Genetic Research Projects

Our genetic research focuses on identifying genetic risk factors and developing novel therapeutic targets for asthma.

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Projects overview

Our Study Populations form the basis for our research below. Sparked by the "Human Genome Project", the last 20+ years have seen amazing advances in the tools available for genetic investigation of traits and disease. We have leveraged this rich variety -omics of data to discover genetic determinants of asthma and related traits in the populations most affected by asthma. Specifically, we use DNA genotyping to perform genome-wide association studies (GWASs) of asthma traits, scour our whole-genome sequencing (WGS) data for rare variants of disease, leverage whole-exome sequencing (WES) and RNA sequencing (RNA-seq) data to identify causal variants of disease that may be good therapeutic targets, and examine how early-life environments can impact DNA expression through epigenetic changes in the genome with our methylation data.  

Ancestry and admixture

migration map
Jennifer Elhawary

Humans migrated >200,00 years ago from Africa. Throughout the years, the migratory populations grew more and more genetically distinct from each other. However, with the founding of the New World, individuals from Europe and Africa migrated west and began genetically mixing with each other and the Native populations of the Americas. This genetic mixture produced what is termed genetically admixed populations.

Latinos are primarily descendants of pre-Columbian Native Americans, Africans, and Europeans, whereas African Americans have varying proportions of European and African ancestry. Scientists have been able for a long time to use genetic markers to differentiate between populations that had been geographically separated for generations. This is possible because the relative frequency of these markers differentiates over time among groups that do not intermix, a process known as genetic drift. Recent advances in genetics have allowed us to go further and estimate the relative proportions of ancestral groups in admixed populations such as Latinos and African Americans.

Race/Ethnicity, Genetic Ancestry, and Clinical Medicine

Race and ethnicity are complex concepts that incorporate both sociocultural and genetic factors. For this reason, their use in clinical practice is controversial. However, race and ethnicity are used to define the normal values in pulmonary function tests (PFTs), and racial/ethnic-specific equations are used to determine expected lung volumes for African Americans, Mexican Americans, and Whites. Since measured lung function is compared to the expected values derived from these reference equations, ensuring that these reference equations are accurate has profound implications in diagnosing disease, determining severity, establishing disability claims, and determining priority for lung transplantation.

lung function by ancestry

In “Genetic ancestry in lung-function predictions,” published July 2010 in the New England Journal of Medicine, we found that the proportion of European and African ancestry in African Americans was associated with lung function across three different studies. We also demonstrated that including ancestry measures improved predicted lung function compared to the current race-based clinical standards, which considers all African Americans as a single, homogenous group. We extended this work by looking at how the variation in ancestry affects lung function in other admixed groups, such as Latinos. In "Genetic ancestry influences asthma susceptibility and lung function among Latinos," published January 2015 in the Journal of Allergy and Clinical Immunology, we found that disparities in asthma prevalence and lung function among Latinos can be partially explained by differences in the proportions of genetic ancestry, independently of early life exposures and socioeconomic status.


Admixture Mapping


We are extending the concepts of ancestry associations with a technique known as admixture mapping, in which we use sophisticated statistical software to infer the ancestry of each region of the genome. We then look across the genome to see whether the ancestry in any region is associated with a trait or disease. Certain genetic variants exclusive to a particular ancestry may be a risk factor or a protective factor for certain traits or diseases. 

We found that having Native American ancestry in the HLA region in chromosome 6, a region important for immune function, protects against asthma in Latinos. We have projects in progress to sequence the HLA region, which is one of the most diverse regions in the genome, so that we can identify which variants and genes are responsible for this protection against asthma. In "Whole-Genome Sequencing Identifies Novel Functional Loci Associated with Lung Function in Puerto Rican Youth," published October 2020 in the American Journal of Respiratory and Critical Care Medicine, we found an African ancestral-specific variant on chromosome 1 that was associated with a decrease in lung volume, and on chromosome 5, we found a Native American ancestral-specific variant associated with an increase in lung function in Puerto Rican children. In "Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand KITLG/SCF and Gene-By-Air-Pollution Interaction," published July 2020 in Genetics, we discovered an African ancestral-specific variant on chromosome 12 that was associated with an increase in lung function. These findings could potentially be used to develop more targeted treatments and interventions for patients with asthma.


