Individuals Of African Ancestry Research Articles

African-specific molecular taxonomy of prostate cancer

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Phenome-wide Association Analysis of Substance Use Disorders in a Deeply Phenotyped Sample

BackgroundSubstance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRSs) and phenome-wide association studies are useful in evaluating pleiotropic effects. However, the comparatively low prevalence of SUDs in population samples and the lack of detailed information available in electronic health records limit these data sets’ informativeness for such analyses. MethodsWe used the deeply phenotyped Yale-Penn sample (n = 10,610 with genetic data; 46.3% African ancestry, 53.7% European ancestry) to examine pleiotropy for 4 major substance-related traits: alcohol use disorder, opioid use disorder, smoking initiation, and lifetime cannabis use. The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism, a comprehensive psychiatric interview. ResultsIn African ancestry individuals, PRS for alcohol use disorder, and in European individuals, PRS for alcohol use disorder, opioid use disorder, and smoking initiation were associated with their respective primary DSM diagnoses. These PRSs were also associated with additional phenotypes involving the same substance. Phenome-wide association study analyses of PRS in European individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in phenome-wide association study analyses, such as family environment and early childhood experiences. ConclusionsSmaller, deeply phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.

Extent to which array genotyping and imputation with large reference panels approximate deep whole-genome sequencing

Understanding the genetic basis of human diseases and traits is dependent on the identification and accurate genotyping of genetic variants. Deep whole-genome sequencing (WGS), the gold standard technology for SNP and indel identification and genotyping, remains very expensive for most large studies. Here, we quantify the extent to which array genotyping followed by genotype imputation can approximate WGS in studies of individuals of African, Hispanic/Latino, and European ancestry in the US and of Finnish ancestry in Finland (a population isolate). For each study, we performed genotype imputation by using the genetic variants present on the Illumina Core, OmniExpress, MEGA, and Omni 2.5M arrays with the 1000G, HRC, and TOPMed imputation reference panels. Using the Omni 2.5M array and the TOPMed panel, ≥90% of bi-allelic single-nucleotide variants (SNVs) are well imputed (r2>0.8) down to minor-allele frequencies (MAFs) of 0.14% in African, 0.11% in Hispanic/Latino, 0.35% in European, and 0.85% in Finnish ancestries. There was little difference in TOPMed-based imputation quality among the arrays with >700k variants. Individual-level imputation quality varied widely between and within the three US studies. Imputation quality also varied across genomic regions, producing regions where even common (MAF>5%) variants were consistently not well imputed across ancestries. The extent to which array genotyping and imputation can approximate WGS therefore depends on reference panel, genotype array, sample ancestry, and genomic location. Imputation quality by variant or genomic region can be queried with our new tool, RsqBrowser, now deployed on the Michigan Imputation Server.

Rare genetic variants explain missing heritability in smoking.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Targeting Inequities in Kidney Transplantation

Targeting Inequities in Kidney Transplantation

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype

Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific Tcell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia.

A probable cis-acting genetic modifier of Huntington disease frequent in individuals with African ancestry.

SummaryHuntington disease (HD)is a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine encoding CAG repeat in the huntingtin gene. Recently, it has been established that disease severity in HD is best predicted by the number of pure CAG repeats rather than total glutamines encoded. Along with uncovering DNA repair gene variants as trans-acting modifiers of HD severity, these data reveal somatic expansion of the CAG repeat as a key driver of HD onset. Using high-throughput DNA sequencing, we have determined the precise sequence and somatic expansion profiles of the HTT repeat tract of 68 HD-affected and 158 HD-unaffected African ancestry individuals. A high level of HTT repeat sequence diversity was observed, with three likely African-specific alleles identified. In the most common disease allele (30 out of 68), the typical proline-encoding CCGCCA sequence was absent. This CCGCCA-loss disease allele was associated with an earlier age of diagnosis of approximately 7.1 years and occurred exclusively on haplotype B2. Although somatic expansion was associated with an earlier age of diagnosis in the study overall, the CCGCCA-loss disease allele displayed reduced somatic expansion relative to the typical HTT expansions in blood DNA. We propose that the CCGCCA loss occurring on haplotype B2 is an African cis-acting modifier that appears to alter disease diagnosis of HD through a mechanism that is not driven by somatic expansion. The assessment of a group of individuals from an understudied population has highlighted population-specific differences that emphasize the importance of studying genetically diverse populations in the context of disease.

