Cluster effect for SNP–SNP interaction pairs for predicting complex traits

TL;DR

This paper explores how clusters of SNP interactions can lead to false positives in predicting complex traits and suggests a new method to improve accuracy.

Contribution

The study identifies the cluster effect as a source of false positives in SNP–SNP interactions and proposes a method (3pRule + bootstrap) to enhance detection accuracy.

Findings

The cluster effect is a major cause of false-positive SNP–SNP interaction findings.

Using the 3pRule + bootstrap approach reduces false positives while maintaining true positives.

Pairs without significant main effects tend to have weak or no interactions.

Abstract

Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP–SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP–SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP–SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP–SNP interaction detection accuracy.

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