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While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRS AD : odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRS AD+ : OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRS AD++ : OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRS AD++ , which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36). This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease. [ABSTRACT FROM AUTHOR]

Background African Americans (AAs) and Hispanic/Latinos (HLs) have higher risk of obesity than European Americans, possibly due to differences in environment and lifestyle, but also reflecting differences in genetic background. Objective To gain insight into factors contributing to BMI (in kg/m2) and obesity risk (BMI ≥ 30) among ancestry groups, we investigate the role of self-reported ancestry, proportion of genetic African ancestry, and country of birth in 6368 self-identified AA and 7569 HL participants of the New York–based Bio Me Biobank. Methods AAs and HLs are admixed populations that trace their genetic ancestry to the Americas, Africa, and Europe. The proportion of African ancestry (PAA), quantified using ADMIXTURE, was higher among self-reported AA (median: 87%; IQR: 79–92%) than among HL (26%; 15–41%) participants. Approximately 18% of AA and 59% of HL participants were non–US-born. Results Because of significant differences between sexes (P PAA*sex interaction = 4.8 × 10−22), we considered women and men separately. Among women, country of birth and genetic ancestry contributed independently to BMI. US-born women had a BMI 1.99 higher than those born abroad (P  = 7.7 × 10−25). Every 10% increase in PAA was associated with a BMI 0.29 higher (P  = 7.1 × 10−10). After accounting for PAA and country of birth, the contribution of self-reported ancestry was small (P  = 0.046). The contribution of PAA to higher BMI was significantly more pronounced among US-born (0.35/10%PAA, P  = 0.003) than among non–US-born (0.26/10%PAA, P  = 0.01) women (P PAA*sex interaction = 0.004). In contrast, among men, only US-born status influenced BMI. US-born men had a BMI 1.33 higher than non–US-born men, whereas PAA and self-reported ancestry were not associated with BMI. Associations with obesity risk were similar to those observed for BMI. Conclusions Being US-born is associated with a substantially higher BMI and risk of obesity in both men and women. Genetic ancestry, but not self-reported ancestry, is associated with obesity susceptibility, but only among US-born women in this New York–based population. [ABSTRACT FROM AUTHOR]

Background Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. Objective We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. Methods We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. Results We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10−6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P =.002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P =.008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10−3, combined P = 2.6 × 10−7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5′ of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P <.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. Conclusion Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations. [ABSTRACT FROM AUTHOR]

Background IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders. Objective We sought to identify genetic variants associated with IgE levels in Latinos. Methods We performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies. Results We confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10 −8 ). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels ( P = 4.95 × 10 −8 ). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10 −6 ) and replicated in non–African American samples ( P = .011). Conclusion We confirmed genetic associations at 6 genes and identified novel associations within ZNF365 , HLA-DQA1 , and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels. [ABSTRACT FROM AUTHOR]

Background Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. Objective To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. Methods We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. Results Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10 −15 ), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV 1 (−77 ± 19 mL; P = 5.8 × 10 −5 and −83 ± 19 mL; P = 1.1 x 10 −5 , respectively) and forced vital capacity (−100 ± 21 mL; P = 2.7 × 10 −6 and −107 ± 22 mL; P = 1.0 x 10 −6 , respectively). Conclusion Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos. [ABSTRACT FROM AUTHOR]

Background Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent. Objective We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. Methods Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. Results We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 x 10-6). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 x 10-13) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. Conclusions Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21. [ABSTRACT FROM AUTHOR]

Background: IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE. Objective: We sought to identify the genetic predictors of serum total IgE levels. Methods: We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects. Results: We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels (P < 5.0 × 10−6) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P = .007 and 2.45 × 10−7, respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis. Conclusion: This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects. [Copyright &y& Elsevier]

Background: Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. Objectives: We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. Methods: We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case–parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. Results: Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. Conclusions: This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations. [Copyright &y& Elsevier]

Background: Bronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma. Objectives: We sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma. Methods: Whole-transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses. Results: We found 90.2% overlap in expressed genes and strong correlation in gene expression (ρ = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (ρ = 0.77, P = 5.6 × 10−9). Clustering analysis identified TH2-high and TH2-low subjects differentiated by expression of 70 genes, including IL13, IL5, periostin (POSTN), calcium-activated chloride channel regulator 1 (CLCA1), and serpin peptidase inhibitor, clade B (SERPINB2). TH2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 × 10−6), atopic asthma (odds ratio, 32.6; P = 6.9 × 10−7), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 × 10−6), and rhinitis (odds ratio, 8.3; P = 4.1 × 10−6) compared with TH2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year (P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status. Conclusion: Nasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13-driven asthma and a TH2-skewed systemic immune response. [Copyright &y& Elsevier]

Background: The primary rescue medication to treat acute asthma exacerbation is the short-acting β2-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). Objective: To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. Methods: We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results: We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10−8), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion: Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR. [Copyright &y& Elsevier]

Background: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. Objective: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. Methods: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. Results: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[β] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[β] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. Conclusions: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization. [Copyright &y& Elsevier]