Genome-wide association studies (GWAS)

In GWAS, we simultaneously genotype hundreds of thousands of single nucleotide polymorphisms (SNPs), variants in the genetic code that could confer risk for disease. Very large disparities exist in the prevalence and mortality of asthma among different racial and ethnic groups, even among those groups that are frequently aggregated, such as Mexicans and Puerto Ricans. By collecting the largest study population for gene-environment studies of asthma in U.S. minority children, our research team is poised to identify genetic, social, and environmental risk factors, which will help to explain these disparities.

GWAS and asthma

replication venn diagram

More than 96% of contemporary genetic association studies have been performed in European populations. We have found that more than 82% of candidate genes that were associated with asthma in other racial/ethnic populations were not associated with asthma in Mexicans and Puerto Ricans in the GALA study. Of those that were associated with asthma in this study, we found that some candidate genes were what can be considered “cosmopolitan” and are risk factors for both Puerto Ricans and Mexicans. Other genes, however, were ethnic-specific, and had differential effects in the two populations. We further verified that a region in chromosome 17, which had originally been associated with asthma in European populations, was also associated with asthma in Latinos and African Americans.

GWAS and markers of inflammation

pie chart: Europeans = 90%, African Americans = 9%; Latinos = 1%

Percentage of individuals included in the discovery phases of previous GWAS by population group.

We have used GWAS analyses to identify novel loci associated with immunoglobulin E (IgE), a biomarker of asthma and other allergic/inflammatory diseases. IgE levels are known to vary by race/ethnicity in the United States, with higher levels reported in both African American and Latino individuals. In addition, African ancestry has been associated with higher IgE levels in African American and Latino populations. In spite of these differences in IgE levels, only 1% of the discovery samples included in previous genome-wide association studies (GWAS) for this trait were Latinos.





Moving Beyond GWAS

Candidate gene sequencing

Genome-wide association studies (GWAS) have identified numerous associations with common variants for asthma and asthma-related traits, including bronchodilator drug response (BDR) and total serum IgE. In many cases the variants identified through GWAS are not the actual mutations that cause disease, and therefore we must identify these variants through sequencing prior to additional studies.

We sequenced the coding exons plus UTRs (Untranslated Regions) of seven genes implicated through GWAS and admixture mapping studies in 2,000 Latinos, including one gene for asthma susceptibility (SMAD2), three genes for BDR (SLC24A2, SLC24A4, SLC22A15), and three genes for total serum IgE (HLA-DQB1, HLA-DRB5, ZNF365). Overall, we identified novel genetic variation associated with drug response and IgE within three of the genes sequenced, including a significant contribution of nonsynonymous rare variants in SLC24A2, SLC24A4, and HLA-DQB1. Our results suggest that deep sequencing of candidate genes identified through GWAS and admixture mapping is essential for the fine mapping of genetic associations. Resequencing in larger, multi-ethnic population samples and functional studies are required to further understand the role of rare and common variation in asthma and asthma-related traits.

SMAD2 and asthma

Mothers against decapentaplegic homolog 2 (SMAD2) is a protein involved in TGF-beta signaling. In our ongoing studies as part of the EVE consortium, we found that Native American ancestry at SMAD2 was associated with an increased risk of asthma in Latinos. This is a strong indication there are population-specific genetic mutations within or nearby the SMAD2 gene that contribute to asthma in Latino children.

We are currently pursuing sequencing and gene expression studies to identify the causal variation behind the association of local Native American ancestry at SMAD2 and asthma. Through the RS&G service at the NHLBI, we are sequencing the SMAD2 locus and its flanking gene (ZBTB7C), including contiguous non-coding regions in 2,000 Latinos with and without asthma. We hypothesize that the SMAD2 locus contains population-specific rare variants that contribute to asthma. We further hypothesize that rare variants nearby SMAD2 are associated with differential BDR and risk of asthma exacerbation through influencing SMAD2 expression.

