WGAViewer: software for genomic annotation of whole genome association studies

Abstract

To meet the immediate need for a framework of post-whole genome association (WGA) annotation, we have developed WGAViewer, a suite of JAVA software tools that provides a user-friendly interface to automatically annotate, visualize, and interpret the set of P-values emerging from a WGA study. Most valuably, it can be used to highlight possible functional mechanisms in an automatic manner, for example, by directly or indirectly implicating a polymorphism with an apparent link to gene expression, and help to generate hypotheses concerning the possible biological bases of observed associations. The easily interpretable diagrams can then be used to identify the associations that seem most likely to be biologically relevant, and to select genomic regions that may need to be resequenced in a search for candidate causal variants. In this report, we used our recently completed study on host control of HIV-1 viral load during the asymptomatic set point period as an illustration for the heuristic annotation of this software and its contributive role in a successful WGA project.

Figure 1.

A screenshot of the results of WGAViewer individual SNP annotation for rs9264942 (Fellay et al. 2007). (A) Ideogram depicting chromosome and annotated region (circled red line). (B) Pairwise LD values (r²) between the associating SNP, rs9264942 (position indicated by circled red arrow), and all other HapMap SNPs in the region (SNP list from HapMap release 22, build 36; genome coordinates based on Ensembl release 46_36h, build 36; [red] r² ≥ 0.8, [yellow] 0.5 ≤ r² < 0.8, [gray] 0.3 ≤ r² < 0.5, [blue] 0.2 ≤ r² < 0.3, [dark gray] missing data). (C) Position of annotated SNP, rs9264942 (genome coordinate based on Ensembl release 46_36h, build 36). (D) Recent selection scores (Voight et al. 2006) for SNPs plotted in B where available. (Red) |iHs| ≥ 2.5, (yellow) 2.0 ≤ |iHs| < 2.5, (blue) |iHs| < 2.0. (E) Gene diagram with introns (horizontal blue lines) and exons (vertical blue lines) depicted. Detailed information for the highlighted gene (HLA-C, with a hand cursor) is shown in a dynamic data sheet (part I). (F) Genome overview of the WGA results. Two genome-wide significant hits (rs2395029 and rs9264942) are plotted (red points). (G) Association test between rs9264942 genotypes and HLA-C expression levels (Stranger et al. 2005), showing highly significant association. It should also be noted that in the case of a highly variable gene like HLA-C, apparent expression effects could result from either an association with expression or an association with variant sites affecting probe binding (T. Urban, W. Yoon, K.V. Shianna, J. Fellay, D. Ge, B.H. Haynes, A.J. McMichael, M. Carrington, A. Telenti, and D.B. Goldstein, unpubl.). (H) Data sheet summarizing important information for the annotated SNP, rs9264942. (I) Dynamic data sheet summarizing important information for items (HLA-C transcript ENST00000376237) highlighted in parts B–E. For detailed descriptions, see Supplemental material: WGAViewer User’s Guide Chapter 3.3: Annotation for top hits.