Validating, augmenting and refining genome-wide association signals

Abstract

Studies using genome-wide platforms have yielded an unprecedented number of promising signals of association between genomic variants and human traits. This Review addresses the steps required to validate, augment and refine such signals to identify underlying causal variants for well-defined phenotypes. These steps include: large-scale exact replication across both similar and diverse populations; fine mapping and resequencing; determination of the most informative markers and multiple independent informative loci; incorporation of functional information; and improved phenotype mapping of the implicated genetic effects. Even in cases for which replication proves that an effect exists, confident localization of the causal variant often remains elusive.

Replication of top markers of a genome-wide association study in multiple sclerosis in Spain

“…16 Often, GWAS use multistage designs to warrant replication of the original findings, otherwise, the confirmation of association signals through largescale replication is recommended. 15 With this limitation in mind, our aim with the present work was to corroborate the best-associated variants identified in the GWAS by Baranzini et al 14 The authors defined top-scoring (non-HLA) markers associated with global MS susceptibility, all of them with modest effects on disease risk, by performing the screen of allele frequencies for 551642 SNPs in 978 MS cases and 883 controls. Our scan of these markers in an independent collection of 2863 MS cases and 2930 controls revealed replication of the GPC5 polymorphism studied, but no other best hit reached significance.…”

“…The accepted measure of genome-wide significance (P ¼ 10 À7 -10 À8 , equivalent to a P ¼ 0.05 for a classical epidemiological study in which only one hypothesis is being tested) warrants corroboration of the relevant genes. 15 Even more so when the proposed associations show less stringent support (Pp10 À5 ), the reported loci need replication in additional data sets before they can be considered reliable susceptibility markers. With this aim, a total of 2863 MS patients and 2930 healthy controls from Spain, matched by age, gender and ethnicity were compared in a case-control study.…”

Non-synonymous single-nucleotide polymorphisms associated with blood pressure and hypertension

“…Despite the massive sequencing and exhaustive association analysis of the originally associated SNP locus, 12 it was difficult to identify any causative genetic variations. Determining these variations is important not only to understand the underlying associations between genotype and phenotype but also to apply the results in the development of diagnostic kits and drug design.…”

The pursuit of genome-wide association studies: where are we now?

“…However, the guidelines and practical details of imputation-based meta-analysis of GWAS, 65 as well as the methodological and analytical issues of GWAS meta-analysis have been outlined and discussed in several papers. 66,67 The timely emergence of imputation methods together with the reference database have been the major driving force for conducting GWAS meta-analysis.…”