ABSTRACT
We analyzed whole genome and RNA sequencing data from 2,733 African American and Hispanic/Latino children to explore ancestry- and heterozygosity-related differences in the genetic architecture of whole blood gene expression. We found that heritability of gene expression significantly increases with greater proportion of African genetic ancestry and decreases with higher levels of Indigenous American ancestry, consistent with a relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of statistically significant ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most of the anc-eQTLs (89%) were driven by population differences in allele frequency, demonstrating the importance of measuring gene expression across multiple populations. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait pairs using models trained in our admixed population than models trained in GTEx. Our study highlights the importance of large and ancestrally diverse genomic studies for enabling new discoveries of complex trait architecture and reducing disparities.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵‡ These authors jointly supervised this work
1.We have uploaded the following files to a public data repository https://doi.org/10.5281/zenodo.6622368: i.cis-eQTL summary statistics from all GALA II/SAGE participants (n=2733) and stratified by race/ethnicity (African American, Puerto Rican, Mexican American) and genetic ancestry (>50% and <10% African ancestry; >50% and <10% Indigenous American ancestry) ii.Comprehensive catalogue of ancestry-specific cis-eQTLs identified in our study for African and Indigenous American ancestry iii.Statistically significant trans-eQTLs identified in the pooled sample and stratified by race/ethnicity (African American, Puerto Rican, Mexican American) and genetic ancestry iv.TWAS models developed in the pooled GALAII/SAGE sample and in each race/ethnicity group 2.We performed extensive sensitivity analyses related to the robustness of the observation that heritability of gene expression is higher in populations of predominantly African ancestry: i.Repeated heritability and eQTL mapping analyses restricting to n=600 across ancestry groups to account for differences in statistical power ii.Partitioned heritability by allele frequency and compared LD-independent eQTL signals iii.Re-estimated heritability using alternative methods (LDAK in addition to GCTA) 3.We conducted TWAS of 22 blood-based biomarkers in the UK Biobank and evaluated the performance of ancestry-matched and ancestry-discordant transcriptome models in European and African ancestry subjects. We conclusively demonstrate the superior performance of ancestry-matched TWAS models, particularly for African ancestry populations. A novel finding of this analysis is that transcriptome prediction models trained in African Americans have improved cross-population portability compared to TWAS models derived in predominantly European ancestry subjects.