Exome sequencing extremes of drug response

Albuterol, a short-acting β2-agonist, is the most commonly prescribed asthma medication in the world. There are marked differences in the therapeutic response to albuterol among patients and racial/ethnic groups. For example, Puerto Rican and African American children with asthma are significantly less responsive to albuterol than Mexican or Caucasian children. We are pursuing studies to understand the genetic basis of differential drug response in minority children with asthma.

We hypothesize that rare variants, with potentially larger effect sizes than common SNPS, contribute to racial/ethnic differences in albuterol response. For example, in our GWAS studies for bronchodilator drug response we identified an excess of small p-values of association driven entirely by low frequency variants. We are further testing this hypothesis by performing exome plus UTR sequencing of 1,500 African American, Puerto Rican, and Mexican asthma patients with extreme phenotypes of BDR. Specifically, we are identifying individual and pooled rare variants that are associated with BDR through association testing between high and low drug responders. Furthermore, in our ongoing studies we are testing for an interaction of genetic factors with known environmental modifiers of bronchodilator drug response.

graph: y axis = observed, x axis = expected

QQplot of a GWAS for BDR in GALA II. Black indicates all SNPs, blue indicates a loss of signal after excluding less common variation (MAF<5%).

chart: y axis = Max BDR, x axis shows high and low measurements

High and low bronchodilator drug response (Max BDR) in the extremes of 500 Puerto Ricans, 500 Mexicans, and 500 African Americans in GALA II and SAGE. Note: Max BDR is on a log scale.

Whole genome sequencing

Whole genome sequencing holds the promise to identify a more complete picture of genetic variants affecting complex traits and disease. As part of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA), we are examining patterns of variation across the genomes of 500 asthma cases and 500 asthma controls. One of the major goals of CAAPA is to use this data to develop a commercial genotyping platform that is better able to capture the high degree of genetic variation in individuals with African ancestry.


Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA).

HLA studies

Genetic variation in the major histocompatibility complex (MHC) region plays an important role in asthma susceptibility and total serum IgE. In our own studies, admixture mapping for both asthma susceptibility and IgE level in Latinos indicated that genetic variation in the MHC has a significant contribution to both of these traits. Specifically, we found Native American ancestry at the MHC class I locus to be associated with lower risk of asthma, and at the MHC class I and II loci to be associated with lower IgE.

We are currently performing pilot studies by sequencing 5 Mb of the MHC region in Latino children using targeted, high-coverage next-generation sequencing. We are currently integrating advanced MHC region capture technology plus next-generation sequencing, with classical methods of human leukocyte antigen (HLA) typing. We will use this data to identify HLA types and genetic variation in the MHC regions that are associated with asthma and total serum IgE levels. Furthermore, we hope to develop an analytic pipeline to promote the study of the MHC region in Latinos by integrating targeted next-generation sequencing data, SNP-based HLA imputation, and classical methods of HLA typing.


It is commonly believed that the genome is almost unchanging and that the genetic code in a person is invariant. However, several biological processes are capable of turning genes on and off through what scientists call epigenetics. (epi- is a Greek prefix meaning, in this case, “above” or “on top of.”) One such process is methylation, in which a methyl group is added to certain DNA base pair patterns known as CpG sites without changing the DNA code itself. Methylation changes how likely a gene is to be converted to a protein. We have used advanced microarray technology to obtain genome-wide methylation data at hundreds of thousands of CpG sites, and we seek to correlate epigenetic changes with asthma and related traits.

Both genetic and environmental factors are capable of driving changes in methylation patterns, though the extent of each has not been fully established. We leverage the rich genetic and environmental diversity among the participants in our GALA II study to explore the extent to which genetic and environmental factors contribute to methylation patterns. We have seen that there are ethnic differences in methylation patterns, even among related ethnic groups such as Puerto Ricans and Mexicans. We have also seen that many of these differences are due to differences in ancestry between the two groups. Those differences in ancestral composition are associated with differences in genetic patterns, which in turn lead to changes in methylation pattern. This has a profound impact on complex diseases such as asthma.