Publications by authors named "Honghuang Lin"

130 Publications

Association of Habitual Physical Activity With Home Blood Pressure in the Electronic Framingham Heart Study (eFHS): Cross-sectional Study.

J Med Internet Res 2021 Jun 24;23(6):e25591. Epub 2021 Jun 24.

Department of Medicine, UMass Medical School, Worcester, MA, United States.

Background: When studied in community-based samples, the association of physical activity with blood pressure (BP) remains controversial and is perhaps dependent on the intensity of physical activity. Prior studies have not explored the association of smartwatch-measured physical activity with home BP.

Objective: We aimed to study the association of habitual physical activity with home BP.

Methods: Consenting electronic Framingham Heart Study (eFHS) participants were provided with a study smartwatch (Apple Watch Series 0) and Bluetooth-enabled home BP cuff. Participants were instructed to wear the watch daily and transmit BP values weekly. We measured habitual physical activity as the average daily step count determined by the smartwatch. We estimated the cross-sectional association between physical activity and average home BP using linear mixed effects models adjusting for age, sex, wear time, antihypertensive drug use, and familial structure.

Results: We studied 660 eFHS participants (mean age 53 years, SD 9 years; 387 [58.6%] women; 602 [91.2%] White) who wore the smartwatch 5 or more hours per day for 30 or more days and transmitted three or more BP readings. The mean daily step count was 7595 (SD 2718). The mean home systolic and diastolic BP (mmHg) were 122 (SD 12) and 76 (SD 8). Every 1000 increase in the step count was associated with a 0.49 mmHg lower home systolic BP (P=.004) and 0.36 mmHg lower home diastolic BP (P=.003). The association, however, was attenuated and became statistically nonsignificant with further adjustment for BMI.

Conclusions: In this community-based sample of adults, higher daily habitual physical activity measured by a smartwatch was associated with a moderate, but statistically significant, reduction in home BP. Differences in BMI among study participants accounted for the majority of the observed association.
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http://dx.doi.org/10.2196/25591DOI Listing
June 2021

Association Between the Digital Clock Drawing Test and Neuropsychological Test Performance: Large Community-Based Prospective Cohort (Framingham Heart Study).

J Med Internet Res 2021 Jun 8;23(6):e27407. Epub 2021 Jun 8.

Framingham Heart Study, School of Medicine, Boston University, Boston, MA, United States.

Background: The Clock Drawing Test (CDT) has been widely used in clinic for cognitive assessment. Recently, a digital Clock Drawing Text (dCDT) that is able to capture the entire sequence of clock drawing behaviors was introduced. While a variety of domain-specific features can be derived from the dCDT, it has not yet been evaluated in a large community-based population whether the features derived from the dCDT correlate with cognitive function.

Objective: We aimed to investigate the association between dCDT features and cognitive performance across multiple domains.

Methods: Participants from the Framingham Heart Study, a large community-based cohort with longitudinal cognitive surveillance, who did not have dementia were included. Participants were administered both the dCDT and a standard protocol of neuropsychological tests that measured a wide range of cognitive functions. A total of 105 features were derived from the dCDT, and their associations with 18 neuropsychological tests were assessed with linear regression models adjusted for age and sex. Associations between a composite score from dCDT features were also assessed for associations with each neuropsychological test and cognitive status (clinically diagnosed mild cognitive impairment compared to normal cognition).

Results: The study included 2062 participants (age: mean 62, SD 13 years, 51.6% women), among whom 36 were diagnosed with mild cognitive impairment. Each neuropsychological test was associated with an average of 50 dCDT features. The composite scores derived from dCDT features were significantly associated with both neuropsychological tests and mild cognitive impairment.

Conclusions: The dCDT can potentially be used as a tool for cognitive assessment in large community-based populations.
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http://dx.doi.org/10.2196/27407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241432PMC
June 2021

P-wave signal-averaged electrocardiography: Reference values, clinical correlates, and heritability in the Framingham Heart Study.

Heart Rhythm 2021 May 11. Epub 2021 May 11.

National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham, Massachusetts; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.

Background: P-wave signal-averaged electrocardiography (P-SAECG) quantifies atrial electrical activity. P-SAECG measures and their clinical correlates and heritability have had limited characterization in community-based cohorts.

