SynthesisHuman molecular genetics2021
False positive findings during genome-wide association studies with imputation: influence of allele frequency and imputation accuracy.
Synthesis in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 2 syntheses or guidelines pooled it, 24 citations in OpenAlex.
- CPNE1: A novel therapeutic target for myopia progression - from genetic GWAS discovery to functional validation in vitro and vivo.Journal of translational medicine · 2026Pooled it
- Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts.Brain : a journal of neurology · 2025Pooled it
- Facilitating genomic breeding in citrus via reference panel-based whole-genome imputation of low-coverage sequencing-derived genotype data.Breeding science · 2026Article
- Trans-ancestry genome-wide analyses of bipolar disorder in East Asian and European populations improve genetic discovery.Nature neuroscience · 2026Article
- Advances in haplotype phasing and genotype imputation.Nature reviews. Genetics · 2026Review
- Genome-wide association study identifies novel and confirms established loci associated with serum lipids levels in Brazilians.Human genetics · 2026Article
- An Advanced Entropy Approach for Minimizing False Discoveries in Imputation-Based Association Analyses.Research square · 2025Article
- Integrative Gene-Centric Analysis Reveals Cellular Pathways Associated with Heritable Breast Cancer Predisposition.Cancers · 2025Article
- Adjustment for Genotype Imputation Uncertainty Corrects for Inflated Type I Error in Family-Based Association Testing.Genetic epidemiology · 2025Article
- Inferring Domestic Goat Demographic History Through Ancient Genome Imputation.Genome biology and evolution · 2025Article
- Establishing Best Practices for Clinical GWAS: Tackling Imputation and Data Quality Challenges.International journal of molecular sciences · 2025Review
- Aggregating single nucleotide polymorphisms improves filtering for false-positive associations postimputation.G3 (Bethesda, Md.) · 2025Article
- Role of metabolic dysfunction-associated fatty liver disease in atrial fibrillation and heart failure: molecular and clinical aspects.Frontiers in cardiovascular medicine · 2025Review
- Editorial: Advancements and prospects of genome-wide association studies.Frontiers in genetics · 2025Article
- Population-specific reference panel improves imputation quality for genome-wide association studies conducted on the Japanese population.Communications biology · 2024Article
- A method to estimate the contribution of rare coding variants to complex trait heritability.Nature communications · 2024Article
- Accuracy of genotype imputation based on reference population size and marker density in Hanwoo cattle.Journal of animal science and technology · 2021Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.