Mapping asthma-associated variants in admixed populations.

Tesfaye B Mersha

doi:10.3389/fgene.2015.00292

Abstract

Admixed populations arise when two or more previously isolated populations interbreed. Mapping asthma susceptibility loci in an admixed population using admixture mapping (AM) involves screening the genome of individuals of mixed ancestry for chromosomal regions that have a higher frequency of alleles from a parental population with higher asthma risk as compared with parental population with lower asthma risk. AM takes advantage of the admixture created in populations of mixed ancestry to identify genomic regions where an association exists between genetic ancestry and asthma (in contrast to between the genotype of the marker and asthma). The theory behind AM is that chromosomal segments of affected individuals contain a significantly higher-than-average proportion of alleles from the high-risk parental population and thus are more likely to harbor disease–associated loci. Criteria to evaluate the applicability of AM as a gene mapping approach include: (1) the prevalence of the disease differences in ancestral populations from which the admixed population was formed; (2) a measurable difference in disease-causing alleles between the parental populations; (3) reduced linkage disequilibrium (LD) between unlinked loci across chromosomes and strong LD between neighboring loci; (4) a set of markers with noticeable allele-frequency differences between parental populations that contributes to the admixed population (single nucleotide polymorphisms (SNPs) are the markers of choice because they are abundant, stable, relatively cheap to genotype, and informative with regard to the LD structure of chromosomal segments); and (5) there is an understanding of the extent of segmental chromosomal admixtures and their interactions with environmental factors. Although genome-wide association studies have contributed greatly to our understanding of the genetic components of asthma, the large and increasing degree of admixture in populations across the world create many challenges for further efforts to map disease-causing genes. This review, summarizes the historical context of admixed populations and AM, and considers current opportunities to use AM to map asthma genes. In addition, we provide an overview of the potential limitations and future directions of AM in biomedical research, including joint admixture and association mapping for asthma and asthma-related disorders.

Highlights

Asthma: Its Importance, Prevalence, and Racial Disparities Asthma is the most common chronic illness affecting children in the United States (CDC, 2012)
As the number of generations increases, the ancestral chromosomal segments from different parental populations are spliced into shorter pieces
Studies have shown that the frequency of alleles associated with asthma differ by race

Summary

Introduction

Asthma: Its Importance, Prevalence, and Racial Disparities Asthma is the most common chronic illness affecting children in the United States (CDC, 2012). These include risk variants associated with cardiovascular disease (Zhu et al, 2005; Zhang et al, 2008b); multiple sclerosis (Reich et al, 2005); prostate cancer (Freedman et al, 2006); serum IL-6 levels (Reich et al, 2007); and asthma in populations of African, Latino, Mexican, and Puerto Rican ancestry (Salari et al, 2005; Choudhry et al, 2008; Mathias et al, 2010; Torgerson et al, 2011, 2012; Drake et al, 2014; Galanter et al, 2014; Pino-Yanes et al, 2014) These results indicate that the admixed population provides an excellent opportunity to harness the power of linkage disequilibrium (LD) represented by ancestral markers transmitted together, thereby making use of disease prevalence in the ancestral (founder) populations. The exact numbers of AM studies so far are difficult to establish, several reported studies involved Latino populations compared with African American populations (Table 1)

Procedures for Conducting Admixture Mapping Analysis

Summary and Conclusion