Use of Polygenic Risk Scores for Coronary Heart Disease in Ancestrally Diverse Populations.

A polygenic risk score (PRS) is a measure of genetic liability to a disease and is typically normally distributed in a population. Individuals in the upper tail of thisdistribution often have relative risk equivalent to that of monogenic form of the disease. The majority of currently available PRSs for coronary heart disease (CHD) have been generated from cohorts of European ancestry (EUR) and vary in their applicability to other ancestry groups. In this report, we review the performance of PRSs for CHD across different ancestries and efforts to reduce variability in performance including novel population and statistical genetics approaches. PRSs for CHD perform robustly in EUR populations but lag in performance in non-EUR groups, particularly individuals of African ancestry. Several large consortia have been established to enable genomic studies in diverse ancestry groups and develop methods to improve PRS performance in multi-ancestry contexts as well as admixed individuals. These include fine-mapping to ascertain causal variants, trans ancestry meta-analyses, and ancestry deconvolution in admixed individuals. PRSs are being used in the clinical setting but enthusiasm has been tempered by the variable performance in non-EUR ancestry groups. Increasing diversity in genomic association studies and continued innovation in methodological approaches are needed to improve PRS performance in non-EUR individuals for equitable implementation of genomic medicine.

Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait

Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. The hemoglobin beta S (HbS) allele (rs334-T). This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

Glaucoma Genetic Risk Scores in the Million Veteran Program

Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS). Cross-sectional study. MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls. We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS. Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS. GRS were significantly associated with POAG (P < 5× 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases. Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Abstract LB162: Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers

Abstract Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent. Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT). Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56). Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs. Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.

Increased blood-derived mitochondrial DNA copy number in African ancestry individuals with Parkinson's disease

IntroductionAltered levels of mitochondrial DNA copy number (mtDNA-CN) have been proposed as a proxy for mitochondrial dysfunction. Following reports of mtDNA depletion in the blood and substantia nigra of Parkinson's disease (PD) cases, mtDNA-CN was also suggested as a possible biomarker for PD. Therefore, this study aimed to investigate whether blood mtDNA-CN levels of African ancestry PD cases would be altered compared to controls, as previously reported in individuals of Asian and European ancestry. MethodsDroplet digital polymerase chain reaction (ddPCR) was performed to quantify blood-derived mtDNA-CN levels as a ratio of a mitochondrial gene (MT-TL1) to a nuclear gene (B2M) in 72 PD cases and 79 controls of African ancestry (i.e. individuals with African mtDNA haplogroups) from South Africa. mtDNA-CN per cell was calculated by the formula 2 × MT-TL1/B2M. ResultsAccepting study limitations, we report significantly higher mtDNA-CN in whole blood of our PD cases compared to controls (median difference = 81 copies/cell), independent of age (95% CI [64, 98]; P < 0.001]). These findings contradict previous reports of mtDNA depletion in PD cases. ConclusionsWe caution that the observed differences in mtDNA-CN between the present and past studies may be a result of unaccounted-for factors and variability in study designs. Consequently, larger well-designed investigations may help determine whether mtDNA-CN is consistently altered in the blood of PD cases across different ancestries and whether it can serve as a viable biomarker for PD.

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection.

Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis.

