Genome-wide detection of intervals of genetic heterogeneity associated with complex traits

Motivation: Genetic heterogeneity, the fact that several sequence variants give rise to the same phenotype, is a phenomenon that is of the utmost interest in the analysis of complex phenotypes. Current approaches for finding regions in the genome that exhibit genetic heterogeneity suffer from at least one of two shortcomings: (i) they require the definition of an exact interval in the genome that is to be tested for genetic heterogeneity, potentially missing intervals of high relevance, or (ii) they suffer from an enormous multiple hypothesis testing problem due to the large number of potential candidate intervals being tested, which results in either many false positives or a lack of power to detect true intervals.

Results: Here, we present an approach that overcomes both problems: it allows one to automatically find all contiguous sequences of single nucleotide polymorphisms in the genome that are jointly associated with the phenotype. It also solves both the inherent computational efficiency problem and the statistical problem of multiple hypothesis testing, which are both caused by the huge number of candidate intervals. We demonstrate on Arabidopsis thalianagenome-wide association study data that our approach can discover regions that exhibit genetic heterogeneity and would be missed by single-locus mapping.

Conclusions: Our novel approach can contribute to the genome-wide discovery of intervals that are involved in the genetic heterogeneity underlying complex phenotypes.

Availability and implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/sis.html.

Publikationsart
Zeitschriftenbeiträge (peer-reviewed)
Titel
Genome-wide detection of intervals of genetic heterogeneity associated with complex traits
Medien
Bioinformatics
Heft
12
Band
31
Autoren
Felipe Llinares-López, Prof. Dr. Dominik Grimm , Dean A Bodenham, Udo Gieraths, Mahito. Sugiyama, Beth Rowan, Karsten Borgwardt
Seiten
i240-i249
Veröffentlichungsdatum
15.06.2015
Zitation
Llinares-López, Felipe; Grimm, Dominik; Bodenham, Dean A; Gieraths, Udo; Sugiyama, Mahito.; Rowan, Beth; Borgwardt, Karsten (2015): Genome-wide detection of intervals of genetic heterogeneity associated with complex traits. Bioinformatics 31 (12), S. i240-i249. DOI: 10.1093/bioinformatics/btv263