Background

There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American subjects are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care or whether there is a predisposing genetic component.

Objective

We sought to assess the relationship between genetic ancestry and severe exacerbations among African American subjects with asthma.

Methods

Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These subjects were 12 to 56 years of age, received care from a single large health system, and had a physician's diagnosis of asthma. Genetic ancestry was estimated by using a set of validated ancestry informative markers. Severe exacerbations (ie, asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims.

Results

We assessed genetic ancestry in 392 African American subjects with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among male but not female subjects. The association among male subjects persisted after adjusting for potential confounders (relative rate, 4.30 for every 20% increase in African ancestry; P = .029).

Conclusions

African ancestry was significantly and positively associated with severe exacerbations among male African American subjects. These findings suggest that a portion of the risk of asthma exacerbations in this high-risk group is attributable to a genetic risk factor that partitions with ancestry.

Motivation

Local ancestry analysis of genotype data from recently admixed populations (e.g. Latinos, African Americans) provides key insights into population history and disease genetics. Although methods for local ancestry inference have been extensively validated in simulations (under many unrealistic assumptions), no empirical study of local ancestry accuracy in Latinos exists to date. Hence, interpreting findings that rely on local ancestry in Latinos is challenging.

Results

Here, we use 489 nuclear families from the mainland USA, Puerto Rico and Mexico in conjunction with 3204 unrelated Latinos from the Multiethnic Cohort study to provide the first empirical characterization of local ancestry inference accuracy in Latinos. Our approach for identifying errors does not rely on simulations but on the observation that local ancestry in families follows Mendelian inheritance. We measure the rate of local ancestry assignments that lead to Mendelian inconsistencies in local ancestry in trios (MILANC), which provides a lower bound on errors in the local ancestry estimates. We show that MILANC rates observed in simulations underestimate the rate observed in real data, and that MILANC varies substantially across the genome. Second, across a wide range of methods, we observe that loci with large deviations in local ancestry also show enrichment in MILANC rates. Therefore, local ancestry estimates at such loci should be interpreted with caution. Finally, we reconstruct ancestral haplotype panels to be used as reference panels in local ancestry inference and show that ancestry inference is significantly improved by incoroprating these reference panels.

Availability and implementation

We provide the reconstructed reference panels together with the maps of MILANC rates as a public resource for researchers analyzing local ancestry in Latinos at http://bogdanlab.pathology.ucla.edu

Supplementary information

Supplementary data are available at Bioinformatics online.

Background

Asthma disproportionately affects minority populations and is associated with psychosocial stress such as racial/ethnic discrimination. We aimed to examine the association of perceived discrimination with asthma and poor asthma control in African American and Latino youth.

Methods

We included African American (n = 954), Mexican American (n = 1,086), other Latino (n = 522), and Puerto Rican Islander (n = 1,025) youth aged 8 to 21 years from the Genes-Environments and Admixture in Latino Americans study and the Study of African Americans, Asthma, Genes, and Environments. Asthma was defined by physician diagnosis, and asthma control was defined based on the National Heart, Lung, and Blood Institute guidelines. Perceived racial/ethnic discrimination was assessed by the Experiences of Discrimination questionnaire, with a focus on school, medical, and public settings. We examined the associations of perceived discrimination with each outcome and whether socioeconomic status (SES) and global African ancestry modified these associations.

Results

African American children reporting any discrimination had a 78% greater odds of experiencing asthma (OR, 1.78; 95% CI, 1.33-2.39) than did those not reporting discrimination. Similarly, African American children faced increased odds of poor asthma control with any experience of discrimination (OR, 1.97; 95% CI, 1.42-2.76) over their counterparts not reporting discrimination. These associations were not observed among Latino children. We observed heterogeneity of the association between reports of discrimination and asthma according to SES, with reports of discrimination increasing the odds of having asthma among low-SES Mexican American youth (interaction P = .01) and among high-SES other Latino youth (interaction P = .04).

Conclusions

Perceived discrimination is associated with increased odds of asthma and poorer control among African American youth. SES exacerbates the effect of perceived discrimination on having asthma among Mexican American and other Latino youth.

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.

The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63-68%), 31% Indigenous American (28-33%) and 4% African (3-4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73-79%; Northeast (NEA) 54%, 95%CI: 49-58%; Northwest (NWA) 33%, 95%CI: 21-41%; South 54%, 95%CI: 49-59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75-86%) versus 68% (95%CI: 58-77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88-94%) compared to 54% (95%CI: 51-57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population.

Background

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the incidence of ALL varies by ethnicity. Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined.

Methods

We performed a multiethnic genome-wide association study in 1605 children with ALL and 6661 control subjects after adjusting for population structure, with validation in three replication series of 845 case subjects and 4316 control subjects. Association was tested by two-sided logistic regression.

Results

A novel ALL susceptibility locus at 10p12.31-12.2 (BMI1-PIP4K2A, rs7088318, P = 1.1 × 10(-11)) was identified in the genome-wide association study, with independent replication in European Americans, African Americans, and Hispanic Americans (P = .001, .009, and .04, respectively). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. Associations at ARID5B, IKZF1, and BMI1-PIP4K2A variants were consistent across ethnicity, with multiple independent signals at IKZF1 and BMI1-PIP4K2A loci. The frequency of ARID5B and BMI1-PIP4K2A variants differed by ethnicity, in parallel with ethnic differences in ALL incidence. Suggestive evidence for modifying effects of age on genetic predisposition to ALL was also observed. ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at a ninefold (95% confidence interval = 6.9 to 11.8) higher ALL risk relative to those carrying zero to one risk allele at these four single nucleotide polymorphisms.

Conclusions

These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children and shed new light on ALL molecular etiology in diverse ancestry.

Background

Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes.

Methodology/principal findings

Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05) in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05). Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049) or selected based on the literature alone (p = 0.0049), substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001) and increased the odds of allergic disease (OR = 1.8, p<0.008). Our data indicate that KIF3A rs7737031 (T-allele) has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach.

Conclusions/significance

Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and evaluation of novel candidate susceptibility genes.

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.