Objective: The purpose of this study was to (1) establish reference values; (2) identify clinical risk factors associated with P-SAECG; and (3) estimate genetic heritability for P-SAECG traits.

Methods: We performed P-SAECG in 2 generations of Framingham Heart Study participants. We performed backward elimination regression models to assess associations of clinical factors with each SAECG trait (P-wave [PW] duration, root mean square voltage in terminal 40 ms [RMS40], terminal 30 ms RMS30, terminal 20 ms RMS20, RMS PW, and PW integral). We estimated the adjusted genetic heritability of P-SAECG measures using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) program.

Results: We included 4307 participants (age 55 ± 14 years; 56% female). The reference values were derived from 1752 participants without cardiovascular risk factors. Median (2.5th percentile; 97.5th percentile) total PW duration was 118 ms (93; 146) in women and 128 ms (104; 158) in men in the reference sample, and 121 ms (94; 151) in women and 129 ms (103; 159) in the entire study cohort (broad sample). In the broad sample, after adjusting for age and sex, total PW duration was positively associated with height, weight, prevalent heart failure, history of atrial fibrillation (AF), and atrioventricular node blockers, and negatively associated with smoking, waist circumference, heart rate, and diabetes. The estimated heritability of P-SAECG traits was moderate, ranging from 11.9% for RMS30 to 24.9% for PW integral.

Conclusion: P-SAECG traits are associated with multiple AF-related risk factors and are moderately heritable.
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http://dx.doi.org/10.1016/j.hrthm.2021.05.009DOI Listing
May 2021

Fresh frozen plasma transfusion in acute variceal haemorrhage: Results from a multicentre cohort study.

Liver Int 2021 Aug 24;41(8):1901-1908. Epub 2021 May 24.

Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM, USA.

Background: Fresh frozen plasma (FFP) transfusion is often used in the management of acute variceal haemorrhage (AVH) despite best practice advice suggesting otherwise.

Objective: We investigated if FFP transfusion affects clinical outcomes in AVH.

Design, Setting And Patients: We performed a retrospective cohort study of 244 consecutive, eligible patients admitted to five tertiary health care centres between 2013 and 2018 with AVH.

Main Outcome Measurements: Multivariable regression analyses were used to study the association of FFP transfusion with mortality at 42 days (primary outcome) and failure to control bleeding at 5 days and length of stay (secondary outcomes).

Results: Patients who received FFP transfusion (n = 100) had higher mean Model for End Stage Liver Disease (MELD) score and more severe variceal bleeding than those who did not received FFP transfusion (n = 144). Multivariable analysis showed that FFP transfusion was associated with increased odds of mortality at 42 days (odds ratio [OR] 9.41, 95% confidence interval [CI] 3.71-23.90). FFP transfusion was also associated with failure to control bleeding at 5 days (OR 3.87, 95% CI 1.28-11.70) and length of stay >7 days (adjusted OR 1.88, 95% CI 1.03-3.42). The independent association of FFP transfusion with mortality at 42 days persisted when the cohort was restricted to high-risk patients and in patients without active bleeding.

Limitations And Conclusions: Fresh frozen plasma transfusion in AVH is independently associated with poor clinical outcomes. As this an observational study, there may be residual bias due to confounding; however, we demonstrate no benefit and potential harm with FFP transfusions in AVH.
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http://dx.doi.org/10.1111/liv.14936DOI Listing
August 2021

New biomarkers from multiomics approaches: improving risk prediction of atrial fibrillation.

Cardiovasc Res 2021 Jun;117(7):1632-1644

National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702, USA.

Atrial fibrillation (AF) is a common cardiac arrhythmia leading to many adverse outcomes and increased mortality. Yet the molecular mechanisms underlying AF remain largely unknown. Recent advances in high-throughput technologies make large-scale molecular profiling possible. In the past decade, multiomics studies of AF have identified a number of potential biomarkers of AF. In this review, we focus on the studies of multiomics profiles with AF risk. We summarize recent advances in the discovery of novel biomarkers for AF through multiomics studies. We also discuss limitations and future directions in risk assessment and discovery of therapeutic targets for AF.
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http://dx.doi.org/10.1093/cvr/cvab073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208748PMC
June 2021

Adherence of Mobile App-Based Surveys and Comparison With Traditional Surveys: eCohort Study.

