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Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10−14), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner’s Curse (p < 10−16). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per-locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium. [ABSTRACT FROM AUTHOR]

The prediction of phenotypic traits using high-density genomic data has many applications such as the selection of plants and animals of commercial interest; and it is expected to play an increasing role in medical diagnostics. Statistical models used for this task are usually tested using cross-validation, which implicitly assumes that new individuals (whose phenotypes we would like to predict) originate from the same population the genomic prediction model is trained on. In this paper we propose an approach based on clustering and resampling to investigate the effect of increasing genetic distance between training and target populations when predicting quantitative traits. This is important for plant and animal genetics, where genomic selection programs rely on the precision of predictions in future rounds of breeding. Therefore, estimating how quickly predictive accuracy decays is important in deciding which training population to use and how often the model has to be recalibrated. We find that the correlation between true and predicted values decays approximately linearly with respect to either FST or mean kinship between the training and the target populations. We illustrate this relationship using simulations and a collection of data sets from mice, wheat and human genetics. [ABSTRACT FROM AUTHOR]

Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by-environment interactions (GEIs). Recently, several studies have conducted genome-wide gene-by-environment association analyses and demonstrated important roles of GEIs in complex traits. One of the main challenges in these association studies is to control effects of population structure that may cause spurious associations. Many studies have analyzed how population structure influences statistics of genetic variants and developed several statistical approaches to correct for population structure. However, the impact of population structure on GEI statistics in GWASs has not been extensively studied and nor have there been methods designed to correct for population structure on GEI statistics. In this paper, we show both analytically and empirically that population structure may cause spurious GEIs and use both simulation and two GWAS datasets to support our finding. We propose a statistical approach based on mixed models to account for population structure on GEI statistics. We find that our approach effectively controls population structure on statistics for GEIs as well as for genetic variants. [ABSTRACT FROM AUTHOR]