Publications by authors named "Joanne M Murabito"

196 Publications

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 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

Association Between Frailty and Atrial Fibrillation in Older Adults: The Framingham Heart Study Offspring Cohort.

J Am Heart Assoc 2021 Jan 29;10(1):e018557. Epub 2020 Dec 29.

Department of Biostatistics Boston University School of Public Health Boston MA.

Background Frailty is associated bidirectionally with cardiovascular disease. However, the relations between frailty and atrial fibrillation (AF) have not been fully elucidated. Methods and Results Using the FHS (Framingham Heart Study) Offspring cohort, we sought to examine both the association between frailty (2005-2008) and incident AF through 2016 and the association between prevalent AF and frailty status (2011-2014). Frailty was defined using the Fried phenotype. Models adjusted for age, sex, and smoking. Cox proportional hazards models, adjusted for competing risk of death, assessed the association between prevalent frailty and incident AF. Logistic regression models assessed the association between prevalent AF and new-onset frailty. For the incident AF analysis, we included 2053 participants (56% women; mean age, 69.7±6.9 years). By Fried criteria, 1018 (50%) were robust, 903 (44%) were prefrail, and 132 (6%) were frail. In total, 306 incident cases of AF occurred during an average 9.2 (SD, 3.1) follow-up years. After adjustment, there was no statistically significant association between prevalent frailty status and incident AF (prefrail versus robust: hazard ratio [HR], 1.22 [95% CI, 0.95-1.55]; frail versus robust: HR, 0.92 [95% CI, 0.57-1.47]). At follow-up, there were 111 new cases of frailty. After adjustment, there was no statistically significant association between prevalent AF and new-onset frailty (odds ratio, 0.48 [95% CI, 0.17-1.36]). Conclusions Although a bidirectional association between frailty and cardiovascular disease has been suggested, we did not find evidence of an association between frailty and AF. Our findings may be limited by sample size and should be further explored in other populations.
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http://dx.doi.org/10.1161/JAHA.120.018557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955470PMC
January 2021

The Association of Aging Biomarkers, Interstitial Lung Abnormalities, and Mortality.

Am J Respir Crit Care Med 2021 May;203(9):1149-1157

Division of Pulmonary and Critical Care Medicine and.

The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated. To evaluate the associations among aging biomarkers, ILA, and all-cause mortality. In the FHS (Framingham Heart Study), we evaluated associations among plasma biomarkers (IL-6, CRP [C-reactive protein], TNFR [tumor necrosis factor α receptor II], GDF15 [growth differentiation factor 15], cystatin-C, HGBA1C [Hb A1C], insulin, IGF1 [insulin-like growth factor 1], and IGFBP1 [IGF binding protein 1] and IGFBP3]), ILA, and mortality. Causal inference analysis was used to determine whether biomarkers mediated age. GDF15 results were replicated in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) Study. In the FHS, there were higher odds of ILA per increase in natural log-transformed GDF15 (odds ratio [95% confidence interval], 3.4 [1.8-6.4];  = 0.0002), TNFR (3.1 [1.6-5.8];  = 0.004), IL-6 (1.8 [1.4-2.4];  < 0.0001), and CRP (1.7 [1.3-2.0];  < 0.0001). In the FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but the associations of GDF15 (hazard ratio, 2.0 [1.1-3.5];  = 0.02), TNFR (1.8 [1.0-3.3];  = 0.05), and IGFBP1 (1.3 [1.1-1.7];  = 0.01) approached significance. In the COPDGene Study, higher natural log-transformed GDF15 was associated with ILA (odds ratio, 8.1 [3.1-21.4];  < 0.0001) and mortality (hazard ratio, 1.6 [1.1-2.2];  = 0.01). Causal inference analysis showed that the association of age with ILA was mediated by IL-6 ( < 0.0001) and TNFR ( = 0.002) and was likely mediated by GDF15 ( = 0.008) in the FHS and was mediated by GDF15 ( = 0.001) in the COPDGene Study. Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the associations among age, ILA, and mortality.
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http://dx.doi.org/10.1164/rccm.202007-2993OCDOI Listing
May 2021

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

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.