J Med Internet Res 2021 01 20;23(1):e24773. Epub 2021 Jan 20.

Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.

Background: eCohort studies offer an efficient approach for data collection. However, eCohort studies are challenged by volunteer bias and low adherence. We designed an eCohort embedded in the Framingham Heart Study (eFHS) to address these challenges and to compare the digital data to traditional data collection.

Objective: The aim of this study was to evaluate adherence of the eFHS app-based surveys deployed at baseline (time of enrollment in the eCohort) and every 3 months up to 1 year, and to compare baseline digital surveys with surveys collected at the research center.

Methods: We defined adherence rates as the proportion of participants who completed at least one survey at a given 3-month period and computed adherence rates for each 3-month period. To evaluate agreement, we compared several baseline measures obtained in the eFHS app survey to those obtained at the in-person research center exam using the concordance correlation coefficient (CCC).

Results: Among the 1948 eFHS participants (mean age 53, SD 9 years; 57% women), we found high adherence to baseline surveys (89%) and a decrease in adherence over time (58% at 3 months, 52% at 6 months, 41% at 9 months, and 40% at 12 months). eFHS participants who returned surveys were more likely to be women (adjusted odds ratio [aOR] 1.58, 95% CI 1.18-2.11) and less likely to be smokers (aOR 0.53, 95% CI 0.32-0.90). Compared to in-person exam data, we observed moderate agreement for baseline app-based surveys of the Physical Activity Index (mean difference 2.27, CCC=0.56), and high agreement for average drinks per week (mean difference 0.54, CCC=0.82) and depressive symptoms scores (mean difference 0.03, CCC=0.77).

Conclusions: We observed that eFHS participants had a high survey return at baseline and each 3-month survey period over the 12 months of follow up. We observed moderate to high agreement between digital and research center measures for several types of surveys, including physical activity, depressive symptoms, and alcohol use. Thus, this digital data collection mechanism is a promising tool to collect data related to cardiovascular disease and its risk factors.
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http://dx.doi.org/10.2196/24773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857942PMC
January 2021

Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study.

J Am Heart Assoc 2021 01 29;10(1):e018020. Epub 2020 Dec 29.

Boston University Department of Medicine Boston MA.

Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted value indicated statistical significance (based on number of proteins and traits tested, <4.2×10 in the discovery sample; <6.85×10 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.
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http://dx.doi.org/10.1161/JAHA.120.018020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955453PMC
January 2021

Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation.

Circ Genom Precis Med 2020 12 6;13(6):e003085. Epub 2020 Nov 6.

Cardiovascular Research Center, Massachusetts General Hospital, Boston (A.W.H., S.A.L., N.R.T., P.T.E.).

Background: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes.

Methods: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes.

Results: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (<2×10). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (<2×10). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by , , , and .

Conclusions: Profiling the noncoding genome provides new insights into the gene expression and chromatin regulation in human LA tissue. These findings enabled identification of a gene network underlying AF; our experimental and analytic approach can be extended to identify molecular mechanisms for other cardiac diseases and traits.
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http://dx.doi.org/10.1161/CIRCGEN.120.003085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240092PMC
December 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Transcriptomic Heterogeneity of Alzheimer's Disease Associated with Lipid Genetic Risk.

Neuromolecular Med 2020 12 29;22(4):534-541. Epub 2020 Aug 29.

Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, E-632, Boston, MA, 02118, USA.

Alzheimer's disease (AD) is a multifactorial disease that affects more than 5 million Americans. Multiple pathways might be involved in the AD pathogenesis. The implication of lipid genetic susceptibility on brain gene expression is yet to be investigated. The current study included 192 brain samples from AD patients who were enrolled in the ROSMAP study. The samples were genotyped and imputed to the HRC Reference Panel. Lipid polygenetic risk score was constructed from the weighted sum of genetic variants associated with low-density lipoprotein cholesterol (LDL-C). The gene expression was profiled by RNA sequencing, and the  association of gene expression with lipid polygenetic risk scores was tested by linear regression models adjusted for age, sex and APOE e4 alleles. Three genes were found to associate with lipid polygenetic risk scores, including HMCN2 (P = 3.6 × 10), PDLIM5 (P = 1.2 × 10), and FHL5 (P = 2.0 × 10). Network analysis revealed multiple related pathways, including dopaminergic synapse (P = 4.5 × 10), circadian entrainment (P = 1.1 × 10), and cholinergic synapse (P = 2.3 × 10). Our study underscores the importance of lipid regulation and metabolism to AD heterogeneity.
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http://dx.doi.org/10.1007/s12017-020-08610-6DOI Listing
December 2020

Association of Habitual Physical Activity With Cardiovascular Disease Risk.

