Methods for High-Density Admixture Mapping of Disease Genes

Abstract

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) has been proposed as an efficient approach to localizing disease-causing variants that differ in frequency (because of either drift or selection) between two historically separated populations. Near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles derived from the ethnic group that carries more disease-susceptibility alleles. The central attraction of admixture mapping is that, since gene flow has occurred recently in modern populations (e.g., in African and Hispanic Americans in the past 20 generations), it is expected that admixture-generated linkage disequilibrium should extend for many centimorgans. High-resolution marker sets are now becoming available to test this approach, but progress will require (a). computational methods to infer ancestral origin at each point in the genome and (b). empirical characterization of the general properties of linkage disequilibrium due to admixture. Here we describe statistical methods to estimate the ancestral origin of a locus on the basis of the composite genotypes of linked markers, and we show that this approach accurately estimates states of ancestral origin along the genome. We apply this approach to show that strong admixture linkage disequilibrium extends, on average, for 17 cM in African Americans. Finally, we present power calculations under varying models of disease risk, sample size, and proportions of ancestry. Studying approximately 2500 markers in approximately 2500 patients should provide power to detect many regions contributing to common disease. A particularly important result is that the power of an admixture mapping study to detect a locus will be nearly the same for a wide range of mixture scenarios: the mixture proportion should be 10%-90% from both ancestral populations.

Estimation of individual admixture: Analytical and study design considerations

“…The effect of genetic drift is ignored in the present method. One potential approach to model the divergence between the true and the pseudo-ancestral populations is to introduce additional hyper-parameters (Patterson et al 2004). Diagnostic procedures for detecting inappropriate pseudo-ancestors are under development.…”

“…As a result, the majority of marker pairs in the simulated data are unlinked. In contrast, the SNPs in the map of Smith et al (2004) cover the genome in a continuous fashion such that many pairs are linked. Therefore, admixture linkage disequilibrium (ALD) decays faster in the simulated data.…”

Multiple sclerosis genetics: leaving no stone unturned

“…As the sections of the genome in African-Americans inherited from their European or African ancestors have only had an average of six generations of recombination, extended LD is present, and non-MHC disease genes are potentially amenable to identification through admixture mapping using reasonable numbers of ancestry informative genetic markers that are readily available. 45,46 A primary role for HLA-DRB1 in susceptibility to MS is consistent with a pathogenesis model, which involves a T-cell mediated autoimmune response against the 85-99 peptide of myelin basic protein (MBP). [47][48][49][50] The crystal structure of DRb1501 differs from other non DR2-related DRb molecules in that aromatic residues in the ligand are preferred in the large hydrophobic P4 pocket of the peptide binding domain.…”

Genetic ancestry inference using support vector machines, and the active emergence of a unique American population

“…Indeed, methods that explicitly quantify admixture by identifying the ancestries of chromosomal segments are almost exclusively applied to populations whose ancestral inputs are separate species or historically allopatric populations. [6][7][8][9][10] In general, the resolution of ancestry inference in the United States will be conditional on the level of admixture in the target population (Figure 1a). High rates of admixture will efface detailed genetic connections between a local US population and its ancestral sources.…”