Aging (Albany NY) 2020 07 22;12(14):14092-14124. Epub 2020 Jul 22.

Section General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02215, USA.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality ( < 9.3x10) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to , and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to , and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes () linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
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http://dx.doi.org/10.18632/aging.103408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425458PMC
July 2020

Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies.

Atherosclerosis 2020 03 14;297:102-110. Epub 2020 Feb 14.

Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Backgrounds And Aims: Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change.

Methods: We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies.

Results: We identified a novel association for HDL-C with GRID1 (p = 5.43 × 10), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways.

Conclusions: Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098811PMC
March 2020

Accelerating the Search for Interventions Aimed at Expanding the Health Span in Humans: The Role of Epidemiology.

J Gerontol A Biol Sci Med Sci 2020 01;75(1):77-86

Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

Background: Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow.

Methods: Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging.

Results: Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals.

Conclusions: Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.
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http://dx.doi.org/10.1093/gerona/glz230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175971PMC
January 2020

Accelerometer-determined physical activity and cognitive function in middle-aged and older adults from two generations of the Framingham Heart Study.

Alzheimers Dement (N Y) 2019 15;5:618-626. Epub 2019 Oct 15.

Framingham Heart Study, Framingham, MA, USA.

Introduction: Physical activity (PA) may play a role in maintenance of cognitive function in both middle and older ages and prevention of outcomes such as dementia and Alzheimer's disease.

Methods: Cross-sectional regression analyses were performed in Framingham Heart Study Third Generation (n = 1861) and Offspring (n = 909) cohort participants assessing the association of accelerometry-measured PA with cognitive function, adjusting for age, sex, accelerometer wear time, education, occupational status/PA, and smoking status.

Results: In each cohort, achieving just 10-21.4 min/day moderate-to-vigorous PA related to better executive function ( < .02); and just 10 min/day moderate-to-vigorous PA was associated with better verbal memory in middle-aged adults in the Third Generation cohort ( = .02). In older adults of the Offspring cohort, total PA (measured in steps/day) was associated with better executive function ( < .02).

Discussion: PA at levels lower than the current PA Guidelines (just 10 min/day moderate-to-vigorous PA and total PA including lower intensity PA) were associated with better cognitive function.
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http://dx.doi.org/10.1016/j.trci.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807299PMC
October 2019

Comparison of On-Site Versus Remote Mobile Device Support in the Framingham Heart Study Using the Health eHeart Study for Digital Follow-up: Randomized Pilot Study Set Within an Observational Study Design.

JMIR Mhealth Uhealth 2019 09 30;7(9):e13238. Epub 2019 Sep 30.

Framingham Heart Study, Framingham, MA, United States.

Background: New electronic cohort (e-Cohort) study designs provide resource-effective methods for collecting participant data. It is unclear if implementing an e-Cohort study without direct, in-person participant contact can achieve successful participation rates.

Objective: The objective of this study was to compare 2 distinct enrollment methods for setting up mobile health (mHealth) devices and to assess the ongoing adherence to device use in an e-Cohort pilot study.

Methods: We coenrolled participants from the Framingham Heart Study (FHS) into the FHS-Health eHeart (HeH) pilot study, a digital cohort with infrastructure for collecting mHealth data. FHS participants who had an email address and smartphone were randomized to our FHS-HeH pilot study into 1 of 2 study arms: remote versus on-site support. We oversampled older adults (age ≥65 years), with a target of enrolling 20% of our sample as older adults. In the remote arm, participants received an email containing a link to enrollment website and, upon enrollment, were sent 4 smartphone-connectable sensor devices. Participants in the on-site arm were invited to visit an in-person FHS facility and were provided in-person support for enrollment and connecting the devices. Device data were tracked for at least 5 months.