Circ Res 2020 10 26;127(10):1253-1260. Epub 2020 Aug 26.

Cardiology Division, Department of Medicine (D.D.M.), University of Massachusetts Medical School, Worcester.

Rationale: A sedentary lifestyle is associated with increased risk for cardiovascular disease (CVD). Smartwatches enable accurate daily activity monitoring for physical activity measurement and intervention. Few studies, however, have examined physical activity measures from smartwatches in relation to traditional risk factors associated with future risk for CVD.

Objective: To investigate the association of habitual physical activity measured by smartwatch with predicted CVD risk in adults.

Methods And Results: We enrolled consenting FHS (Framingham Heart Study) participants in an ongoing eFHS (electronic Framingham Heart Study) at the time of their FHS research center examination. We provided participants with a smartwatch (Apple Watch Series 0) and instructed them to wear it daily, which measured their habitual physical activity as the average daily step count. We estimated the 10-year predicted risk of CVD using the American College of Cardiology/American Heart Association 2013 pooled cohort risk equation. We estimated the association between physical activity and predicted risk of CVD using linear mixed effects models adjusting for age, sex, wear time, and familial structure. Our study included 903 eFHS participants (mean age 53±9 years, 61% women, 9% non-White) who wore the smartwatch ≥5 hours per day for ≥30 days. Median daily step count was similar among men (7202 with interquartile range 3619) and women (7260 with interquartile range 3068; =0.52). Average 10-year predicted CVD risk was 4.5% (interquartile range, 6.1%) for men and 1.2% (interquartile range, 2.2%) for women (=1.3×10). Every 1000 steps higher habitual physical activity was associated with 0.18% lower predicted CVD risk (=3.2×10). The association was attenuated but remained significant after further adjustment for body mass index (=0.01).

Conclusions: In this community-based sample of adults, higher daily physical activity measured by a study smartwatch was associated with lower predicted risk of CVD. Future research should examine the longitudinal association of prospectively measured daily activity and incident CVD.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581630PMC
October 2020

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.

Circ Genom Precis Med 2020 10 21;13(5):387-395. Epub 2020 Aug 21.

DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (, , , , , , , ). The top variants at known sarcomere genes () were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, and ) were associated with longer PWD but lower AF risk.

Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
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http://dx.doi.org/10.1161/CIRCGEN.119.002874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578098PMC
October 2020

Relations between plasma microRNAs, echocardiographic markers of atrial remodeling, and atrial fibrillation: Data from the Framingham Offspring study.

PLoS One 2020 19;15(8):e0236960. Epub 2020 Aug 19.

Division of Cardiology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

Background: Circulating microRNAs may reflect or influence pathological cardiac remodeling and contribute to atrial fibrillation (AF).

Objective: The purpose of this study was to identify candidate plasma microRNAs that are associated with echocardiographic phenotypes of atrial remodeling, and incident and prevalent AF in a community-based cohort.

Methods: We analyzed left atrial function index (LAFI) of 1788 Framingham Offspring 8 participants. We quantified expression of 339 plasma microRNAs. We examined associations between microRNA levels with LAFI and prevalent and incident AF. We constructed pathway analysis of microRNAs' predicted gene targets to identify molecular processes involved in adverse atrial remodeling in AF.

Results: The mean age of the participants was 66 ± 9 years, and 54% were women. Five percent of participants had prevalent AF at the initial examination and 9% (n = 157) developed AF over a median 8.6 years of follow-up (IQR 8.1-9.2 years). Plasma microRNAs were associated with LAFI (N = 73, p<0.0001). Six of these plasma microRNAs were significantly associated with incident AF, including 4 also associated with prevalent AF (microRNAs 106b, 26a-5p, 484, 20a-5p). These microRNAs are predicted to regulate genes involved in cardiac hypertrophy, inflammation, and myocardial fibrosis.

