Diverse forces have shaped the genomes of individuals throughout the world. It is crucial to understand those historical processes to study the genetics of individuals alive today. Nowhere else is this more important than in the study of admixed populations. A majority of individuals across the Americas are admixed, having received ancestry from sub-Saharan Africans, Europeans, and Indigenous Americans. However, to this day, admixed populations remain understudied, particularly because harnessing all information from their genomes requires in-depth population genetic analysis. This is not typically part of standard practice in genome-wide association studies. In this work I focus on two important aspects of understanding the history of admixed populations of the Americas to identify important associations with medical traits not possible using standard genetic analysis techniques. This work consists of two primary parts:

1) I develop a framework for genome-wide admixture mapping meta-analysis from high density SNP genotyping data. I use it to identify a novel, heritable risk factor for asthma in over 7,000 Latinos at the SMAD2 locus that could not be discovered using standard genotype association techniques. I then demonstrate the downstream use of blood-based expression of SMAD2 as a biomarker for both risk of exacerbation and poor response to bronchodilators in people with asthma.

2) Along with collaborators I developed the first fine-scale genetic map of indigenous and admixed populations across the country of Mexico, to determine how fine-scale differentiation of indigenous populations impacts the local communities of mixed ancestry. Using novel extensions of Principal Component Analysis we identify striking geographic correlations with the indigenous component of ancestry in admixed individuals, and use this data to identify for the first time a clinically meaningful association between indigenous American origins and lung function.

This work also includes an Introduction and Best Practices recommendations on local ancestry estimation and methods for admixture mapping, and an Appendix on generating ancestry informative marker panels. Relevant code and important functions for running admixture mapping and meta-analyzing output will be made publicly available online.

Background: In the U.S., Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the beta2 adrenergic receptor (2AR) may modify asthma severity and albuterol responsiveness. We tested the association of 2AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Rican and Mexican asthmatics.

Methods: We used both family-based and cross-sectional tests of association with eight 2AR SNPs in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity and bronchodilator drug responsiveness.

Results: Among asthmatic Puerto Ricans, the Arg16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.01-0.00001). We found a strong interaction of baseline Forced Expiratory Volume in one second or FEV1 with the Arg16Gly polymorphism in predicting bronchodilator response. Among Puerto Rican asthmatics with baseline FEV1 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Glygenotypes and drug responsiveness among Mexican asthmatics.

Conclusions: Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity and bronchodilator response in asthmatic Puerto Ricans and Mexicans. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness.

Asthma is the most common chronic disease among children. Despite the high prevalence of asthma, there is no cure and its etiology is poorly understood. Of all racial/ethnic groups, African Americans and Puerto Ricans have the highest rates of asthma in the US. Asthma is a multifaceted disease, with genetic, social and environmental risk factors. Outdoor air pollution is a known risk factor, associated with asthma exacerbations and emergency room hospitalizations. US minorities often live in neighborhoods that are disproportionately exposed to higher levels of air pollution, yet few studies are conducted in minority groups. The objective of this dissertation was to evaluate the effects of air pollution on asthma in Latinos and African Americans.

This work utilized data from two parallel case-control studies: the Genes-environments and Admixture in Latino Americans (GALA II) and the Study of African Americans, Asthma, Genes and Environments (SAGE II). Children were recruited from five urban regions in the US, and were assigned estimates of air pollution exposure to five common pollutants for each year of their lives.

The first chapter describes the associations between early-life air pollution exposures and the subsequent risk for developing childhood asthma. Early-life exposure to NO2, a traffic-related pollutant, was associated with an increased risk for subsequent asthma. The second chapter describes the association between recent air pollution exposures and lung function in children with asthma. Exposure to SO2 and coarse particulate matter, both industrial-related pollutants, were associated with poorer lung function. Significant effect modification by race/ethnicity was also detected. The third chapter describes the variation in total IgE and atopy prevalence and outlines the associations between early-life air pollution exposures and the risk for developing non-atopic asthma. Ozone exposure in the first year of life was found to be associated with an increased risk for developing non-atopic asthma.

In summary, our findings suggest that air pollution impacts numerous aspects of asthma risk and morbidity. Gaining a better understanding of these associations could potentially prevent a substantial proportion of current and future asthma disparities. Replication of these findings is needed in addition populations and regions.

Asthma is a disease characterized by chronic inflammation of the airway, thought to result from inappropriate activation of the Th2 immune response. Recent work has shown that chitinase proteins are strongly upregulated during Th2 inflammation in the lungs of mice. Studies in mouse models have implicated chitinase activity in both promotion of Th2 inflammation and protection from the Th2-priming effects of chitin in the lungs.

Herein we detail investigation of chitinases in human asthma. Namely, we explored the possibility that variants affecting the enzymatic activity of the two active chitinase proteins, acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1), may alter risk for human asthma. Secondly, we have determined expression and activity of these enzymes in lungs of healthy and asthmatic subjects.

We identified a coding haplotype in the AMCase gene strongly associated with protection from asthma among African American asthma case-control groups. This association was also observed in family-based analysis of a group of Latino American asthmatic trios. Through recombinant protein expression and biochemical characterization we have found the protective AMCase isoform to be considerably more active at pH values corresponding to the lung, stomach, and lysosomes. In contrast, no association was observed with a common null genetic variant in the CHIT1 gene in either African Americans, or Latinos.

We found CHIT1 to be responsible for the majority of chitinase activity in the human lung based on pH profile of enzymatic activity and genetic analysis of a CHIT1 null variant. Median chitinase activity in BAL tended to be lower than normal in asthma. AMCase protein was detectable in the lung, but mRNA transcripts expressed from lung tissues was consistent with an isoform lacking enzymatic activity. AMCase protein expression was observed to be lower in the BAL of asthmatics.

This work is the first evidence that functional genetic variants in chitinase genes are associated with risk for asthma, and are consistent with possible Th2-priming effects of environmental chitin. Additionally, we find differential expression of the two active chitinases in the human lung and reveal differences in chitinase protein expression and enzymatic activity in lung disease.

Asthma, like other common diseases, has both genetic and environmental causes. Understanding the heterogeneity in asthma, the genetics of associated traits, and how we introduce error by using certain methods are critical to determining the causes of asthma and other complex diseases.

We examined two ways to define asthma heterogeneity: using statistical clustering methods and using principal components analysis. We compared the fit of these variables and how well they predicted asthma exacerbations in data from 1,085 Latino and African American children with asthma. We found that principal components both fit the data better and predicted exacerbations better than cluster groups. These variables need to be compared to other known predictors of exacerbations.

In addition, we conducted a genome-wide association study and admixture mapping study of bronchodilator response (BDR) in 1,782 Latino children with asthma. Four of the genome-wide significant SNPs were promising rare variants. All four had good dose-response relationships with BDR and two were in promising candidate genes. Our admixture mapping found five regions where a specific ancestry was significantly associated with BDR. Since rare variants are often present on specific ancestral backgrounds, this result supports the hypothesis that rare variants are important for BDR. Unfortunately, replication of individual rare variants is difficult. Future efforts should focus on sequencing the regions we identified to find other rare variants and better understand their function.

Finally, we compared the accuracy of haplotype inference error between four populations from HapMap Phase 3. We found that haplotype inference error was highest in the African populations, intermediate in the Mexican population, and lowest in the European population. In addition, some regions had higher haplotype inference error than others and this was not explained by several measured features of the regions. Comparisons between haplotype association studies across populations should account for possible differences in haplotype inference error between populations.

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