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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, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-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, β=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.

Background: The effect of omega-3 (n-3) treatment on cardiovascular disease (CVD) outcomes in randomized controlled trials remains inconsistent. We hypothesize that the downstream products of n-3 metabolism, including bioactive lipids (BALs), have a heterogeneous relationship with CVD, which may provide insight into response heterogeneity. Methods: Using state of the art LC-MS, we assayed the plasma bioactive lipidome (>10K BALs) across 3,512 individuals at baseline and Y1 or -2, in the VITAL substudies (CVD case control N=1540; CTSC subcohort N=1054; 45% women, median age 70, 20% non-white) and JUPITER CVD case control (N=918) (NCT01169259, NCT00239681). Linear regression revealed BALs that change consistently with n-3 treatment (n3BALs) (discovery in VITAL controls, validation in an independent VITAL CTSC substudy, cumulative FDR .05). n3BALs that are also associated with CVD in VITAL CVD were identified using adjusted conditional logistic regression (p Results: 354 BALs changed in response to randomized n-3 vs placebo. Baseline levels of 8 of these BALs were significantly associated with incident CVD (Figure, panels A, B). When combined into the multivariable BAL score, 5 were inversely and 3 positively associated with the CVD risk. The BAL score was significantly associated with CVD with fully adjusted HR/SD of 1.32, 95%CI [1.12 - 1.55] in external study, Figure panel C. N-3 therapy, statin therapy and baseline fish intake were associated with weak Y1 or -2 reduction in BAL score. Conclusions: Downstream BALs are altered in response to n-3 treatment and associate with both decreased as well as increased risk of CVD. BAL response to n-3 treatment may explain clinical heterogeneity associated with fish oil supplementation and may be utilized for selection of more specific treatment.

Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants inATMandMPLshowed strong associations with mCAs incis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants inATMandMPLwith mCAs incis. Individual rare variants inDCPS, ADM17, PPP1R16B, andTET2were all associated with autosomal mCAs and rare variants inOR4C16were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genesTET2, DNMT3A, JAK2, CUX1, andTP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation.

Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants in ATM and MPL showed strong associations with mCAs in cis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants in ATM and MPL with mCAs in cis. Individual rare variants in DCPS, ADM17, PPP1R16B, and TET2 were all associated with autosomal mCAs and rare variants in OR4C16 were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genes TET2, DNMT3A, JAK2, CUX1, and TP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation. Citation Format: Yasminka A. Jakubek, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Josh Bis, Eric Boerwinkle, April Carson, Daniel Chasman, Michael Cho, Matthew Conomos, Nancy Cox, Margaret Doyle, Myriam Fornage, Xiuqing Guo, Sharon Kardia, Joshua Lewis, Ruth Loos, Xiaolong Ma, Mitchell Machiela, Taralynn Mack, Rasika Mathias, Braxton Mitchell, Kari North, Nathan Pankratz, Patricia Peyser, Michael Preuss, Bruce Psaty, Laura Raffield, Ramachandran Vasan, Susan Redline, Stephen Rich, Jerome Rotter, Edwin Silverman, Jennifer Smith, Margaret Taub, Jeong Yun, Yun Li, Pinkal Desai, Alexander Bick, Alexander Reiner, Paul Scheet, Paul Auer. Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3507.

Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P − 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 individuals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA); leisure screen time (LST); sedentary commuting; and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type IIA muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.

Introduction: Migraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Systematic exploration of their shared genetics may inform shared and divergent etiology. Methods: The largest available GWASs for all three disorders were used, including for subtypes of stroke (ischemic stroke [IS], large artery stroke [LAS], small vessel stroke [SVS], cardioembolic stroke [CE]) and migraine (with aura [MA] and without aura [MO]). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within candidate loci for each disorder. Cross-trait meta-analysis was used to identify shared novel candidate loci. Causality of migraine susceptibility on stroke and CeAD was evaluated by Mendelian randomization (MR). Results: Among all pairs of disorders, genome-wide genetic correlation was only observed for CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than migraine and stroke or CeAD and stroke, identifying novel CeAD associations at rs6693567 ( ADAMTSL4/ECM1 ), rs11187838 ( PLCE1 ), and rs7940646 ( MRVI1 ), while strengthening prior subthreshold evidence at rs9486725 ( FHL5 ) and rs650724 ( LRP1 ). At known migraine loci, novel associations with stroke had concordant risk alleles for SVS at rs191602009 ( CARF ), and for CE at rs55884259 ( NKX2-5 ). However, at other migraine loci, there were novel associations with opposite risk alleles for all stroke, IS, and SVS at rs55928386 ( HTRA1 ), for LAS at rs11172113 ( LRP1 ), and for all stroke and IS, respectively, at rs1535791 and rs4942561 (both LRCH1 ). rs182923402 (near PTCH1 ) was a novel locus for both migraine and CE with concordant effects. MR supported causal influence of migraine on CeAD (OR [95%CI] per doubling migraine prevalence=1.69 [1.24-2.3], p=0.0009) with concordant risk, but with opposite risk on LAS (0.86 [0.76 - 0.96], p=0.0067). Conclusions: Genetic effects between migraine and CeAD had concordant effects on risk, highlighting vascular functions in migraine and novel CeAD loci. Most shared loci for migraine and stroke subtypes had opposite effects on risk. The LRP1 locus was common to all three disorders.