Conclusions: Circulating microRNAs 106b, 26a-5p, 484, 20a-5p are associated with atrial remodeling and AF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236960PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437902PMC
October 2020

Low oxygen saturation during sleep reduces CD1D and RAB20 expressions that are reversed by CPAP therapy.

EBioMedicine 2020 Jun 5;56:102803. Epub 2020 Jun 5.

Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA.

Background: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment.

Methods: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses.

Findings: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT).

Interpretation: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.
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http://dx.doi.org/10.1016/j.ebiom.2020.102803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276515PMC
June 2020

Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases.

Epigenomics 2020 05 4;12(9):789-800. Epub 2020 Jun 4.

Department of Psychiatry, Boston University School of Medicine, MA, USA.

This study aimed to investigate the function of genome-wide association study (GWAS)-identified variants associated with alcohol use disorder (AUD)/comorbid psychiatric disorders. Genome-wide genotype, transcriptome and DNA methylome data were obtained from postmortem prefrontal cortex (PFC) of 48 Caucasians (24 AUD cases/24 controls). Expression/methylation quantitative trait loci (eQTL/mQTL) were identified and their enrichment in GWAS signals for the above disorders were analyzed. PFC -eQTLs (923 from cases+controls, 27 from cases and 98 from controls) and -mQTLs (9,932 from cases+controls, 264 from cases and 695 from controls) were enriched in GWAS-identified genetic variants for the above disorders. -eQTLs from AUD cases were mapped to morphine addiction-related genes. PFC -eQTLs/-mQTLs influence gene expression/DNA methylation patterns, thus increasing the disease risk.
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http://dx.doi.org/10.2217/epi-2019-0270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607393PMC
May 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits.

Circ Heart Fail 2020 05 15;13(5):e006749. Epub 2020 May 15.

Framingham Heart Study, Framingham, MA (M.N., M.G.L, R.S.V).

Background: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals.

Methods: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia.

Results: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (<3.8×10; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (=0.001).

Conclusions: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236427PMC
May 2020

Exploring the Hierarchical Influence of Cognitive Functions for Alzheimer Disease: The Framingham Heart Study.

J Med Internet Res 2020 04 23;22(4):e15376. Epub 2020 Apr 23.

The Framingham Heart Study, Framingham, MA, United States.

Background: Although some neuropsychological (NP) tests are considered more central for the diagnosis of Alzheimer disease (AD), there is a lack of understanding about the interaction between different cognitive tests.

Objective: This study aimed to demonstrate a global view of hierarchical probabilistic dependencies between NP tests and the likelihood of cognitive impairment to assist physicians in recognizing AD precursors.

Methods: Our study included 2091 participants from the Framingham Heart Study. These participants had undergone a variety of NP tests, including Wechsler Memory Scale, Wechsler Adult Intelligence Scale, and Boston Naming Test. Heterogeneous cognitive Bayesian networks were developed to understand the relationship between NP tests and the cognitive status. The performance of probabilistic inference was evaluated by the 10-fold cross validation.

Results: A total of 4512 NP tests were used to build the Bayesian network for the dementia diagnosis. The network demonstrated conditional dependency between different cognitive functions that precede the development of dementia. The prediction model reached an accuracy of 82.24%, with sensitivity of 63.98% and specificity of 92.74%. This probabilistic diagnostic system can also be applied to participants that exhibit more heterogeneous profiles or with missing responses for some NP tests.

Conclusions: We developed a probabilistic dependency network for AD diagnosis from 11 NP tests. Our study revealed important psychological functional segregations and precursor evidence of AD development and heterogeneity.
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http://dx.doi.org/10.2196/15376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206516PMC
April 2020

Novel Risk Modeling Approach of Atrial Fibrillation With Restricted Mean Survival Times: Application in the Framingham Heart Study Community-Based Cohort.

Circ Cardiovasc Qual Outcomes 2020 04 31;13(4):e005918. Epub 2020 Mar 31.

National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, MA (L.S., S.R.P., H.L., E.J.B., L.T.).

