CoAIMs: a cost-effective panel of ancestry informative markers for determining continental origins

Abstract

Background: Genetic 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 findings: Here 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/significance: CoAIMs 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.

Figure 1. The Set of 19 MSATs (ABI Identifiler and Coriell 6-plex) Do Not Adequately Distinguish Among Continental Groups.

(A) STRUCTURE results based upon 19 MSAT genotypes from 710 samples from 6 geographical regions at K = 2 through K = 4. Each individual is represented by a thin vertical line, which is portioned into K colored segments representing the individual's estimated assignment in K clusters. Black lines separate individuals into different populations (EU-Europe; ME- Middle East; OC- Oceania; AM- Americas; AF- Africa; EA- East Asia). (B) PCA results based upon the 19 markers.

Figure 2. Strucuture Analysis of the HGDP Marker Sets.

STRUCTURE analysis of four sets of markers consisting of 78, 48, 36 and 24 MSATs. Shown is the STRUCTURE plot with the highest probability of the number of population clusters K as determined by the SructureSum program. For the 78, 48 and 36 marker sets, plots of K = 5 is shown. Here, five continental population regions can be distinguished representing African, Americas, East Asian, Oceania and Caucasian populations. Reducing the number of markers to 24 results in four population clusters (K = 4) being distinguished (see Table 1 ).

Figure 3. PCA of the HGDP Marker Sets.

PCA plots of the (A) 78, (B) 48, (C) 36, and (D) 24 MSAT sets from the HGDP. The top two PCs are plotted. The percent of the variance explained by each component is labeled next to the axis.

Figure 4. STRUCTURE Analysis of CoAIMs.

The number of clusters assumed (K) is shown for each panel. Color assignments correspond to the continental group (cluster) with the largest membership in that cluster. Ancestral population groups from NHGRI and NIGMS (Ancestral Populations) include: Europe (EU), Middle East (ME), Oceania (OC), Americas (AM), Africa (AF) and East Asia (EA). Self-declared NINDS Repository groups (NINDS Repository Samples) include: Caucasian (CA), African American (AFM), Hispanic Caucasian (HC), Hispanic non-Caucasian (HNC), Asian (AS), American Indian (AI), Pacific Islander (PI), Mixed Race or Undeclared (UND).

Figure 5. PCA Analysis of CoAIMs.

The analysis used the same data set (Ancestral Populations) indicated in Figure 3 . The population groups are shown by the color-coded symbols. The results for PC1 and PC2 are shown.

Figure 6. Ancestry Proportions of Admixed and Non-Admixed Populations of the NINDS Repository Using the CoAIMs.

Box plot of ancestry proportions derived from STRUCTURE (K = 5). The lengths of the boxes are the inter-quartile ranges (25^th–75^th) with the median value indicated by the bar. The whiskers represent the value within 10^th and 90^th percentiles quartile of the lower and upper ranges and dots are extreme outlying samples. Panels A–E quantify percent (along the y axis) of the five continental ancestries measured using CoAIMs versus reported group indicated (along the x-axis; Ancestral Populations, NINDS Repository Samples) as follows: (A) Caucasian ancestry, (B) African ancestry, (C) East Asian ancestry, (D) and Native American ancestry, (E) Oceania ancestry. Ancestral Populations and NINDS Repository Samples are arranged across the x-axes as follows: Europe (EU), Middle East (ME), Oceania (OC), Americas (NA), Africa (AF), East Asia (EA), Caucasian (CA), African American (AFM), Caucasian Hispanic (HC), non-Caucasian Hispanic (HNC), Asian (11), American Indian (AI), Pacific Islander (PI), and Undeclared (UN; includes samples indicated as being of more than one race).