False positive findings during genome-wide association studies with imputation: influence of allele frequency and imputation accuracy is a research paper published in Human Molecular Genetics (2021). On theSindex it has a DataRank of 0.860. It has been cited 25 times, with 25 citing works in its 1-hop citation network. Its calibrated FAIR score is 49/100.
Abstract Genotype imputation is widely used in genetic studies to boost the power of GWAS, to combine multiple studies for meta-analysis and to perform fine mapping. With advances of imputation tools and large reference panels, genotype imputation has become mature and accurate. However, the uncertain nature of imputed genotypes can cause bias in the downstream analysis. Many studies have compared the performance of popular imputation approaches, but few investigated bias characteristics of downstream association analyses. Herein, we showed that the imputation accuracy is diminished if the real genotypes contain minor alleles. Although these genotypes are less common, which is particularly true for loci with low minor allele frequency, a large discordance between imputed and observed genotypes significantly inflated the association results, especially in data with a large portion of uncertain SNPs. The significant discordance of P-values happened as the P-value approached 0 or the imputation quality was poor. Although elimination of poorly imputed SNPs can remove false positive (FP) SNPs, it sacrificed, sometimes, more than 80% true positive (TP) SNPs. For top ranked SNPs, removing variants with moderate imputation quality cannot reduce the proportion of FP SNPs, and increasing sample size in reference panels did not greatly benefit the results as well. Additionally, samples with a balanced ratio between cases and controls can dramatically improve the number of TP SNPs observed in the imputation based GWAS. These results raise concerns about results from analysis of association studies when rare variants are studied, particularly when case–control studies are unbalanced.
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Base Score Contribution
0.489
From this paper's citation signal
Citation Network Contribution
0.371
From 14 citing papers with measurable signal
Ranked by citation count — the same ordering the engine uses when summing log1p(Cq) over citers.
DataRank blends this paper's own citation count with the influence of the papers that cite it. Here, roughly 57% comes from its base citations and 43% from the citation network (14 citing papers contributed measurable signal).
Citers are pulled from OpenAlex sorted by cited_by_count:descand capped per paper, so when the cap binds we keep the highest-signal references and the score is reproducible across reruns.
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