A parametric bootstrap approach for computing confidence intervals for genetic correlations with application to genetically-determined protein-protein networks.

Genetic correlation refers to the correlation between genetic determinants of a pair of traits. When using individual-level data, it is typically estimated based on a bivariate model specification where the correlation between the two variables is identifiable and can be estimated from a covariance model that incorporates the genetic relationship between individuals, e.g., using a pre-specified kinship matrix. Inference relying on asymptotic normality of the genetic correlation parameter estimates may be inaccurate when the sample size is low, when the genetic correlation is close to the boundary of the parameter space, and when the heritability of at least one of the traits is low. We address this problem by developing a parametric bootstrap procedure to construct confidence intervals for genetic correlation estimates. The procedure simulates paired traits under a range of heritability and genetic correlation parameters, and it uses the population structure encapsulated by the kinship matrix. Heritabilities and genetic correlations are estimated using the close-form, method of moment, Haseman-Elston regression estimators. The proposed parametric bootstrap procedure is especially useful when genetic correlations are computed on pairs of thousands of traits measured on the same exact set of individuals. We demonstrate the parametric bootstrap approach on a proteomics dataset from the Jackson Heart Study.

A parametric bootstrap approach for computing confidence intervals for genetic correlations with application to genetically-determined protein-protein networks.

Genetic correlation refers to the correlation between genetic determinants of a pair of traits. When using individual-level data, it is typically estimated based on a bivariate model specification where the correlation between the two variables is identifiable and can be estimated from a covariance model that incorporates the genetic relationship between individuals, e.g., using a pre-specified kinship matrix. Inference relying on asymptotic normality of the genetic correlation parameter estimates may be inaccurate when the sample size is low, when the genetic correlation is close to the boundary of the parameter space, and when the heritability of at least one of the traits is low. We address this problem by developing a parametric bootstrap procedure to construct confidence intervals for genetic correlation estimates. The procedure simulates paired traits under a range of heritability and genetic correlation parameters, and it uses the population structure encapsulated by the kinship matrix. Heritabilities and genetic correlations are estimated using the close-form, method of moment, Haseman-Elston regression estimators. The proposed parametric bootstrap procedure is especially useful when genetic correlations are computed on pairs of thousands of traits measured on the same exact set of individuals. We demonstrate the parametric bootstrap approach on a proteomics dataset from the Jackson Heart Study.

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P<0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; P<0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (ß=0.091; P=0.11) or in the reverse direction (ß=-0.012; P=0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (ß=-0.084; P<0.001), but the reverse direction was not significant (P=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (P=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (ß=-0.092; P<0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

The Relationship of Duffy Gene Polymorphism, High Sensitivity C-Reactive Protein, and Long-term Outcomes.

Background: Black adults have higher incidence of all-cause death and worse cardiovascular outcomes when compared to other populations. The Duffy chemokine receptor is not expressed in a large majority of Black adults and the clinical implications of this are unclear. Methods: Here, we investigated the relationship of Duffy receptor status, high-sensitivity C-reactive protein (hs-CRP), and long-term cardiovascular outcomes in Black members of two contemporary, longitudinal cohort studies (the Jackson Heart Study and Multi-Ethnic Study of Atherosclerosis). Data on 4,307 Black participants (2,942 Duffy null and 1,365 Duffy receptor positive, as defined using Single Nucleotide Polymorphism (SNP) rs2814778) were included in this analysis. Results: Duffy null was not independently associated with elevated levels of serum hs-CRP levels once conditioning for known CRP locus alleles in linkage disequilibrium with the Duffy gene. Duffy null status was not found to be independently associated with higher incidence of all-cause mortality or secondary outcomes after adjusting for possible confounders in Black participants. Conclusions: These findings suggest that increased levels of hs-CRP found in Duffy null individuals is due to co-inheritance of CRP alleles known to influence circulating levels hs-CRP and that Duffy null status was not associated with worse adverse outcomes over the follow-up period in this cohort of well-balanced Black participants.

Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma.

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.

Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery ß = 0.0561, Q = 4.05 × 10-10; ß = 0.0421, Q = 1.12 × 10-3; and ß = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; ß = -4.3 ml/yr, Q = 0.049; ß = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Canonical correlation analysis for multi-omics: Application to cross-cohort analysis.

Integrative approaches that simultaneously model multi-omics data have gained increasing popularity because they provide holistic system biology views of multiple or all components in a biological system of interest. Canonical correlation analysis (CCA) is a correlation-based integrative method designed to extract latent features shared between multiple assays by finding the linear combinations of features-referred to as canonical variables (CVs)-within each assay that achieve maximal across-assay correlation. Although widely acknowledged as a powerful approach for multi-omics data, CCA has not been systematically applied to multi-omics data in large cohort studies, which has only recently become available. Here, we adapted sparse multiple CCA (SMCCA), a widely-used derivative of CCA, to proteomics and methylomics data from the Multi-Ethnic Study of Atherosclerosis (MESA) and Jackson Heart Study (JHS). To tackle challenges encountered when applying SMCCA to MESA and JHS, our adaptations include the incorporation of the Gram-Schmidt (GS) algorithm with SMCCA to improve orthogonality among CVs, and the development of Sparse Supervised Multiple CCA (SSMCCA) to allow supervised integration analysis for more than two assays. Effective application of SMCCA to the two real datasets reveals important findings. Applying our SMCCA-GS to MESA and JHS, we identified strong associations between blood cell counts and protein abundance, suggesting that adjustment of blood cell composition should be considered in protein-based association studies. Importantly, CVs obtained from two independent cohorts also demonstrate transferability across the cohorts. For example, proteomic CVs learned from JHS, when transferred to MESA, explain similar amounts of blood cell count phenotypic variance in MESA, explaining 39.0% ~ 50.0% variation in JHS and 38.9% ~ 49.1% in MESA. Similar transferability was observed for other omics-CV-trait pairs. This suggests that biologically meaningful and cohort-agnostic variation is captured by CVs. We anticipate that applying our SMCCA-GS and SSMCCA on various cohorts would help identify cohort-agnostic biologically meaningful relationships between multi-omics data and phenotypic traits.

Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations.

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.

N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genomic associations of four plasma N-acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2351 individuals from the Jackson Heart Study. We find that plasma levels of specific N-acyl amino acids are associated with cardiometabolic disease endpoints independent of free amino acid plasma levels and in patterns according to the amino acid head group. By integrating whole genome sequencing data with N-acyl amino acid levels, we identify that the genetic determinants of N-acyl amino acid levels also cluster according to the amino acid head group. Furthermore, we identify the CYP4F2 locus as a genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels in human plasma. In experimental studies, we demonstrate that CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids. These studies provide a structural framework for understanding the regulation and disease associations of N-acyl amino acids in humans and identify that the diversity of this lipid signaling family can be significantly expanded through CYP4F-mediated ω-hydroxylation.

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.

N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genetic regulation of four plasma N-fatty acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2,351 individuals from the Jackson Heart Study. N-oleoyl-leucine and N-oleoyl-phenylalanine were positively associated with traits related to energy balance, including body mass index, waist circumference, and subcutaneous adipose tissue. In addition, we identify the CYP4F2 locus as a human-specific genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels. In vitro, CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids (FAHFAs). By contrast, FAAH-regulated N-oleoyl-glycine and N-oleoyl-serine were inversely associated with traits related to glucose and lipid homeostasis. These data uncover a human-specific enzymatic node for the metabolism of a subset of N-fatty acyl amino acids and establish a framework for understanding the cardiometabolic roles of individual N-fatty acyl amino acids in humans.

Investigating Gene-Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits.

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry. ARTICLE HIGHLIGHTS: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions.

Protein Markers of Diabetes Discovered in an African American Cohort.

Proteomics has been used to study type 2 diabetes, but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans in the Jackson Heart Study (n = 1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and sample batch (false discovery rate q < 0.05) measured using a single-stranded DNA aptamer affinity-based method on fasting plasma samples. A subset was independent of established markers of diabetes development pathways, such as adiposity, glycemia, and/or insulin resistance, suggesting potential novel biological processes associated with disease development. Thirty-six associations remained significant after additional adjustments for BMI, fasting plasma glucose, cholesterol levels, hypertension, statin use, and renal function. Twelve associations, including the top associations of complement factor H, formimidoyltransferase cyclodeaminase, serine/threonine-protein kinase 17B, and high-mobility group protein B1, were replicated in a meta-analysis of two self-identified White cohorts-the Framingham Heart Study and the Malmö Diet and Cancer Study-supporting the generalizability of these biomarkers. A selection of these diabetes-associated proteins also improved risk prediction. Thus, we uncovered both novel and broadly generalizable associations by studying a diverse population, providing a more complete understanding of the diabetes-associated proteome.

Protein biomarkers of cardiac remodeling and inflammation associated with HFpEF and incident events.

There is increasing evidence that HFpEF is a heterogeneous clinical entity and distinct molecular pathways may contribute to pathophysiology. Leveraging unbiased proteomics to identify novel biomarkers, this study seeks to understand the underlying molecular mechanisms of HFpEF. The discovery cohort consisted of HFpEF cases and non-HF controls from the CATHGEN study (N = 176); the validation cohort consisted of participants from the TECOS trial of patients with diabetes (N = 109). Proteins associated with HFpEF were included in a LASSO model to create a discriminative multi-protein model and assessed in the validation cohort. Survival models and meta-analysis were used to test the association of proteins with incident clinical outcomes, including HF hospitalization, mortality and HFpEF hospitalization in CATHGEN, TECOS and the Jackson Heart Study. In the derivation set, 190 proteins were associated with HFpEF in univariate analysis, of which 65 remained significant in the multivariate model. Twenty (30.8%) of these proteins validated in TECOS, including LCN2, U-PAR, IL-1ra, KIM1, CSTB and Gal-9 (OR 1.93-2.77, p < 0.01). LASSO regression yielded a 13-protein model which, when added to a clinical model inclusive of NT-proBNP, improved the AUC from 0.82 to 0.92 (p = 1.5 × 10-4). Five proteins were associated with incident HF hospitalization, four with HFpEF hospitalization and eleven with mortality (p < 0.05). We identified and validated multiple circulating biomarkers associated with HFpEF as well as HF outcomes. These biomarkers added incremental discriminative capabilities beyond clinical factors and NT-proBNP.

Proteomic profiling platforms head to head: Leveraging genetics and clinical traits to compare aptamer- and antibody-based methods.

High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K (N = 1301 reagents), the SomaScan5K platform (N = 4979 reagents), and the Olink Explore (N = 1472 reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome.

Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans.

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or "known" and 2,342 nontargeted or "unknown" compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)-a community cohort of self-identified African Americans-who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of <0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose. Of these, 144 and 68 associations, respectively, replicated in a multiethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ = 0.29), and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10-16 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease.

BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, ß=0.61±0.05, P=3.27×10-30) and MMP-3 (ß=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, ß=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.