EPIQ—efficient detection of SNP–SNP epistatic interactions for quantitative traits

Motivation: Gene–gene interactions are of potential biological and medical interest, as they can shed light on both the inheritance mechanism of a trait and on the underlying biological mechanisms. Evidence of epistatic interactions has been reported in both humans and other organisms. Unlike single-locus genome-wide association studies (GWAS), which proved efficient in detecting numerous genetic loci related with various traits, interaction-based GWAS have so far produced very few reproducible discoveries. Such studies introduce a great computational and statistical burden by necessitating a large number of hypotheses to be tested including all pairs of single nucleotide polymorphisms (SNPs). Thus, many software tools have been developed for interaction-based case–control studies, some leading to reliable discoveries. For quantitative data, on the other hand, only a handful of tools exist, and the computational burden is still substantial. Results: We present an efficient algorithm for detecting epistasis in quantitative GWAS, achieving a substantial runtime speedup by avoiding the need to exhaustively test all SNP pairs using metric embedding and random projections. Unlike previous metric embedding methods for case–control studies, we introduce a new embedding, where each SNP is mapped to two Euclidean spaces. We implemented our method in a tool named EPIQ (EPIstasis detection for Quantitative GWAS), and we show by simulations that EPIQ requires hours of processing time where other methods require days and sometimes weeks. Applying our method to a dataset from the Ludwigshafen risk and cardiovascular health study, we discovered a pair of SNPs with a near-significant interaction (P = 2.2 × 10(−13)), in only 1.5 h on 10 processors. Availability: https://github.com/yaarasegre/EPIQ Contact: heran@post.tau.ac.il