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GWAS to Sequencing: Divergence in Study Design and Analysis

Department of Health Studies, University of Chicago, Chicago, IL 60637, USA
Departments of Medicine, Statistics, and Human Genetics, University of Chicago, Chicago,IL 60637, USA
Author to whom correspondence should be addressed.
Genes 2014, 5(2), 460-476;
Received: 27 December 2013 / Revised: 13 May 2014 / Accepted: 15 May 2014 / Published: 28 May 2014
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
PDF [766 KB, uploaded 28 May 2014]


The success of genome-wide association studies (GWAS) in uncovering genetic risk factors for complex traits has generated great promise for the complete data generated by sequencing. The bumpy transition from GWAS to whole-exome or whole-genome association studies (WGAS) based on sequencing investigations has highlighted important differences in analysis and interpretation. We show how the loss in power due to the allele frequency spectrum targeted by sequencing is difficult to compensate for with realistic effect sizes and point to study designs that may help. We discuss several issues in interpreting the results, including a special case of the winner’s curse. Extrapolation and prediction using rare SNPs is complex, because of the selective ascertainment of SNPs in case-control studies and the low amount of information at each SNP, and naive procedures are biased under the alternative. We also discuss the challenges in tuning gene-based tests and accounting for multiple testing when genes have very different sets of SNPs. The examples we emphasize in this paper highlight the difficult road we must travel for a two-letter switch. View Full-Text
Keywords: sequencing; GWAS; prediction; power of genetic association sequencing; GWAS; prediction; power of genetic association
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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King, C.R.; Nicolae, D.L. GWAS to Sequencing: Divergence in Study Design and Analysis. Genes 2014, 5, 460-476.

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