Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized ...that cumulative DNA damage during aging contributes to vascular dysfunction.
In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity.
Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
Abstract The central nervous system has the second highest concentration of lipids after adipose tissue. Alterations in neural membrane phospho- and sphingolipid composition can influence crucial ...intra- and intercellular signalling and alter the membrane's properties. Recently, the polyunsaturated fatty acids (PUFA) hypothesis for depression suggests that phospho- and sphingolipid metabolism includes potential pathways for the disease. In 742 people from a Dutch family-based study, we assessed the relationships between 148 different plasma phospho- and sphingolipid species and depression/anxiety symptoms as measured by the Hospital Anxiety and Depression Scales (HADS-A and HADS-D) and the Centre for Epidemiological Studies Depression Scale (CES-D). We observed significant differences in plasma sphingomyelins (SPM), particularly the SPM 23:1/SPM 16:0 ratio, which was inversely correlated with depressive symptom scores. We observed a similar trend for plasma phosphatidylcholines (PC), particularly the molar proportion of PC O 36:4 and its ratio to ceramide CER 20:0. Absolute levels of PC O 36:4 were also associated with depression symptoms in an independent replication. To our knowledge this is the first study on depressive symptoms that focuses on specific phospho- and sphingolipid molecules in plasma rather than total PUFA concentrations. The findings of this lipidomic study suggests that plasma sphingomyelins and ether phospholipids should be further studied for their potential as biomarkers and for a better understanding of the underlying mechanisms of this systemic disease.
Background Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group ...exclusively. Objective The aim of this study was to identify common genetic variants associated with FEV1 and its ratio to forced vital capacity (FVC) in never-smokers. Methods Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results ( P < 10−5 ) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n = 1966). Furthermore, we aimed to assess the effects of the replicated variants in more detail by performing genetic risk score, expression quantitative trait loci, and variant*ever-smoking interaction analyses. Results We identified associations between the FEV1 /FVC ratio and 5 common genetic variants in the identification cohort, and 2 of these associations were replicated. The 2 variants annotated to the genes hedgehog interacting protein (HHIP) and family with sequence similarity 13 member A (FAM13A) were shown to have an additive effect on FEV1 /FVC levels in the genetic risk score analysis; were associated with gene expression of HHIP and FAM13A in lung tissue, respectively; and were genome-wide significant in a meta-analysis including both identification and 4 verification cohorts ( P < 2.19 × 10−7 ). Finally, we did not identify significant interactions between the variants and ever smoking. Results of the FEV1 identification analysis were not replicated. Conclusion The genes HHIP and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease.
Abstract
Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of ...Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive ...manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with 'true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05-0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r(2), increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r(2) improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r(2) increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results.
Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of ...almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
IMPORTANCE: Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as ...depression. OBJECTIVE: To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD. DESIGN, SETTING AND PARTICIPANTS: This cohort study used data from participants in the UK Biobank cohort (n = 500 000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD = 59 851; control individuals = 113 154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118 000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021. MAIN OUTCOMES AND MEASURES: Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform. RESULTS: The study included 6811 individuals with lifetime MDD compared with 51 446 control individuals and 4370 individuals with recurrent MDD compared with 62 508 control individuals. Individuals with lifetime MDD were younger (median IQR age, 56 49-62 years vs 58 51-64 years) and more often female (4447 65% vs 2364 35%) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (β SE, −0.07 0.02; FDR = 4 × 10−04) and pyruvate was significantly increased (β SE, 0.04 0.02; FDR = 0.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not. CONCLUSIONS AND RELEVANCE: The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.
In this prospective cohort study of 6989 subjects 55 years old or older, the risk of Alzheimer's disease was reduced significantly among those who were long-term users of nonsteroidal ...antiinflammatory drugs. There was no significant reduction in risk among those with less than 24 months' cumulative use of these medications, and there was no evidence of a protective effect against the development of vascular dementia.
In this prospective cohort study, the risk of Alzheimer's disease was reduced among the long-term users.
The neuropathologic features of Alzheimer's disease include the accumulation of microglia around plaques, a local cytokine-mediated acute-phase response, and activation of the complement cascade.
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This inflammatory response may damage neurons and exacerbate the pathologic processes underlying the disease.
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Nonsteroidal antiinflammatory drugs (NSAIDs) may influence this inflammatory response by inhibiting cyclooxygenase-1 and cyclooxygenase-2 and by activating the peroxisome proliferator γ (PPARγ) nuclear transcription factor.
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In addition, cyclooxygenase-mediated oxidation is important in the calcium-dependent glutamate-signaling pathway that involves
N
-methyl-D-aspartate. In this way, NSAIDs may be able to protect neurons directly by reducing cellular responses to glutamate.
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The results of . . .
Abstract Background The neural substrate of genetic risk variants for Alzheimer’s disease (AD) remains unknown. We studied their effect on healthy brain morphology to provide insight into disease ...etiology in the pre-clinical phase. Methods We included 4071 non-demented, elderly participants of the population-based Rotterdam Study who underwent brain MRI and genotyping. We performed voxel-based morphometry (VBM) on all gray matter voxels for 19 previously identified, common AD risk variants. Whole-brain expression data from the Allen Human Brain Atlas was used to examine spatial overlap between VBM association results and expression of genes in AD risk loci regions. Results Brain regions most significantly associated with AD risk variants were the left postcentral gyrus with ABCA7 (rs4147929, p = 4.45 × 10-6 ), right superior frontal gyrus by ZCWPW1 (rs1476679, p = 5.12 × 10-6 ), and right postcentral gyrus by APOE (p = 6.91 × 10-6 ). Though no individual voxel passed multiple testing correction, we found significant spatial overlap between the effects of AD risk loci on VBM and the expression of genes ( MEF2C, CLU, SLC24A4) in the Allen Brain Atlas. Results are available online on www.imagene.nl/ADSNPs/. Conclusion In this single largest imaging genetics dataset worldwide, we found that AD risk loci affect cortical gray matter in several brain regions known to be involved in AD, as well as regions that have not been implicated before.
Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA ...methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages.
Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers. This distinct pattern extends to other tissues and multiple cancer types. Finally, genes associated with aVMPs in trans whose expression is variably upregulated with age (733 genes) play a key role in DNA repair and apoptosis, whereas downregulated aVMP-associated genes (121 genes) are mapped to defined pathways in cellular metabolism.
Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing.
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