Genome-wide Admixture Mapping Research Articles

Genome-wide admixture mapping identifies wild ancestry-of-origin segments in cultivated Robusta coffee.

Humans have had a major influence on the dissemination of crops beyond their native range, thereby offering new hybridization opportunities. Characterizing admixed genomes with mosaic origins generates valuable insight into the adaptive history of crops and the impact on current varietial diversity. We applied the ELAI tool-an efficient local ancestry inference method based on a two-layer hidden Markov model to track segments of wild origin in cultivated accessions in the case of multiway admixtures. Source populations-which may actually be limited and partially admixed-must be generally specified when using such inference models. We thus developed a framework to identify local ancestry with admixed source populations. Using sequencing data for wild and cultivated Coffea canephora (commonly called Robusta), our approach was found to be highly efficient and accurate on simulated hybrids. Application of the method to assess elite Robusta varieties from Vietnam led to the identification of an accession derived from a likely backcross between two genetic groups from the Congo Basin and the western coastal region of Central Africa. Admixtures resulting from crop hybridization and diffusion could thus lead to the generation of elite high-yielding varieties. Our methods should be widely applicable to gain insight into the role of hybridization during plant and animal evolutionary history.

Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans.

This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p=2.2×10-5 ) and 18q21.33 (p=1.2×10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2. Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.

Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles.

Asthma is ranked among the most common chronic conditions and has become a significant public health issue due to the recent and rapid increase in its prevalence. Investigations into the underlying genetic factors predict a heritable component for its incidence, estimated between 35% and 90% of causation. Despite the application of large-scale genome-wide association studies (GWAS) and admixture mapping approaches, the proportion of variants identified accounts for less than 15% of the observed heritability of the disease. The discrepancy between the predicted heritable component of disease and the proportion of heritability mapped to the currently identified susceptibility loci has been termed the ‘missing heritability problem.’ Here, we examine recent studies involving both the analysis of genetically encoded features that contribute to asthma and also the role of non-encoded heritable characteristics, including epigenetic, environmental, and developmental aspects of disease. The importance of vertical maternal microbiome transfer and the influence of maternal immune factors on fetal conditioning in the inheritance of disease are also discussed. In order to highlight the broad array of biological inputs that contribute to the sum of heritable risk factors associated with allergic disease incidence that, together, contribute to the induction of a pro-atopic state. Currently, there is a need to develop in-depth models of asthma risk factors to overcome the limitations encountered in the interpretation of GWAS results in isolation, which have resulted in the missing heritability problem. Hence, multiomics analyses need to be established considering genetic, epigenetic, and functional data to create a true systems biology-based approach for analyzing the regulatory pathways that underlie the inheritance of asthma and to develop accurate risk profiles for disease.

Genome-Wide Admixture Mapping of Estimated Glomerular Filtration Rate and Chronic Kidney Disease Identifies European and African Ancestry-of-Origin Loci in Hispanic and Latino Individuals in the United States.

Admixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture, such as Hispanic or Latino individuals in the United States. These individuals have an increased risk of CKD. We performed genome-wide admixture mapping for both CKD and eGFR in a sample of 12,601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 Black participants from the Women's Health Initiative (WHI). We also compared the findings with those from a conventional genome-wide association study. Three novel ancestry-of-origin loci were identified on chromosomes 2, 14, and 15 for CKD and eGFR. The chromosome 2 locus comprises two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased CKD risk. The chromosome 14 locus, found within the DLK1-DIO3 imprinted domain, was associated with lower eGFR and driven by European ancestry. The eGFR-associated locus on chromosome 15 included intronic variants of RYR3 and was within an African-specific genomic region associated with higher eGFR. The genome-wide association study failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci associated with eGFR in the WHI Black participants. This study provides evidence of shared ancestry-specific genomic regions influencing eGFR in Hispanic or Latino individuals and Black individuals and illustrates the potential for leveraging genetic ancestry in recently admixed populations for the discovery of novel candidate loci for kidney phenotypes.

Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer\u2019s disease in Caribbean Hispanics

BackgroundGenetic studies have primarily been conducted in European ancestry populations, identifying dozens of loci associated with late-onset Alzheimer’s disease (AD). However, much of AD’s heritability remains unexplained; as the prevalence of AD varies across populations, the genetic architecture of the disease may also vary by population with the presence of novel variants or loci.MethodsWe conducted genome-wide analyses of AD in a sample of 2565 Caribbean Hispanics to better understand the genetic contribution to AD in this population. Statistical analysis included both admixture mapping and association testing. Evidence for differential gene expression within regions of interest was collected from independent transcriptomic studies comparing AD cases and controls in samples with primarily European ancestry.ResultsOur genome-wide association study of AD identified no loci reaching genome-wide significance. However, a genome-wide admixture mapping analysis that tests for association between a haplotype’s ancestral origin and AD status detected a genome-wide significant association with chromosome 3q13.11 (103.7–107.7Mb, P = 8.76E−07), driven by a protective effect conferred by the Native American ancestry (OR = 0.58, 95%CI = 0.47−0.73). Within this region, two variants were significantly associated with AD after accounting for the number of independent tests (rs12494162, P = 2.33E−06; rs1731642, P = 6.36E−05). The significant admixture mapping signal is composed of 15 haplotype blocks spanning 5 protein-coding genes (ALCAM, BBX, CBLB, CCDC54, CD47) and four brain-derived topologically associated domains, and includes markers significantly associated with the expression of ALCAM, BBX, CBLB, and CD47 in the brain. ALCAM and BBX were also significantly differentially expressed in the brain between AD cases and controls with European ancestry.ConclusionThese results provide multiethnic evidence for a relationship between AD and multiple genes at 3q13.11 and illustrate the utility of leveraging genetic ancestry diversity via admixture mapping for new insights into AD.

Transient PAX8 Expression in Islets During Pregnancy Correlates With β-Cell Survival, Revealing a Novel Candidate Gene in Gestational Diabetes Mellitus.

Transient Pax8 expression was reported in mouse islets during gestation, whereas a genome-wide linkage and admixture mapping study highlighted PAX8 as a candidate gene for diabetes mellitus (DM). We sought the significance of PAX8 expression in mouse and human islet biology. PAX8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species-specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8 A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her father with type 2 DM but was absent in control patients. The p.T356M variant did not alter protein stability or cellular localization, whereas its transactivation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 affects islet viability and that PAX8 could be considered as a candidate gene for the study of GDM.

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Short-acting β2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69×10−9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5×10−8). Our results failed to replicate in three additional populations of 416 Latinos and 1,615 African Americans. Our findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. 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. 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. 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.

Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits.

Admixture mapping can be used to detect genetic association regions in admixed populations, such as Hispanics/Latinos, by estimating associations between local ancestry allele counts and the trait of interest. We performed admixture mapping of the blood pressure traits systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), and pulse pressure (PP), in a dataset of 12,116 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanics/Latinos have three predominant ancestral populations (European, African, and Amerindian), for each of which we separately tested local ancestry intervals across the genome. We identified four regions that were significantly associated with a blood pressure trait at the genome-wide admixture mapping level. A 6p21.31 Amerindian ancestry association region has multiple known associations, but none explained the admixture mapping signal. We identified variants that completely explained this signal. One of these variants had p-values of 0.02 (MAP) and 0.04 (SBP) in replication testing in Pima Indians. A 11q13.4 Amerindian ancestry association region spans a variant that was previously reported (p-value = 0.001) in a targeted association study of Blood Pressure (BP) traits and variants in the vitamin D pathway. There was no replication evidence supporting an association in the identified 17q25.3 Amerindian ancestry association region. For a region on 6p12.3, associated with African ancestry, we did not identify any candidate variants driving the association. It may be driven by rare variants. Whole genome sequence data may be necessary to fine map these association signals, which may contribute to disparities in BP traits between diverse populations.

