ABSTRACT
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. Next, we applied PRIME to functionally characterize 1,304 genome-wide association study (GWAS)-identified non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate that PRIME is capable of characterizing genetic variants at single-base resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.
Subject(s)
Genome, Human , Genome-Wide Association Study , Humans , Genome, Human/genetics , Reproducibility of Results , Regulatory Sequences, Nucleic Acid , DNA , Gene Editing/methods , CRISPR-Cas SystemsABSTRACT
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 MYC enhancer via PRIME-mediated saturation mutagenesis. Next, we applied PRIME to functionally characterize 1,304 non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate PRIME capable of characterizing genetic variants at base-pair resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.
ABSTRACT
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. RESULTS: We identified 8182 BCa cases during a median follow-up of 11.1 years. We found no overall association between diabetes and BCa risk (aHR = 1.02, 95% CI = 0.92-1.14). When accounting for diabetes subtype, women with T1D had a higher risk of BCa than women without diabetes (aHR = 1.52, 95% CI = 1.03-2.23). T2D was not associated with BCa risk overall (aHR = 1.00, 95% CI = 0.90-1.12). However, there was a significantly increased risk of BCa in the short time window after T2D diagnosis. CONCLUSIONS: Though we did not find an association between diabetes and BCa risk overall, an increased risk of BCa was observed shortly after T2D diagnosis. In addition, our data suggest that women with T1D may have an increased risk of BCa.
Subject(s)
Breast Neoplasms , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Humans , Female , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 1/complications , Breast Neoplasms/epidemiology , Breast Neoplasms/complications , Prospective Studies , Risk FactorsABSTRACT
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. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS's association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06-1.21, p = 4.0 × 10-4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.
ABSTRACT
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. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes. Methods: We conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk. Results: We saw a strong association of LoF variants in FANCM with ER-negative BC (p=4.1×10-7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes, BRCA1 (p=2.3×10-10, OR [CI]: 24.9 [6.1-102.5]), BRCA2 (p=8.4×10-10, OR [CI]: 7.0 [3.5-14.0]), and PALB2 (p=1.8×10-8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53. Conclusion: In H/L women, LoF variants in FANCM were strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate that FANCM should be added to BC gene panels.
ABSTRACT
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). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. RESULTS: We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. CONCLUSIONS: Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.
Subject(s)
Genetic Predisposition to Disease , Neoplasms, Multiple Primary , Exome/genetics , Genetic Predisposition to Disease/genetics , Humans , Neoplasms, Multiple Primary/genetics , Phenotype , Exome SequencingABSTRACT
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 NTN4 locus (12q22) and NTN4 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. The protective T allele of rs11837367 increases the binding of GATA3 to the distal enhancer and up-regulates NTN4 expression. In addition, we demonstrate that loss of NTN4 gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that NTN4, as a tumor suppressor, can attenuate the Wnt signaling pathway by directly binding to Wnt ligands. Our findings bridge the gaps among breast cancer-associated single-nucleotide polymorphisms, transcriptional regulation of NTN4, and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.
Subject(s)
Genome-Wide Association Study , Neoplasms , Netrins/metabolism , Alleles , Animals , Genetic Predisposition to Disease , Mice , Neoplasms/genetics , Netrins/genetics , Polymorphism, Single Nucleotide , Wnt Signaling Pathway/geneticsABSTRACT
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 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
Subject(s)
Genome-Wide Association Study , Hypertension , Blood Pressure/genetics , Genetic Loci/genetics , Humans , Hypertension/genetics , Polymorphism, Single Nucleotide/genetics , Sleep/geneticsABSTRACT
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. Methods: We included 1493 African- and 1581 European-ancestry participants from the Chronic Renal Insufficiency Cohort who were followed for 12 years. We examined associations of BP genetic risk scores with development of cardiovascular disease (myocardial infarction, congestive heart failure, or stroke) and CKD progression (incident ESKD or halving of eGFR) using Cox proportional hazards models. Analyses were stratified by race and included adjustment for age, sex, study site, and ancestry principal components. Results: Among European-ancestry participants, each SD increase in systolic BP and pulse pressure genetic risk score conferred a 15% (95% CI, 4% to 27%) and 11% (95% CI, 1% to 23%), respectively, higher risk of cardiovascular disease, with a similar, marginally significant trend for diastolic BP. Among African-ancestry participants, each SD increase in systolic and diastolic BP genetic risk score conferred a 10% (95% CI, 1% to 20%) and 9% (95% CI, 0% to 18%), respectively, higher risk of cardiovascular disease. Higher genetic risk was not associated with CKD progression. Conclusions: Genetic risk for elevation in BP was associated with increased risk of cardiovascular disease, but not CKD progression.