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest‐neighbor feature selection

Novel HLA associations with outcomes of <i>Mycobacterium tuberculosis</i> exposure and sarcoidosis in individuals of African ancestry using nearest‐neighbor feature selection

1284-P: Genetic and Lifestyle Associations with Cardiometabolic Traits and Diabetes Risk Factors in Ethnically Diverse Africans

African ancestry populations are underrepresented in human genetic studies, which leaves a knowledge gap about genetic and environmental risk factors for metabolic disease which can bias healthcare treatment. To alleviate these shortcomings, we conducted a series of genome-wide association studies of cardiometabolic traits in a diverse sampling of ∼2,500 (max sample size) ethnically and geographically diverse Africans from populations practicing agriculturalist, hunter-gatherer, and pastoralist subsistence strategies. This study includes the Fulani pastoralists who have a relatively high incidence of adult-onset diabetes, despite having a low average body mass index (BMI) . All individuals in the present study are sampled from rural populations that have relatively homogeneous lifestyles and diet within a community. This unique aspect to the study cohort allows for within- and between- group comparisons to identify trait variation attributable to genetics vs. lifestyle variation. Subjects were genotyped on a new African-focused SNP array from the Human Heredity and Health in Africa (H3 Africa) consortium. Genome-wide data was imputed based on a panel of African whole-genome sequences and data from the 1000 genomes project, resulting in a total of million variants for trait association analysis. Genetic associations were tested for BMI, blood pressure, and blood biomarkers of cardiometabolic health. We checked for replication of genotype/phenotype associations by comparison to large non-African cohorts studied for the same traits. We find that most associations identified in non-African populations do not replicate in the Africans. However, we identified a number of novel loci associated with cardiometabolic traits in the African populations. This study has important implications for identifying genetic risk factors that may play a role in metabolic disease in individuals of African ancestry. Funded by ADA Pathway award 1-19-VSN-02. Disclosure D.Hui: None. T.B.Nyambo: None. S.Chanock: None. S.A.Tishkoff: None. D.Harris: None. M.Mcquillan: None. M.Hansen: None. A.Ranciaro: None. W.Beggs: None. S.W.Mpoloka: None. D.Woldemeskel: None. A.K.K.Njamnshi: None. Funding American Diabetes Association (1-19-VSN-02) ; National Institutes of Health (R35 GM134957-01, R01AR076241, 5T32DK007314-39, 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154-01)

Role of genetic ancestry in endometrial cancers: Understanding disparities in black women.

e17631 Background: Endometrial cancer is the most common gynecological malignancy in the United States. Endometrial cancer disproportionately affects black women in terms of incidence and survival despite advancement in treatment, and preventive strategies. Identifying distinct tumor markers in patients with African ancestry will help distinguish biological determinants underlying the disparities in endometrial cancer. In this study, we investigated the genetic alterations in endometrial cancer in individuals of African (AFR) ancestry using The Cancer Genome Atlas (TCGA). Methods: The genomic and clinical data of TCGA PanCancer Atlas uterine corpus endometrial carcinoma (UCEC) were explored using CBioportal (http://www.cbioportal.org/). We utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral composition. This dataset contains 529 patients, including 357 self-reported whites and 107 blacks. For each case the proportion of European, West African, East Asian, Native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global genetic ancestry analysis identified 115 AFR ancestry cases with mean ancestry of 80.4%. The dominant AFR ancestry subject matched the self-reported race with 94% accuracy. We identified 23 subjects with ≥90% AFR ancestry, 43 subjects with 80-90% AFR ancestry, 34 subjects with 70-80% AFR ancestry, and 15 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene in patients with AFR ancestry(49.5%). ≥90% AFR ancestry had the highest rate of TP53 mutations (52.2%) compared with 80-90% AFR ancestry (51.2%), 70-80% AFR ancestry (43.8%), and 50-70% AFR ancestry (41.7%). PTEN was less commonly mutated in patients with higher proportion of AFR ancestry (47.8% in ≥90% AFR ancestry, 39.0% in 80-90% AFR ancestry, 59.4% in 70-80% AFR ancestry, and 66.7% in 50-70% AFR ancestry). PIK3CA mutation frequency was almost identical in all AFR ancestry groups studied. No significant differences in overall survival was observed between AFR ancestry groups. Conclusions: We aimed to investigate the etiology of endometrial cancer disparities by analyzing the effect of ancestry on genetic alterations in endometrial cancer. This study demonstrated differences in the mutation frequency among patients with AFR ancestry. We have shown that TP53 mutations were seen more frequently in patients with higher AFR ancestry, which may confer a poorer prognosis. Nonetheless, to validate the findings of this study, future studies should be conducted with larger sample sizes and more diverse ancestral groups to explore how genetic ancestry impacts tumorigenesis and cancer progression.

