Participants Of African Ancestry Research Articles

Genotype-based “virtual” metabolomics in a clinical biobank identifies novel metabolite-disease associations

Introduction: Circulating metabolites act as biomarkers of dysregulated metabolism and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based “virtual” metabolomics approach can identify novel metabolite-disease associations.Methods: We examined the association between polygenic scores for 724 metabolites with 1,247 clinical phenotypes in the BioVU DNA biobank, comprising 57,735 European ancestry and 15,754 African ancestry participants. We applied Mendelian randomization (MR) to probe significant relationships and validated significant MR associations using independent GWAS of candidate phenotypes.Results and Discussion: We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes in African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolitephenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p < 0.05). These included associations between bilirubin and X–21796 with cholelithiasis, phosphatidylcholine (16:0/22:5n3,18:1/20:4) and arachidonate with inflammatory bowel disease and Crohn’s disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3′ UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

430 Genome-wide meta-analysis identifies novel risk loci for uterine fibroids across multiple ancestry groups

OBJECTIVES/GOALS: Uterine fibroids are benign tumors of the uterus with a high disease prevalence and burden, yet there are few multi-ancestry genetic studies. This is the largest and most diverse fibroid GWAS to-date. Our goal is to identify novel genetic variants and gene expression pathways associated with fibroids and characterize their biological relevance. METHODS/STUDY POPULATION: We performed a cross-ancestry meta-analysis of GWAS summary statistics from eight datasets. The total sample size was 74,294 cases and 465,810 controls with participants of European (80% of sample), African (4%), East Asian, and Central South Asian (16%) ancestry. We mapped variants to genes with OpenTarget Genetics and used Functional Mapping and Annotation to conduct tissue expression gene-set enrichment and identify lead variants. We used S-PrediXcan to estimate genetically predicted gene expression (GPGE) associated with fibroid risk. This was with models that predicted gene expression across 49 different tissue types. Ingenuity Pathway Analysis compiled significant GPGE genes and their weights with a scientific literature database to identify overlapping pathways. RESULTS/ANTICIPATED RESULTS: We identified 370 independent significant variants. Among these, we identified variants mapped to three novel genes (PAX2, VIP, FOXO3) and eight genes not previously validated (TEKT1, SLC16A11, RPEL1, RASL11B, ASGR1, SLC12A7, TTC28, POLR2A). Many loci have roles in cell cycle regulation or are associated with fibroid risk factors like blood pressure, BMI, and vitamin D levels. Loci were significantly enriched in DNA damage and cell cycle pathways. Of 588 significant predicted expression gene-tissue pairs, 173 unique genes were novel fibroid associations. These genes are also associated with cancers, estradiol, and endometriosis. Top enriched pathways included p53 signaling, HOTAIR, BRCA1DNA damage response, and pulmonary fibrosis signaling. In uterine tissue there were 15 novel GPGE associations. DISCUSSION/SIGNIFICANCE: Using this large and diverse data, we identified novel loci associated with fibroids that are enriched in hormone-response, DNA damage, and cell-cycle pathways. GPGE loci were in tumorigenesis and fibrosis pathways. These novel genetic loci and uterine gene expression findings may provide translational opportunities for novel fibroid treatments.

