ArticleScientific reports2021
Controlling for human population stratification in rare variant association studies.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Large-scale Whole-Exome Sequencing Defines the Protein-Coding Architecture of Retinal Structure, Visual Function, and Major Blinding Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Challenges and Opportunities in Characterizing the Genetics of Stuttering: From Sample Acquisition to Functional Interpretation of the Genome.Journal of speech, language, and hearing research : JSLHR · 2025Review
- Article
- Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2024Article
- Article
- Genetic architecture and biology of youth-onset type 2 diabetes.Nature metabolism · 2024Article
- Insights from rare variants into the genetic architecture and biology of youth-onset type 2 diabetes.Research square · 2023Article
- An exploration of linkage fine-mapping on sequences from case-control studies.Genetic epidemiology · 2023Article
- Rare genetic variants explain missing heritability in smoking.Nature human behaviour · 2022Article
- Clarifying the causes of consistent and inconsistent findings in genetics.Genetic epidemiology · 2022Review
- Recent advances and challenges of rare variant association analysis in the biobank sequencing era.Frontiers in genetics · 2022Review
- A unifying framework for rare variant association testing in family-based designs, including higher criticism approaches, SKATs, and burden tests.Bioinformatics (Oxford, England) · 2021Article
- Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.Science (New York, N.Y.) · 2020Article
- The role of genetic and epigenetic factors in sports-related muscle, bone, and brain injuries.Science progressReview
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Population stratification is a confounder of genetic association studies. In analyses of rare variants, corrections based on principal components (PCs) and linear mixed models (LMMs) yield conflicting conclusions. Studies evaluating these approaches generally focused on limited types of structure and large sample sizes. We investigated the properties of several correction methods through a large simulation study using real exome data, and several within- and between-continent stratification scenarios. We considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. Large samples showed that accounting for stratification was more difficult with a continental than with a worldwide structure. When considering a sample of 50 cases, an inflation of type-I-errors was observed with PCs for small numbers of controls (≤ 100), and with LMMs for large numbers of controls (≥ 1000). We also tested a novel local permutation method (LocPerm), which maintained a correct type-I-error in all situations. Powers were equivalent for all approaches pointing out that the key issue is to properly control type-I-errors. Finally, we found that power of analyses including small numbers of cases can be increased, by adding a large panel of external controls, provided an appropriate stratification correction was used.
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