Results: Compared with the individuals who declined, individuals who consented to our pilot study (on-site, n=101; remote, n=93) were more likely to be women, highly educated, and younger. In the on-site arm, the connection and initial use of devices was ≥20% higher than the remote arm (mean percent difference was 25% [95% CI 17-35] for activity monitor, 22% [95% CI 12-32] for blood pressure cuff, 20% [95% CI 10-30] for scale, and 43% [95% CI 30-55] for electrocardiogram), with device connection rates in the on-site arm of 99%, 95%, 95%, and 84%. Once connected, continued device use over the 5-month study period was similar between the study arms.

Conclusions: Our pilot study demonstrated that the deployment of mobile devices among middle-aged and older adults in the context of an on-site clinic visit was associated with higher initial rates of device use as compared with offering only remote support. Once connected, the device use was similar in both groups.
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http://dx.doi.org/10.2196/13238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792023PMC
September 2019

Age-related DNA hydroxymethylation is enriched for gene expression and immune system processes in human peripheral blood.

Epigenetics 2020 03 26;15(3):294-306. Epub 2019 Sep 26.

Department of Human Genetics, Emory University, Atlanta, GA, USA.

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.
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http://dx.doi.org/10.1080/15592294.2019.1666651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028349PMC
March 2020

Advantages of Continuous-Valued Risk Scores for Predicting Long-Term Costs: The Framingham Coronary Heart Disease 10-Year Risk Score.

Adv Geriatr Med Res 2019 6;1(1). Epub 2019 Jun 6.

Operations and Technology Management Department, Boston University, Questrom School of Business, Boston, MA 02215, USA.

Background: The few studies that have examined the relationship between midlife cardiovascular disease risk and longer-term costs have differentiated risk using a small number of risk categories. In this paper, we illustrate the advantages of a continuous-valued score to examine the relationship between risk and longer-term costs: the Framingham 10-year coronary heart disease risk score.

Methods: Our study cohort consisted of 1333 Second Generation Framingham Heart Study participants enrolled in fee-for-service Medicare for at least 8 quarters and who had a risk score assessment between age 40 and 50 years. We used generalized linear models to examine the relationships between quarterly Medicare costs and risk scores.

Results: Using risk categories defined by the Framingham score, the cost differences between a low and high risk group were 40% to over 200% greater than differences in comparable studies using a small number of risk categories. A continuous-valued score facilitates comparison of the cost consequences of impacting risk score changes. For example, an intervention that is able to reduce a person's score change between midlife and later-life from the 75th percentile to the 25th percentile would result in almost a 20% reduction in longer-term costs. In contrast, an intervention that is able to reduce a person's midlife score from the 75th percentile to the 25th percentile would result in a 38% reduction in costs.

Conclusions: A continuous-valued risk score has advantages compared to defining risk based on a small number of risk categories.
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http://dx.doi.org/10.20900/agmr20190004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707532PMC
June 2019

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Nat Commun 2019 08 14;10(1):3669. Epub 2019 Aug 14.

Department of Public Health, University of Southern Denmark, 5000, Odense C, Denmark.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
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http://dx.doi.org/10.1038/s41467-019-11558-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694136PMC
August 2019

Epigenome-wide association study of DNA methylation and microRNA expression highlights novel pathways for human complex traits.

Epigenetics 2020 Jan - Feb;15(1-2):183-198. Epub 2019 Jul 17.

The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at < 0.2. miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 -miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.
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http://dx.doi.org/10.1080/15592294.2019.1640547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961684PMC
April 2021

Genetic associations with age of menopause in familial longevity.

Menopause 2019 10;26(10):1204-1212

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

Objective: We hypothesize that mechanisms associated with extended reproductive age may overlap with mechanisms for the selection of genetic variants that slow aging and decrease risk for age-related diseases. Therefore, the goal of this analysis is to search for genetic variants associated with delayed age of menopause (AOM) among women in a study of familial longevity.

Methods: We performed a meta-analysis of genome-wide association studies for AOM in 1,286 women in the Long Life Family Study (LLFS) and 3,151 women in the Health and Retirement Study, and then sought replication in the Framingham Heart Study (FHS). We used Cox proportional hazard regression of AOM to account for censoring, with a robust variance estimator to adjust for within familial relations.

