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Autor/a:
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Van Lishout, François; Mahachie John, Jestinah M.; Gusareva, Elena S.; Urrea Gales, Víctor; Cleynen, Isabelle; Théâtre, Emilie; Charloteaux, Benoït; Calle, M. Luz; Wehenkel, Louis; Van Steen, Kristel
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Notas:
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Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown over the
last few years. It has been marked by promising methodological developments, improved translation efforts of
statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the
epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems.
In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed
by this algorithm rises linearly with the amount of hypothesis tests. Gene-gene interaction studies will require a
memory proportional to the squared number of SNPs. A genome-wide epistasis search would therefore require
terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. In this work we
present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to
be investigated. This algorithm was implemented in C++ in our epistasis screening software MBMDR-3.0.3. We
evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is
illustrated on real-life data for Crohn’s disease.
Results: In the case of a binary (affected/unaffected) trait, the parallel workflow of MBMDR-3.0.3 analyzes all
gene-gene interactions with a dataset of 100,000 SNPs typed on 1000 individuals within 4 days and 9 hours, using 999
permutations of the trait to assess statistical significance, on a cluster composed of 10 blades, containing each four
Quad-Core AMD Opteron(tm) Processor 2352 2.1 GHz. In the case of a continuous trait, a similar run takes 9 days. Our
program found 14 SNP-SNP interactions with a multiple-testing corrected p-value of less than 0.05 on real-life Crohn’s
disease (CD) data.
Conclusions: Our software is the first implementation of the MB-MDR methodology able to solve large-scale
SNP-SNP interactions problems within a few days, without using much memory, while adequately controlling the
type I error rates. A new implementation to reach genome-wide epistasis screening is under construction. In the
context of Crohn’s disease, MBMDR-3.0.3 could identify epistasis involving regions that are well known in the field and
could be explained from a biological point of view. This demonstrates the power of our software to find relevant
phenotype-genotype higher-order associations.
is paper presents research results of the Belgian Network DYSCO (Dynamical Systems, Control, and Optimization), funded by the Interuniversity Attraction Poles Programme, initiated by the Belgian State, Science Policy Office. The scientific responsibility rests with its author(s). Their work was also supported in part by the IST Programme of the European Community, under the PASCAL2 Network of Excellence (Pattern Analysis, Statistical Modelling and Computational Learning), IST-2007-216886. FVL, LW and KVS also acknowledges support by Alma in Silico, funded by the European Commission and Walloon Region through the Interreg IV Program. For MC and VU, this work was partially supported by Grant MTM2008-06747-C02-02 from el Ministerio de Educacion y Ciencia (Spain), Grant 050831 from La Marato de TV3 Foundation, Grant 2009SGR-581 from AGAUR-Generalitat de Catalunya. VU is the recipient of a pre-doctoral FPU fellowship award from the Spanish Ministry of Education (MEC). |