We tested for pleiotropy in European ancestry subjects (N>90K) via GWAS of systolic and diastolic blood pressure (BP), mean arterial pressure, and pulse pressure, using gene (G)-alcohol consumption (E) interactions. The approach was a correlated meta-analysis (PMCID-PMC3773990) that combined simultaneously the 4 BP traits genome-wide GxE interactions summary meta-P values. This approach adjusts for correlations among single traits at the genomic level. A variant was considered pleiotropic when the overall correlated meta-analysis yielded P ≤5E-08 and GxE meta- P ≤E-04 for at least two single traits. The novel pleiotropic variants localize in eight loci. TTLL7 (1p31.1) is a tubulin modifier. DYRK3 (1q32.1) is a transcription regulator. MAPKAPK2 (1q32.1) is a stress-activated serine/threonine-protein kinase involved in cytokine production especially for TNF , IL6 and phosphorylates (among others) LSP1 , identified in our GWAS GxE study for individual BP traits. FSTL5 (4q32.2) is annotated as calcium ion binding . A locus at 11q13.1 includes SNX32 , EFEMP2, and FOSL1 . FOSL1 variants may regulate expression of SNX32 . EFEMP2 is implicated in blood coagulation. CATSPER2 (15q15.3) is a cation channel. CCDC151 (19p13.2) is an outer dynein arm assembly. The functions of two other loci (17q22 and 18q22.3) are unknown. We also identified 4 pleiotropic loci ( SGK223 , TNKS , GATA4 , FTO ) that were found significant at our GxE meta-GWAS of single traits in 572K multi-ancestry individuals. In addition, we detected 24 pleiotropic BP-known loci. Some of these genes relate to alcohol consumption (e.g., BLK , GATA4 , FTO ). TNKS , MAPKAPK2 and FSTL5 interact with the Wnt/β-catenin signaling pathway, which contributes to hypertension. Several pleiotropic variants showed features of regulation by locating at promoter and enhancer histone marks, at DNAse, at proteins binding sites and being eQTL. The 36 novel and BP-known loci comprising 86 significant genes were enriched for Hypertension , Cardiac arrhythmias , Myocardial infarction , Atrial fibrillation, and Left ventricular hypertrophy . Our correlated meta-analysis of GxE interaction approach identified novel pleiotropic loci and validated known BP loci, thus providing insights into the mechanisms of hypertension.

Background: Whether dietary quality modifies genetic association with body mass index (BMI) is unknown. Methods: We examined the interactions prospectively of a genetic risk score (GRS) based on 97 BMI-associated variants with three diet quality scores (alternative healthy eating index 2010 (AHEI-2010), Alternative Mediterranean Diet score (AMED) and Dietary Approach to Stop Hypertension (DASH) diet score) on BMI in 30,904 participants from three large US cohorts. According to the enrichment of genes near the BMI-associated loci in the central nervous system (CNS), we further created two subsets of GRSs: CNS GRS based on 54 variants and non-CNS GRS based on 43 variants. Findings: We found significant interactions between total GRS and all three diet scores on BMI assessed after 2 to 3 years, with an attenuated genetic effect observed in individuals with healthier diets (AHEI: P for interaction = 0.003; AMED: P = 0.001; DASH: P = 0.004). For example, the difference in BMI per 10 unit increment of the GRS was smaller among participants in the highest tertile of AHEI score compared to those in the lowest tertile (0.84 [95% CI: 0.72, 0.96] vs. 1.14 [0.99, 1.29] kg/m 2 ). Results were consistent across the three cohorts with no significant heterogeneity. The interactions with diet scores on BMI appeared more significant for CNS GRS (AHEI: P = 0.009; AMED and DASH: P < 0.001) than for non-CNS GRS (AHEI: P = 0.10; AMED: P = 0.50; DASH: P = 0.68). Among individual components of diet scores, higher consumption of red/processed meat, sugar-sweetened beverages, and trans fat accentuated genetic associations with BMI (P Interpretation: A higher diet quality may mitigate genetic predisposition to obesity. These findings provide insights into complex interplays between diet and genetic influences and underscore the importance of adopting a healthful diet for the prevention of obesity, particularly those individuals with a strong genetic predisposition to obesity.

Obesity, especially central obesity, and cigarette smoking (SMK) are both important risk factors for cardiovascular disease (CVD). Yet, smokers often exhibit lower body mass index (BMI) and higher waist circumference (WC) compared to non-smokers; also, smoking cessation leads to weight gain. Genome-wide association (GWA) studies have identified genetic loci that are associated with risk of overall and central obesity; yet little is known about whether and how SMK influences the genetic susceptibility to obesity. This study aims to discover genetic loci that are associated with obesity, measured as BMI and WC adjusted for BMI (WC a ), and where the effects are hidden by SMK. We used results from 42 studies including up to 126,767 subjects with GWA data available through the GIANT Consortium. Each study employed three association models while considering smoking status (current vs. not current smokers): 1) SNP effects adjusted for SMK (SNPadjSmk), 2) SNP by SMK interaction effects (SNPxSMK), and 3) joint effect of SNP and the SNP x SMK interaction effect (SNPxSMK J ). Study specific results were combined by inverse-variance weighted fixed-effects meta-analyses of the study specific results in men and women separately and then combined sexes. A total of 53 SNPs for WC a reached genome-wide significance (GWS) (pJ ), 27 of these loci are novel for WC a . Additionally, SNPadjSMK and SNPxSMK J models identified a total of 49 SNPs associated with BMI that reached GWS, including 15 novel loci. While no loci reached GWS for SNPxSMK on BMI, one novel SNPxSMK association with WC a near PRNP reached GWS in women. PRNP is highly expressed throughout the CNS and especially the hippocampus, as are many obesity-related genes. PRNP also plays a role in the body’s response to oxidative stress, making it a likely candidate gene for interaction with smoking as well. Of the GWS SNPs, 47 WC a and 41 BMI loci are nearby (