Genome-wide searching of rare genetic variants in WTCCC data
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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 (r 2 < 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.
KeywordsRare Variant Risk Haplotype Major Histocompatibility Complex Region Wellcome Trust Case Control Consortium Haplotype Inference
We thank Dr. RC Elston for his constructed reading and comments of the manuscript. The work was supported by the National Institutes of Health, Grant numbers HL074166, HL086718 from National Heart, Lung, Blood Institute, HG003054 from the National Human Genome Research Institute, RR03655 from the National Center for Research Resources. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/info/participants.shtml. Funding for that project was provided by the Wellcome Trust under award 076113. The Framingham Heart Study research was supported by NHLBI Contract: 2 N01-HC-25195-06 and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). The authors are grateful to the many investigators within the Framingham Heart Study who have collected and managed the data and especially to the participants for their invaluable time, patience, and dedication to the Study.
Conflict of interest statement
The authors declare that they have no competing financial interests.
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