Background: Genetic variants that contribute to asthma susceptibility might be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations. Objective: We sought to identify asthma-associated loci in African American subjects. Methods: We compared local African and European ancestry estimated from dense single nucleotide polymorphism genotype data in African American adults with asthma and nonasthmatic control subjects. Allelic tests of association were performed within the candidate regions identified, correcting for local European admixture. Results: We identified a significant ancestry association peak on chromosome 6q. Allelic tests for association within this region identified a single nucleotide polymorphism (rs1361549) on 6q14.1 that was associated with asthma exclusively in African American subjects with local European admixture (odds ratio, 2.2). The risk allele is common in Europe (42% in the HapMap population of Utah residents with Northern and Western European ancestry from the Centre d’Etude du Polymorphisme Humain collection) but absent in West Africa (0% in the HapMap population of Yorubans in Ibadan, Nigeria), suggesting the allele is present in African American subjects because of recent European admixture. We replicated our findings in Puerto Rican subjects and similarly found that the signal of association is largely specific to subjects who are heterozygous for African and non-African ancestry at 6q14.1. However, we found no evidence for association in European American or Puerto Rican subjects in the absence of local African ancestry, suggesting that the association with asthma at rs1361549 is due to an environmental or genetic interaction. Conclusion: We identified a novel asthma-associated locus that is relevant to admixed populations with African ancestry and highlight the importance of considering local ancestry in genetic association studies of admixed populations. [Copyright &y& Elsevier]

Background: Polymorphisms in more than 100 genes have been associated with asthma susceptibility, yet much of the heritability remains to be explained. Asthma disproportionately affects different racial and ethnic groups in the United States, suggesting that admixture mapping is a useful strategy to identify novel asthma-associated loci. Objective: We sought to identify novel asthma-associated loci in Latino populations using case-control admixture mapping. Methods: We performed genome-wide admixture mapping by comparing levels of local Native American, European, and African ancestry between children with asthma and nonasthmatic control subjects in Puerto Rican and Mexican populations. Within candidate peaks, we performed allelic tests of association, controlling for differences in local ancestry. Results: Between the 2 populations, we identified a total of 62 admixture mapping peaks at a P value of less than 10−3 that were significantly enriched for previously identified asthma-associated genes (P = .0051). One of the peaks was statistically significant based on 100 permutations in the Mexican sample (6q15); however, it was not significant in Puerto Rican subjects. Another peak was identified at nominal significance in both populations (8q12); however, the association was observed with different ancestries. Conclusion: Case-control admixture mapping is a promising strategy for identifying novel asthma-associated loci in Latino populations and implicates genetic variation at 6q15 and 8q12 regions with asthma susceptibility. This approach might be useful for identifying regions that contribute to both shared and population-specific differences in asthma susceptibility. [ABSTRACT FROM AUTHOR]

Background: Although Mexicans and Puerto Ricans are jointly classified as “Hispanic/Latino,” there are significant differences in asthma prevalence, severity, and mortality between the 2 groups. We sought to examine the possibility that population-specific genetic risks contribute to this disparity. Objectives: More than 100 candidate genes have been associated with asthma and replicated in an independent population, and 7 genome-wide association studies in asthma have been performed. We compared the pattern of replication of these associations in Puerto Ricans and Mexicans. Methods: We genotyped Mexican and Puerto Rican trios using an Affymetrix 6.0 GeneChip and used a family-based analysis to test for genetic associations in 124 genes previously associated with asthma. Results: We identified 32 single nucleotide polymorphisms (SNPs) in 17 genes associated with asthma in at least 1 of the 2 populations. Twenty-two of these SNPs in 11 genes were significantly associated with asthma in the combined population and showed no significant heterogeneity of association, whereas 5 SNPs were associated in only 1 population and showed statistically significant heterogeneity. In a gene-based approach 2 additional genes were associated with asthma in the combined population, and 3 additional genes displayed ethnic-specific associations with heterogeneity. Conclusions: Our results show that only a minority of genetic association studies replicate in our population of Mexican and Puerto Rican asthmatic subjects. Among SNPs that were successfully replicated, most showed no significant heterogeneity across populations. However, we identified several population-specific genetic associations. [ABSTRACT FROM AUTHOR]

The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis. We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n = 1,703) and confirming controls (n = 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses. The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95% CI 1.15–1.53; p <0.0001) among whom a NAFLD diagnosis was 15% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95% CI 1.349–1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95% CI 1.28–1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95 × 10−6) where the risk variant also associated with earlier age of diagnosis. Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies. Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies. • Natural language processing increased NAFLD detection over ICD codes by 2.5 times. • rs738409 "GG" carriers were diagnosed with NAFLD 3 years earlier than non-carriers. • PNPLA3 rs738409 effects were most pronounced in Hispanics. • PheWAS showed rs738409 was associated with other NAFLD-related liver diseases. • rs738409 was associated with earlier diagnosis for PheWAS-identified diseases. [ABSTRACT FROM AUTHOR]

Hispanic/Latino (H/L) populations, although linked by culture and aspects of shared history, reflect the complexity of history and migration influencing the Americas. The original settlement by indigenous Americans, followed by postcolonial admixture from multiple continents, has yielded localized genetic patterns. In addition, numerous H/L populations appear to have signatures of pre-colonization and post-colonization bottlenecks, indicating that tens of millions of H/Ls may harbor signatures of founder effects today. Based on both population and medical genetic findings we highlight the extreme differentiation across the Americas, providing evidence for why H/Ls should not be considered a single population in modern human genetics. We highlight the need for additional sampling of understudied H/L groups, and ramifications of these findings for genomic medicine in one-tenth of the world's population. [ABSTRACT FROM AUTHOR]