Subject(s)
Cardiovascular Diseases , Renal Insufficiency, Chronic , Blood Pressure/genetics , Cardiovascular Diseases/epidemiology , Disease Progression , Glomerular Filtration Rate , Humans , Prospective Studies , Renal Insufficiency, Chronic/epidemiology , Risk FactorsABSTRACT
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. METHODS: This analysis consisted of 655 participants of the Bogalusa Heart Study (25% black, 61% women, aged 34-58 years) who were not taking antihypertensive medication. Fasting serum 1-MH was measured using liquid chromatography-tandem mass spectroscopy. Animal food intakes were quantified by food-frequency questionnaires. Multivariable linear regression assessed the association between 1-MH and BP in combined and race-stratified analyses, adjusting for demographic, dietary, and cardiometabolic factors. RESULTS: A significant dose--response relationship was observed for the association of red meat (P-trend <0.01) and poultry (P-trendâ=â0.03) intake with serum 1-MH among all individuals. Serum 1-MH, per standard deviation increase, had a significant positive association with SBP (ß=3.4â±â1.6âmmHg, Pâ=â0.04) and DBP (ß=2.0â±â1.1âmmHg, Pâ=â0.05) in black participants, whereas no appreciable association was observed in white participants. Among a subgroup of black participants with repeat outcome measures (median follow-upâ=â3.0 years), one standard deviation increase in 1-MH conferred a 3.1 and 2.2âmmHg higher annual increase in SBP (Pâ=â0.03) and DBP (Pâ=â0.03), respectively. CONCLUSION: Serum 1-MH associates with higher SBP and DBP in blacks, but not whites. These results suggest a utility for further assessing the role of dietary 1-MH among individuals with hypertension to help minimize racial disparities in cardiovascular health.
Subject(s)
Animal Proteins, Dietary/metabolism , Black or African American/statistics & numerical data , Blood Pressure/physiology , Methylhistidines/blood , White People/statistics & numerical data , Adult , Biomarkers/blood , Female , Humans , Hypertension/physiopathology , Longitudinal Studies , Male , Middle AgedABSTRACT
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). In a sub-sample of participants with repeated assessments of gait speed (N=282) and grip strength (N=201), significant metabolites from the cross-sectional analyses were tested for association with change in physical performance over 2.9 years of follow-up. Thirty-five and seven metabolites associated with baseline gait speed and grip strength respectively, including six metabolites that associated with both phenotypes. Three metabolites associated with preservation or improvement in gait speed over follow-up, including: sphingomyelin (40:2) (P=2.6×10-4) and behenoyl sphingomyelin (d18:1/22:0) and ergothioneine (both P<0.05). Seven metabolites associated with declines in gait speed, including: 1-carboxyethylphenylalanine (P=8.8×10-5), and N-acetylaspartate, N-formylmethionine, S-adenosylhomocysteine, N-acetylneuraminate, N2,N2-dimethylguanosine, and gamma-glutamylphenylalanine (all P<0.05). Two metabolite modules reflecting sphingolipid and bile acid metabolism associated with physical performance (minimum P=7.6×10-4). These results add to the accumulating evidence suggesting an important role of the human metabolome in physical performance and specifically implicate lipid, nucleotide, and amino acid metabolism in early physical performance decline.
Subject(s)
Aging/blood , Metabolome/physiology , Physical Functional Performance , Adult , Aging/metabolism , Biomarkers/blood , Biomarkers/metabolism , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Metabolomics , Middle AgedSubject(s)
Biomedical Research , Cardiology , Cardiovascular Diseases , American Heart Association , Animals , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/therapy , Health Status , Healthy Aging , Humans , Longevity , United States/epidemiologyABSTRACT
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 (34.98% African American, 57.41% female, aged 33.6-57.5 years). Measures of LV mass and relative wall thickness (RWT) were obtained using two-dimensional-guided echocardiographic measurements via validated eqs. LV mass was indexed to height2.7 to calculate left ventricular mass index (LVMI). Untargeted metabolomic analysis of fasting serum samples was conducted. In combined and ethnicity-stratified analyses, multivariable linear and multinomial logistic regression models tested the associations of metabolites with the continuous LVMI and RWT and categorical LV geometry phenotypes, respectively, after adjusting for demographic and traditional cardiovascular disease risk factors. RESULTS: Pseudouridine (B = 1.38; p = 3.20 × 10-5) and N-formylmethionine (B = 1.65; 3.30 × 10-6) were significantly associated with LVMI in the overall sample as well significant in Caucasians, with consistent effect direction and nominal significance (p < .05) in African Americans. Upon exclusion of individuals with self-report myocardial infarction or congestive HF, we similarly observed a 1.33 g/m2.7 and 1.52 g/m2.7 higher LVMI for each standard deviation increase in pseudouridine and N-formylmethionine, respectively. No significant associations were observed for metabolites with RWT or categorical LV remodeling outcomes. CONCLUSIONS: The current analysis identified novel associations of pseudouridine and N-formylmethionine with LVMI, suggesting that mitochondrial-derived metabolites may serve as early biomarkers for LV remodeling and subclinical HF.
