Proportion Of European Ancestry Research Articles

Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer

KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, the detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1450 patients with NSCLC. This comprehensive analysis included detailed covariates including age at diagnosis, sex, clinical stage, cancer histology, and smoking status. We report that SIRE is significantly associated with KRAS mutations, modified by sex, with SIRE-Asian patients showing lower rates of KRAS mutation, transversion substitution, and the allele-specific subtype KRASG12C compared to SIRE-White patients, after adjusting for potential confounders. Moreover, GIA was found to correlate with KRAS mutations, where patients with a higher proportion of European ancestry had an increased risk of KRAS mutations, especially more transition substitutions and KRASG12D. Notably, among SIRE-White patients, an increase in European ancestry was linked to a higher likelihood of KRAS mutations, whereas an increase in Admixed American ancestry was associated with a reduced likelihood, suggesting that quantitative GIA offers additional information beyond SIRE. The association of SIRE, GIA, and their interplay with KRAS driver mutations in NSCLC highlights the importance of incorporating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities.

A genome‐wide association study in Puerto Ricans suggests new risk loci for Alzheimer disease

AbstractBackgroundAlzheimer disease (AD) is the fourth leading cause of death in Puerto Rico. The Puerto Rican (PR) population has a high proportion of older adults (18%, over > 65), with 12.5% of them suffering from ADThese statistics highlight the need to investigate the genetic risk factors underlying AD in the PR population, as it could lead to the development of targeted treatments and therapies. Moreover, the ancestrally admixed makeup of the PR population provides an opportunity to assess the role of the European (∼67%), African (∼20%) and Amerindian (∼13%) ancestry in AD risk. We performed genome wide association analysis (GWAS) using whole genome sequence data to identify genetic risk/protective factors associated with AD in the PR population.MethodThe PR dataset includes WGS and phenotype data from 640 individuals, comprising 335 AD and 305 cognitively unimpaired (CU) controls. To account for the population substructure, we calculated the global ancestry (principal components) using EIGENSTRAT. We performed GWAS analyses with a generalized linear mixed‐model using the SAIGE software. The model included genotype, sex, age, and principal components (population substructure) as fixed effects and genetic relationship matrix as a random effect. The genetic relationship matrix was calculated based on genomic data and accounted for the relatedness among the individuals in the dataset.ResultWe identified four suggestive significant loci (P<1×10−6) associated with the risk of AD in PRs: NACC2 (pv = 4.8×10−7) on chromosome 9, SCN8A (pv = 9.3×10−7) on chromosome 12, FOXK2 (pv = 9.9×10−7) on chromosome 17, and APOEe4 (pv = 6.8×10−8) on chromosome 19. Eight additional AD loci with the same lead marker from European GWAS study (Bellenquez et al.) showed nominal significance: FERMT2 (pv = 6.2×10−3), TREM2 (pv = 8.0×10−3), CLU (pv = 1.8×10−2), RASGEF1C (pv = 2.4×10−2), ADAM17 (pv = 3.5×10−2), DOC2A (pv = 4.3×10−2), GRN (pv = 4.4×10−2) and SORL1 (pv = 5.1×10−2).ConclusionThis study identified three suggestive novel significant loci (NACC2, SCN8A, and FOXK2) associated with AD risk in PRs. In addition, GWAS study on PRs with a high proportion of European ancestry was able to replicate nine AD loci previously identified in European studies. These findings provide new insights into the genetic architecture of AD in the PR population.

