@article {37, title = {An ancestry-based approach for detecting interactions.}, journal = {Genet Epidemiol}, volume = {42}, year = {2018}, month = {2018 Feb}, pages = {49-63}, abstract = {

BACKGROUND: Epistasis and gene-environment interactions are known to contribute significantly to variation of complex phenotypes in model organisms. However, their identification in human association studies remains challenging for myriad reasons. In the case of epistatic interactions, the large number of potential interacting sets of genes presents computational, multiple hypothesis correction, and other statistical power issues. In the case of gene-environment interactions, the lack of consistently measured environmental covariates in most disease studies precludes searching for interactions and creates difficulties for replicating studies.

RESULTS: In this work, we develop a new statistical approach to address these issues that leverages genetic ancestry, defined as the proportion of ancestry derived from each ancestral population (e.g., the fraction of European/African ancestry in African Americans), in admixed populations. We applied our method to gene expression and methylation data from African American and Latino admixed individuals, respectively, identifying nine interactions that were significant at P<5{\texttimes}10-8. We show that two of the interactions in methylation data replicate, and the remaining six are significantly enriched for low P-values (P<1.8{\texttimes}10-6).

CONCLUSION: We show that genetic ancestry can be a useful proxy for unknown and unmeasured covariates in the search for interaction effects. These results have important implications for our understanding of the genetic architecture of complex traits.

}, keywords = {Black or African American, Black People, DNA Methylation, Epistasis, Genetic, Gene-Environment Interaction, Hispanic or Latino, Humans, Models, Genetic, Phenotype, White People}, issn = {1098-2272}, doi = {10.1002/gepi.22087}, author = {Park, Danny S and Eskin, Itamar and Kang, Eun Yong and Gamazon, Eric R and Eng, Celeste and Gignoux, Christopher R and Galanter, Joshua M and Burchard, Esteban and Ye, Chun J and Aschard, Hugues and Eskin, Eleazar and Halperin, Eran and Zaitlen, Noah} } @article {7, title = {The Effects of Migration and Assortative Mating on Admixture Linkage Disequilibrium.}, journal = {Genetics}, volume = {205}, year = {2017}, month = {2017 Jan}, pages = {375-383}, abstract = {

Statistical models in medical and population genetics typically assume that individuals assort randomly in a population. While this simplifies model complexity, it contradicts an increasing body of evidence of nonrandom mating in human populations. Specifically, it has been shown that assortative mating is significantly affected by genomic ancestry. In this work, we examine the effects of ancestry-assortative mating on the linkage disequilibrium between local ancestry tracks of individuals in an admixed population. To accomplish this, we develop an extension to the Wright-Fisher model that allows for ancestry-based assortative mating. We show that ancestry-assortment perturbs the distribution of local ancestry linkage disequilibrium (LAD) and the variance of ancestry in a population as a function of the number of generations since admixture. This assortment effect can induce errors in demographic inference of admixed populations when methods assume random mating. We derive closed form formulae for LAD under an assortative-mating model with and without migration. We observe that LAD depends on the correlation of global ancestry of couples in each generation, the migration rate of each of the ancestral populations, the initial proportions of ancestral populations, and the number of generations since admixture. We also present the first direct evidence of ancestry-assortment in African Americans and examine LAD in simulated and real admixed population data of African Americans. We find that demographic inference under the assumption of random mating significantly underestimates the number of generations since admixture, and that accounting for assortative mating using the patterns of LAD results in estimates that more closely agrees with the historical narrative.

}, keywords = {Alleles, Black or African American, Datasets as Topic, Gene Frequency, Genetics, Population, Genomics, Human Migration, Humans, Linkage Disequilibrium, Models, Genetic, Models, Statistical, Polymorphism, Single Nucleotide}, issn = {1943-2631}, doi = {10.1534/genetics.116.192138}, author = {Zaitlen, Noah and Huntsman, Scott and Hu, Donglei and Spear, Melissa and Eng, Celeste and Oh, Sam S and White, Marquitta J and Mak, Angel and Davis, Adam and Meade, Kelly and Brigino-Buenaventura, Emerita and LeNoir, Michael A and Bibbins-Domingo, Kirsten and Burchard, Esteban G and Halperin, Eran} }