Subject(s)
Heart Failure/blood , Heart Failure/diagnostic imaging , Heart Ventricles/diagnostic imaging , Metabolome , N-Formylmethionine/blood , Pseudouridine/blood , Ventricular Remodeling , Adult , Black or African American , Biomarkers/blood , Cohort Studies , Echocardiography , Female , Heart Failure/ethnology , Humans , Hypertrophy, Left Ventricular , Male , Middle Aged , Phenotype , Risk FactorsABSTRACT
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. RESULTS: A total of 24 novel metabolites robustly associated with BP, achieving Bonferroni-corrected P less than 4.16â×â10 in the overall analysis and consistent effect sizes across race groups. The identified metabolites included three amino acid and nucleotide metabolites from histidine, pyrimidine, or tryptophan metabolism sub-pathways, seven cofactor and vitamin or xenobiotic metabolites from the ascorbate and aldarate metabolism, bacterial/fungal, chemical, and food component sub-pathways, 10 lipid metabolites from the eicosanoid, phosphatidylcholine, phosphatidylethanolamine, and sphingolipid metabolism sub-pathways, and four still unnamed metabolites. Six previously described metabolites were robustly confirmed by our study (Bonferroni-corrected Pâ<â4.95â×â10 and consistent effect directions across studies). Furthermore, previously reported metabolites for SBP, DBP, and hypertension demonstrated 5.92-fold, 4.77-fold, and 4.54-fold enrichment for nominally significant signals in the BHS (Pâ=â3.08â×â10, 5.93â×â10, and 2.30â×â10, respectively). CONCLUSION: In aggregate, our study provides new information about potential molecular mechanisms underlying BP regulation. We also demonstrate reproducibility of findings across studies despite differences in study populations and metabolite profiling methods.
Subject(s)
Biomarkers/blood , Blood Pressure , Hypertension/blood , Hypertension/ethnology , Metabolomics , Adult , Black or African American , Chromatography, High Pressure Liquid , Female , Humans , Lipids , Longitudinal Studies , Male , Middle Aged , Phenotype , Regression Analysis , Reproducibility of Results , Risk Factors , Tandem Mass Spectrometry , White People , Young AdultABSTRACT
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. Measures of left ventricular diastolic function included the ratio of peak early filling velocity to peak late filling velocity, ratio of peak early filling velocity to mitral annular velocity, deceleration time, isovolumic relaxation time, and left atrial maximum volume index (LAVI). Analyses adjusted for multiple cardiovascular disease risk factors and used Bonferroni-corrected alpha thresholds. Eight metabolites robustly associated with left ventricular diastolic function in the overall population and demonstrated consistent associations in white and black study participants. N-formylmethionine (B=0.05; P=1.50×10-7); 1-methylhistidine (B=0.05; P=1.60×10-7); formiminoglutamate (B=0.07; P=5.60×10-7); N2, N5-diacetylornithine (B=0.05; P=1.30×10-7); N-trimethyl 5-aminovalerate (B=0.04; P=5.10×10-6); 5-methylthioadenosine (B=0.04; P=1.40×10-5); and methionine sulfoxide (B=0.04; P=3.80×10-6) were significantly associated with the natural log of the ratio of peak early filling velocity to mitral annular velocity. Butyrylcarnitine (B=3.18; P=2.10×10-6) was significantly associated with isovolumic relaxation time. Conclusions The current study identified novel findings of metabolite associations with left ventricular diastolic function, suggesting that the serum metabolome, and its underlying biological pathways, may be implicated in heart failure with preserved ejection fraction pathogenesis.
