Ancestry Background Research Articles

Abstract C153: Transcriptome-wide study identifies unique pathway functional clusters associated with breast cancer subtypes in population with high indigenous american ancestry

Abstract Purpose: Breast cancer incidence and outcomes differ by US census racial/ethnic category. Since large-scale genetic studies of human disease are predominately focused on populations of European ancestry, little is known about breast cancer molecular biology in Hispanic/Latinos which can widen cancer health disparities due to suboptimal translation of discoveries into clinical practice or public health policy. We aim to identify most relevant pathways in breast cancer subtype differentiation in breast cancer patients from Peru and compared them with those obtained analyzing the Cancer Genome Atlas (TCGA) Breast Cancer (BRCA) dataset and with the published results of the Molecular Profile of Breast Cancer Study (MPBCS), a multi-country Latin American cohort. Patients and Methods: Formalin fixed paraffin embedded tumor tissues samples were whole exome sequenced for a total of 271 patients recruited by the Peruvian Breast Cancer Genomics Study (PEGEN-BC). Quality control was conducted to remove genes with low counts for PEGEN and TCGA-BRCA cohorts, and only female stage II-III breast cancer patients were kept for downstream analysis. Intrinsic tumor subtypes were classified using the estrogen receptor (ER) status-adjusted PAM50 method with genefu package in R. Differential gene expression and pathway analyses between subtypes were performed by the GSEA 4.3.2 software. [LF1] [CX2] Statistical and biological significance was determined using p-values < 0.1 and absolute value of enrichment score > 1.5. Top 20 pathways for each cohort were selected and ranked for comparison. Results: PAM50 classification of the PEGEN-BC cohort defined 20.2% of tumors as Luminal A (LumA), 27.9% as Luminal B (LumB), 27.1% as HER2E, 22.5% as Basal and 2.3% as Normal. Transcriptomic pathway analysis showed that most of the significantly changed pathways were similar to previous findings in the literature, for example, proliferation pathways being upregulated in LumB, HER2E and Basal tumors, compared to the LumA subtype, and a strong dependency on the estrogen pathways for LumA and LumB. Within cohorts, we identified novel clusters of pathways that share related functions. For example, 6 out of the 20 top significant pathways in LumB vs. HER2E comparison for the PEGEN-BC cohort were glycan/glycosylation-related, suggesting the possibility of tumor immune response differences between LumB and HER2E due to glycan related pathway differences among Peruvian patients. Conclusions: We identified novel pathway clusters associated with specific breast cancer subtypes in a population with high Indigenous American ancestry from Peru. Further analyses will be conducted next to explore if the observed patterns were specific to genetic ancestry background or observed independently of genetic ancestry. Citation Format: Chenghuiyun Xu, Valentina A. Zavala, David Rocke, Xiaosong Huang, Sandro Casavilca-Zambrano, Jeannie Navarro-Vásquez, Ruddy Liendo-Picoaga, Monica Calderón, Guillermo Valencia, Patricia Rioja, Carlos A Castañeda, Zaida Morante, Silvia P. Neciosup, Hugo A Fuentes, Julio E. Abugattas, Jose M. Cotrina, Luis A. Salinas, Marco Gálvez-Nino, Jovanny Zabaleta, Andrea S. Llera, Tatiana Vidaurre, Laura Fejerman. Transcriptome-wide study identifies unique pathway functional clusters associated with breast cancer subtypes in population with high indigenous american ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C153.