Results: In the meta-analysis, a single nucleotide polymorphism (SNP) previously associated with AOM reached genome-wide significance (rs16991615; HR = 0.74, P = 6.99 × 10). A total of 35 variants reached >10 level of significance and replicated in the FHS and in a 2015 large meta-analysis (ReproGen Consortium). We also identified several novel SNPs associated with AOM including rs3094005: MICB, rs13196892: TXNDC5 | MUTED, rs72774935: SSBP2 | ATG10, rs9447453: COL12A1, rs114298934: FHL2 | NCK2, rs6467223: TNPO3, rs9666274 and rs10766593: NAV2, and rs7281846: HSPA13.

Conclusions: This work indicates novel associations and replicates known associations between genetic variants and AOM. A number of these associations make sense for their roles in aging.

Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A420.
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http://dx.doi.org/10.1097/GME.0000000000001367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008937PMC
October 2019

Healthy diet is associated with gene expression in blood: the Framingham Heart Study.

Am J Clin Nutr 2019 09;110(3):742-749

National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA.

Background: Genes in metabolic and nutrient signaling pathways play important roles in lifespan in model organisms and human longevity.

Objective: The aim of this study was to examine the relation of a quantitative measure of healthy diet to gene expression in a community-based cohort.

Methods: We used the 2015 Dietary Guidelines for Americans Adherence Index (DGAI) score to quantify key dietary recommendations of an overall healthy diet. Our current analyses included 2220 Offspring participants (mean age 66 ± 9 y, 55.4% women) and 2941 Third-Generation participants (mean age 46 ± 9 y, 54.5% women) from the Framingham Heart Study. Gene expression was profiled in blood through the use of the Affymetrix Human Exon 1.0 ST Array. We conducted a transcriptome-wide association study of DGAI adjusting for age, sex, smoking, cell counts, and technical covariates. We also constructed a combined gene score from genes significantly associated with DGAI.

Results: The DGAI was significantly associated with the expression of 19 genes (false discovery rate <0.05). The most significant gene, ARRDC3, is a member of the arrestin family of proteins, and evidence in animal models and human data suggests that this gene is a regulator of obesity and energy expenditure. The DGAI gene score was associated with body mass index (P = 1.4 × 10-50), fasting glucose concentration (P = 2.5 × 10-11), type 2 diabetes (P = 1.1 × 10-5), and metabolic syndrome (P = 1.8 × 10-32).

Conclusions: Healthier diet was associated with genes involved in metabolic function. Further work is needed to replicate our findings and investigate the relation of a healthy diet to altered gene regulation.
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http://dx.doi.org/10.1093/ajcn/nqz060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736078PMC
September 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Association of Accelerometer-Measured Light-Intensity Physical Activity With Brain Volume: The Framingham Heart Study.

JAMA Netw Open 2019 04 5;2(4):e192745. Epub 2019 Apr 5.

Framingham Heart Study, Framingham, Massachusetts.

Importance: Dementia risk may be attenuated by physical activity (PA); however, the specific activity levels optimal for dementia prevention are unclear. Moreover, most older adults are unable to meet the nationally recommended PA guidelines, set at 150 minutes of moderate to vigorous PA per week.

Objective: To assess the association of total steps walked per day and total dose (intensity × duration) of PA with brain volumes on magnetic resonance imaging (MRI) among Framingham Heart Study participants.

Design, Setting, And Participants: This cross-sectional, community-based cohort study of the association of accelerometry-determined PA with brain MRI measures in Framingham, Massachusetts, included the Framingham Heart Study third-generation (examination 2, 2008-2011) and offspring (examination 9, 2011-2014) cohorts. Of 4021 participants who agreed to wear an accelerometer and had valid data (≥10 hours/day for ≥3 days), 1667 participants who did not undergo brain MRI (n = 1604) or had prevalent dementia or stroke (n = 63) were excluded. Data analysis began in 2016 and was completed in February 2019.

Exposures: Physical activity achieved using accelerometry-derived total activity (steps per day) and 2 intensity levels (light intensity and moderate to vigorous intensity).

