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On Using Local Ancestry to Characterize the Genetic Architecture of Human Phenotypes: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations as a Model

Yizhen Zhong, View ORCID ProfileMinoli Perera, View ORCID ProfileEric R. Gamazon
doi: https://doi.org/10.1101/483107
Yizhen Zhong
1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Minoli Perera
1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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  • For correspondence: minoli.perera@northwestern.edu
Eric R. Gamazon
2Vanderbilt Genetics Institute and Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
3Clare Hall, University of Cambridge, Cambridge, UK
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Abstract

Background Understanding the nature of the genetic regulation of gene expression promises to advance our understanding of the genetic basis of disease. However, the methodological impact of use of local ancestry on high-dimensional omics analyses, including most prominently expression quantitative trait loci (eQTL) mapping and trait heritability estimation, in admixed populations remains critically underexplored.

Results Here we develop a statistical framework that characterizes the relationships among the determinants of the genetic architecture of an important class of molecular traits. We estimate the trait variance explained by ancestry using local admixture relatedness between individuals. Using National Institute of General Medical Sciences (NIGMS) and Genotype-Tissue Expression (GTEx) datasets, we show that use of local ancestry can substantially improve eQTL mapping and heritability estimation and characterize the sparse versus polygenic component of gene expression in admixed and multiethnic populations respectively. Using simulations of diverse genetic architectures to estimate trait heritability and the level of confounding, we show improved accuracy given individual-level data and evaluate a summary statistics based approach. Furthermore, we provide a computationally efficient approach to local ancestry analysis in eQTL mapping while increasing control of type I and type II error over traditional approaches.

Conclusion Our study has important methodological implications on genetic analysis of omics traits across a range of genomic contexts, from a single variant to a prioritized region to the entire genome. Our findings highlight the importance of using local ancestry to better characterize the heritability of complex traits and to more accurately map genetic associations.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 29, 2018.
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On Using Local Ancestry to Characterize the Genetic Architecture of Human Phenotypes: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations as a Model
Yizhen Zhong, Minoli Perera, Eric R. Gamazon
bioRxiv 483107; doi: https://doi.org/10.1101/483107
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On Using Local Ancestry to Characterize the Genetic Architecture of Human Phenotypes: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations as a Model
Yizhen Zhong, Minoli Perera, Eric R. Gamazon
bioRxiv 483107; doi: https://doi.org/10.1101/483107

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