Abstract 4801: Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening

Abstract Introduction: Lifetime risk of prostate cancer (PCa) is strongly associated with three factors: ancestry, family history, and genetics. We previously developed a polygenic hazard score (PHS) for PCa comprised of 290 common genetic variants (PHS290). When accounting for family history and ancestry (self-reported or genetically determined), PHS290 remained a powerful independent predictor of age at PCa diagnosis, metastatic PCa diagnosis, and PCa death. Additional variants associated with PCa susceptibility or benign elevation of prostate-specific antigen (PSA) have since been published. Here, we evaluate their impact on lifetime risk predictions for metastatic and fatal PCa and develop an updated polygenic score. This score will inform the design of the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS, ClinicalTrials.gov ID NCT05926102), a nationwide randomized controlled trial evaluating precision PCa screening in the VA healthcare system. Methods: We utilized a machine learning approach to update the PHS. Over 450 variants associated with PCa, aggressive PCa, benign prostatic hyperplasia, or benign PSA elevation were evaluated for inclusion. First, we identified pairs of variants with highly correlated genotype (defined as R2 &amp;gt; 0.95) and utilized univariable Cox proportional hazards models (using age at diagnosis of PCa) to exclude one variant from each pair. We then evaluated all remaining candidate variants for inclusion in a new PHS using a LASSO-regularized Cox proportional hazards model. We combined the new PHS with clinical predictors (ancestry and family history) to create a comprehensive, quantitative polygenic score in a diverse, population-based cohort of n=590,750 (Million Veteran Program). Both self-reported and genetic ancestry (based on 2,309 ancestry informative markers) were assessed. We estimated hazard ratios (HRs) to compare men with high versus low polygenic score and evaluated absolute predictions of any, metastatic, and fatal PCa. Results: The updated polygenic score included 356 variants, as well as family history and genetic ancestry. When comparing the highest to the lowest quintile of the population for polygenic score, the HRs for any PCa, metastatic PCa, and fatal PCa were 5.6, 5.8, and 5.2 respectively. These HRs are all greater than those achieved with PHS290, which yielded 5.2, 4.9, and 4.4 respectively. Risk stratification improved within each ancestry group, including within the &amp;gt;100,000 participants of African ancestry—a group known to have elevated risk of fatal PCa. Absolute risk prediction was accurate for both metastatic and fatal PCa. Conclusion: The polygenic score accurately predicts risk of metastatic and fatal PCa in multiple ancestry groups. A clinical polygenic model has potential utility for precision PCa screening and will now be evaluated prospectively in the ProGRESS trial. Citation Format: Anna M. Dornisch, Roshan Karunamuni, Kara N. Maxwell, Julie Lynch, Isla P. Garraway, Adam Kibel, Charles A. Brunette, Morgan E. Danowski, Kyung M. Lee, Scott L. DuVall, J M. Gaziano, Brent S. Rose, Richard L. Hauger, Jason L. Vassy, Tyler M. Seibert. Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4801.

Abstract P493: A Multivariate Analysis of Genetic Risk Scores for Heart Failure and Left Ventricular Mass Derived From Multi-Ancestry Populations and Left Ventricular Mass Amongst African Americans: The Jackson Heart Study

Background: Increased left ventricular (LV) mass is an outcome of LV remodeling that can result in development of left ventricular hypertrophy (LVH), a maladaptive disorder that increases the risk of heart failure. Elevated LV mass is a sensitive predictor of adverse cardiovascular events. African Americans experience a disproportionate burden of heart failure risk and development of LVH. The influence of genetics on this health disparity is unclear and a topic of interest. Genome-wide association studies (GWAS) have uncovered many variants associated with numerous adverse cardiovascular outcomes, such as heart failure and LV phenotypes. However, the relevance of these studies for African Americans may be limited as these analyses have been conducted in multi-ancestry populations with limited representation of African heritage. The question of whether these genetic risk variants can be used to predict LV phenotypes in an independent African American population remains unanswered. Hypothesis: Variant loci that have been associated with heart failure and LV mass in multi-ancestry populations will be associated with LV mass amongst African Americans in the Jackson Heart Study (JHS). Methods: Thirty-nine (39) SNPs associated with heart failure and ten (10) SNPs associated with LV mass were identified from two published studies in which participants of African ancestry or Black individuals comprised less than 15% and 2%, respectively. Using the published effect size estimates, genetic risk scores (GRSs) for heart failure and LV mass were computed for 2,175 African American participants (mean age 55, 63% female) in the JHS with complete data and consent for genetic research. We assessed the linear association of heart failure and LV mass GRSs with LV mass indexed to height (LVM h ) and indexed to body surface area (LVM bsa ). A multivariate general linear model was fit to both LVM h and LVM bsa containing both GRS predictors and accounting for age, sex, BMI (mean 31.5), diabetes (22%), and hypertension (52%). No multicollinearity was noted among these explanatory variables using variance inflation factors. Due to non-constant error variance, a log transformation was conducted on both LV mass response variables. Type III MANOVA Pillai tests were run to assess the effects of the GRSs on the log LVM bsa and log LVM h values. Conclusion: When accounting for age, BMI, sex, diabetes, and hypertension, we found that neither the heart failure GRS (p-val = 0.4012) nor the LV mass GRS (p-val = 0.8332) had an effect on both log LVM bsa and log LVM h . There is insufficient evidence to suggest that heart failure and LV mass variants derived from predominantly European multi-ancestry populations are linearly associated with log LV mass amongst African Americans in the Jackson Heart Study. Our work highlights the need for greater recruitment and targeted studies of populations with African ancestry for GWAS of LV phenotypes.