Amerindian/Asian Ancestry and Mortality Are Associated with Allo-Immunization in Adults with Sickle Cell Disease in a Genome Wide Racial Admixture Study

▪Background: Transfusion is a standard therapy for acute and chronic complications of sickle cell disease (SCD). They are complicated by a high prevalence of red cell antigen alloimmunization, which is not seen in other frequently transfused patients. Reasons for this increased prevalence are unclear. Some studies have suggested genetic predisposition to alloimmunization in all transfused patient populations. Others suggested that mismatched red cell antigens occurring commonly between blood donors of European ancestry and patients with SCD who are of African ancestry is a primary cause in SCD. Accordingly, phenotypic antigen matching and transfusion from African American donors are proposed strategies to minimize alloimmunization risk. We hypothesized that if these population differences are the etiologic basis that analysis of ancestry at the genetic level could identify significant genetic susceptibility contributions and localize susceptibility loci.Methods: The Bethesda Sickle Cell Cohort Study consisting of adults evaluated at NIH from 2001-2015 (n=721) was reviewed for transfusion history and the presence of allo-antibodies confirmed with a blood bank. Genomic DNA was genotyped with an admixture panel consisting of 2251 ancestry informative SNPs in 359 patients and in HapMap controls. A final panel of 1622 SNPs was used to infer ancestry proportions using Structure assuming 3 ancestral populations. Ancestry was analyzed in regression models along with clinical variables. Genome wide admixture mapping was performed to identify regions of the genome where the ancestry proportions differed significantly between cases and controls. We used AncestryMap for a log-additive case control study assuming various risk models.Results: Five hundred fifty four subjects (77% of cohort) had a transfusion history with 153 (27.6 %) with allo-antibodies, 336 (60.6 %) with a history of transfusions and no antibodies and 65 (11.7 %) with no prior transfusions. Sixty five percent had a history of more than 1 antibody. The RH, Kell, MNS and Duffy systems were most commonly associated with antibodies (Fig 1A and B). Clinical factors associated with cases in univariate analysis included transfusion burden (P<0.0001), pain hospitalizations (P=0.0007), hemoglobin (P=0.02), ferritin (P=0.002), alkaline phosphatase (P=0.02) and ESR (P=0.05). Only transfusion history remained significant in multivariable models, both when using logistic (antibody status, β=0.56, P=6.31 x 10-6) or linear (number of antibodies, β=0.35, P=0.0004) regressions. Given the univariate associations with pain hospitalizations and ferritin which are known mortality risk factors, it was not surprising that allo-immunization was associated with mortality when compared to the no antibody and non-transfusion groups (Fig 1C; median follow-up 3.8 years, range 0-14.4). The absence of allo-immunization showed decreased risk of death when limited to only those with prior transfusions (Fig 1D; Hazard Ratio 0.53, P=0.006). When considering genotype data, Asian/Amerindian ancestry was associated with antibody status (logistic, β=4.60, P=0.03) and number of antibodies (linear, β=4.92, P=0.006) by regression, while African and European ancestry were not. The relative ancestry contribution remained unchanged when the number of prior transfusions was also included in both models, P=0.09 and P=0.06, respectively (Fig 1E). Genetic data also indicated that 21% (n=77) of genotyped subjects were not admixed (100% African ancestry) which violates AncestryMap’s assumption that all subjects are admixed. These subjects were removed from the admixture scan: an analysis of 81 cases and 159 controls with prior transfusions is underway to identify specific susceptibility loci.Conclusions: In a large cohort of adults with SCD, the prevalence of red cell alloimmunization is 27.6%, with approximately 60% of antibodies attributable to RH and Kell. Asian/Amerindian ancestry is a risk factor, as is the number of prior transfusions. This study demonstrates genetic susceptibility to this complication which is associated with an ancestral population not typically considered in SCD. Identification of additional Amerindian ancestry SNPs will help to fine map susceptibility loci. Long term studies will be necessary to determine the relative contribution of alloimmunization to mortality in adults with SCD. [Display omitted] DisclosuresKato:Mast Therapeutics: Consultancy; Bayer: Research Funding.

Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.

White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors. To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon. Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015. Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data. A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified. The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.

Evolutionary context for the association of γ-globin, serum uric acid, and hypertension in African Americans.