Abstract A079: The impact of Indigenous American ancestry on the risk of acute lymphoblastic leukemia and the implications for future study designs

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino (H/L) children having up to 1.4 times the rate of ALL compared to their non-Hispanic White counterparts. This disparity has not been fully explained by environmental factors, suggesting the role of understudied genetic variants, particularly ones found in Indigenous American (IA) ancestry inherited by Latinos. In this study, we characterized the impact of IA ancestry on the frequency and effect size of known ALL risk alleles. We found that elevated risk of ALL in Latinos may be conferred by increased frequency of risk alleles due to IA ancestry. For instance, in an analysis of Latinos from the California Cancer Linkage Project (CCRLP; 1,930 cases, 2,103 controls) and the California Childhood Leukemia Study (CCLS; N = 605 cases, 515 controls), we found that, across independent known ALL loci (N=21), more loci than expected by chance showed a significant association between IA ancestry and increasing risk (p = 0.015). Compared to randomly-sampled, frequency-matched alleles from the genome, the risk alleles at all known ALL loci also showed a significant association with IA ancestry (46.9 % for known risk alleles vs. 43.5 % for matched alleles; ). The IA haplotype had 1.39 times the odds (95% CI: 1.35 – 1.43; ) of harboring the risk allele compared to the non-IA haplotype. Conversely, in a combined Latino sample of 2,535 cases and 9,035 controls, we found no evidence of GxAncestry interaction on ALL risk across all known loci (min P = 0.0026, prior to adjusting for multiple testing), suggesting that ALL risk alleles do not have increased effects on the IA ancestry background. This lack of synergism between local ancestry and genotype in ALL has methodological implications for gene discovery in admixed populations. To explore this, we implemented Tractor, a method that models genotype effects by ancestry, and thus is best powered in the presence of effect size heterogeneity by ancestry. Across known loci, we found that Tractor had 36.1% decreased power compared to standard GWAS. Taken together, our results suggest that the disproportionate burden of ALL in Latino populations may arise from the enrichment of risk alleles within the IA ancestry component, possibly driven by immunity- related selective pressures. Finally, future genetic studies of ALL in Latino patients may benefit from methods that incorporate contributions from ancestry to increase the statistical power in identifying associations, rather than leverage effect size heterogeneity across ancestries. Citation Format: Jalen Langie, Libby Morimoto, Xiaomei Ma, Catherine Metayer, Joseph L. Wiemels, Adam J. de Smith, Charleston W.K. Chiang. The impact of Indigenous American ancestry on the risk of acute lymphoblastic leukemia and the implications for future study designs [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A079.

Allele frequency of pathogenic variants causing acid sphingomyelinase deficiency and Gaucher disease in the general Japanese population

Acid sphingomyelinase deficiency (ASMD) and Gaucher disease (GD) are lysosomal storage disorders associated with hepatosplenomegaly and thrombocytopenia. The incidences of ASMD and GD are known to be particularly high in the Ashkenazi Jewish population. Conversely, the number of reported patients with these diseases has been limited in Asian countries, including Japan. Here, we reviewed the allele frequencies of pathogenic variants causing ASMD and GD in the Japanese population and populations with various ancestry backgrounds using the Japanese Multi-Omics Reference Panel 54KJPN and the Genome Aggregation Database v4.0.0. The estimated carrier frequencies of ASMD- and GD-related variants were 1/180 and 1/154 in Japanese individuals, equivalent to disease occurrence frequencies of 1/128,191 and 1/94,791 individuals, respectively. These frequencies are much higher than previously expected. Our data also suggest that there are more patients with a milder form of ASMD and nonspecific clinical findings who have not yet been diagnosed.

Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI

Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals with mosaic continental ancestry backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across segments with shared ancestry in admixed genomes. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses for traits with associated variants exhibiting ancestral-differential effects. Leveraging data from the Women’s Health Initiative study, we show that GAUDI improves PRS prediction of white blood cell count and C-reactive protein in African Americans by > 64% compared to alternative methods, and even outperforms PRS-CSx with large European GWAS for some scenarios. We believe GAUDI will be a valuable tool to mitigate disparities in PRS performance in admixed individuals.

Haplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data

Expression Quantitative Trait Loci (eQTLs) are critical to understanding the mechanisms underlying disease-associated genomic loci. Nearly all protein-coding genes in the human genome have been associated with one or more eQTLs. Here we introduce a multi-variant generalization of allelic Fold Change (aFC), aFC-n, to enable quantification of the cis-regulatory effects in multi-eQTL genes under the assumption that all eQTLs are known and conditionally independent. Applying aFC-n to 458,465 eQTLs in the Genotype-Tissue Expression (GTEx) project data, we demonstrate significant improvements in accuracy over the original model in estimating the eQTL effect sizes and in predicting genetically regulated gene expression over the current tools. We characterize some of the empirical properties of the eQTL data and use this framework to assess the current state of eQTL data in terms of characterizing cis-regulatory landscape in individual genomes. Notably, we show that 77.4% of the genes with an allelic imbalance in a sample show 0.5 log2 fold or more of residual imbalance after accounting for the eQTL data underlining the remaining gap in characterizing regulatory landscape in individual genomes. We further contrast this gap across tissue types, and ancestry backgrounds to identify its correlates and guide future studies.

Trans-ancestry analysis in over 799,000 individuals yields new insights into the genetic etiology of colorectal cancer.

Recent studies have demonstrated the relevance of circulating factors in the occurrence and development of colorectal cancer (CRC); however, the causal relationship remains unclear. Summary-level data for CRC were obtained from the UK Biobank (5,657 cases and 372,016 controls), FinnGen cohort (3,022 cases and 215,770 controls), and BioBank Japan Project (BBJ, 7,062 cases and 195,745 controls). Thirty-two peripheral markers with consistent definitions were collected from the three biobanks. Mendelian randomization (MR) was used to evaluate the causal effect of circulating factors on CRC. The effects from the three consortiums were combined using trans-ancestry meta-analysis methods. Our analysis provided compelling evidence for the causal association of higher genetically predicted eosinophil cell count (EOS, odds ratio [OR], 0.8639; 95% confidence interval [CI] 0.7922-0.9421) and red cell distribution width (RDW, OR, 0.9981; 95% CI, 0.9972-0.9989) levels with a decreased risk of CRC. Additionally, we found suggestive evidence indicating that higher levels of total cholesterol (TC, OR, 1.0022; 95% CI, 1.0002-1.0042) may increase the risk of CRC. Conversely, higher levels of platelet count (PLT, OR, 0.9984; 95% CI, 0.9972-0.9996), total protein (TP, OR, 0.9445; 95% CI, 0.9037-0.9872), and C-reactive protein (CRP, OR, 0.9991; 95% CI, 0.9983-0.9999) may confer a protective effect against CRC. Moreover, we identified six ancestry-specific causal factors, indicating the necessity of considering patients' ancestry backgrounds before formulating prevention strategies. MR findings support the independent causal roles of circulating factors in CRC, which might provide a deeper insight into early detection of CRC and supply potential preventative strategies.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.

Prevalence of FH-Causing Variants and Impact on LDL-C Concentration in European, South Asian, and African Ancestry Groups of the UK Biobank-Brief Report.

Familial hypercholesterolemia (FH) is a monogenic disease that causes high low-density lipoprotein cholesterol (LDL-C) and higher risk of premature coronary heart disease. The prevalence of FH-causing variants and their association with LDL-C in non-European populations remains largely unknown. Using DNA diagnosis in a population-based cohort, we aimed to estimate the prevalence of FH across 3 major ancestry groups in the United Kingdom. Principal component analysis was used to distinguish genetic ancestry in UK Biobank participants. Whole exome sequencing data were analyzed to provide a genetic diagnosis of FH. LDL-C concentrations were adjusted for statin use. Principal component analysis distinguished 140 439 European, 4067 South Asian, and 3906 African participants with lipid and whole exome sequencing data. There were significant differences between the 3 groups, including total and LDL-C concentrations, and prevalence and incidence of coronary heart disease. We identified 488, 18, and 15 participants of European, South Asian, and African ancestry carrying a likely pathogenic or pathogenic FH-variant. No statistical difference in the prevalence of an FH-causing variant was observed: 1 out of 288 (95% CI, 1/316-1/264) in European, 1 out of 260 (95% CI, 1/526-1/173) in African, and 1 out of 226 (95% CI, 1/419-1/155) in South Asian. Carriers of an FH-causing variant had significantly higher LDL-C concentration than noncarriers in every ancestry group. There was no difference in median (statin-use adjusted) LDL-C concentration in FH-variant carriers depending on their ancestry background. Self-reported statin use was nonsignificantly highest in FH-variant carriers of South Asian ancestry (55.6%), followed by African (40.0%) and European (33.8%; P=0.15). The prevalence of FH-causing variants in the UK Biobank is similar across the ancestry groups analyzed. Despite overall differences in lipid concentrations, FH-variant carriers across the 3 ancestry groups had similar LDL-C levels. In all ancestry groups, the proportion of FH-variant carriers treated with lipid-lowering therapy should be improved to reduce future risk of premature coronary heart disease.