The role of admixture in the rare variant contribution to inflammatory bowel disease

BackgroundIdentification of rare variants involved in complex, polygenic diseases like Crohn’s disease (CD) has accelerated with the introduction of whole exome/genome sequencing association studies. Rare variants can be used in both diagnostic and therapeutic assessments; however, since they are likely to be restricted to specific ancestry groups, their contributions to risk assessment need to be evaluated outside the discovery population. Prior studies implied that the three known rare variants in NOD2 are absent in West African and Asian populations and only contribute in African Americans via admixture.MethodsWhole genome sequencing (WGS) data from 3418 African American individuals, 1774 inflammatory bowel disease (IBD) cases, and 1644 controls were used to assess odds ratios and allele frequencies (AF), as well as haplotype-specific ancestral origins of European-derived CD variants discovered in a large exome-wide association study. Local and global ancestry was performed to assess the contribution of admixture to IBD contrasting European and African American cohorts.ResultsTwenty-five rare variants associated with CD in European discovery cohorts are typically five-fold lower frequency in African Americans. Correspondingly, where comparisons could be made, the rare variants were found to have a predicted four-fold reduced burden for IBD in African Americans, when compared to European individuals. Almost all of the rare CD European variants were found on European haplotypes in the African American cohort, implying that they contribute to disease risk in African Americans primarily due to recent admixture. In addition, proportion of European ancestry correlates the number of rare CD European variants each African American individual carry, as well as their polygenic risk of disease. Similar findings were observed for 23 mutations affecting 10 other common complex diseases for which the rare variants were discovered in European cohorts.ConclusionsEuropean-derived Crohn’s disease rare variants are even more rare in African Americans and contribute to disease risk mainly due to admixture, which needs to be accounted for when performing cross-ancestry genetic assessments.

The Genomic Basis of Adaptation to High Elevations in Africanized Honey Bees.

A range of different genetic architectures underpin local adaptation in nature. Honey bees (Apis mellifera) in the Eastern African Mountains harbor high frequencies of two chromosomal inversions that likely govern adaptation to this high-elevation habitat. In the Americas, honey bees are hybrids of European and African ancestries and adaptation to latitudinal variation in climate correlates with the proportion of these ancestries across the genome. It is unknown which, if either, of these forms of genetic variation governs adaptation in honey bees living at high elevations in the Americas. Here, we performed whole-genome sequencing of 29 honey bees from both high- and low-elevation populations in Colombia. Analysis of genetic ancestry indicated that both populations were predominantly of African ancestry, but the East African inversions were not detected. However, individuals in the higher elevation population had significantly higher proportions of European ancestry, likely reflecting local adaptation. Several genomic regions exhibited particularly high differentiation between highland and lowland bees, containing candidate loci for local adaptation. Genes that were highly differentiated between highland and lowland populations were enriched for functions related to reproduction and sperm competition. Furthermore, variation in levels of European ancestry across the genome was correlated between populations of honey bees in the highland population and populations at higher latitudes in South America. The results are consistent with the hypothesis that adaptation to both latitude and elevation in these hybrid honey bees are mediated by variation in ancestry at many loci across the genome.

Single Nucleotide Polymorphisms of MTHFR (rs1051266) and SLC19A1 (rs1801133) Associated to Genomic Ancestry in Cuban Healthy Population

Background: Several single nucleotide polymorphisms on methotrexate pathway have been implicated with hyperhomocysteinemia, susceptibility to autoimmune diseases and the therapy effectiveness of methotrexate Objective: The present study estimates the ethnogeographic prevalence of rs1801133 (c.665C>T) in methylenetetrahydrofolate reductase and rs1051266 (c.80A>G) in solute carrier family Methods: Genomic data was collected from a dense genome-wide genotyping array analysis of a large sample of individuals from all provinces of Cuba, with a final sample of 946 individuals for rs1801133 and 948 individuals for rs1051266. Results: For rs1801133, T allele and TT genotype were more prevalent in Mayabeque, the province with the highest European (p<0.0001) and the lowest African ancestry proportion (p<0.0001). Whereas, T allele and TT genotype frequency were low in Guantánamo (23.7% and 1.8%), the province with the highest African ancestry proportion (p<0.0001) and the lowest European ancestry proportion (p<0.0001). For rs1051266, the higher frequency of G allele was observed in Villa Clara, Las Tunas, Holguín and Granma and this group was associated with AG and GG genotypes (p=0.0045). This seems to be related to high Native American ancestry proportion in Las Tunas (p<0.0001), Holguín (p<0.0001) and Granma (p<0.0001); with the low African ancestry proportion in Villa Clara (p<0.0001) and with a Native American ancestry-enriched pattern observed for these provinces (p=0.0005). Conclusion: These results provide evidence that ancestry contribution impacts in the ethnogeographic prevalence of rs1801133 (c.665C>T) and rs1051266 (c.80A>G) polymorphisms in healthy Cuban individuals.