BackgroundHyperuricemia and associated cardio-metabolic disorders are more prevalent in African Americans than in European Americans. We used genome-wide admixture mapping and association testing to identify loci with ancestry effects on serum uric acid levels.MethodsWe analyzed 1,976 African Americans from Washington, D.C, including 1,322 individuals from 328 pedigrees and 654 unrelated individuals, enrolled in the Howard University Family Study. We performed admixture mapping and genome-wide association testing using ~800 k autosomal single-nucleotide polymorphisms (SNPs). We performed fine mapping by dense genotyping. We assessed functionality by a combination of bioinformatic annotation, reporter gene assays, and gel shift experiments. We also analyzed 12,641 individuals enrolled in the National Health and Nutrition Examination Survey.ResultsWe detected a genome-wide significant locus on chromosome 11p15.4 at which serum uric acid levels increased with increasing African ancestry, independent of kidney function. Fine-mapping identified two independent signals in the β-globin locus. The ancestral allele at SNP rs2855126, located upstream of the hemoglobin, gamma A gene HBG1, was associated with increased serum uric acid levels and higher expression of a reporter gene relative to the derived allele. Hyperuricemia was associated with increased risk of hypertension in 3,767 African Americans (Odds Ratio = 2.48, p = 2.71 × 10− 19).ConclusionsGiven that increased expression of γ-globin leads to increased levels of fetal hemoglobin which confers protection against malaria, we hypothesize that evolution in Africa of protection against malaria may have occurred at the cost of increased serum uric acid levels, contributing to the high rates of hyperuricemia and associated cardio-metabolic disorders observed in African Americans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0249-z) contains supplementary material, which is available to authorized users.

Direct Estimates of the Genomic Contributions to Blood Pressure Heritability within a Population-Based Cohort (ARIC).

Blood pressure (BP) is a heritable trait with multiple environmental and genetic contributions, with current heritability estimates from twin and family studies being ~ 40%. Here, we use genome-wide polymorphism data from the Atherosclerosis Risk in Communities (ARIC) study to estimate BP heritability from genomic relatedness among cohort members. We utilized data on 6,365,596 and 9,578,528 genotyped and imputed common single nucleotide polymorphisms (SNPs), in 8,901 European ancestry (EA) and 2,860 African Ancestry (AA) ARIC participants, respectively, and a mixed linear model for analyses, to make four observations. First, for BP measurements, the heritability is ~20%/~50% and ~27%/~39% for systolic (SBP)/diastolic (DBP) blood pressure in European and African ancestry individuals, respectively, consistent with prior studies. Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data. Third, the vast majority of BP heritability varies by chromosome, depending on its length, and is largely concentrated in noncoding genomic regions annotated as DNaseI hypersensitive sites (DHSs). Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes. Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.

Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping.

In the Americas, women with Indigenous American ancestry are at increased risk of intrahepatic cholestasis of pregnancy (ICP), relative to women of other ethnicities. We hypothesized that ancestry-related genetic factors contribute to this increased risk. We collected clinical and laboratory data, and performed biochemical assays on samples from U.S. Latinas and Chilean women, with and without ICP. The study sample included 198 women with ICP (90 from California, U.S., and 108 from Chile) and 174 pregnant control women (69 from California, U.S., and 105 from Chile). SNP genotyping was performed using Affymetrix arrays. We compared overall genetic ancestry between cases and controls, and used a genome-wide admixture mapping approach to screen for ICP susceptibility loci. We identified commonalities and differences in features of ICP between the 2 countries and determined that cases had a greater proportion of Indigenous American ancestry than did controls (p = 0.034). We performed admixture mapping, taking country of origin into account, and identified one locus for which Native American ancestry was associated with increased risk of ICP at a genome-wide level of significance (P = 3.1 x 10-5, Pcorrected = 0.035). This locus has an odds ratio of 4.48 (95% CI: 2.21-9.06) for 2 versus zero Indigenous American chromosomes. This locus lies on chromosome 2, with a 10 Mb 95% confidence interval which does not contain any previously identified hereditary ‘cholestasis genes.’ Our results indicate that genetic factors contribute to the risk of developing ICP in the Americas, and support the utility of clinical and genetic studies of ethnically mixed populations for increasing our understanding of ICP.

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders. We sought to identify genetic variants associated with IgE levels in Latinos. 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. 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). 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 associatedwith total IgE levels.

Using multi-way admixture mapping to elucidate TB susceptibility in the South African Coloured population.

