categories of RNA/DNA mismapping caused by segmental duplications.
• Utilized long-range genotypic disequilibrium as a footprint for spurious trans-QTLs.
• Applied the developed method to GTEx trans-QTL data.

Main Results:

• Quantified false-positive trans-QTLs arising from segmental duplication mismapping.
• Estimated that 14% of expression QTLs, 10% of splicing QTLs, and 3% of protein QTLs are artifacts.
• Demonstrated the utility of the genotypic disequilibrium footprint for identifying spurious distant genetic associations.

Conclusions:

• A significant proportion of identified trans-QTLs can be artifacts due to mismapping.
• The developed framework can improve the accuracy of trans-QTL identification.
• This approach has broader applications for detecting spurious signals in other genome-wide studies.