Background: Risk prediction models for atrial fibrillation (AF) do not give information about when AF might develop. Restricted mean survival time (RMST) quantifies risk into the time domain. Our objective was to use RMST to re-express individualized AF risk predictions.

Methods And Results: We included AF-free participants from the Framingham Heart Study community-based cohorts. We predicted new-onset AF over 10-year follow-up according to baseline covariates: age, height, weight, systolic blood pressure, diastolic blood pressure, current smoking, antihypertensive treatment, diabetes mellitus, prevalent heart failure, and prevalent myocardial infarction. First, we fitted a Cox regression model and estimated the 10-year predicted risk of AF. Second, we fitted an RMST model and estimated the predicted mean time free of AF and alive over a time horizon of 10 years. We included 7586 AF-free participants contributing to 11 088 examinations (mean age 61±11 years, 44% were men). During 10-year follow-up, 822 participants developed AF. The Cox and RMST models were in agreement regarding the direction, strength, and statistical significance of associations for all covariates. Low (<5%), intermediate (5%-15%), and high (>15%) 10-year predicted risk of AF corresponded to predicted mean time alive and free of AF of 9.9, 9.6, and 8.8 years, respectively. A 60-year-old woman with a body mass index of 25 kg/m, no use of hypertension treatment and no history of heart failure had a predicted mean time alive and free of AF of 9.9 years, whereas a 70-year-old man with a body mass index of 30 kg/m, use of hypertension treatment, and with prevalent heart failure had a predicted mean time alive and free of AF of 7.9 years.

Conclusions: The RMST can be used to develop risk prediction models to express results in a time scale. RMST may offer a complementary risk communication tool for AF in clinical practice.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.119.005918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176529PMC
April 2020

EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression.

iScience 2020 Apr 11;23(4):100973. Epub 2020 Mar 11.

Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA. Electronic address:

Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very-low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and endoplasmic reticulum protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.
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http://dx.doi.org/10.1016/j.isci.2020.100973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093811PMC
April 2020

FAM13A Represses AMPK Activity and Regulates Hepatic Glucose and Lipid Metabolism.

iScience 2020 Mar 22;23(3):100928. Epub 2020 Feb 22.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Obesity commonly co-exists with fatty liver disease with increasing health burden worldwide. Family with Sequence Similarity 13, Member A (FAM13A) has been associated with lipid levels and fat mass by genome-wide association studies (GWAS). However, the function of FAM13A in maintaining metabolic homeostasis in vivo remains unclear. Here, we demonstrated that rs2276936 in this locus has allelic-enhancer activity in massively parallel reporter assays (MPRA) and reporter assay. The DNA region containing rs2276936 regulates expression of endogenous FAM13A in HepG2 cells. In vivo, Fam13a mice are protected from high-fat diet (HFD)-induced fatty liver accompanied by increased insulin sensitivity and reduced glucose production in liver. Mechanistically, loss of Fam13a led to the activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes. These findings demonstrate that FAM13A mediates obesity-related dysregulation of lipid and glucose homeostasis. Targeting FAM13A might be a promising treatment of obesity and fatty liver disease.
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http://dx.doi.org/10.1016/j.isci.2020.100928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063182PMC
March 2020

Convex combination sequence kernel association test for rare-variant studies.

Genet Epidemiol 2020 06 26;44(4):352-367. Epub 2020 Feb 26.

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.

We propose a novel variant set test for rare-variant association studies, which leverages multiple single-nucleotide variant (SNV) annotations. Our approach optimizes a convex combination of different sequence kernel association test (SKAT) statistics, where each statistic is constructed from a different annotation and combination weights are optimized through a multiple kernel learning algorithm. The combination test statistic is evaluated empirically through data splitting. In simulations, we find our method preserves type I error at and has greater power than SKAT(-O) when SNV weights are not misspecified and sample sizes are large ( ). We utilize our method in the Framingham Heart Study (FHS) to identify SNV sets associated with fasting glucose. While we are unable to detect any genome-wide significant associations between fasting glucose and 4-kb windows of rare variants ( ) in 6,419 FHS participants, our method identifies suggestive associations between fasting glucose and rare variants near ROCK2 ( ) and within CPLX1 ( ). These two genes were previously reported to be involved in obesity-mediated insulin resistance and glucose-induced insulin secretion by pancreatic beta-cells, respectively. These findings will need to be replicated in other cohorts and validated by functional genomic studies.
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http://dx.doi.org/10.1002/gepi.22287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205561PMC
June 2020

Protein Biomarkers and Risk of Atrial Fibrillation: The FHS.