1091-P: Genetic Ancestry Influences Metformin Treatment Response in Youth with Type 2 Diabetes

In youth with type 2 diabetes (T2D), glycemic response to metformin varies by racial and ethnic group. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study metformin failure rates were lower in non-Hispanic White (NHW) youth by self-report compared with non-Hispanic Black (NHB) and Hispanic youth. Understanding and addressing the mechanisms for differences in response are critical to reducing health disparities. We aimed to examine the association between genetic ancestry and risk for metformin treatment failure and evaluate whether individual global ancestry proportions predict metformin response in TODAY participants. Global ancestry proportions were estimated using FastStructure. Cox-proportional hazards analysis with genetic ancestry as a covariate was performed with the primary outcome the need for insulin or A1C ≥ 8%. Age, sex, BMI Z score, baseline A1C, and treatment arms were the other covariates. After quality control, 506 participants of mean age 14±2 y, 65% female, mean BMI Z score 2.2±0.5 kg/m2 and mean baseline A1C 6.0±0.7% were analyzed. Similar to by self-report, when stratified by genetic ancestry NHB youth had significantly higher treatment failure rates compared with other groups (P=0.02). The proportion of European ancestry in self-reported ethnic strata of admixed participants was associated with improved metformin response in the NHB (n=185) and Hispanic (n=208) groups (HR 0.4, 95% CI 0.16-0.98, P=0.04). Proportion of Native American ancestry was associated with worse response (HR 1.5, 95% CI 1.02-2.2, P=0.04) across all participants and associations with proportion African ancestry were not significant. In sum, genetic ancestry influences metformin response with greater proportion of European and Native American ancestry associated with improved and worse glycemic response respectively in TODAY. These differences could be related to biological, social or cultural factors and should be examined to reduce health disparities in T2D. Disclosure S.Srinivasan: None. T.I.Pollin: None. A.Manning: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. L.Chen: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc., Lilly. J.Todd: None. S.A.Arslanian: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Consultant; Société des Produits Nestlé SA,, Other Relationship; Eli Lilly and Company, AstraZeneca, Research Support; Novo Nordisk, Eli Lilly and Company. N.T.Chang: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. L.L.Levitsky: None. J.E.Sprague: Research Support; Eli Lilly and Company, Rhythm Pharmaceuticals, Inc. Funding National Institutes of Health (K23DK120932)

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program

BackgroundThe Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]).ResultsAncestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen’s d < 0.259, p < 7.80 × 10−4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics.ConclusionsThis study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

Genetic ancestry, differential gene expression, and survival in pediatric B-cell acute lymphoblastic leukemia.

