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BioData Min. 2019 Jul 9;12:14. doi: 10.1186/s13040-019-0201-4. eCollection 2019.

Exploration of a diversity of computational and statistical measures of association for genome-wide genetic studies.

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1Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA USA.
2Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA USA.
3Department of Genetics, University of Pennsylvania, Philadelphia, PA USA.



The principal line of investigation in Genome Wide Association Studies (GWAS) is the identification of main effects, that is individual Single Nucleotide Polymorphisms (SNPs) which are associated with the trait of interest, independent of other factors. A variety of methods have been proposed to this end, mostly statistical in nature and differing in assumptions and type of model employed. Moreover, for a given model, there may be multiple choices for the SNP genotype encoding. As an alternative to statistical methods, machine learning methods are often applicable. Typically, for a given GWAS, a single approach is selected and utilized to identify potential SNPs of interest. Even when multiple GWAS are combined through meta-analyses within a consortium, each GWAS is typically analyzed with a single approach and the resulting summary statistics are then utilized in meta-analyses.


In this work we use as case studies a Type 2 Diabetes (T2D) and a breast cancer GWAS to explore a diversity of applicable approaches spanning different methods and encoding choices. We assess similarity of these approaches based on the derived ranked lists of SNPs and, for each GWAS, we identify a subset of representative approaches that we use as an ensemble to derive a union list of top SNPs. Among these are SNPs which are identified by multiple approaches as well as several SNPs identified by only one or a few of the less frequently used approaches. The latter include SNPs from established loci and SNPs which have other supporting lines of evidence in terms of their potential relevance to the traits.


Not every main effect analysis method is suitable for every GWAS, but for each GWAS there are typically multiple applicable methods and encoding options. We suggest a workflow for a single GWAS, extensible to multiple GWAS from consortia, where representative approaches are selected among a pool of suitable options, to yield a more comprehensive set of SNPs, potentially including SNPs that would typically be missed with the most popular analyses, but that could provide additional valuable insights for follow-up.


Association analysis; Canberra metric; GWAS; Ranked list; Univariate analysis

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

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