Impact of cross-ancestry genetic architecture on GWASs in admixed populations

Rachel Mester; Kangcheng Hou; Yi Ding; Gillian Meeks; Kathryn S Burch; Arjun Bhattacharya; Brenna M Henn; Bogdan Pasaniuc

doi:10.1016/j.ajhg.2023.05.001

Impact of cross-ancestry genetic architecture on GWASs in admixed populations

Am J Hum Genet. 2023 Jun 1;110(6):927-939. doi: 10.1016/j.ajhg.2023.05.001. Epub 2023 May 23.

Authors

Rachel Mester¹, Kangcheng Hou², Yi Ding², Gillian Meeks³, Kathryn S Burch², Arjun Bhattacharya⁴, Brenna M Henn⁵, Bogdan Pasaniuc⁶

Affiliations

¹ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rmester@ucla.edu.
² Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Integrative Genetics and Genomics Graduate Group, University of California, Davis, Davis, CA 95616, USA.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Anthropology, Center for Population Biology and the Genome Center, University of California, Davis, Davis, CA 95616, USA.
⁶ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: pasaniuc@ucla.edu.

Abstract

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust for population stratification. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing a GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes, we find that controlling for and conditioning effect sizes on local ancestry can reduce statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs, HetLanc is not large enough for GWASs to benefit from modeling heterogeneity in this way.

Keywords: GWAS; Tractor; admixture; complex trait; effect sizes; genetic ancestry; genetic correlation; heterogeneity; local ancestry; simulation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Gene Frequency / genetics
Genetics, Population*
Genome-Wide Association Study* / methods
Genotype
Humans
Phenotype
Polymorphism, Single Nucleotide / genetics

Abstract

Publication types

MeSH terms

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