A twist on admixture mapping. Nat Genet

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Nature Genetics (Impact Factor: 29.35). 03/2011; 43(3):178-9. DOI: 10.1038/ng0311-178
Source: PubMed


A new study uses genome-wide SNP genotypes to identify a subset of children undergoing therapy for acute lymphoblastic leukemia that are at increased risk for relapse. Borrowing from the classical approach of admixture mapping, the work shows how genome-wide assessment of genetic ancestry can be used as a biomarker for disease outcome.

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    ABSTRACT: Genome-wide association studies in cancer have already identified over 150 regions associated with two dozen specific cancers. Already, a handful of multi-cancer susceptibility regions have been uncovered, providing new insights into perhaps common mechanisms of carcinogenesis. For each new susceptibility allele, investigators now face the arduous task of interrogating each region beginning with fine mapping prior to pursuing the biological basis for the direct association of one or more variants. It appears that there may be a significant number of common alleles that contribute to the heritability of a specific cancer. Since each region confers a small contribution to the risk for cancer, it is daunting to consider any single nucleotide polymorphism (SNP) as a clinical test. Since the complex genomic architecture of each cancer differs, additional genotyping and sequence analysis will be required to comprehensively catalog susceptibility alleles followed by the formidable task of understanding the interactions between genetic regions as well as the environment. It will be critical to assess the applicability of genetic tests in specific clinical settings, such as when to perform screening tests with calculable risks (e.g., biopsies or chemoprevention), before incorporating SNPs into clinical practice. To advance the current genomic observations to the clinical venue, new studies will need to be designed to validate the utility of known genetic variants in assessing risk for cancer as well as its outcomes.
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    ABSTRACT: Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans. We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV₁) per pack-year of smoking (-5.7 ml FEV₁/ smoking pack-year) compared with smokers with lower African ancestry (-4.6 ml in FEV₁/ smoking pack-year) (interaction P value  = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV(1) decline in Health ABC and independently replicated in CARDIA. African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.
    PLoS ONE 06/2012; 7(6):e39541. DOI:10.1371/journal.pone.0039541 · 3.23 Impact Factor
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    ABSTRACT: Admixture mapping is a popular tool to identify regions of the genome associated with traits in a recently admixed population. Existing methods have been developed primarily for identification of a single locus influencing a dichotomous trait within a case-control study design. We propose a generalized admixture mapping (GLEAM) approach, a flexible and powerful regression method for both quantitative and qualitative traits, which is able to test for association between the trait and local ancestries in multiple loci simultaneously and adjust for covariates. The new method is based on the generalized linear model and utilizes a quadratic normal moment prior to incorporate admixture prior information. Through simulation, we demonstrate that GLEAM achieves lower type I error rate and higher power than ANCESTRYMAP both for qualitative traits and more significantly for quantitative traits. We applied GLEAM to genome-wide SNP data from the Illumina African American panel derived from a cohort of black woman participating in the Healthy Pregnancy, Healthy Baby study and identified a locus on chromosome 2 associated with the averaged maternal mean arterial pressure during 24 to 28 weeks of pregnancy.
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