Black children have lower incidence yet worse survival than White and Latinx children with B-cell acute lymphoblastic leukemia (B-ALL). It is unclear how reported race/ethnicity (RRE) is associated with death in B-ALL after accounting for differentially expressed genes associated with genetic ancestry. Using Phase 1 and 2 NCI TARGET B-ALL cases (N= 273; RRE-Black=21, RRE-White=162, RRE-Latinx=69, RRE-Other=9, RRE-Unknown=12), we estimated proportions of African (AFR), European (EUR), and Amerindian (AMR) genetic ancestry. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) between ancestry and death while adjusting for RRE and clinical measures. We identified genes associated with genetic ancestry and adjusted for them in RRE and death associations. Genetic ancestry varied within RRE (RRE-Black, AFR proportion: Mean: 78.5%, Range: 38.2%-93.6%; RRE-White, EUR proportion: Mean: 94%, Range: 1.6%-99.9%; RRE-Latinx, AMR proportion: Mean: 52.0%, Range: 1.2%-98.7%). We identified 10, 1, and 6 differentially expressed genes (padjusted <0.05) associated with AFR, AMR, and EUR ancestry proportion, respectively. We found AMR and AFR ancestry were statistically significantly associated with death (AMR each 10% HR: 1.05, 95% CI: 1.03-1.17, AFR each 10% increase HR: 1.03, 95% CI:1.01-1.19). RRE differences in the risk of death were larger in magnitude upon adjustment for genes associated with genetic ancestry for RRE-Black, but not RRE-Latinx children (RRE-Black HR: 3.35, 95% CI: 1.31, 8.53; RRE-Latinx HR: 1.47, 0.88-2.45). Our work highlights B-ALL survival differences by RRE after adjusting for ancestry differentially expressed genes suggesting other factors impacting survival are important.

Genetic European Ancestry and Incident Diabetes in Black Individuals: Insights From the SPRINT Trial.

Black individuals have high incident diabetes risk, despite having paradoxically lower triglyceride and higher HDL (high-density lipoprotein) cholesterol levels. The basis of this is poorly understood. We evaluated the participants of SPRINT (Systolic Blood Pressure Intervention Trial) to assess the association of estimated European genetic ancestry with the risk of incident diabetes in self-identified Black individuals. Self-identified non-Hispanic Black SPRINT participants free of diabetes at baseline were included. Black participants were stratified into tertiles (T1-T3) of European ancestry proportions estimated using 106 biallelic ancestry informative genetic markers. The multivariable-adjusted association of European ancestry proportion with indices of baseline metabolic syndrome (ie, fasting plasma glucose, triglycerides, HDL cholesterol, body mass index, and blood pressure) was assessed. Multivariable-adjusted Cox regression determined the risk of incident diabetes (fasting plasma glucose ≥126 mg/dL or self-reported diabetes treatment) across tertiles of European ancestry proportion. Among 2466 Black SPRINT participants, a higher European ancestry proportion was independently associated with higher baseline triglyceride and lower HDL cholesterol levels (P<0.001 for both). European ancestry proportion was not associated with baseline fasting plasma glucose, body mass index, and blood pressure (P>0.05). Compared with the first tertile, those in the second (hazard ratio, 0.64 [95% CI, 0.45-0.90]) and third tertiles (hazard ratio, 0.61 [95% CI, 0.44-0.89]) of the European ancestry proportion had a lower risk of incident diabetes. A 5% point higher European ancestry was associated with a 29% lower risk of incident diabetes (hazard ratio, 0.71 [95% CI, 0.55-0.93]). There was no evidence of a differential association between the European ancestry proportion tertiles and incident diabetes between those randomized to intensive versus standard blood pressure treatment. The higher risk of incident diabetes in Black individuals may have genetic determinants in addition to adverse social factors. Further research may help understand the interplay between biological and social determinants of cardiometabolic health in Black individuals. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Heterogeneity of Genetic Admixture Determines SLE Susceptibility in Mexican.

