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Inference of human continental origin and admixture proportions using a highly discriminative ancestry informative 41-SNP panel.

ABSTRACT: BACKGROUND:Accurate determination of genetic ancestry is of high interest for many areas such as biomedical research, personal genomics and forensics. It remains an important topic in genetic association studies, as it has been shown that population stratification, if not appropriately considered, can lead to false-positive and -negative results. While large association studies typically extract ancestry information from available genome-wide SNP genotypes, many important clinical data sets on rare phenotypes and historical collections assembled before the GWAS area are in need of a feasible method (i.e., ease of genotyping, small number of markers) to infer the geographic origin and potential admixture of the study subjects. Here we report on the development, application and limitations of a small, multiplexable ancestry informative marker (AIM) panel of SNPs (or AISNP) developed specifically for this purpose. RESULTS:Based on worldwide populations from the HGDP, a 41-AIM AISNP panel for multiplex application with the ABI SNPlex and a subset with 31 AIMs for the Sequenome iPLEX system were selected and found to be highly informative for inferring ancestry among the seven continental regions Africa, the Middle East, Europe, Central/South Asia, East Asia, the Americas and Oceania. The panel was found to be least informative for Eurasian populations, and additional AIMs for a higher resolution are suggested. A large reference set including over 4,000 subjects collected from 120 global populations was assembled to facilitate accurate ancestry determination. We show practical applications of this AIM panel, discuss its limitations for admixed individuals and suggest ways to incorporate ancestry information into genetic association studies. CONCLUSION:We demonstrated the utility of a small AISNP panel specifically developed to discern global ancestry. We believe that it will find wide application because of its feasibility and potential for a wide range of applications.

SUBMITTER: Nievergelt CM

PROVIDER: S-EPMC3699392 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Inference of human continental origin and admixture proportions using a highly discriminative ancestry informative 41-SNP panel.

Nievergelt Caroline M CM Maihofer Adam X AX Shekhtman Tatyana T Libiger Ondrej O Wang Xudong X Kidd Kenneth K KK Kidd Judith R JR

Investigative genetics 20130701 1

<h4>Background</h4>Accurate determination of genetic ancestry is of high interest for many areas such as biomedical research, personal genomics and forensics. It remains an important topic in genetic association studies, as it has been shown that population stratification, if not appropriately considered, can lead to false-positive and -negative results. While large association studies typically extract ancestry information from available genome-wide SNP genotypes, many important clinical data s ...[more]

PMID: 23815888

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Project description:BackgroundGenetic ancestry is known to impact outcomes of genotype-phenotype studies that are designed to identify risk for common diseases in human populations. Failure to control for population stratification due to genetic ancestry can significantly confound results of disease association studies. Moreover, ancestry is a critical factor in assessing lifetime risk of disease, and can play an important role in optimizing treatment. As modern medicine moves towards using personal genetic information for clinical applications, it is important to determine genetic ancestry in an accurate, cost-effective and efficient manner. Self-identified race is a common method used to track and control for population stratification; however, social constructs of race are not necessarily informative for genetic applications. The use of ancestry informative markers (AIMs) is a more accurate method for determining genetic ancestry for the purposes of population stratification.Methodology/principal findingsHere we introduce a novel panel of 36 microsatellite (MSAT) AIMs that determines continental admixture proportions. This panel, which we have named Continental Ancestry Informative Markers or CoAIMs, consists of MSAT AIMs that were chosen based upon their measure of genetic variance (F(st)), allele frequencies and their suitability for efficient genotyping. Genotype analysis using CoAIMs along with a Bayesian clustering method (STRUCTURE) is able to discern continental origins including Europe/Middle East (Caucasians), East Asia, Africa, Native America, and Oceania. In addition to determining continental ancestry for individuals without significant admixture, we applied CoAIMs to ascertain admixture proportions of individuals of self declared race.Conclusion/significanceCoAIMs can be used to efficiently and effectively determine continental admixture proportions in a sample set. The CoAIMs panel is a valuable resource for genetic researchers performing case-control genetic association studies, as it can control for the confounding effects of population stratification. The MSAT-based approach used here has potential for broad applicability as a cost effective tool toward determining admixture proportions.

Project description:Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome-wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa [Formula: see text], ‡Khomani SAN [Formula: see text], European [Formula: see text], Indian [Formula: see text], and Chinese [Formula: see text]. We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks.The collective term for people of mixed ancestry in southern Africa is "Coloured," and this is officially recognized in South Africa as a census term, and for self-classification. Whilst we acknowledge that some cultures may use this term in a derogatory manner, these connotations are not present in South Africa, and are certainly not intended here.

Dataset Information

Inference of human continental origin and admixture proportions using a highly discriminative ancestry informative 41-SNP panel.

Publications

Inference of human continental origin and admixture proportions using a highly discriminative ancestry informative 41-SNP panel.

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