Circ Arrhythm Electrophysiol 2020 02 15;13(2):e007607. Epub 2020 Jan 15.

National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, MA (L.S., H.L., D.L., E.J.B., L.T.).

Background: Identification of protein biomarkers associated with incident atrial fibrillation (AF) may improve the understanding of the pathophysiology, risk prediction, and development of new therapeutics for AF. We examined the associations between 85 protein biomarkers and incident AF.

Methods: We included participants ≥50 years of age from the FHS (Framingham Heart Study) Offspring and Third Generation cohorts, who had 85 fasting plasma proteins measured using Luminex xMAP platform. Hazard ratios (per 1 SD increment of rank-normalized biomarker [hazard ratio]) and 95% CIs for incident AF were calculated using Cox regression models adjusted for age, sex, height, weight, current smoking, systolic blood pressure, diastolic blood pressure, hypertension treatment, diabetes mellitus, valvular heart disease, prevalent myocardial infarction, and prevalent heart failure. We used the false discovery rate to account for multiple testing.

Results: The study sample comprised 3378 participants (54% women) with mean (SD) age of 61.5 (8.4) years. In total, 401 developed AF over a mean follow-up of 12.3±3.8 years. We observed lower hazard of incident AF associated with higher mean levels of IGF1 (insulin-like growth factor 1; hazard ratio per 1 SD increment in protein level, 0.84 [95% CI, 0.76-0.93]), and higher hazard of incident AF associated with higher mean levels of both IGFBP1 (insulin-like growth factor-binding protein 1; hazard ratio, 1.24 [95% CI, 1.1-1.39]) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio, 1.73 [95% CI, 1.52-1.96]).

Conclusions: Decreased levels of IGF1 and increased levels of IGFBP1 and NT-proBNP were associated with higher risk of incident AF.
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http://dx.doi.org/10.1161/CIRCEP.119.007607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031024PMC
February 2020

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Nat Commun 2020 01 9;11(1):163. Epub 2020 Jan 9.

Department of Biostatistics, University of Liverpool, Liverpool, UK.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-13690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952380PMC
January 2020

Identification of digital voice biomarkers for cognitive health.

Explor Med 2020 31;1:406-417. Epub 2020 Dec 31.

The Framingham Heart Study, Boston University School of Medicine, Boston, MA 02118, USA.

Aim: Human voice contains rich information. Few longitudinal studies have been conducted to investigate the potential of voice to monitor cognitive health. The objective of this study is to identify voice biomarkers that are predictive of future dementia.

Methods: Participants were recruited from the Framingham Heart Study. The vocal responses to neuropsychological tests were recorded, which were then diarized to identify participant voice segments. Acoustic features were extracted with the OpenSMILE toolkit (v2.1). The association of each acoustic feature with incident dementia was assessed by Cox proportional hazards models.

Results: Our study included 6, 528 voice recordings from 4, 849 participants (mean age 63 ± 15 years old, 54.6% women). The majority of participants (71.2%) had one voice recording, 23.9% had two voice recordings, and the remaining participants (4.9%) had three or more voice recordings. Although all asymptomatic at the time of examination, participants who developed dementia tended to have shorter segments than those who were dementia free ( < 0.001). Additionally, 14 acoustic features were significantly associated with dementia after adjusting for multiple testing ( < 0.05/48 = 1 × 10). The most significant acoustic feature was jitterDDP_sma_de ( = 7.9 × 10), which represents the differential frame-to-frame Jitter. A voice based linear classifier was also built that was capable of predicting incident dementia with area under curve of 0.812.

Conclusions: Multiple acoustic and linguistic features are identified that are associated with incident dementia among asymptomatic participants, which could be used to build better prediction models for passive cognitive health monitoring.
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http://dx.doi.org/10.37349/emed.2020.00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929495PMC
December 2020

Integrative Omics Approach to Identifying Genes Associated With Atrial Fibrillation.