Impact of cross-ancestry genetic architecture on GWASs in admixed populations

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust for population stratification. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing a GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes, we find that controlling for and conditioning effect sizes on local ancestry can reduce statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs, HetLanc is not large enough for GWASs to benefit from modeling heterogeneity in this way.

Immunogenetics of HLA-B: SNP, allele, and haplotype diversity in populations from different continents and ancestry backgrounds.

HLA-B is among the most variable gene in the human genome. This gene encodes a key molecule for antigen presentation to CD8+ T lymphocytes and NK cell modulation. Despite the myriad of studies evaluating its coding region (with an emphasis on exons 2 and 3), few studies evaluated introns and regulatory sequences in real population samples. Thus, HLA-B variability is probably underestimated. We applied a bioinformatics pipeline tailored for HLA genes on 5347 samples from 80 different populations, which includes more than 1000 admixed Brazilians, to evaluate the HLA-B variability (SNPs, indels, MNPs, alleles, and haplotypes) in exons, introns, and regulatory regions. We observed 610 variable sites throughout HLA-B; the most frequent variants are shared worldwide. However, the haplotype distribution is geographically structured. We detected 920 full-length haplotypes (exons, introns, and untranslated regions) encoding 239 different protein sequences. HLA-B gene diversity is higher in admixed populations and Europeans while lower in African ancestry individuals. Each HLA-B allele group is associated with specific promoter sequences. This HLA-B variation resource may improve HLA imputation accuracy and disease-association studies and provide evolutionary insights regarding HLA-B genetic diversity in human populations.

Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.

Hundreds of genetic variants implicated in Mendelian disease have been characterized in dogs and commercial screening is being offered for most of them worldwide. There is typically limited information available regarding the broader population frequency of variants and uncertainty regarding their functional and clinical impact in ancestry backgrounds beyond the discovery breed. Genetic panel screening of disease-associated variants, commercially offered directly to the consumer or via a veterinary clinician, provides an opportunity to establish large-scale cohorts with phenotype data available to address open questions related to variant prevalence and relevance. We screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of 3.5 million; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries) to examine the prevalence and distribution of a total of 250 genetic disease-associated variants in the general population. Electronic medical records from veterinary clinics were available for 43.5% of the genotyped dogs, enabling the clinical impact of variants to be investigated. We provide detailed frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-associated variant. Focusing on a subset of variants, we provide evidence of full penetrance for 10 variants, and plausible evidence for clinical significance of 22 variants, on diverse breed backgrounds. Specifically, we report that inherited hypocatalasia is a notable oral health condition, confirm that factor VII deficiency presents as subclinical bleeding propensity and verify two genetic causes of reduced leg length. We further assess genome-wide heterozygosity levels in over 100 breeds, and show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease variant load. The accumulated knowledge represents a resource to guide discussions on genetic test relevance by breed.

Mitochondrial haplotype modulates genome expression and mitochondrial structure/function in cardiomyocytes following volume overload.

