Unraveling the genetic landscape of susceptibility to multiple primary cancers.

With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies.

High-throughput PRIME-editing screens identify functional DNA variants in the human genome.

Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and single-base resolution manner remains challenging. Here, we develop a pooled prime-editing screen method, PRIME, that can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bp MYC enhancer via PRIME-mediated single-base resolution analysis.

High throughput PRIME editing screens identify functional DNA variants in the human genome.

Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and base-pair resolution manner remains challenging. Here, we develop a novel pooled prime editing screen method, PRIME, which can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bp enhancer via PRIME-mediated saturation mutagenesis.

Diabetes mellitus and risk of breast cancer: a large-scale, prospective, population-based study.

Background: The objective of this study was to evaluate associations of diabetes overall, type 1 diabetes (T1D), and type 2 diabetes (T2D) with breast cancer (BCa) risk.

Methods: We included 250,312 women aged 40-69 years between 2006 and 2010 from the UK Biobank cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for associations of diabetes and its two major types with the time from enrollment to incident BCa.

Development and testing of a polygenic risk score for breast cancer aggressiveness.

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature.

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies as a susceptibility gene for estrogen-receptor-negative breast cancer.

Introduction: Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants.

Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies.

Background: Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.

Methods: To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls).

The risk variant rs11836367 contributes to breast cancer onset and metastasis by attenuating Wnt signaling via regulating expression.

Most genome-wide association study (GWAS)-identified breast cancer-associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at the locus (12q22) and gene in breast cancer etiology. We find that rs11836367 is the more likely causal variant, disrupting enhancer activity in both enhancer reporter assays and endogenous genome editing experiments.

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

Association of Blood Pressure Genetic Risk Score with Cardiovascular Disease and CKD Progression: Findings from the CRIC Study.

Background: In the general population, genetic risk for high BP has been associated with cardiovascular disease, but not kidney function or incident CKD. These relationships have not been studied longitudinally in participants with CKD. We examined whether BP genetic risk predicts cardiovascular disease and kidney disease progression in patients with CKD.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10).

Race modifies the association between animal protein metabolite 1-methylhistidine and blood pressure in middle-aged adults: the Bogalusa Heart Study.

Objective: Dietary factors mediate racial disparities in hypertension. However, the physiological mechanisms underlying this relationship are incompletely understood. We sought to assess the association between 1-methylhistidine (1-MH), a metabolite marker of animal protein consumption, and blood pressure (BP) in a community-based cohort of black and white middle-aged adults.

Serum metabolites associate with physical performance among middle-aged adults: Evidence from the Bogalusa Heart Study.

Age-related declines in physical performance predict cognitive impairment, disability, chronic disease exacerbation, and mortality. We conducted a metabolome-wide association study of physical performance among Bogalusa Heart Study participants. Bonferroni corrected multivariate-adjusted linear regression was employed to examine cross-sectional associations between single metabolites and baseline gait speed (N=1,227) and grip strength (N=1,164).

Pseudouridine and N-formylmethionine associate with left ventricular mass index: Metabolome-wide association analysis of cardiac remodeling.

Background: Heart failure (HF) is the fastest growing form of cardiovascular disease both nationally and globally, underlining a need to phenotype subclinical HF intermediaries to improve primary prevention.

Objectives: We aimed to identify novel metabolite associations with left ventricular (LV) remodeling, one upstream HF intermediary, among a community-based cohort of individuals.

Methods: We examined 1052 Bogalusa Heart Study participants (34.

An untargeted metabolomics study of blood pressure: findings from the Bogalusa Heart Study.

Objective: To identify novel and confirm previously reported metabolites associated with SBP, DBP, and hypertension in a biracial sample of Bogalusa Heart Study (BHS) participants.

Methods: We employed untargeted, ultra-high performance liquid chromatography tandem mass spectroscopy metabolomics profiling among 1249 BHS participants (427 African-Americans and 822 whites) with BP and covariable data collected during the 2013 to 2016 visit cycle. A total of 1202 metabolites were tested for associations with continuous and binary BP phenotypes using multiple linear and logistic regression models, respectively, in overall and race-stratified analyses.

Novel Findings From a Metabolomics Study of Left Ventricular Diastolic Function: The Bogalusa Heart Study.

Background Diastolic dysfunction is one important causal factor for heart failure with preserved ejection fraction, yet the metabolic signature associated with this subclinical phenotype remains unknown. Methods and Results Ultra-high-performance liquid chromatography-tandem mass spectroscopy was used to conduct untargeted metabolomic analysis of fasting serum samples in 1050 white and black participants of the BHS (Bogalusa Heart Study). After quality control, 1202 metabolites were individually tested for association with 5 echocardiographic measures of left ventricular diastolic function using multivariable-adjusted linear regression.

Novel associations between blood metabolites and kidney function among Bogalusa Heart Study and Multi-Ethnic Study of Atherosclerosis participants.

Introduction: Chronic kidney disease (CKD) is a major public health challenge given its high global prevalence and associated risks of cardiovascular disease and progression to end stage renal disease. Although it is known that numerous metabolic changes occur in CKD patients, identifying novel metabolite associations with kidney function may enhance our understanding of the physiologic pathways relating to CKD.

Objectives: The objective of this study was to elucidate novel metabolite associations with kidney function among participants of two community-based cohorts with carefully ascertained metabolomics, kidney function, and covariate data.

Novel serum metabolites associate with cognition phenotypes among Bogalusa Heart Study participants.

Background: Metabolomics study provides an opportunity to identify novel molecular determinants of altered cognitive function.

Methods: During 2013 to 2016 Bogalusa Heart Study (BHS) visit, 1,177 participants underwent untargeted, ultrahigh performance liquid chromatography-tandem mass spectroscopy metabolomics profiling. Global cognition and five cognition domains were also assessed.

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model.

Blood Pressure Genetic Risk Score Predicts Blood Pressure Responses to Dietary Sodium and Potassium: The GenSalt Study (Genetic Epidemiology Network of Salt Sensitivity).

We examined the association between genetic risk score (GRS) for blood pressure (BP), based on single nucleotide polymorphisms identified in previous BP genome-wide association study meta-analyses, and salt and potassium sensitivity of BP among participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). The GenSalt study was conducted among 1906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/d), 7-day high-sodium (307.