Main Outcomes And Measures: Differences in total brain volume and other MRI markers of brain aging.

Results: The study sample of 2354 participants had a mean (SD) age of 53 (13) years, 1276 (54.2%) were women, and 1099 (46.7%) met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging (β estimate, 0.22; SD, 0.07; P = .003). Among individuals not meeting the PA guidelines, each hour of light-intensity PA (β estimate, 0.28; SD, 0.11; P = .01) and achieving 7500 steps or more per day (β estimate, 0.44; SD, 0.18; P = .02) were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume.

Conclusions And Relevance: Every additional hour of light-intensity PA was associated with higher brain volumes, even among individuals not meeting current PA guidelines. These data are consistent with the notion that the potential benefits of PA on brain aging may accrue at a lower, more achievable level of intensity or duration.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481600PMC
April 2019

Design and Preliminary Findings From a New Electronic Cohort Embedded in the Framingham Heart Study.

J Med Internet Res 2019 03 1;21(3):e12143. Epub 2019 Mar 1.

Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, United States.

Background: New models of scalable population-based data collection that integrate digital and mobile health (mHealth) data are necessary.

Objective: The aim of this study was to describe a cardiovascular digital and mHealth electronic cohort (e-cohort) embedded in a traditional longitudinal cohort study, the Framingham Heart Study (FHS).

Methods: We invited eligible and consenting FHS Generation 3 and Omni participants to download the electronic Framingham Heart Study (eFHS) app onto their mobile phones and co-deployed a digital blood pressure (BP) cuff. Thereafter, participants were also offered a smartwatch (Apple Watch). Participants are invited to complete surveys through the eFHS app, to perform weekly BP measurements, and to wear the smartwatch daily.

Results: Up to July 2017, we enrolled 790 eFHS participants, representing 76% (790/1044) of potentially eligible FHS participants. eFHS participants were, on average, 53±8 years of age and 57% were women. A total of 85% (675/790) of eFHS participants completed all of the baseline survey and 59% (470/790) completed the 3-month survey. A total of 42% (241/573) and 76% (306/405) of eFHS participants adhered to weekly digital BP and heart rate (HR) uploads, respectively, over 12 weeks.

Conclusions: We have designed an e-cohort focused on identifying novel cardiovascular disease risk factors using a new smartphone app, a digital BP cuff, and a smartwatch. Despite minimal training and support, preliminary findings over a 3-month follow-up period show that uptake is high and adherence to periodic app-based surveys, weekly digital BP assessments, and smartwatch HR measures is acceptable.
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http://dx.doi.org/10.2196/12143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418484PMC
March 2019

Objective physical activity and physical performance in middle-aged and older adults.

Exp Gerontol 2019 05 13;119:203-211. Epub 2019 Feb 13.

Framingham Heart Study, Framingham, MA, USA; Department of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.

Background: Older adults may have difficulty meeting the Physical Activity (PA) Guidelines. A favorable balance between PA and sedentary time (SED) is an important determinant of physical performance in older adults. Our objective was to explore associations of PA/SED with physical performance across mid-older age in adults without overt mobility disability.

Methods: Framingham Offspring Study participants free of mobility disability with accelerometry and physical performance data (gait speed, chair stand time, and handgrip strength), were studied in cross-sectional analysis (n = 1352). We regressed physical performance on PA level, measured using steps, moderate to vigorous (MV)PA and SED. We stratified by age groups, adjusted for covariates, and modelled MVPA and SED separately and together as predictors.

Results: Only 38% of adults 50-64 years and 15% of adults ≥75 years met the PA Guidelines (i.e., 150 min MVPA per week). Individuals achieving at least 5 min/day of MVPA had 0.062 ± 0.013 m/s greater gait speed and better chair stands and handgrip strength (in women) than those with <5 min/day of MVPA (p < 0.01) across mid-older age. SED was associated with poorer performance on gait speed and chair stand tests, but results were not significant after adjusting for MVPA (p > 0.05). For adults ≥75 years, every 5000 more steps/day related to ~0.045 m/s greater gait speed (p = 0.006).