Genomic data in the All of Us Research Program

Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics1–4. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health5,6. Here we describe the programme’s genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all.

TRANSETHNIC META-ANALYSIS OF INTERACTIONS BETWEEN GENETICS AND EARLY-LIFE SOCIOECONOMIC CONTEXT ON COGNITION

Abstract Later-life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Using gene-based tests (interaction sequence kernel association test [iSKAT]/iSKAT optimal unified test), we examined whether common and rare variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N = 10,468) and African ancestry (AA, N = 2,252) participants from the Health and Retirement Study. Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, only one, SLC24A4 x father’s education, remained significant after multiple testing correction (false discovery rate [FDR] &amp;lt; .05). In trans-ethnic meta-analysis, 2 genes interacted with childhood socioeconomic context: MS4A4A x mother’s education on memory performance, and SLC24A4 x father’s education on memory decline. Both interactions remained significant after adjusting for respondent’s own education, apolipoprotein-ε4 allele status, lifestyle factors, body mass index, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Examination of common and rare variants in genes discovered through genome-wide association studies shows that childhood context may interact with gene regions to jointly impact later-life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

Abstract 16950: The Genetic Basis of Atrial Fibrillation in a Large-Scale Multi-Ancestry Sample

Introduction: Atrial fibrillation (AF) is a heritable arrhythmia and associated with substantial morbidity. Hypothesis/Aims: We sought to expand our understanding of the genetic basis of AF by examining a large and ancestrally diverse sample. Methods: We performed a meta-analysis of ancestry-specific GWAS results from 600K unrelated individuals (85K with AF) in the Million Veteran Program (MVP) with GWAS results from nearly 2.25 million individuals (267K with AF) in the Atrial Fibrillation Consortium (AFGen). We estimated genetic correlations across ancestry groups and traits in MVP. To evaluate GWAS loci, we examined possible gene functions, prioritized relevant genes and pathways, and explored potential drug targets. We derived a multi-ancestry polygenic risk score (PRS) and independently evaluated associations with AF in the All of Us cohort (nearly 100K individuals; 3K with AF). Results: We identified 376 loci associated with AF, including 63 that have not been reported. We observed closer genetic correlation of AF between individuals of European and Hispanic (r2=1.0) than with African ancestry (r2=0.6). AF is highly correlated genetically with multiple cardiovascular traits, especially coronary artery disease, heart failure, and hypertension. GWAS loci implicate 15 genetic regulators of the cardiac action potential, including targets of commonly used AF drugs and 2 potential therapeutic targets whose predicted cardiac expression is positively associated with AF risk (KCNJ5 and KCND3). A PRS derived from the meta-analysis outperforms all previously reported PRSs in European, African and Hispanic ancestry participants and is strongly associated with multiple cardiovascular outcomes. Conclusions: In the largest genetic study of AF to date, we identify disease-relevant pathways and improve polygenic prediction for AF. We demonstrate the importance of ancestry-specific analyses in assessing AF risk and suggest that further inclusion of participants from more diverse ancestries is likely to accelerate genetic discoveries.

A Protective Role of Low Polygenic Risk Score in Healthy Individuals Carrying Attention-Deficit/Hyperactivity Disorder–Associated Copy Number Variations

