Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric.

Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric. In this work, we extended the original MagicalRsq to allow cross-cohort model training and named the new model MagicalRsq-X. We removed the cohort-specific estimated minor allele frequency and included linkage disequilibrium scores and recombination rates as additional features. Leveraging whole-genome sequencing data from TOPMed, specifically participants in the BioMe, JHS, WHI, and MESA studies, we performed comprehensive cross-cohort evaluations for predominantly European and African ancestral individuals based on their inferred global ancestry with the 1000 Genomes and Human Genome Diversity Project data as reference. Our results suggest MagicalRsq-X outperforms Rsq in almost every setting, with 7.3%-14.4% improvement in squared Pearson correlation with true R2, corresponding to 85-218 K variant gains. We further developed a metric to quantify the genetic distances of a target cohort relative to a reference cohort and showed that such metric largely explained the performance of MagicalRsq-X models. Finally, we found MagicalRsq-X saved up to 53 known genome-wide significant variants in one of the largest blood cell trait GWASs that would be missed using the original Rsq for QC. In conclusion, MagicalRsq-X shows superiority for post-imputation QC and benefits genetic studies by distinguishing well and poorly imputed lower-frequency variants.

Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

Proteome-wide association study using cis and trans variants and applied to blood cell and lipid-related traits in the Women's Health Initiative study.

In most Proteome-Wide Association Studies (PWAS), variants near the protein-coding gene (±1 Mb), also known as cis single nucleotide polymorphisms (SNPs), are used to predict protein levels, which are then tested for association with phenotypes. However, proteins can be regulated through variants outside of the cis region. An intermediate GWAS step to identify protein quantitative trait loci (pQTL) allows for the inclusion of trans SNPs outside the cis region in protein-level prediction models. Here, we assess the prediction of 540 proteins in 1002 individuals from the Women's Health Initiative (WHI), split equally into a GWAS set, an elastic net training set, and a testing set. We compared the testing r2 between measured and predicted protein levels using this proposed approach, to the testing r2 using only cis SNPs. The two methods usually resulted in similar testing r2, but some proteins showed a significant increase in testing r2 with our method. For example, for cartilage acidic protein 1, the testing r2 increased from 0.101 to 0.351. We also demonstrate reproducible findings for predicted protein association with lipid and blood cell traits in WHI participants without proteomics data and in UK Biobank utilizing our PWAS weights.

Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

Integration of rare expression outlier-associated variants improves polygenic risk prediction.

Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual's likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identify rare variants associated with outlier gene expression and integrate their impact into PRS predictions for body mass index (BMI), obesity, and bariatric surgery. Between the top and bottom 10%, we observed a 20.8% increase in risk for obesity (p = 3 × 10-14), 62.3% increase in risk for severe obesity (p = 1 × 10-6), and median 5.29 years earlier onset for bariatric surgery (p = 0.008), as a function of expression outlier-associated rare variant burden when controlling for common variant PRS. We show that these predictions were more significant than integrating the effects of rare protein-truncating variants (PTVs), observing a mean 19% increase in phenotypic variance explained with expression outlier-associated rare variants when compared with PTVs (p = 2 × 10-15). We replicated these findings by using data from the Million Veteran Program and demonstrated that PRSs across multiple traits and diseases can benefit from the inclusion of expression outlier-associated rare variants identified through population-scale transcriptome sequencing.

Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women.

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10-16) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease. CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.

Super interactive promoters provide insight into cell type-specific regulatory networks in blood lineage cell types.

Existing studies of chromatin conformation have primarily focused on potential enhancers interacting with gene promoters. By contrast, the interactivity of promoters per se, while equally critical to understanding transcriptional control, has been largely unexplored, particularly in a cell type-specific manner for blood lineage cell types. In this study, we leverage promoter capture Hi-C data across a compendium of blood lineage cell types to identify and characterize cell type-specific super-interactive promoters (SIPs). Notably, promoter-interacting regions (PIRs) of SIPs are more likely to overlap with cell type-specific ATAC-seq peaks and GWAS variants for relevant blood cell traits than PIRs of non-SIPs. Moreover, PIRs of cell-type-specific SIPs show enriched heritability of relevant blood cell trait (s), and are more enriched with GWAS variants associated with blood cell traits compared to PIRs of non-SIPs. Further, SIP genes tend to express at a higher level in the corresponding cell type. Importantly, SIP subnetworks incorporating cell-type-specific SIPs and ATAC-seq peaks help interpret GWAS variants. Examples include GWAS variants associated with platelet count near the megakaryocyte SIP gene EPHB3 and variants associated lymphocyte count near the native CD4 T-Cell SIP gene ETS1. Interestingly, around 25.7% ~ 39.6% blood cell traits GWAS variants residing in SIP PIR regions disrupt transcription factor binding motifs. Importantly, our analysis shows the potential of using promoter-centric analyses of chromatin spatial organization data to identify biologically important genes and their regulatory regions.

Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations.

AIMS/HYPOTHESIS: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European. METHODS: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations. RESULTS: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development. CONCLUSIONS/INTERPRETATION: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations. DATA AVAILABILITY: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS ).

An empirical Bayes approach to improving population-specific genetic association estimation by leveraging cross-population data.

Populations of non-European ancestry are substantially underrepresented in genome-wide association studies (GWAS). As genetic effects can differ between ancestries due to possibly different causal variants or linkage disequilibrium patterns, a meta-analysis that includes GWAS of all populations yields biased estimation in each of the populations and the bias disproportionately impacts non-European ancestry populations. This is because meta-analysis combines study-specific estimates with inverse variance as the weights, which causes biases towards studies with the largest sample size, typical of the European ancestry population. In this paper, we propose two empirical Bayes (EB) estimators to borrow the strength of information across populations although accounting for between-population heterogeneity. Extensive simulation studies show that the proposed EB estimators are largely unbiased and improve efficiency compared to the population-specific estimator. In contrast, even though the meta-analysis estimator has a much smaller variance, it yields significant bias when the genetic effect is heterogeneous across populations. We apply the proposed EB estimators to a large-scale trans-ancestry GWAS of stroke and demonstrate that the EB estimators reduce the variance of the population-specific estimator substantially, with the effect estimates close to the population-specific estimates.

Transcriptome-wide association study in UK Biobank Europeans identifies associations with blood cell traits.

Previous genome-wide association studies (GWAS) of hematological traits have identified over 10 000 distinct trait-specific risk loci. However, at these loci, the underlying causal mechanisms remain incompletely characterized. To elucidate novel biology and better understand causal mechanisms at known loci, we performed a transcriptome-wide association study (TWAS) of 29 hematological traits in 399 835 UK Biobank (UKB) participants of European ancestry using gene expression prediction models trained from whole blood RNA-seq data in 922 individuals. We discovered 557 gene-trait associations for hematological traits distinct from previously reported GWAS variants in European populations. Among the 557 associations, 301 were available for replication in a cohort of 141 286 participants of European ancestry from the Million Veteran Program. Of these 301 associations, 108 replicated at a strict Bonferroni adjusted threshold ($\alpha$= 0.05/301). Using our TWAS results, we systematically assigned 4261 out of 16 900 previously identified hematological trait GWAS variants to putative target genes. Compared to coloc, our TWAS results show reduced specificity and increased sensitivity in external datasets to assign variants to target genes.

Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality.

BACKGROUND: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. METHODS: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. RESULTS: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or lung cancer (p = .32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p = .01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p < .001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p = .004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p = .06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p = .01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p = .02) with mCA >5%. CONCLUSIONS: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.

eSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data.

Multiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.

A large-scale transcriptome-wide association study (TWAS) of 10 blood cell phenotypes reveals complexities of TWAS fine-mapping.

Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.

Epigenome-wide association study of mitochondrial genome copy number.

We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P < 1 × 10-7), with a 0.7-3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes [PR/SET domain 16, nuclear receptor subfamily 1 group H member 3 (NR1H3), DNA repair protein, DNA polymerase kappa and decaprenyl-diphosphate synthase subunit 2], which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, P = 4 × 10-8) and was positively associated with the NR1H3 expression level (effect size = 0.43, P = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

Genetic examination of hematological parameters in SARS-CoV-2 infection and COVID-19.

People hospitalized with COVID-19 often exhibit altered hematological traits associated with disease prognosis (e.g., lower lymphocyte and platelet counts). We investigated whether inter-individual variability in baseline hematological traits influences risk of acute SARS-CoV-2 infection or progression to severe COVID-19. We report inconsistent associations between blood cell traits with incident SARS-CoV-2 infection and severe COVID-19 in UK Biobank and the Vanderbilt University Medical Center Synthetic Derivative (VUMC SD). Since genetically determined blood cell measures better represent cell abundance across the lifecourse, we also assessed the shared genetic architecture of baseline blood cell traits on COVID-19 related outcomes by Mendelian randomization (MR) analyses. We found significant relationships between COVID-19 severity and mean sphered cell volume after adjusting for multiple testing. However, MR results differed significantly across different freezes of COVID-19 summary statistics and genetic correlation between these traits was modest (0.1), decreasing our confidence in these results. We observed overlapping genetic association signals between other hematological and COVID-19 traits at specific loci such as MAPT and TYK2. In conclusion, we did not find convincing evidence of relationships between the genetic architecture of blood cell traits and either SARS-CoV-2 infection or COVID-19 hospitalization, though we do see evidence of shared signals at specific loci.

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

BACKGROUND: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. METHODS: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease. RESULTS: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005). CONCLUSIONS: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

Clonal Hematopoiesis Is Associated With Higher Risk of Stroke.

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.