Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Genetic variations (polymorphisms) in target mRNA can impede microarray probe binding.
• This interference leads to unreliable expression quantitative trait locus (eQTL) signals, causing false positives and negatives.
• Existing methods inadequately address the impact of polymorphisms on microarray probe performance.

Purpose of the Study:

• To provide a comprehensive solution for identifying polymorphisms within commonly used microarray probe sequences.
• To assess the impact of these polymorphisms on eQTL signal accuracy.
• To recommend improved quality control for eQTL data.

Main Methods:

• Utilized the latest human genome and exome reference data.
• Identified common polymorphisms (>1% frequency in Europeans) within probe sequences of Illumina Human HT12 and Affymetrix Human Exon 1.0 ST arrays.
• Analyzed cerebellum and frontal cortex tissues from 438 individuals.

Main Results:

• A significant proportion of apparent eQTL signals are false positives/negatives due to polymorphism-in-probe issues.
• Despite a small percentage of probes containing polymorphisms, they disproportionately affect eQTL results.
• Previous control protocols were insufficient, as demonstrated by false signals in MAPT and PRICKLE1 genes.

Conclusions:

• Polymorphisms within microarray probes are a major source of eQTL inaccuracies.
• Current eQTL datasets require rigorous checking to mitigate these false signals.
• Implementing robust polymorphism detection is crucial for reliable genetic studies.