BackgroundThe admixed South African Coloured population is ideally suited to the discovery of tuberculosis susceptibility genetic variants and their probable ethnic origins, but previous attempts at finding such variants using genome-wide admixture mapping were hampered by the inaccuracy of local ancestry inference. In this study, we infer local ancestry using the novel algorithm implemented in RFMix, with the emphasis on identifying regions of excess San or Bantu ancestry, which we hypothesize may harbour TB susceptibility genes.ResultsUsing simulated data, we demonstrate reasonable accuracy of local ancestry inference by RFMix, with a tendency towards miss-calling San ancestry as Bantu. Regions with either excess San ancestry or excess African (San or Bantu) ancestry are less likely to be affected by this bias, and we therefore proceeded to identify such regions, found in cases but not in controls (642 cases and 91 controls). A number of promising regions were found (overall p-values of 7.19×10-5 for San ancestry and <2.00×10-16 for African ancestry), including chromosomes 15q15 and 17q22, which are close to genomic regions previously implicated in TB. Promising immune-related susceptibility genes such as the GADD45A, OSM and B7-H5 genes are also harboured in the identified regions.ConclusionAdmixture mapping is feasible in the South African Coloured population and a number of novel TB susceptibility genomic regions were uncovered.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1021) contains supplementary material, which is available to authorized users.

Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids

To conduct a follow-up association mapping to independent genome-wide linkage and admixture mapping studies of uterine leiomyoma. Case-control, cross-sectional study. Not applicable. A total of 1,045 premenopausal North American participants in the National Institute of Environmental Health Sciences Uterine Fibroid Study. None. We genotyped 2,772 single-nucleotide polymorphisms from candidate genes located in peaks of linkage (2q37, 3p21, 5p13, 10p11, 11p15, 12q14, and 17q25) or admixture linkage disequilibrium (2q37, 4p16.1, and 10q26) mapping and reported to have regulated expression in uterine fibroids. We report significant associations of variant members of the collagen gene family with risk and tumor size, including missense variants in COL6A3 and COL13A, with replications in African American and European American study groups. Furthermore, the cell-matrix Rho GTPase-encoding ARHGAP26 gene, and MAN1C1, a gene encoding a Golgi mannosidase involved in the maturation of procollagens, emerged as new candidate uterine leiomyoma genes affecting both risk and tumor size. Our data converge onto a possible model of uterine leiomyoma pathogenesis resulting from altered regulation, maintenance, and/or renewal of the extracellular matrix.

Abstract P254: Genome-wide Association and Admixture Study of Iron-related Phenotypes in African Americans

Introduction: Iron deficiency is a heritable risk factor for various serious diseases, including cardiovascular disease (CVD). Genome-wide association studies (GWAS) have identified several variants associated with iron-related phenotypes in individuals of primarily European descent. African Americans (AA) have, on average, greater levels of iron deficiency compared to European Americans, but no large-scale genetic studies for iron-related phenotypes have been performed in individuals of African ancestry to date. Methods: We conducted genome-wide admixture mapping studies and GWASs for serum iron, serum ferritin, transferrin saturation (SAT), and total binding iron capacity (TIBC) in 2347 AA participating in the Jackson Heart Study (JHS). Results: Higher proportions of estimated global African ancestry were significantly associated with lower levels of iron (p=2.4x10 -5 ), SAT (p=0.0019) and TIBC (p=0.042) and a number of chromosomal regions were observed to have local ancestry estimates nominally associated with these measures. We observed significant associations (P &lt; 5x10 -8 ) between serum TIBC levels and multiple independent single nucleotide polymorphisms (SNPs) around TF, a well-established region for iron and transferrin levels in Caucasians, and SNPs near two novel genes: HDGFL1 and MAF. In addition, we replicated four other established loci in our AA samples including SLC17A1 , HFE , HIST1H2BJ and TMPRSS6 . Conclusions: 1) We observed SNPs in or near three genes, TF , HDGFL1 and MAF that were significantly associated with TIBC in AA. 2) We observed that both global and local genetic admixture are important predictors of iron measures in AA, further implicating the importance of certain genetic risk factors in the AA population. 3) We have also replicated four other established loci in our AA samples demonstrating the importance of some genetic risk factors for iron related measure across multiple populations. Future fine-mapping studies, incorporating less common variants, and functional studies should be undertaken to better characterize these loci and to ultimately identify the functional variants directly influencing TIBC levels in AA.

Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: The Genes-environments & Admixture in Latino Americans study

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. We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. 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. We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 × 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 × 10(-13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. 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.

Genome-wide association study and admixture mapping of age-related cognitive decline in African-Americans

Genome-wide association study and admixture mapping of age-related cognitive decline in African-Americans