Custodio, N. | Search bioRxiv

bioRxiv2023

A benchmark study on current GWAS models in admixed populations

ObjectiveThe performances of popular Genome-wide association study (GWAS) models havent been examined yet in a consistent manner under the scenario of genetic admixture, which introduces several challenging aspects such as heterogeneity of minor allele frequency (MAF), a wide spectrum of case-control ratio, and varying effect sizes etc. MethodsWe generated a cohort of synthetic individuals (N=19,234) that simulates 1) a large sample size; 2) two-way admixture [Native American-European ancestry] and 3) a binary phenotype. We then examined the inflation factors produced by three popular GWAS tools: GMMAT, SAIGE, and Tractor. We also computed power calculations under different MAFs, case-control ratios, and varying ancestry percentages. Then, we employed a cohort of Peruvians (N=249) to further examine the performances of the testing models on 1) real genetic data and 2) small sample sizes. Finally, we validated these findings using an independent Peruvian cohort (N=109) included in 1000 Genome project (1000G). ResultIn the synthetic cohort, SAIGE performed better than GMMAT and Tractor in terms of type-I error rate, especially under severe unbalanced case-control ratio. On the contrary, power analysis identified Tractor as the best method to pinpoint ancestry-specific causal variants, but showed decreased power when no adequate heterogeneity of the true effect sizes was simulated between ancestries. The real Peruvian data showed that Tractor is severely affected by small sample sizes, and produced severely inflated statistics, which we replicated in the 1000G Peruvian cohort. DiscussionThe current study illustrates the limitations of available GWAS tools under different scenarios of genetic admixture. We urge caution when interpreting results under complex population scenarios.

bioinformatics↗

bioRxiv2020

Dissecting the role of Amerindian genetic ancestry and ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. ApoE {varepsilon}4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in{varepsilon} 4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to [~]80 of Amerindian ancestry provides a unique opportunity to assess the role of Amerindian ancestry in Alzheimer disease. In this study we assess the effect of the ApoE {varepsilon}4 allele on AD in the Peruvian population. A total of 78 AD cases and 128 unrelated cognitive healthy controls were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE {varepsilon}4 allele on Alzheimer disease was tested using a logistic regression model by adjusting for age, gender, and population substructure (first three principal components). Logistic regression results showed that ApoE {varepsilon}4 allele is significantly associated with AD in Peruvian population with the high-risk effect (OR = 5.02, CI: 2.3-12.5, p-value = 2e-4). The average values of the local ancestries surrounding the ApoE gene (chr19:44Mb-46Mb) have the highest proportion of Amerindian (60.6%), followed by European (33.9%) and African (5.5%) ancestral backgrounds. Our results showed that the risk for AD from ApoE {varepsilon}4 in Peruvians is higher than we have observed in non-Hispanic White populations. Given the high admixture of Amerindian ancestry in the Peruvian population, it suggests that the Amerindian local ancestry is contributing to a strong risk for AD in ApoE {varepsilon}4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE {varepsilon}4 and the ancestral backgrounds located around the genomic region of ApoE gene.

genetics↗