Conclusion: Our cross-sectional study demonstrated that, across mid-older adulthood, MVPA related to better physical performance, but in adults ≥75 years, total steps walked associated with better gait speed. These data warrant future research on the impact of PA on physical performance and health outcomes in older age.
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http://dx.doi.org/10.1016/j.exger.2019.02.003DOI Listing
May 2019

Self-Reported Physical Activity and Relations to Growth and Neurotrophic Factors in Diabetes Mellitus: The Framingham Offspring Study.

J Diabetes Res 2019 9;2019:2718465. Epub 2019 Jan 9.

Framingham Heart Study, Framingham, MA, USA.

Aims: Circulating insulin-like growth factor- (IGF-) 1, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) levels are often lower in individuals with diabetes mellitus (DM) and are important for repairing vascular and neuronal dysfunction. The purpose of this investigation was to determine the cross-sectional relations of physical activity to circulating concentrations of IGF-1, VEGF, and BDNF in individuals with and without DM.

Methods: In 1730 participants from the Framingham Offspring Study examination cycle 7, including those with DM ( = 179, mean age 64 years, 39% women) and without DM ( = 1551, mean age 60 years, 46% women), we related self-reported physical activity variables to circulating concentrations of IGF-1, VEGF, and BDNF using linear multivariable regression models. We also tested for interactions by age. Participants with prevalent cardiovascular disease, stroke, and dementia or taking hormone replacement therapy were excluded.

Results: In participants with DM, more ambulatory physical activity was associated with higher IGF-1 levels ( ± standard error (SE) = 0.22 ± 0.08, = 0.009), and more total physical activity was related to higher BDNF levels ( ± SE = 0.18 ± 0.08, = 0.035), but physical activity was not significantly related to circulating VEGF. In participants without DM, no associations were observed. Moreover, in the examination of interactions by age, the association of ambulatory physical activity with IGF-1 levels was only observed in older adults with DM (age ≥ 60 years, ± SE = 0.23 ± 0.11, = 0.042) but not in middle-aged adults with DM (age < 60 years, ± SE = 0.06 ± 0.13, = 0.645).

Conclusion: Our results suggest that more physical activity is associated with higher circulating IGF-1 and BDNF in participants with DM. These results, dissecting interactions by both age and DM status, may also help to explain some of the inconsistent results in studies relating physical activity to growth and neurotrophic factors.
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http://dx.doi.org/10.1155/2019/2718465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343169PMC
June 2019

Whole Blood Gene Expression Associated With Clinical Biological Age.

J Gerontol A Biol Sci Med Sci 2019 01;74(1):81-88

National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.

Background: Biologic age may better reflect an individual's rate of aging than chronologic age.

Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at 1 second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array.

Results: Our discovery sample included 2,163 participants from the Framingham Offspring cohort (mean age 67 ± 9 years, 55% women). A total of 481 genes were significantly associated with ∆age (p < 2.8 × 10-6). Among them, 415 genes were validated (p < .05/481 = 1.0 × 10-4) in 2,946 participants from the Framingham Third Generation cohort (mean age 46 ± 9 years, 53% women). Many of the significant genes were involved in the ubiquitin-mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59 ± 8, 52% women) found 104 of 415 validated genes reached nominal significance (p < .05).

Conclusion: We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults.
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http://dx.doi.org/10.1093/gerona/gly164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298179PMC
January 2019

Cross-Sectional Association of Frailty and Arterial Stiffness in Community-Dwelling Older Adults: The Framingham Heart Study.

J Gerontol A Biol Sci Med Sci 2019 02;74(3):373-379

Framingham Heart Study, National Heart, Lung, and Blood Institute, Boston University, Framingham, Massachusetts.

Background: Frailty is a risk factor for cardiovascular disease (CVD). Underlying mechanisms to explain the connection between frailty and CVD are unclear. We sought to examine the association between frailty and arterial stiffness, a precursor of hypertension and CVD.

