Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx

Michael J Gloudemans ,Christopher D Brown,François Aguet,Yoson Park,Shaila Musharoff,Nathan S Abell,Kristin Ardlie ,Rodrigo Bonazzola,Xiaoquan Wen,Tuuli Lappalainen,Brunilda Balliu,Alicia R Martin,Alvaro N Barbeira,Margaret L Antonio,Abhiram Rao ,Hae Kyung Im,Farhad Hormozdiari,S Montgomery

doi:10.1186/s13059-020-02113-0

Abstract

BackgroundPopulation structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization.ResultsHere, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up.ConclusionsWe provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.

Highlights

Thousands of genome-wide association studies (GWAS) have been published to date
We describe the degree of admixture in the Genotype-Tissue Expression (GTEx) v8 cohort and estimate local ancestry (LA) for a subset of 117 individuals with at least 10% admixture from European, African, and East Asian ancestral populations
To understand the degree of population admixture represented in GTEx, we compared the first two genotype principal components (gPCs) with self-reported ancestry (Fig. 1a)

Summary

Introduction

Thousands of genome-wide association studies (GWAS) have been published to date. Subsequently, large-scale expression quantitative trait loci (eQTL) datasets are studied to provide insights for genetic variants associated with complex traits. Global ancestry (GA), or the proportions of different ancestral populations represented across the entire genome, is routinely used to adjust for population structure in genetic association studies [6]. This approach has the advantage of averaging genomic background effects and was used in eQTL mapping for the main GTEx releases [1, 7]. The potential disadvantage of correcting only for GA is that it does not precisely account for ancestry at any specific locus This can be problematic when genes are differentially expressed in ancestral populations of admixed individuals. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization

Methods

Results

Discussion

Conclusion