ArticleGenetic epidemiology2019
A fully adjusted two-stage procedure for rank-normalization in genetic association studies.
Article in Genetic epidemiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 2 of them syntheses that pooled it.
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Who cites it
58 citing papers in PubMed, 2 syntheses or guidelines pooled it.
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- A stop-gain variant inHGG advances · 2023Pooled it
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- Genome-wide investigation of prosody perception: Shared genetic influences between speech rhythm, musical rhythm, and reading traits.HGG advances · 2026Article
- Cumulative genetic risk for asthma contributes to disease severity in children with asthma.The journal of allergy and clinical immunology. Global · 2026Article
- Genomic, phenomic and geographic associations of leukocyte telomere length in the United States.Nature genetics · 2026Article
- Right and Left Atrial Dysfunction as Independent Cardiovascular Risk Factors: A UK Biobank Study.Circulation. Arrhythmia and electrophysiology · 2026Article
- Genetic underpinnings of chills from art and music.PLoS genetics · 2026Article
- Whole genome sequence analysis of pulmonary function and COPD in 44,287 multi-ancestry participants.Genome biology · 2026Article
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- Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.American journal of human genetics · 2025Article
- Robust Mixed Model Association Test for Gene-Environment Interactions.medRxiv : the preprint server for health sciences · 2025Article
- Cumulative Genetic Risk for Asthma Contributes to Disease Severity in Children with Asthma living in Urban Environments.medRxiv : the preprint server for health sciences · 2025Article
- Disentangling multivariate relationships between cognition, language and social traits: structures of G, E, andbioRxiv : the preprint server for biology · 2025Article
- A Robust Association Test Leveraging Unknown Genetic Interactions: Application to Cystic Fibrosis Lung Disease.Genetic epidemiology · 2025Article
- Whole-genome Sequencing Association Analysis of Quantitative Platelet Traits in A Large Cohort of β-thalassemia.Genomics, proteomics & bioinformatics · 2025Article
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- On the analysis of metabolite quantitative trait loci: Impact of different data transformations and study designs.Science advances · 2025Article
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
When testing genotype-phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. Because genotypes are expected to have small effects (if any) investigators now routinely use a two-stage method, in which they first regress the trait on covariates, obtain residuals, rank-normalize them, and then use the rank-normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice, no further adjustment is done in the second stage. Here, we show that this widely used approach can lead to tests with undesirable statistical properties, due to both combination of a mis-specified mean-variance relationship and remaining covariate associations between the rank-normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome-wide and whole-genome sequencing association studies. We further propose and evaluate an alternative fully adjusted two-stage approach that adjusts for covariates both when residuals are obtained and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.
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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.