Mitochondrial DNA (mtDNA) haplotype regulates mitochondrial structure/function and reactive oxygen species in aortocaval fistula (ACF) in mice. Here, we unravel the mitochondrial haplotype effects on cardiomyocyte mitochondrial ultrastructure and transcriptome response to ACF in vivo. Phenotypic responses and quantitative transmission electron microscopy (TEM) and RNA sequence at 3 days were determined after sham surgery or ACF in vivo in cardiomyocytes from wild-type (WT) C57BL/6J (C57n:C57mt) and C3H/HeN (C3Hn:C3Hmt) and mitochondrial nuclear exchange mice (C57n:C3Hmt or C3Hn:C57mt). Quantitative TEM of cardiomyocyte mitochondria C3HWT hearts have more electron-dense compact mitochondrial cristae compared with C57WT. In response to ACF, mitochondrial area and cristae integrity are normal in C3HWT; however, there is mitochondrial swelling, cristae lysis, and disorganization in both C57WT and MNX hearts. Tissue analysis shows that C3HWT hearts have increased autophagy, antioxidant, and glucose fatty acid oxidation-related genes compared with C57WT. Comparative transcriptomic analysis of cardiomyocytes from ACF was dependent upon mtDNA haplotype. C57mtDNA haplotype was associated with increased inflammatory/protein synthesis pathways and downregulation of bioenergetic pathways, whereas C3HmtDNA showed upregulation of autophagy genes. In conclusion, ACF in vivo shows a protective response of C3Hmt haplotype that is in large part driven by mitochondrial nuclear genome interaction.NEW & NOTEWORTHY The results of this study support the effects of mtDNA haplotype on nuclear gene expression in cardiomyocytes. Currently, there is no acceptable therapy for volume overload due to mitral regurgitation. The findings of this study could suggest that mtDNA haplotype activates different pathways after ACF warrants further investigations on human population of heart disease from different ancestry backgrounds.

A genome-wide association study identifies distinct variants associated with pulmonary function among European and African ancestries from the UK Biobank

Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. We analysed the UK Biobank genome-wide association summary statistics of pulmonary function for Europeans and individuals of recent African descent to identify variants associated with the trait in the two ancestries. Here, we show 627 variants in Europeans and 3 in Africans associated with three pulmonary function parameters. In addition to the 110 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identify 279 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans. Remarkably, we find no shared variants among Africans and Europeans. Furthermore, enrichment analyses of variants separately for each ancestry background reveal significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes reveals that individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings extend our understanding of the different variants that modify the pulmonary function in Africans and Europeans, a promising finding for future GWASs and medical studies.

Abstract C082: Breast cancer risk in Hispanic/Latina women and the 6q25 chromosomal region: Fine mapping and eQTL identification