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well identified as risk factors. SLE patients present different clinical phenotypes, which are partly explained by admixture patterns variation among Mexicans. Population genetic has insight into the high genetic variability of Mexicans, mainly described through HLA gene studies with anthropological and biomedical importance. A prospective, case-control study was performed. In this study, we recruited 146 SLE patients, and 234 healthy individuals were included as a control group; both groups were admixed Mexicans from Mexico City. The HLA typing methods were based on Next Generation Sequencing and Sequence-Based Typing (SBT). The data analysis was performed with population genetic programs and statistical packages. The admixture estimations based on HLA-B and -DRB1 revealed that SLE patients have a higher Southwestern European ancestry proportion (48 ± 8%) than healthy individuals (30 ± 7%). In contrast, Mexican Native American components are diminished in SLE patients (44 ± 1%) and augmented in Healthy individuals (63 ± 4%). HLA alleles and haplotypes’ frequency analysis found variants previously described in SLE patients from Mexico City. Moreover, a conserved extended haplotype that confers risk to develop SLE was found, the HLA-A∗29:02∼C∗16:01∼B∗44:03∼DRB1∗07:01∼DQB1∗02:02, pC = 0.02, OR = 1.41. Consistent with the admixture estimations, the origin of all risk alleles and haplotypes found in this study are European, while the protection alleles are Mexican Native American. The analysis of genetic distances supported that the SLE patient group is closer to the Southwestern European parental populace and farthest from Mexican Native Americans than healthy individuals. Heterogeneity of genetic admixture determines SLE susceptibility and protection in Mexicans. HLA sequencing is helpful to determine susceptibility alleles and haplotypes restricted to some populations.

Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals.

Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N=463), average European ancestry was significantly higher than noncarriers (N=708; p=.011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR=0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.

Abstract P075: Genetic European Ancestry And Incident Diabetes Mellitus In Black Individuals-Insights From The SPRINT Trial

Background: A metabolic paradox of lower triglyceride (TG) and higher high-density lipoprotein cholesterol (HDL-C) levels but a higher incidence of diabetes has been described in Blacks. We evaluated the association of genetic ancestry-related variants with the risk of incident diabetes in self-identified Black individuals in the Systolic Blood Pressure (BP) Intervention Trial (SPRINT). Methods: The genetic European ancestry proportions were estimated using 106 biallelic genotype markers in non-diabetic Black participants. Participants were stratified into tertiles (T1-T3) of European ancestry proportions. Multivariable-adjusted association of baseline metabolic syndrome indices (fasting plasma glucose [FPG], TG, HDL-C, body mass index [BMI], and BP) with the ancestry proportion was assessed. Multivariable-adjusted Cox regression was used to assess the risk of incident diabetes (FPG ≥126 mg/dL or self-reported diabetes treatment) across tertiles. Results: In 2,466 participants with median European ancestry 19% (13 - 27%), those in T1 were relatively younger, with lower Framingham risk score, and worse renal function (p&lt;0.05 for all). At baseline, higher European ancestry proportion was associated with higher TG and lower HDL-C levels after controlling for clinical and demographic factors (p&lt;0.05 for both). FPG, BMI, and BP were not significantly associated with ancestry proportion. Compared with T1, those in second (HR: 0.64 [95% CI: 0.45-0.90]) and third tertiles (HR: 0.61 [0.44-0.89]) had a lower risk of incident diabetes after controlling for covariates. Specifically, a 5% increment in European ancestry was associated with a 29% lower risk of incident diabetes (HR: 0.71 [0.55-0.93]). No interaction was observed between intensive BP control strategy and European ancestry proportion tertiles on incident diabetes. Conclusions: Genetic factors may account for racial differences in TG and HDL-C levels. The higher risk of incident diabetes in Blacks may similarly be genetically determined.

Abstract PO-187: Identification of ancestry-specific gene expression profiles of African triple- negative breast tumors

