Detecting gene-gene interactions that underlie human diseases.

Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
Nature Reviews Genetics (Impact Factor: 39.79). 06/2009; 10(6):392-404. DOI: 10.1038/nrg2579
Source: PubMed

ABSTRACT Following the identification of several disease-associated polymorphisms by genome-wide association (GWA) analysis, interest is now focusing on the detection of effects that, owing to their interaction with other genetic or environmental factors, might not be identified by using standard single-locus tests. In addition to increasing the power to detect associations, it is hoped that detecting interactions between loci will allow us to elucidate the biological and biochemical pathways that underpin disease. Here I provide a critical survey of the methods and related software packages currently used to detect the interactions between genetic loci that contribute to human genetic disease. I also discuss the difficulties in determining the biological relevance of statistical interactions.

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    ABSTRACT: Epistasis (synergistic interaction) among SNPs governing gene expression is likely to arise within transcriptional networks. However, the power to detect it is limited by the large number of combinations to be tested and the modest sample sizes of most datasets. By limiting the interaction search space firstly to cis-trans and then cis-cis SNP pairs where both SNPs had an independent effect on the expression of the most variable transcripts in the liver and brain, we greatly reduced the size of the search space. Within the cis-trans search space we discovered three transcripts with significant epistasis. Surprisingly, all interacting SNP pairs were located nearby each other on the chromosome (within 290 kb-2.16 Mb). Despite their proximity, the interacting SNPs were outside the range of linkage disequilibrium (LD), which was absent between the pairs (r2 < 0.01). Accordingly, we redefined the search space to detect cis-cis interactions, where a cis-SNP was located within 10 Mb of the target transcript. The results of this show evidence for the epistatic regulation of 50 transcripts across the tissues studied. Three transcripts, namely, HLA-G, PSORS1C1 and HLA-DRB5 share common regulatory SNPs in the pre-frontal cortex and their expression is significantly correlated. This pattern of epistasis is consistent with mediation via long-range chromatin structures rather than the binding of transcription factors in trans. Accordingly, some of the interactions map to regions of the genome known to physically interact in lymphoblastoid cell lines while others map to known promoter and enhancer elements. SNPs involved in interactions appear to be enriched for promoter markers. In the context of gene expression and its regulation, our analysis indicates that the study of cis-cis or local epistatic interactions may have a more important role than interchromosomal interactions.
    BMC Genomics 02/2015; 16(1):109. DOI:10.1186/s12864-015-1300-3 · 4.04 Impact Factor
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    ABSTRACT: Background Deciphering the genetic architecture of complex traits is still a major challenge for human genetics. In most cases, genome-wide association studies have only partially explained the heritability of traits and diseases. Epistasis, one potentially important cause of this missing heritability, is difficult to explore at the genome-wide level. Here, we develop and assess a tool based on interactive odds ratios (IOR), Fast Odds Ratio-based sCan for Epistasis (FORCE), as a novel approach for exhaustive genome-wide epistasis search. IOR is the ratio between the multiplicative term of the odds ratio (OR) of having each variant over the OR of having both of them. By definition, an IOR that significantly deviates from 1 suggests the occurrence of an interaction (epistasis). As the IOR is fast to calculate, we used the IOR to rank and select pairs of interacting polymorphisms for P value estimation, which is more time consuming. Results FORCE displayed power and accuracy similar to existing parametric and non-parametric methods, and is fast enough to complete a filter-free genome-wide epistasis search in a few days on a standard computer. Analysis of psoriasis data uncovered novel epistatic interactions in the HLA region, corroborating the known major and complex role of the HLA region in psoriasis susceptibility. Conclusions Our systematic study revealed the ability of FORCE to uncover novel interactions, highlighted the importance of exhaustiveness, as well as its specificity for certain types of interactions that were not detected by existing approaches. We therefore believe that FORCE is a valuable new tool for decoding the genetic basis of complex diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0174-3) contains supplementary material, which is available to authorized users.
    BMC Genetics 02/2015; 16(11). DOI:10.1186/s12863-015-0174-3 · 2.36 Impact Factor
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    ABSTRACT: Detecting complex interactions among risk factors in case-control studies is a fundamental task in clinical and population research. However, though hypothesis testing using logistic regression (LR) is a convenient solution, the LR framework is poorly powered and ill-suited under several common circumstances in practice including missing or unmeasured risk factors, imperfectly correlated "surrogates", and multiple disease sub-types. The weakness of LR in these settings is related to the way in which the null hypothesis is defined. Here we propose the Asymmetric Independence Model (AIM) as a biologically-inspired alternative to LR, based on the key observation that the mechanisms associated with acquiring a "disease" versus maintaining "health" are asymmetric. We prove mathematically that, unlike LR, AIM is a robust model under the abovementioned confounding scenarios. Further, we provide a mathematical definition of a "synergistic" interaction, and prove that theoretically AIM has better power than LR for such interactions. We then experimentally show the superior performance of AIM as compared to LR on both simulations and four real datasets. While the principal application here involves genetic or environmental variables in the life sciences, our methodology is readily applied to other types of measurements and inferences, e.g. in the social sciences.


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