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An enormous challenge in the post-genome era is to annotate and resolve the consequences of genetic variation on diverse phenotypes. The genome-wide association study (GWAS) is a well-known method to identify potential genetic loci for complex traits from huge genetic variations, following which it is crucial to identify expression quantitative trait loci (eQTL). However, the conventional eQTL methods usually disregard the systematical role of single-nucleotide polymorphisms (SNPs) or genes, thereby overlooking many network-associated phenotypic determinates. Such a problem motivates us to recognize the network-based quantitative trait loci (QTL), i.e., network QTL (nQTL), which is to detect the cascade association as genotype → network → phenotype rather than conventional genotype → expression → phenotype in eQTL. Specifically, we develop the nQTL framework on the theory and approach of single-sample networks, which can identify not only network traits (e.g., the gene subnetwork associated with genotype) for analyzing complex biological processes but also network signatures (e.g., the interactive gene biomarker candidates screened from network traits) for characterizing targeted phenotype and corresponding subtypes. Our results show that the nQTL framework can efficiently capture associations between SNPs and network traits (i.e., edge traits) in various simulated data scenarios, compared with traditional eQTL methods. Furthermore, we have carried out nQTL analysis on diverse biological and biomedical datasets. Our analysis is effective in detecting network traits for various biological problems and can discover many network signatures for discriminating phenotypes, which can help interpret the influence of nQTL on disease subtyping, disease prognosis, drug response, and pathogen factor association. Particularly, in contrast to the conventional approaches, the nQTL framework could also identify many network traits from human bulk expression data, validated by matched single-cell RNA-seq data in an independent or unsupervised manner. All these results strongly support that nQTL and its detection framework can simultaneously explore the global genotype–network–phenotype associations and the underlying network traits or network signatures with functional impact and importance.

Interpreting Functional Impact of Genetic Variations by Network QTL for Genotype–Phenotype Association Study