Abstract Women with shared West African ancestry suffer from disproportionately higher breast cancer (BC) mortality and are more frequently diagnosed with the most aggressive form of BC, triple negative BC (TNBC). We and others have shown a higher prevalence of TNBC in West African (Ghanaian) and AA women, compared to lower levels of TNBC in East African (Ethiopian) and White/European American (EA) women, and that higher levels of quantified West African ancestry are found among women with TNBC compared to non-TNBC breast tumors. To further understand the role of West African ancestry in the TNBC tumor microenvironment, we conducted RNA sequencing on a pilot cohort of archival FFPE tumor tissue obtained from Ghanaian (n = 19) and Ethiopian (n = 20) women with TNBC disease to study differences in gene expression profiles. SNV calls were obtained from the RNAseq data, and 1K Genome subpopulations were used as references to quantify ancestry of each patient. We observed that our Ghanaian samples have over 94% African ancestry (corresponding to West African populations), where our Ethiopian samples showed between 37-48% African ancestry (corresponding to East African populations). Quantified ancestry among our Ethiopian samples also revealed a significant proportion of European ancestry (30-49%), corresponding to Italian ancestry. Differentially expressed genes (DEGs) were identified by comparing self- reported ethnicity and correlations with genetic ancestry. We have identified over 600 DEGs between Ghanaian vs Ethiopian TNBC samples (p &amp;lt; 0.01). We found over 900 genes that were associated with quantified African ancestry (p &amp;lt; 0.01), using African ancestry as a continuous variable with linear regression methods. Unsupervised hierarchical clustering of this gene set was able to separate Ghanaian and Ethiopian samples. We compared the output of both approaches, and found that only ~200 genes were shared, showing the distinct value of both approaches. We have begun to investigate the role of our differential gene lists in canonical pathways and gene networks using Ingenuity Pathway analysis methods. Using our overlapping differential gene list from both approaches, we observed differences such as quantity of T lymphocytes, where downregulation of genes may indicate differing levels this immune cell population in the TNBC tumor environment. In our ongoing analysis, we are using deconvolution methods, such as CIBERSORT and xCell, to validate and further characterize the presence of various immune cell populations in our TNBC tumors. This study shows that quantified genetic ancestry can be used to identify ancestry-specific gene regulation in African TNBC tumors. Specifically, with our ongoing analysis of the immune cell representation in our samples, we can define differences in tumor heterogeneity and immune response in an ancestry- specific manor. Citation Format: Rachel Martini, Endale Gebregzabher, Princesca Dorsaint, Timothy Chu, Kanika Arora, Lee Gibbs, Zarko Manojlovic, Nicolas Rovine, Andrea Sboner, Olivier Elemento, John Carpten, Lisa Newman, Melissa Davis. Identification of ancestry-specific gene expression profiles of African triple- negative breast tumors [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-187.

Impact of Genetic Ancestry on Prognostic Biomarkers in Uveal Melanoma.

Simple SummaryGenomic prognostic biomarkers play an important role in the application of precision medicine in patients with uveal melanoma (UM). In this study, we performed a pilot study to assess the impact of global and local genetic ancestry on the presence of these prognostic biomarkers. We found a trend for correlations between high risk biomarkers and European ancestry. These results highlight the need for a rigorous genetic ancestry methodology to study the role of ancestry in determining prognosis in patients with UM.Uveal melanoma (UM) is the most common cancer of the eye and leads to metastatic death in up to half of patients. Genomic prognostic biomarkers play an important role in clinical management in UM. However, research has been conducted almost exclusively in patients of European descent, such that the association between genetic admixture and prognostic biomarkers is unknown. In this study, we compiled 1381 control genomes from West African, European, East Asian, and Native American individuals, assembled a bioinformatic pipeline for assessing global and local ancestry, and performed an initial pilot study of 141 UM patients from our international referral center that manages many admixed individuals. Global and local estimates were associated with genomic prognostic determinants. Expression quantitative trait loci (eQTL) analysis was performed on variants found in segments. Globally, after correction for multiple testing, no prognostic variable was significantly enriched in a given ancestral group. However, there was a trend suggesting an increased proportion of European ancestry associated with expression of the PRAME oncogene (q = 0.06). Locally enriched European haplotypes were associated with the poor prognosis class 2 gene expression profile and with genes involved in immune regulation (q = 4.7 × 10−11). These findings reveal potential influences of genetic ancestry on prognostic variables, implicate immune genes in prognostic differences based on ancestry, and provide a basis for future studies of admixed patients with UM using rigorous genetic ancestry methodology.

