Human Genetics

, Volume 128, Issue 3, pp 269–280 | Cite as

Genome-wide searching of rare genetic variants in WTCCC data

Original Investigation

Abstract

Although they have demonstrated success in searching for common variants for complex diseases, genome-wide association (GWA) studies are less successful in detecting rare genetic variants because of the poor statistical power of most of current methods. We developed a two-stage method that can apply to GWA studies for detecting rare variants. Here we report the results of applying this two-stage method to the Wellcome Trust Case Control Consortium (WTCCC) dataset that include seven complex diseases: bipolar disorder, cardiovascular disease, hypertension (HT), rheumatoid arthritis, Crohn’s disease, type 1 diabetes and type 2 diabetes (T2D). We identified 24 genes or regions that reach genome wide significance. Eight of them are novel and were not reported in the WTCCC study. The cumulative risk (or protective) haplotype frequency for each of the 8 genes or regions is small, being at most 11%. For each of the novel genes, the risk (or protective) haplotype set cannot be tagged by the common SNPs available in chips (r2 < 0.32). The gene identified in HT was further replicated in the Framingham Heart Study, and is also significantly associated with T2D. Our analysis suggests that searching for rare genetic variants is feasible in current GWA studies and candidate gene studies, and the results can severe as guides to future resequencing studies to identify the underlying rare functional variants.

Supplementary material

439_2010_849_MOESM1_ESM.doc (97 kb)
Supplementary Figure 1. QQ plots of –log10(P value) for testing association of risk haplotype set at stage 2 between the 2 disease cases RA and T1D without SNPs in the MHC and HLA regions and the common controls against the uniform distribution (left panel), and the Manhattan plot of the genome-wide –log10(P value) according to the chromosomal positions of genes in association tests (right panel). Supplementary Figure 2. QQ plots of –log10(P value) for testing association of protective haplotype set at stage 2 between the 2 disease cases RA and T1D without SNPs in the MHC and HLA regions and the common controls against the uniform distribution (left panel), and the Manhattan plot of the genome-wide −log10(P value) according to the chromosomal positions of genes in association tests (right panel). (DOC 97 kb)
439_2010_849_MOESM2_ESM.doc (928 kb)
Supplementary Tables (DOC 928 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Epidemiology and BiostatisticsCase Western Reserve UniversityClevelandUSA

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