Fine-scale patterns of population stratification confound rare variant association tests

Area of Science:

• Genetics
• Bioinformatics
• Population Genetics

Background:

• Next-generation sequencing facilitates rare variant analysis in diseases.
• Population stratification is known to cause spurious associations with common alleles.
• The effect of population structure on rare variant association methods is not well understood.

Purpose of the Study:

• To evaluate the performance of rare variant association methods under fine-scale population structure.
• To quantify the impact of population stratification on spurious association rates.

Main Methods:

• Exhaustive coalescent simulations using demographic parameters from exome data.
• Evaluation of nine different rare variant association methods.
• Empirical assessment using a dataset of 4,298 European American exomes.

Main Results:

• All tested methods showed inflated spurious association rates with European-like population differentiation.
• At a 5% significance level, some methods exhibited up to 40% spurious association rates.
• Empirical analysis confirmed the impact of population stratification.

Conclusions:

• Population stratification poses a significant challenge for rare variant association studies.
• Current rare variant association methods are susceptible to false positives due to population structure.
• Results necessitate careful consideration of population stratification in the design and analysis of rare variant GWAS.