ArticlePloS one2009
Failure to replicate a genetic association may provide important clues about genetic architecture.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers, 11 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
142 citing papers in PubMed, 11 syntheses or guidelines pooled it.
- Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging.Molecular psychiatry · 2022Pooled it
- A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility.Journal of neurology · 2022Pooled it
- Pooled it
- Association between LRP1 C766T polymorphism and Alzheimer's disease susceptibility: a meta-analysis.Scientific reports · 2017Pooled it
- Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects.Circulation. Cardiovascular genetics · 2017Pooled it
- MEF2C rs190982 polymorphism with late-onset Alzheimer's disease in Han Chinese: A replication study and meta-analyses.Oncotarget · 2016Pooled it
- Meta-GWAS and Meta-Analysis of Exome Array Studies Do Not Reveal Genetic Determinants of Serum Hepcidin.PloS one · 2016Pooled it
- Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity.Human molecular genetics · 2014Pooled it
- CAG-repeat variant in the polymerase γ gene and male infertility in the Chinese population: a meta-analysis.Asian journal of andrology · 2011Pooled it
- Lack of association between alpha-adducin G460W polymorphism and hypertension: evidence from a case-control study and a meta-analysis.Journal of human hypertension · 2010Pooled it
- A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level.BMC medical genetics · 2010Pooled it
- Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study.BMC medical genetics · 2011Trial
- Article
- A global genetic interaction map of a human cell reveals conserved principles of genetic networks.bioRxiv : the preprint server for biology · 2025Article
- Enhancer RNA transcription pinpoints functional genetic variants linked to asthma.Nature communications · 2025Article
- Considerations in the search for epistasis.Genome biology · 2024Review
- Variance quantitative trait loci reveal gene-gene interactions which alter blood traits.medRxiv : the preprint server for health sciences · 2024Article
- Pleiotropy, epistasis and the genetic architecture of quantitative traits.Nature reviews. Genetics · 2024Review
- Gene-environment interactions within a precision environmental health framework.Cell genomics · 2024Review
- Interaction models matter: an efficient, flexible computational framework for model-specific investigation of epistasis.BioData mining · 2024Article
82 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors.
Funding
Abstract
Replication has become the gold standard for assessing statistical results from genome-wide association studies. Unfortunately this replication requirement may cause real genetic effects to be missed. A real result can fail to replicate for numerous reasons including inadequate sample size or variability in phenotype definitions across independent samples. In genome-wide association studies the allele frequencies of polymorphisms may differ due to sampling error or population differences. We hypothesize that some statistically significant independent genetic effects may fail to replicate in an independent dataset when allele frequencies differ and the functional polymorphism interacts with one or more other functional polymorphisms. To test this hypothesis, we designed a simulation study in which case-control status was determined by two interacting polymorphisms with heritabilities ranging from 0.025 to 0.4 with replication sample sizes ranging from 400 to 1600 individuals. We show that the power to replicate the statistically significant independent main effect of one polymorphism can drop dramatically with a change of allele frequency of less than 0.1 at a second interacting polymorphism. We also show that differences in allele frequency can result in a reversal of allelic effects where a protective allele becomes a risk factor in replication studies. These results suggest that failure to replicate an independent genetic effect may provide important clues about the complexity of the underlying genetic architecture. We recommend that polymorphisms that fail to replicate be checked for interactions with other polymorphisms, particularly when samples are collected from groups with distinct ethnic backgrounds or different geographic regions.
Indexed as
Identifiers
What OpenQuestion holds
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.