Abstract B073: Estimating genetic ancestry of commonly used cancer cell lines

Abstract Given the scarcity of human cell lines from under-represented populations available for study, it is crucial that these cell lines be accurately characterized regarding their genetic ancestry so findings can be properly contextualized. Mischaracterization of a cell line's race/ethnicity can lead to wasted time and resources and potentially publication retractions. Here we calculated genetic ancestry proportions for 22 commercially available cell lines to test the accuracy of the “race/ethnicity” categorization assigned to these cells and to provide previously unknown genetic ancestry estimates to the scientific community. To determine cellular genetic ancestry proportions, DNA was extracted from the cell lines and genotyped for ancestry informative markers using the Agena MassARRAY platform with iPLEX chemistry. Genotypes for each cell line were analyzed with STRUCTURE software using settings of 30,000 for burn-in length, 70,000 replications, and K = 3 ancestral populations, representing West African (WA), Native American (NA), and European (EA) input genotype data. Commercially available cell lines designated as “Caucasian” in ethnicity were accurately described with mean European ancestry proportions of 97% (range 92-99%). Recently, using a much smaller panel of markers, the 22Rv1 cell line was found to have 41% WA ancestry. Our genetic ancestry analysis found the 22Rv1 cell line to have mostly EA ancestry, 91% EA, while also containing a non-negligible proportion of WA ancestry (8%). Three of the commercially available cell lines ascribed “Black” race appear to be accurate (HeLa, MDA-MB-PCa2, MDA-MB-468), although two of the three, HeLa and MDA-MBPCa2, fall far below the mean of ~80% WA ancestry for US-born African Americans with 60% and 66% WA ancestry, respectively. Interestingly, the MDA-MB-468 “Black” cell line had an appreciable amount of NA ancestry, 23% NA and 77% WA ancestry, which could suggest possible Afro-Caribbean ethnicity. Most notably, the E006 cell line, designated as “Black,” is as European as the previously mentioned cell lines ascribed Caucasian ethnicity with &amp;gt; 92% EA genetic ancestry. Cell lines with unassigned ethnicity varied widely in genetic ancestry with ranges of WA, NA, and EA ancestry proportions of 1%-92%, 0%-30%, and 2%-96%, respectively. Our results suggest predominantly European ancestry for the Caucasian-designated cell lines and high variance in genetic ancestry proportions for the Black-designated cell lines. However, the E006 cell line is an example of extreme misclassification, which has led to erroneous findings in the disparities literature and leave open the possibility of mischaracterization of other unanalyzed cell lines. Genetic ancestry estimates add more advanced and detailed ancestral characterization to these cell lines and allow for better contextualization of comparisons, applicability, and significant findings. We suggest robust genetic ancestry estimates as a requirement for all current and novel cell lines used in research. Citation Format: Stanley E. Hooker Jr., Madhavi Bathina, Stacy Lloyd, Priyatham Gorjala, Ranjana Mitra, Kevin S. Kimbro, Rick A. Kittles. Estimating genetic ancestry of commonly used cancer cell lines [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B073.

Colonialism and the co-evolution of ethnic and genetic structure in New Mexico.

Socially constructed ethnic identities are frequently rooted in beliefs about common descent that form when people with disparate cultures, languages, and biology come into contact. This study explores connections between beliefs about common descent, as represented by ethnic nomenclatures, and histories of migration and isolation ascertained from genomic data in New Mexicans of Spanish-speaking descent (NMS). We interviewed 507 NMS who further identified using one of seven ethnic terms that they associated with beliefs about connections to past ancestors. For groups of individuals who identified using each term, we estimated biogeographic ancestry, fit admixture models to ancestry distributions, and partitioned genetic distance into admixture and drift components. Regardless of which ethnic term they used, all NMS had appreciable Native American (avg. 27%) and European ancestry (avg.71%). However, individuals who identified using terms associated with beliefs connecting them to colonial-period Spanish ancestors had significantly higher European ancestry than individuals who identified using terms associated with ancestral connections to post-colonial-period migrants from Mexico. Model-fitting analyses show that this ancestry difference reflects post-colonial gene flow with non-NMS European Americans, not colonial-period gene flow with Spaniards. Drift, not admixture, accounted for most of the genetic distance between NMS who expressed connections to Mexican versus Spanish ancestors, reflecting relative isolation of New Mexico and Mexico through the 19th century. Patterns of genomic diversity in NMS are consistent with beliefs about common descent in showing that New Mexico was isolated for generations following initial colonization. They are inconsistent with these beliefs in showing that all NMS have substantial European and Native American ancestry, and in showing that a proportion of European ancestry derives from post-colonial-period admixture with non-NMS European Americans. Our findings provide insights into the construction of ethnic identity in contexts of migration and isolation in New Mexico and, potentially, throughout human prehistory.

