Local and Global Ancestry Inference and Applications to Genetic Association Analysis for Admixed Populations

Abstract

Genetic association studies in recently admixed populations offer exciting opportunities for the identification of variants underlying phenotypic diversity. At the same time, genetic heterogeneity due to population admixture has to be accounted for in order to ensure validity of association tests. The whole genome sequence data and the genome-wide single nucleotide polymorphism chip data for Mexican American individuals provided by the Genetic Analysis Workshop 18 (GAW18) presents a unique opportunity to evaluate and compare methods for the statistical analysis of admixed genetic data. We summarize here the five contributions from the GAW18 Admixture group. Although group members considered a variety of research topics, the general theme was inference and consideration of ancestry admixture in genetic analyses. The topics considered can be grouped into three categories: (1) global and local ancestry inference and estimation; (2) association and admixture mapping; and (3) genotype imputation in admixed samples. We describe the approaches that were used and the most relevant findings from individual contributions. We also provide insight into the strengths and limitations of the state-of-the-art methods considered for genetic analyses in admixed populations.

Robust Inference of Population Structure for Ancestry Prediction and Correction of Stratification in the Presence of Relatedness

“…For example, the top principal components from PCA, as well as the top dimensions from MDS, can reflect family relatedness rather than population structure when applied to samples that include relatives [Price et al, 2010]. Model-based ancestry estimation methods similarly fail in the presence of relatedness as they are not able to distinguish between ancestral groups and clusters of relatives [Thornton and Bermejo, 2014]. For certain family-based study designs with known pedigrees, the population structure inference method proposed by Zhu et al [2008], where SNP loadings calculated from a PCA on pedigree founders are used to obtain principal components values for genotyped offspring, can be used.…”

Conclusion: Special issue on genetic and alcohol use disorder research with diverse racial/ethnic groups: Key findings and potential next steps

“…The use of PCA approaches and external reference panels to define ancestry groups does seem to provide an increase in accuracy and to improve the retention of markers and subjects. Investigators should also consider the strengths and limitations of other methods of analysis for admixed genetic data (e.g., Thornton and Bermejo 15 ), and new approaches are sure to be developed.…”

Drinking From the Holy Grail: Analysis of Whole‐Genome Sequencing From the Genetic Analysis Workshop 18

“…Thornton and Lorenzo Bermejo [] have summarized the analysis of population structure in the pedigrees. They estimated the proportion of Native American and European ancestries to be 50% and 45%, respectively (SD = 14%, ranges, 0–84% and 0–96%, respectively).…”

“…In addition, the question of how to deal with multiple alternative transcripts of genes has not been adequately addressed; Ensembl.org lists 18 different splice variants of MAP4. Thornton and Lorenzo Bermejo [2014] have summarized the analysis of population structure in the pedigrees. They estimated the proportion of Native American and European ancestries to be 50% and 45%, respectively (SD = 14%, ranges, 0-84% and 0-96%, respectively).…”