Circ Res 2020 01 5;126(3):350-360. Epub 2019 Dec 5.

Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA (K.L.L., J.D., L.T., E.J.B., H.L.).

GWAS (Genome-Wide Association Studies) have identified hundreds of genetic loci associated with atrial fibrillation (AF). However, these loci explain only a small proportion of AF heritability. To develop an approach to identify additional AF-related genes by integrating multiple omics data. Three types of omics data were integrated: (1) summary statistics from the AFGen 2017 GWAS; (2) a whole blood EWAS (Epigenome-Wide Association Study) of AF; and (3) a whole blood TWAS (Transcriptome-Wide Association Study) of AF. The variant-level GWAS results were collapsed into gene-level associations using fast set-based association analysis. The CpG-level EWAS results were also collapsed into gene-level associations by an adapted SNP-set Kernel Association Test approach. Both GWAS and EWAS gene-based associations were then meta-analyzed with TWAS using a fixed-effects model weighted by the sample size of each data set. A tissue-specific network was subsequently constructed using the NetWAS (Network-Wide Association Study). The identified genes were then compared with the AFGen 2018 GWAS that contained more than triple the number of AF cases compared with AFGen 2017 GWAS. We observed that the multiomics approach identified many more relevant AF-related genes than using AFGen 2018 GWAS alone (1931 versus 206 genes). Many of these genes are involved in the development and regulation of heart- and muscle-related biological processes. Moreover, the gene set identified by multiomics approach explained much more AF variance than those identified by GWAS alone (10.4% versus 3.5%). We developed a strategy to integrate multiple omics data to identify AF-related genes. Our integrative approach may be useful to improve the power of traditional GWAS, which might be particularly useful for rare traits and diseases with limited sample size.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004281PMC
January 2020

Integrated Multiomics Approach to Identify Genetic Underpinnings of Heart Failure and Its Echocardiographic Precursors: Framingham Heart Study.

Circ Genom Precis Med 2019 12 8;12(12):e002489. Epub 2019 Nov 8.

Framingham Heart Study, MA (C.A., H.L., C.L., D.L., M.G.L., R.S.V.).

Background: Heart failure (HF) may arise from alterations in metabolic, structural, and signaling pathways, but its genetic architecture is incompletely understood. To elucidate potential genetic contributors to cardiac remodeling and HF, we integrated genome-wide single-nucleotide polymorphisms, gene expression, and DNA methylation using a transomics analytical approach.

Methods: We used robust rank aggregation (where the position of a certain gene in a rank order list [based on statistical significance level] is tested against a randomly shuffled rank order list) to derive an integrative transomic score for each annotated gene associated with a HF trait.

Results: We evaluated ≤8372 FHS (Framingham Heart Study) participants (54% women; mean age, 55±17 years). Of these, 62 (0.7%) and 35 (0.4%) had prevalent HF with reduced ejection fraction and HF with preserved left ventricular ejection fraction, respectively. During a mean follow-up of 8.5 years (minimum-maximum, 0.005-18.6 years), 223 (2.7%) and 234 (2.8%) individuals developed incident HF with reduced ejection fraction and HF with reduced ejection fraction, respectively. Top genes included and (promotes actin assembly at intercellular junctions) for left ventricular systolic function; (receptor for [vascular cell protein 1]) and for left ventricular remodeling; (expressed during myogenic differentiation) and (cytoskeletal protein) for diastolic function; and (involved in regulation of actin cytoskeleton) for prevalent HF with reduced ejection fraction; and for incident HF with reduced ejection fraction; and for prevalent HF with reduced ejection fraction; and (close to the enzyme) and (close to -the riboflavin transporter) for incident HF with reduced ejection fraction. We tested the HF-related top single-nucleotide polymorphisms in the UK biobank, where in (minor allele frequency, 0.023; odds ratio, 0.83; =0.002) remained statistically significant upon Bonferroni correction.

Conclusions: Our integrative transomics approach offers insights into potential molecular and genetic contributors to HF and its precursors. Although several of our candidate genes have been implicated in HF in animal models, independent replication is warranted.
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http://dx.doi.org/10.1161/CIRCGEN.118.002489DOI Listing
December 2019

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019