Alcohol use disorder, psychiatric comorbidities, marriage and divorce in a high-risk sample.

To examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample. Participants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit. Among EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce. In a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

1273-P: The Interplay between Polygenic and Rare HNF1A Variant Risk in Type 2 Diabetes

Rare variants in HNF1A, a pancreatic beta cell transcription factor, have been shown to be associated with T2D and monogenic diabetes. Here, we examine the effect of functionally validated rare (MAF&amp;lt;1%) nonsynonymous variants (RNVs) in a functional domain of HNF1A on T2D risk, and whether their effect is influenced by an overall genetic susceptibility to T2D. Using exome sequencing data of 3,443 African ancestry (AA) and 157,182 European ancestry (EA) individuals in the UK Biobank and 5,018 AA, 5,6EA and 7,1Hispanic-Latino Ancestry (HA) individuals in the BioMe Biobank, we identified 132 AA, 287 EA, and 64 HA RNV carriers (NRNVs= 30) of HNF1A variants that impair protein function ≤ 60%. T2D Polygenic Risk Scores (PRSs) were built using either trans-ethnic or EA GWAS summary statistics and standardized per ancestry. We tested the association between RNV carrier status and the PRS with T2D risk, and meta-analyzed the ancestry-specific results. Carrying any of the HNF1A RNV mutations was associated with a 1.5 increase in the odds of T2D in the EA, albeit non-significantly (P=0.06) , but not in the AA (OR=1.1, P=0.6) or HA (OR=1 , P=1) . We then restricted analyses to RNVs within a functional domain, which results in more pronounced effects in the AA (OR=1.5, P=0.07) and EA (OR=1.9, P=0.002) but not in the HA (OR=0.8, P=0.5) . Per SD increase in the PRS, there is a significant 1.7, 1.6 and 2.1 higher odds of T2D in AA, EA and HA individuals, respectively. Even though we observed no interaction between the PRS and HNF1A RNVs (P &amp;gt;; 0.05) , the association between RNVs and T2D was more pronounced among EA individuals with a high PRS. Functional domain carriers (NEA = 50) in the top PRS quintile had a 3.6 (P=0.0008) higher odds of T2D as compared to non-carriers in the same quintile. Our study shows the value of large biobanks in studying rare variants, the importance of variant selection, and the need to include non-European ancestry populations. We demonstrate the utility of combining rare and common variant risks to better assess T2D risk. Disclosure L.Stalbow: None. M.H.Preuss: None. N.Chami: None. R.A.J.Smit: None. R.J.Loos: None.

Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol.

BackgroundElevated plasma levels of alpha‐aminoadipic acid (2‐AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown.Methods and ResultsWe identified genetic determinants of plasma 2‐AAA through meta‐analysis of genome‐wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women’s and Men’s Health Studies. No single nucleotide polymorphisms reached genome‐wide significance across all samples. However, the top associations from the meta‐analysis included single‐nucleotide polymorphisms in the known 2‐AAA pathway gene DHTKD1, and single‐nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2‐AAA and cardiometabolic phenotypes in large disease genome‐wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2‐AAA and lower high‐density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2‐AAA and high‐density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2‐AAA and high‐density lipoprotein (r s=−0.53, P<0.0001).Conclusions2‐AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2‐AAA associates with reduced levels of high‐density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2‐AAA to future cardiometabolic risk.