Abstract Breast cancer subtype distribution differs between populations with dissimilar genetic ancestry backgrounds. Several breast cancer risk single nucleotide polymorphisms (SNPs) were discovered in individuals of European and Asian origin. Hispanic/Latina women remain underrepresented in studies and public databases. The 6q25 locus contains multiple breast cancer risk-associated SNPs. Some SNPs within this region have been associated with the expression of genes (eQTLs), such as the Estrogen Receptor 1 gene (ESR1). Two breast cancer genetic association studies in Hispanics/Latinas identified two SNPs (rs140068132 and rs3778609), near ESR1, that correlate with Indigenous American ancestry and reduce the odds of breast cancer, especially for Estrogen Receptor-negative (ER-) disease. The underrepresentation of Latin American populations in public databases has hindered the study of the mechanisms by which these SNPs confer a protective effect. We integrated genetic and transcriptomic data from breast cancer patients with high Indigenous American ancestry to test the association between the protective variants in the 6q25 region and tumor gene expression. Breast cancer patients were recruited at the National Cancer Institute in Peru to be part of The Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC, N=1809). Healthy women from a pregnancy outcomes study in Peru were included as controls (N=3334). Genome-wide genotype data were available and missing genotypes were imputed using the TOPMED Imputation Server to perform fine-mapping within the 6q25 locus. Logistic regression was used to test the association between each SNP and breast cancer risk. We exome-sequenced 155 breast tumors of these patients. Transcripts per million counts and imputed genotypes within the 6q25 region were used for eQTL analysis. Colocalization was performed using summary statistics from the fine-mapping and eQTL analysis, including SNPs with minor allele frequency >5%. Only two SNPs, rs140068132 and rs851984 were independently associated with breast cancer risk, as we previously reported. eQTL signals colocalized with the subregion in 6q25 that contains these breast cancer-associated SNPs. Within this subregion, the gene with more eQTLs using a nominal p-value of <=0.01 was MTHFD1L (136 eQTLs), followed by ESR1 (58) and CCDC170 (32). Colocalization showed that MTHFD1L and ESR1 eQTLs were more likely to overlap with breast cancer risk SNPs, including rs140068132. The protective rs140068132-G variant was associated with lower expression of MTHFD1L. MTHFD1L has been found deregulated in breast cancer and higher expression is associated with poor prognosis. Our preliminary results suggest that the rs140068132-G variant in the 6q25 region identified in Hispanic/Latina women might exert its protective effect through the downregulation of MTHFD1L. Analyses with additional samples will allow us to confirm this result and further explore the functional implications of the rs140068132 variant. Citation Format: Valentina A. Zavala, Xiaosong Huang, Sandro Casavilca-Zambrano, Jeannie Navarro-Vásquez, Carlos A. Castañeda, Guillermo Valencia, Zaida Morante, Monica Calderon, Julio E. Abugattas, Henry Gómez, Hugo A. Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Silvia Neciosup, Katia Roque, Jule Vásquez, Luis MAs, Marco Gálvez-Nino, Sixto E. Sánchez, Michelle A. Williams, Elad Ziv, Jovanny Zabaleta, Bizu Gelaye, Tatiana Vidaurre Vidaurre, Laura Fejerman. Breast cancer risk in Hispanic/Latina women and the 6q25 chromosomal region: Fine mapping and eQTL identification [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C082.

Incorporating local ancestry improves identification of ancestry-associated methylation signatures and meQTLs in African Americans

Here we report three epigenome-wide association studies (EWAS) of DNA methylation on self-reported race, global genetic ancestry, and local genetic ancestry in admixed Americans from three sets of samples, including internal and external replications (Ntotal = 1224). Our EWAS on local ancestry (LA) identified the largest number of ancestry-associated DNA methylation sites and also featured the highest replication rate. Furthermore, by incorporating ancestry origins of genetic variations, we identified 36 methylation quantitative trait loci (meQTL) clumps for LA-associated CpGs that cannot be captured by a model that assumes identical genetic effects across ancestry origins. Lead SNPs at 152 meQTL clumps had significantly different genetic effects in the context of an African or European ancestry background. Local ancestry information enables superior capture of ancestry-associated methylation signatures and identification of ancestry-specific genetic effects on DNA methylation. These findings highlight the importance of incorporating local ancestry for EWAS in admixed samples from multi-ancestry cohorts.

Rare variant association tests for ancestry-matched case-control data based on conditional logistic regression.

With the increasing volume of human sequencing data available, analysis incorporating external controls becomes a popular and cost-effective approach to boost statistical power in disease association studies. To prevent spurious association due to population stratification, it is important to match the ancestry backgrounds of cases and controls. However, rare variant association tests based on a standard logistic regression model are conservative when all ancestry-matched strata have the same case-control ratio and might become anti-conservative when case-control ratio varies across strata. Under the conditional logistic regression (CLR) model, we propose a weighted burden test (CLR-Burden), a variance component test (CLR-SKAT) and a hybrid test (CLR-MiST). We show that the CLR model coupled with ancestry matching is a general approach to control for population stratification, regardless of the spatial distribution of disease risks. Through extensive simulation studies, we demonstrate that the CLR-based tests robustly control type 1 errors under different matching schemes and are more powerful than the standard Burden, SKAT and MiST tests. Furthermore, because CLR-based tests allow for different case-control ratios across strata, a full-matching scheme can be employed to efficiently utilize all available cases and controls to accelerate the discovery of disease associated genes.