BackgroundPrevious studies have implicated both rare copy number variations (CNVs) and common variants in liability for attention-deficit/hyperactivity disorder (ADHD). However, how common and rare genetic variants jointly contribute to individual liability requires further investigation in larger cohorts. MethodsThis study comprises 9385 participants of European descent and 7810 participants of African American ancestry who were recruited from the greater Philadelphia area by the Children’s Hospital of Philadelphia. The polygenic risk score (PRS) of each participant was estimated by linkage disequilibrium pruning and p-value thresholding (P + T) methods using PRSice-2. We investigated whether the risk of ADHD follows a polygenic liability threshold model wherein 1) the risk of ADHD requires less contribution from common variants in the presence of a rare CNV, and 2) control carriers of ADHD-associated CNVs have lower common risk allele burden than noncarriers. ResultsCNVs previously reported in ADHD cases were significantly associated with ADHD risk in both the European American cohort and the African American cohort. Healthy control participants carrying those same risk CNVs had lower PRSs than those without risk CNVs in the European American cohort. This result was replicated in the African American cohort. However, PRSs were not significantly different in case participants carrying risk CNVs versus those without risk CNVs. ConclusionsThese findings provide evidence in support of interactive effects of PRS and ADHD-associated CNVs on disease risk and add novel insights into the genetic basis of ADHD by highlighting a protective role of low PRS in ADHD.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.

African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

Resilience Phenotypes and Psychological Functioning among Individuals with Opioid Use Disorder

Background Opioid use disorder (OUD) is a heterogeneous disorder. However, there is a lack of deep phenotyping investigations focusing on important psychological constructs such as resilience that may impact OUD. The present study aimed to investigate the relationship between trait resilience and the five-factor model of personality (FFM) among individuals with opioid use disorder (OUD). We also explored whether the FFM and trait resilience form specific phenotypes associated with psychological functioning. Methods This secondary analysis of an epigenetic study included participants of African ancestry (n = 72), an understudied population, who met DSM-5 criteria for OUD. Participants completed measures to assess personality traits, trait resilience, current and previous drug use, and psychological functioning (depression, anxiety, and stress). Results Linear regression revealed a significant relationship between resilience (CD-RISC-25 score) and the FFM, R 2 = 0.56, F(5,62) = 15.7, p<.001. Further, a two-cluster classification emerged as the optimal solution from the cluster analysis. Cluster 1 (n = 33, 45.8% of the sample) showed lower resilience (CD-RISC-25 score: M = 58.6, SD = 11.2) compared to Cluster 2 (n = 35, 48.6%; CD-RISC-25 score: M = 76.1, SD = 11.9). The “High-Resilience Cluster” (Cluster 2) was characterized by higher FFM traits of: Extraversion, Openness, Agreeableness, and Conscientiousness, and lower Neuroticism versus Cluster 1. Multivariate analysis of variance revealed statistically significant differences between the two resilience clusters concerning other psychological symptoms, Λ = 0.732, F(4, 50) = 7.05, p < 0.003. Conclusions These findings suggest associations between the FFM and trait resilience among individuals with OUD. Two distinct “resilience phenotypes” emerged, with high-resilience individuals displaying less stress, anxiety, and depressive symptoms. Results highlight the clinical importance of resilience as a potential target for intervention in people with OUD.

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.

A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease

Identification of individuals at highest risk of coronary artery disease (CAD)—ideally before onset—remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMult strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10–2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMult was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70–1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMult demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMult for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.

The collaborative study on the genetics of alcoholism: Genetics.

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.

Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders

Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N = 3533) and Million Veterans Program GWAS of PTSD (N = 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B = 0.126, p < 0.001), alcohol dependence (B = 0.231, p < 0.001), and cocaine dependence (B = 0.086, p < 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B = 0.090, p < 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders.

The physical and psychiatric health conditions related to autism genetic scores, across genetic ancestries, sexes and age-groups in electronic health records

