From Single-SNP to Wide-Locus: Genome-Wide Association Studies Identifying Functionally Related Genes and Intragenic Regions in Small Sample Studies

Abstract

Background: Genome-wide association studies (GWAS) have had limited success when applied to complex diseases. Analyzing SNPs individually requires several large studies to integrate the often divergent results. In the presence of epistasis, multivariate approaches based on the linear model (including stepwise logistic regression) often have low sensitivity and generate an abundance of artifacts. Methods: Recent advances in distributed and parallel processing spurred methodological advances in nonparametric statistics. U-statistics for structured multivariate data (µStat) are not confounded by unrealistic assumptions (e.g., linearity, independence). Results: By incorporating knowledge about relationships between SNPs, µGWAS (GWAS based on µStat) can identify clusters of genes around biologically relevant pathways and pinpoint functionally relevant regions within these genes. Conclusion: With this computational biostatistics approach increasing power and guarding against artifacts, personalized medicine and comparative effectiveness will advance while subgroup analyses of Phase III trials can now suggest risk factors for adverse events and novel directions for drug development.

Original submitted 13 December 2012; Revision submitted 6 February 2013

KEYWORDS::

• common disease
• epilepsy
• epistasis
• genome-wide association study
• GWAS
• Phase III trials
• Ras pathway
• U-statistics

Acknowledgements

The authors would like to acknowledge S Wrigley, D Politis and R Cauley for collecting the samples, K Olden, LE Thorpe, M Dornbaum and F Steen of the City University of New York School of Public Health for providing access to computational resources for the grid operation, D Kaplun, B Zhou and E Schiffmiller for help with data inspection and analysis, WH Greer and GS Zhang for implementing GPU cloud instances, E Horn for editorial assistance, and the reviewers and editors for many helpful suggestions.

Financial & competing interests disclosure

KM Wittkowski, V Sonakya and T Song are in part funded by grant #2 UL1 RR024143 from the US National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA) and #8 UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS). M Durner and V Sonakya are in part funded by grant #2 R01NS037466 from the US National Institute of Neurological Disorders and Stroke (NINDS). MP Seybold was in part funded by the German National Academic Foundation and the German Academic Exchange Agency. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

KM Wittkowski, V Sonakya and T Song are in part funded by grant #2 UL1 RR024143 from the US National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA) and #8 UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS). M Durner and V Sonakya are in part funded by grant #2 R01NS037466 from the US National Institute of Neurological Disorders and Stroke (NINDS). MP Seybold was in part funded by the German National Academic Foundation and the German Academic Exchange Agency. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materialsdiscussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.