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Abstract The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological...
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Abstract The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45?years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40?years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
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Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribut...
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Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
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Background Limited population‐based data on the (sex‐specific) link between subclinical measures of peripheral atherosclerosis and new‐onset atrial fibrillation (AF) exist. Methods and Results Subclinical measures of peripheral...
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Background Limited population‐based data on the (sex‐specific) link between subclinical measures of peripheral atherosclerosis and new‐onset atrial fibrillation (AF) exist. Methods and Results Subclinical measures of peripheral atherosclerosis including carotid intima‐media thickness (cIMT), carotid plaque, and ankle‐brachial index (ABI) were assessed at baseline and follow‐up examinations. A total of 12?840 participants free of AF at baseline from the population‐based Rotterdam Study were included. Cox proportional hazards models and joint models, adjusted for cardiovascular risk factors, were used to determine the associations between baseline and longitudinal measures of cIMT, carotid plaque, and ABI with new‐onset AF. During a median follow‐up of 9.2?years, 1360 incident AF cases occurred among 12 840 participants (mean age 65.2 years, 58.3% women). Higher baseline cIMT (fully‐adjusted hazard ratio [HR], 95% CI, 1.81, 1.21–2.71; P =0.0042), presence of carotid plaque (fully‐adjusted HR, 95% CI, 1.19, 1.04–1.35; P =0.0089), lower ABI (fully‐adjusted HR, 95% CI, 1.57, 1.14–2.18; P =0.0061) and longitudinal measures of higher cIMT (fully‐adjusted HR, 95% CI, 2.14, 1.38–3.29; P =0.0021), presence of carotid plaque (fully‐adjusted HR, 95% CI, 1.61, 1.12–2.43; P =0.0112), and lower ABI (fully‐adjusted HR, 95% CI, 4.43, 1.83–10.49; P =0.0007) showed significant associations with new‐onset AF in the general population. Sex‐stratified analyses showed that the associations for cIMT, carotid plaque, and ABI were mostly prominent among women. Conclusions Baseline and longitudinal subclinical measures of peripheral atherosclerosis (carotid atherosclerosis, and lower extremity peripheral atherosclerosis) were significantly associated with an increased risk of new‐onset AF, especially among women. Registration URL: https://www.trialregister.nl , https://www.apps.who.int/trialsearch/ ; Unique identifier: NL6645/NTR6831.
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Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data...
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Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1 ), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1 /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
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Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear mor...
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Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology.
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BACKGROUND:DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation.?Here, we identify 818 genes that affect DNA methylation pattern...
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BACKGROUND:DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation.?Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.RESULTS:By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.CONCLUSION:We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
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Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic...
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Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% ( P =9.6*10?8) of the variance in adult systolic blood pressure and 0.8% ( P =0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [ P =8.9*10?10] and 1.4% [ P =3.3*10?5], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.
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Background Consensus lacks concerning a bidirectional association between kidney function and atrial fibrillation (AF), but this is crucial information for prevention/treatment efforts for both chronic kidney disease and AF. There...
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Background Consensus lacks concerning a bidirectional association between kidney function and atrial fibrillation (AF), but this is crucial information for prevention/treatment efforts for both chronic kidney disease and AF. Therefore, we investigated the bidirectional association between kidney function and AF. Methods and Results This study was a prospective cohort study including 9228 participants (mean age, 64.9?years; 57.2% women) with information on kidney function (estimated glomerular filtration rate [eGFR] based on serum creatinine [eGFRcreat], cystatin C [eGFRcys], or both [eGFRcreat‐cys], and urine albumin‐to‐creatinine ratio) and AF. Reduced kidney function was defined as eGFRcreat <60?mL/min per 1.73?m ~(2). Cox proportional‐hazards, logistic regression, linear mixed, and joint models were used to investigate the association of kidney function with AF and vice versa. During follow‐up (median of 8.0?years), 780 events of incident AF occurred. Lower eGFRcys and eGFRcreat‐cys were associated with increased AF risk (hazard ratio [HR], 1.08 [95% CI, 1.03–1.14] and HR, 1.07 [95% CI, 1.01–1.14], respectively, per 10?mL/min per 1.73?m ~(2) eGFR decrease). For eGFRcys and eGFRcreat‐cys, 10‐year cumulative incidence of AF was 16% (eGFR <60) and 6% (eGFR ≥60). Prevalent AF (versus no prevalent AF) was associated with 2.85?mL/min per 1.73?m ~(2) lower eGFRcreat and with a faster decline of eGFRcreat with age. Prevalent AF was associated with a 1.3‐fold increased risk of incident reduced kidney function. Conclusions Kidney function, especially eGFRcys, and AF are bidirectionally associated. There are currently no targeted prevention efforts for AF in patients with mild chronic kidney disease and vice versa. Our results could provide the first step to improve prediction/prevention of both conditions.
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Background Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of ...
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Background Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks. Results We perform a functional genomics analysis on four epigenetic clocks, including Hannum’s blood predictor and Horvath’s multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans . The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells. Conclusions The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.
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