BackgroundAlthough polygenic scores (PGS) for autism have been related to various psychiatric and medical conditions, most studies to date have been conducted in research ascertained populations. We aimed to identify the psychiatric and physical conditions associated with autism PGS in a health care setting.MethodsWe computed PGS for 12,383 unrelated participants of African genetic ancestry (AF) and 65,363 unrelated participants of European genetic ancestry (EU) from Vanderbilt’s de-identified biobank. Next, we performed phenome wide association studies of the autism PGS within these two genetic ancestries.ResultsSeven associations surpassed the Bonferroni adjusted threshold for statistical significance (p = 0.05/1374 = 3.6 × 10−5) in the EU participants, including mood disorders (OR (95%CI) = 1.08(1.05 to 1.10), p = 1.0 × 10−10), autism (OR (95%CI) = 1.34(1.24 to 1.43), p = 1.2 × 10–9), and breast cancer (OR (95%CI) = 1.09(1.05 to 1.14), 2.6 × 10−5). There was no statistical evidence for PGS-phenotype associations in the AF participants. Conditioning on the diagnosis of autism or on median body mass index (BMI) did not impact the strength of the reported associations. Although we observed some sex differences in the pattern of associations, there was no significant interaction between sex and autism PGS. Finally, the associations between autism PGS and autism diagnosis were stronger in childhood and adolescence, while the associations with mood disorders and breast cancer were stronger in adulthood.DiscussionOur findings indicate that autism PGS is not only related to autism diagnosis but may also be related to adult-onset conditions, including mood disorders and some cancers.ConclusionsOur study raises the hypothesis that genes associated with autism may also increase the risk for cancers later in life. Future studies are necessary to replicate and extend our findings.

#2528 APOL1 GENOTYPING AND PROTEINURIC KIDNEY DISEASE IN EUROPE

Abstract Background and Aims Apolipoprotein L1 (APOL1) toxic gain-of-function variants (G1 or G2) are genetic factors driving a broad spectrum of progressive, proteinuric nephropathies referred to as APOL1-mediated kidney disease (AMKD). APOL1 genotyping is not routinely performed in kidney disease care, and prevalence of APOL1 variants among persons with chronic kidney disease (CKD) in Europe is not well known. These variants are common in persons of recent African ancestry. We report interim data of a global study estimating the prevalence of APOL1 genotypes in participants of recent African ancestry and proteinuric CKD, with a focus on data from Europe. Method Enrollment in this ongoing study will include up to 2,500 participants across different geographies who are of recent African ancestry and have focal segmental glomerulosclerosis (FSGS) or other proteinuric nondiabetic kidney disease (NDKD). The study includes a single visit during which blood samples are collected from participants to determine their APOL1 genotype using a validated polymerase chain reaction (PCR)-based assay. The percent of participants with two APOL1 variants and percent of participants in each genotype category (e.g., G1/G1, G1/G2, G2/G2) are assessed; genetic counseling services are available to participants, if desired. Results This interim analysis included 1,256 participants of whom 174 (13.9%) were from Europe. As shown in the table, among the 88 participants with FSGS and 86 participants with proteinuric NDKD, 54 (61.4%) and 32 (37.2%) have two APOL1 variants, respectively. Conclusion Our study will generate one of the largest global APOL1 genotyping data sets in participants with proteinuric kidney disease. These data begin to address a critical knowledge gap and highlight the importance of APOL1 genotyping in kidney disease care to identify AMKD, potentially optimize disease management, and enable referral for interventional clinical trials evaluating targeted therapies for AMKD.

Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood.

Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers. Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32). The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors. Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

No evidence of accelerated epigenetic aging among black heroin users: A case vs control analysis

This study sought to assess the association between illicit opioid use and accelerated epigenetic aging (A.K.A. DNAm Age) among people of African ancestry who use heroin. DNA was obtained from participants with opioid use disorder (OUD) who confirmed heroin as their primary drug of choice. Clinical inventories of drug use included: the Addiction Severity Index (ASI) Drug-Composite Score (range: 0–1), and Drug Abuse Screening Test (DAST-10; range: 0–10). A control group of participants of African ancestry who did not use heroin was recruited and matched to heroin users on sex, age, socioeconomic level, and smoking status. Methylation data were assessed in an epigenetic clock to determined and compare Epigenetic Age to Chronological Age (i.e., age acceleration or deceleration). Data were obtained from 32 controls [mean age 36.3 (±7.5) years] and 64 heroin users [mean age 48.1 (±6.6) years]. The experimental group used heroin for an average of 18.1 (±10.6) years, reported use of 6.4 (±6.1) bags of heroin/day, with a mean DAST-10 score of 7.0 (±2.6) and ASI Score of 0.33 (±0.19). Mean age acceleration for heroin users [+0.56 (± 9.5) years] was significantly (p< 0.05) lower than controls [+5.19 (± 9.1) years]. This study did not find evidence that heroin use causes epigenetic age acceleration.