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Mapping by admixture linkage disequilibrium: advances, limitations and guidelines

Key Points

  • Mapping by admixture linkage disequilibrium (MALD) is a genetic strategy for discovering genes that underlie complex diseases. The method is based on differences in disease-gene frequency between the parental racial groups of admixed populations.

  • A MALD-based full-genome scan can be carried out using a few thousand markers that are able to differentiate, to a high degree, between chromosomal ancestries in relation to the parental popultions. This enables the discovery of regions that harbour genes associated with complex diseases.

  • Differences in the proportion of admixture for a particular chromosomal segment between cases and controls can implicate a region that is several centimorgans in size as being involved in a disease. This can also be done using cases only, by looking for differences in admixture proportions between specific locations and the rest of the genome in the same individual.

  • MALD-based genome scans are already possible in African-Americans, and are now underway. These studies are using a published set of MALD markers that are highly enriched for the ability to differentiate between chromosomal segments derived from African and European ancestors. The marker set will improve as frequency data accumulate from the HapMap project.

  • MALD scans in other groups (Latinos, Pacific Islanders and other admixed populations) will become possible in the near future as appropriate markers are mined from HapMap allele frequencies.

  • Proof of the efficacy of MALD awaits its successful application among African-Americans for potentially amenable diseases, such as prostate cancer, multiple sclerosis and end-stage renal disease. If these studies are successful, MALD could then be applied to other groups over the next few years.

Abstract

Mapping by admixture linkage disequilibrium (MALD) is a theoretically powerful, although unproven, approach to mapping genetic variants that are involved in human disease. MALD takes advantage of long-range haplotypes that are generated by gene flow among recently admixed ethnic groups, such as African-Americans and Latinos. Under ideal circumstances, MALD will have more power to detect some genetic variants than other types of genome-wide association study that are carried out among more ethnically homogeneous populations. It will also require 200–500 times fewer markers, providing a significant economic advantage. The MALD approach is now being applied, with results expected in the near future.

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Figure 1: Detecting disease-associated genomic regions using mapping by admixture linkage disequilibrium.
Figure 2: Assessment of linkage disequilibrium that is caused by admixture in African-Americans.
Figure 3: Ancestry-assessment estimates using the ANCESTRYMAP algorithm.

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Correspondence to Michael W. Smith.

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DATABASES

Entrez

AT3

FY

FURTHER INFORMATION

ADMIXMAP software

ANCESTRYMAP software

Family Linkage Mapping resources at the Marshfield Center for Medical Genetics

International HapMap Project

MALDsoft software

Glossary

LINKAGE MAPPING

A method for localizing genes that is based on the co-inheritance of genetic markers and phenotypes in families over several generations.

ASSOCIATION STUDIES

A gene-discovery strategy that compares cases with controls to assess the contribution of genetic variants to phenotypes in specific populations.

HAPLOTYPE

The sequence of a single chromosome, summarized as a unique combination of known polymorphic sites.

ADMIXTURE

The formation of a new population by interbreeding between individuals from genetically divergent parental populations, and subsequently by interbreeding between their offspring.

ADMIXTURE LINKAGE DISEQUILIBRIUM

The non-random association of genetic variants due to admixture that decays rapidly (in a few generations) between unlinked genes and more slowly between linked ones.

FIXATION

Fixation occurs when a specific allele at a locus is found exclusively in one population but in another, an alternative allele is exclusively present.

CONTINGENC Y ANALYSIS

A chi-squared analysis of the numbers of observations to test for differences between categories in a data table.

LEAST-SQUARED APPROACH

A statistical estimation technique that estimates parameters on the basis of minimizing the square of the differences between a model and the observations.

MAXIMUM LIKELIHOOD APPROACH

A method for estimating parameter values in a model that have the highest probability of explaining the data observed.

BAYESIAN APPROACH

A statistical methodology that takes prior knowledge into account.

PANMIXIA

The process by which individuals in a population choose each other as mates with equal likelihood.

DUFFY BLOOD GROUP

Encoded by the FY gene, this is an antigen expressed on red blood cells that is a scavenger receptor for chemokines and also serves as a receptor for the malarial parasite, Plasmodium vivax.

SHANNON INFORMATION CONTENT

A measure that is used to quantify the informativeness of a marker or set of markers for determining the ancestral state of a chromosomal segment or locus.

HIDDEN MARKOV MODEL

(HMM). A statistical model of a sequence of events for which the probability of an event occurring depends on previous and subsequent events occurring. It is useful in admixture mapping as a complex and interdependent model can be calculated to fit the segmental nature of admixed chromosomes.

MARKOV CHAIN MONTE CARLO

(MCMC). The distributions underlying the hidden Markov model are extremely complex, making their direct estimation a huge task. This is simplified in MCMC analysis by generating averages of the expectations from the underlying distributions to model and analyse the results of admixture mapping.

PARAMETRIC TESTS

Statistical tests which use models that make assumptions about the distributions of sample values and parameters.

NON-PARAMETRIC TESTS

Statistical procedures that are not based on models or assumptions pertaining to the distribution of the variable.

PERMUTATION TESTING

An approach in which the actual data are randomized many times to generate a distribution of outcomes, so that the fraction of observations with values that are more extreme than the outcome that is observed with the real data reflects the statistical significance.

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Smith, M., O'Brien, S. Mapping by admixture linkage disequilibrium: advances, limitations and guidelines. Nat Rev Genet 6, 623–632 (2005). https://doi.org/10.1038/nrg1657

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