Subject(s)
Energy Metabolism , Metabolomics , Ventricular Dysfunction, Left/blood , Ventricular Function, Left , Adult , Biomarkers/blood , Chromatography, High Pressure Liquid , Cross-Sectional Studies , Diastole , Echocardiography, Doppler , Female , Humans , Louisiana , Male , Middle Aged , Tandem Mass Spectrometry , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/physiopathologyABSTRACT
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. METHODS: Untargeted ultrahigh-performance liquid chromatography-tandem mass spectrometry was used to detect and quantify blood metabolites. We used multivariate adjusted linear regression to examine associations between single metabolites and creatinine-based estimated glomerular filtration rate (eGFRcr) among 1243 Bogalusa Heart Study (BHS) participants (median eGFRcr: 94.4, 5th-95th percentile: 66.0-119.6 mL/min/1.73 m2). Replication, determined by statistical significance and consistent effect direction, was tested using gold standard measured glomerular filtration rate (mGFR) among 260 Multi-Ethnic Study of Atherosclerosis (MESA) participants (median mGFR: 72.0, 5th-95th percentile: 43.5-105.0 mL/min/1.73 m2). All analyses used Bonferroni-corrected alpha thresholds. RESULTS: Fifty-one novel metabolite associations with kidney function were identified, including 12 from previously unrelated sub-pathways: N6-carboxymethyllysine, gulonate, quinolinate, gamma-CEHC-glucuronide, retinol, methylmalonate, 3-hydroxy-3-methylglutarate, 3-aminoisobutyrate, N-methylpipecolate, hydroquinone sulfate, and glycine conjugates of C10H12O2 and C10H14O2(1). Significant metabolites were generally inversely associated with kidney function and smaller in mass-to-charge ratio than non-significant metabolites. CONCLUSION: The 51 novel metabolites identified may serve as early, clinically relevant, kidney function biomarkers.
Subject(s)
Biomarkers/blood , Renal Insufficiency, Chronic/metabolism , Aged , Aged, 80 and over , Atherosclerosis/complications , Atherosclerosis/metabolism , Chromatography, Liquid/methods , Creatinine/blood , Female , Glomerular Filtration Rate/physiology , Humans , Kidney Function Tests/methods , Longitudinal Studies , Male , Metabolomics/methods , Middle Aged , Renal Insufficiency, Chronic/physiopathologyABSTRACT
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. The cross-sectional associations of single metabolites with cognition were tested using multiple linear regression models. Weighted correlation network analysis was used to examine the covariable-adjusted correlations of modules of co-abundant metabolites with cognition. Analyses were conducted in the overall sample and according to both ethnicity and sex. RESULTS: Five known metabolites and two metabolite modules robustly associated with cognition across overall and stratified analyses. Two metabolites were from lipid sub-pathways including fatty acid metabolism [9-hydroxystearate; minimum P-value (min-P)=1.11×10-5], and primary bile acid metabolism (glyco-alpha-muricholate; min-P=4.10×10-5). One metabolite from the glycogen metabolism sub-pathway (maltose; min-P=9.77×10-6), one from the polyamine metabolism sub-pathway (N-acetyl-isoputreanine; min-P=1.03×10-5), and one from the purine metabolism sub-pathway (7-methylguanine; min-P=1.19×10-5) were also identified. Two metabolite modules reflecting bile acid metabolism and androgenic steroids correlated with cognition (min-P=5.00×10-4 and 3.00×10-3, respectively). CONCLUSION: The novel associations of 5 known metabolites and 2 metabolite modules with cognition provide insights into the physiological mechanisms regulating cognitive function.
Subject(s)
Cognition/physiology , Metabolome , Cross-Sectional Studies , Female , Humans , Longitudinal Studies , Male , Metabolomics , Middle Aged , PhenotypeABSTRACT
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. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
Subject(s)
Blood Pressure/physiology , Asian People , Blood Pressure/genetics , Europe , Female , Genetic Loci/genetics , Genome-Wide Association Study , Humans , Linkage Disequilibrium/genetics , Male , Polymorphism, Single Nucleotide/genetics , Racial Groups/genetics , White PeopleABSTRACT
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 (307.8 mmol sodium/d), and 7-day high-sodium plus potassium (60 mmol potassium/d) intervention. BP was measured 9× at baseline and at the end of each intervention period using a random zero sphygmomanometer. Associations between systolic BP (SBP), diastolic BP, and mean arterial pressure GRS and respective SBP, diastolic BP, and mean arterial pressure responses to the dietary interventions were assessed using mixed linear regression models that accounted for familial dependencies and adjusted for age, sex, field center, body mass index, and baseline BP. As expected, baseline SBP, diastolic BP, and mean arterial pressure significantly increased per quartile increase in GRS (P=2.7×10-8, 9.8×10-8, and 6.4×10-6, respectively). In contrast, increasing GRS quartile conferred smaller SBP, diastolic BP, and mean arterial pressure responses to the low-sodium intervention (P=1.4×10-3, 0.02, and 0.06, respectively) and smaller SBP responses to the high-sodium and potassium interventions (P=0.10 and 0.05). In addition, overall findings were similar when examining GRS as a continuous measure. Contrary to our initial hypothesis, we identified an inverse relationship between BP GRS and salt and potassium sensitivity of BP. These data may provide novel implications on the relationship between BP responses to dietary sodium and potassium and hypertension.