Distribution of local ancestry and evidence of adaptation in admixed populations

Admixed American populations have different global proportions of European, Sub-Saharan African, and Native-American ancestry. However, individuals who display the same global ancestry could exhibit remarkable differences in the distribution of local ancestry blocks. We studied for the first time the distribution of local ancestry across the genome of 264 Brazilian admixed individuals, ascertained within the scope of the Brazilian Initiative on Precision Medicine. We found a decreased proportion of European ancestry together with an excess of Native-American ancestry on chromosome 8p23.1 and showed that this is due to haplotypes created by chromosomal inversion events. Furthermore, Brazilian non-inverted haplotypes were more similar to Native-American haplotypes than to European haplotypes, in contrast to what was found in other American admixed populations. We also identified signals of recent positive selection on chromosome 8p23.1, and one gene within this locus, PPP1R3B, is related to glycogenesis and has been associated with an increased risk of type 2 diabetes and obesity. These findings point to a selection event after admixture, which is still not entirely understood in recent admixture events.

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

Adaptation to milking agropastoralism in Chilean goat herders and nutritional benefit of lactase persistence.

The genetic trait of lactase persistence (LP) evolved as an adaptation to milking pastoralism in the Old World and is a well‐known example of positive natural selection in humans. However, the specific mechanisms conferring this selective advantage are unknown. To understand the relationship between milk drinking, LP, growth, reproduction, and survival, communities of the Coquimbo Region in Chile, with recent adoption of milking agropastoralism, were used as a model population.DNA samples and data on stature, reproduction, and diet were collected from 451 participants. Lactose tolerance tests were done on 41 of them. The European −13,910*T (rs4988235) was the only LP causative variant found, showing strong association (99.6%) with LP phenotype.Models of associations of inferred LP status and milk consumption, with fertility, mortality, height, and weight were adjusted with measures of ancestry and relatedness to control for population structure. Although we found no statistically significant effect of LP on fertility, a significant effect (P = 0.002) was observed of LP on body mass index (BMI) in males and of BMI on fertility (P = 0.003). These results fail to support a causal relationship between LP and fertility yet suggest the idea of a nutritional advantage of LP. Furthermore, the proportion of European ancestry around the genetic region of −13,910*T is significantly higher (P = 0.008) than the proportion of European ancestry genome‐wide, providing evidence of recent positive selection since European–Amerindian admixture. This signature was absent in nonpastoralist Latin American populations, supporting the hypothesis of specific adaptation to milking agropastoralism in the Coquimbo communities.

Abstract 233: Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos

Abstract Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with &amp;gt;50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1). Citation Format: Quinn T. Ostrom, Kathleen M. Egan, L. Burt Nabors, Travis Gerke, Reid C. Thompson, Jeffrey J. Olson, Renato LaRocca, Sajeel Chowdhary, Jeanette E. Eckel-Passow, Georgina Armstrong, John K. Wiencke, Christopher I. Amos, Jonine L. Bernstein, Elizabeth B. Claus, Dora Il'yasova, Christoffer Johansen, Daniel H. Lachance, Rose Lai, Ryan T. Merrell, Sara H. Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Melissa L. Bondy, Jill S. Barnholtz-Sloan. Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 233.