Methods: We conducted a cross-sectional analysis of community-dwelling Framingham Heart Study Offspring and Omni participants ≥60 years of age examined in 2005-2008. Frailty was defined primarily according to the Fried physical phenotype definition, which identifies nonfrail, prefrail, and frail individuals. Arterial stiffness was assessed using carotid-femoral pulse wave velocity (CFPWV). Generalized linear regression was used to examine the association between frailty level and CFPWV (modeled as -1000/CFPWV in msec/m, then transformed back to the original scale, m/s), adjusted for age, sex, cohort, mean arterial pressure, heart rate, height, and smoking.

Results: Of 2,171 participants (55% women, 91% white), 45% were prefrail and 7% were frail. Mean ages were 67, 70, and 73 years, and adjusted CFPWV least squares means were 10.0 (95% CI, 9.9-10.1), 10.3 (10.2-10.5), and 10.5 m/s (10.1-11.0); p = .0002 for nonfrail, prefrail, and frail groups, respectively. Results were similar using the Rockwood cumulative deficit model of frailty, and in a sensitivity analysis adjusting for prevalent coronary heart disease and diabetes.

Conclusions: Prefrailty and frailty were associated with higher arterial stiffness in a cohort of community-dwelling older adults. Arterial stiffness may help explain the relationship between frailty and CVD.
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http://dx.doi.org/10.1093/gerona/gly134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599281PMC
February 2019

Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study.

Front Pharmacol 2018 24;9:207. Epub 2018 Apr 24.

National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, United States.

Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk. We conducted an epigenome-wide association study of sTNFR2 levels in the Framingham Heart Study Offspring cohort (examination 8; 2005-2008). sTNFR2 was quantitated by enzyme immunoassay and DNA methylation by microarray. The concentration of sTNFR2 was log-transformed and outliers were excluded. We conducted linear mixed effects models to test the association between sTNFR2 level and methylation at over 400,000 CpGs, adjusting for age, sex, BMI, smoking, imputed cell count, technical covariates, and accounting for familial relatedness. The study sample included 2468 participants (mean age: 67 ± 9 years, 52% women, mean sTNFR2 level 2661 ± 1078 pg/ml). After accounting for multiple testing, we identified 168 CpGs ( < 1.2 × 10) that were differentially methylated in relation to sTNFR2. A substantial proportion (27 CpGs; 16%) are in the major histocompatibility complex region and in loci overrepresented for antigen binding molecular functions ( = 1.7 × 10) and antigen processing and presentation biological processes ( = 1.3 × 10). Identified CpGs are enriched in active regulatory regions and associated with expression of 48 -genes (±500 kb) in whole blood ( < 1.1 × 10) that coincide with genes identified in GWAS of diseases of immune dysregulation (inflammatory bowel disease, type 1 diabetes, IgA nephropathy). Differentially methylated loci in leukocytes associated with sTNF2 levels reside in active regulatory regions, are overrepresented in antigen processes, and are linked to inflammatory diseases.
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http://dx.doi.org/10.3389/fphar.2018.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928448PMC
April 2018

GWAS of epigenetic aging rates in blood reveals a critical role for TERT.

Nat Commun 2018 01 26;9(1):387. Epub 2018 Jan 26.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
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http://dx.doi.org/10.1038/s41467-017-02697-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786029PMC
January 2018

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

J Clin Endocrinol Metab 2018 03;103(3):991-1004

Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.

Objective: To investigate the genetic regulation of serum E2 and E1 in men.

Design, Setting, And Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.

Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.

Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.

Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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http://dx.doi.org/10.1210/jc.2017-02060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868407PMC
March 2018

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Nat Commun 2017 07 12;8:16015. Epub 2017 Jul 12.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
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http://dx.doi.org/10.1038/ncomms16015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510175PMC
July 2017

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Hum Mol Genet 2018 02;27(4):742-756

FIMM Institute for Molecular Medicine Finland, Helsinki University, Helsinki FI-00014, Finland.

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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http://dx.doi.org/10.1093/hmg/ddx429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886200PMC
February 2018