Polygenic risk prediction based on singular value decomposition with applications to alcohol use disorder

Background/aimThe polygenic risk score (PRS) shows promise as a potentially effective approach to summarize genetic risk for complex diseases such as alcohol use disorder that is influenced by a combination of multiple variants, each of which has a very small effect. Yet, conventional PRS methods tend to over-adjust confounding factors in the discovery sample and thus have low power to predict the phenotype in the target sample. This study aims to address this important methodological issue.MethodsThis study proposed a new method to construct PRS by (1) approximating the polygenic model using a few principal components selected based on eigen-correlation in the discovery data; and (2) conducting principal component projection on the target data. Secondary data analysis was conducted on two large scale databases: the Study of Addiction: Genetics and Environment (SAGE; discovery data) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; target data) to compare performance of the conventional and proposed methods.Result and conclusionThe results show that the proposed method has higher prediction power and can handle participants from different ancestry backgrounds. We also provide practical recommendations for setting the linkage disequilibrium (LD) and p value thresholds.

P70.02 Clinicopathological and Genetic Ancestry Impact of TP53 Mutations in Brazilian Lung Adenocarcinoma Patients

TP53 is the most mutated gene in lung adenocarcinoma tumors. TP53 gene plays a crucial role in maintaining genome stability, and the presence of alterations in this gene may lead to uncontrolled cell proliferation and cancer. However, the frequency of TP53 mutation and its clinical impact in admixture lung adenocarcinoma populations, such as the Brazilian population, is unclear. Aim: To describe the frequency of TP53 mutations and their association with clinicopathological and genetic ancestry background data in lung adenocarcinoma patients in Brazil. We evaluated a retrospective FFPE series of lung adenocarcinoma (n=363) diagnosed at Barretos Cancer Hospital, Barretos, Brazil, between 2018 and 2020. TP53 mutational status was assessed by NGS (TruSight Tumor 15, Illumina). The genetic ancestry analysis was assessed on tumor DNA by a specific panel of 46 ancestry informative markers, and the ancestry proportions for Asian, African, European, and Native American was calculated. In accordance with the AJCC 7thedition, the following disease stage was present at diagnosis: I/II (n=51); III (n=43), and IV (n=245). We observed the presence of TP53 mutations in 59% (n=215) of cases. About 71.0% of mutations were missense variants and the majority were located in the DNA-binding domain of the TP53 gene (Figure1). Furthermore, the codon Arg273 was the most mutated (n=13), and the R337H variant (founder-effect in Brazil) was identified in 10 cases (4.65%). TP53 mutations were associated with younger age at diagnosis(p=0.006) quitter and current smokers(p=0.006 and p=0.001), and intermedium and high African genetic ancestry(p=0.012 and p<0.0001). TP53 mutated patients presented a significantly worse overall survival (14 months) compared to wild-type patients (22months) (p=0.024). The adjusted cox regression model showed TP53 mutational status(TP53m HR=1.15, p=0.386) was not independently associated with worse outcomes. Apart from, EGFR mutational status(EGFRm HR=0.44, p<0.0001), advanced disease at diagnosis(HR=15.78, p<0.0001), and PS ECOG at diagnosis(PS1 HR=2.25, p=0.032; PS2 HR=3.71, p=0.01; PS3/4 HR=5.91, p<0.0001) were independently associated with worse outcomes regardless of disease course. TP53 mutations are present in 59.0% in Brazilian lung adenocarcinoma patients. TP53 mutations are associated with younger patients, quitter and current smokers, patients with African genetic ancestry background.

Transcriptome-Wide Association Study of Blood Cell Traits in African Ancestry and Hispanic/Latino Populations.

Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1 × 10−4) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. Conclusions: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. N/A. Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.