RESUMO
Genome-wide association studies of human personality have been carried out, but transcription of the whole genome has not been studied in relation to personality in humans. We collected genome-wide expression profiles of adults to characterize the regulation of expression and function in genes related to human personality. We devised an innovative multi-omic approach to network analysis to identify the key control elements and interactions in multi-modular networks. We identified sets of transcribed genes that were co-expressed in specific brain regions with genes known to be associated with personality. Then we identified the minimum networks for the co-localized genes using bioinformatic resources. Subjects were 459 adults from the Young Finns Study who completed the Temperament and Character Inventory and provided peripheral blood for genomic and transcriptomic analysis. We identified an extrinsic network of 45 regulatory genes from seed genes in brain regions involved in self-regulation of emotional reactivity to extracellular stimuli (e.g., self-regulation of anxiety) and an intrinsic network of 43 regulatory genes from seed genes in brain regions involved in self-regulation of interpretations of meaning (e.g., production of concepts and language). We discovered that interactions between the two networks were coordinated by a control hub of 3 miRNAs and 3 protein-coding genes shared by both. Interactions of the control hub with proteins and ncRNAs identified more than 100 genes that overlap directly with known personality-related genes and more than another 4000 genes that interact indirectly. We conclude that the six-gene hub is the crux of an integrative network that orchestrates information-transfer throughout a multi-modular system of over 4000 genes enriched in liquid-liquid-phase-separation (LLPS)-related RNAs, diverse transcription factors, and hominid-specific miRNAs and lncRNAs. Gene expression networks associated with human personality regulate neuronal plasticity, epigenesis, and adaptive functioning by the interactions of salience and meaning in self-awareness.
RESUMO
Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10-9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.
Assuntos
Genoma Mitocondrial , Estado Pré-Diabético , Metilação de DNA/genética , DNA Mitocondrial/genética , Epigênese Genética , Genoma Mitocondrial/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Estado Pré-Diabético/genética , Locos de Características Quantitativas/genéticaRESUMO
Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes.
Assuntos
Biomarcadores/análise , Doenças Cardiovasculares/genética , Citocinas/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/imunologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Criança , Citocinas/imunologia , Feminino , Seguimentos , Redes Reguladoras de Genes , Predisposição Genética para Doença , Genoma Humano , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences.
Assuntos
Caráter , Estudo de Associação Genômica Ampla , Humanos , Personalidade/genética , Inventário de Personalidade , Filogenia , TemperamentoRESUMO
The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control.
Assuntos
DNA Mitocondrial/genética , Regulação da Expressão Gênica/genética , Adulto , Sequência de Bases , Células Sanguíneas/metabolismo , Células Sanguíneas/fisiologia , DNA Mitocondrial/sangue , Diabetes Mellitus Tipo 2/genética , Feminino , Expressão Gênica , Estudos de Associação Genética/métodos , Variação Genética/genética , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Transcriptoma/genéticaRESUMO
Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.
Assuntos
Estudo de Associação Genômica Ampla , Temperamento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Finlândia , Genótipo , Alemanha , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , República da Coreia , Adulto JovemRESUMO
Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.
Assuntos
Caráter , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Finlândia , Alemanha , Humanos , Individualidade , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , República da Coreia , Temperamento , Adulto JovemRESUMO
Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 Finns we identified 27 genome-widely significant loci (p < 1.2 × 10-9) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.
Assuntos
Citocinas/sangue , Estudo de Associação Genômica Ampla , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Locos de Características Quantitativas/genética , Doenças Autoimunes/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Humanos , Inflamação/genética , Masculino , Esclerose Múltipla/genéticaRESUMO
Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Assuntos
Plaquetas/metabolismo , Exoma/genética , Variação Genética/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Volume Plaquetário Médio , Contagem de PlaquetasRESUMO
Objective- Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored. Approach and Results- First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce N-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability. N-acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE-/-) mice during atherogenesis. N-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE-/- mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties. Conclusions- The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Etanolaminas/farmacologia , Macrófagos/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Fagocitose/efeitos dos fármacos , Placa Aterosclerótica , Amidas , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fenótipo , Fosfolipase D/metabolismo , Proto-Oncogene Mas , Ratos , Receptores de Canabinoides/genética , Receptores de Canabinoides/metabolismo , Fatores de Tempo , c-Mer Tirosina Quinase/metabolismoRESUMO
BACKGROUND: The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand α-melanocyte-stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of MC1-R beyond anti-inflammation. METHODS: Human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was assessed in apolipoprotein E-deficient mice. RESULTS: Characterization of human and mouse atherosclerotic plaques revealed that MC1-R expression localizes in lesional macrophages and is significantly associated with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for initiating reverse cholesterol transport. Using bone marrow-derived macrophages, we observed that α-melanocyte-stimulating hormone and selective MC1-R agonists similarly promoted cholesterol efflux, which is a counterregulatory mechanism against foam cell formation. Mechanistically, MC1-R activation upregulated the levels of ABCA1 and ABCG1. These effects were accompanied by a reduction in cell surface CD36 expression and in cholesterol uptake, further protecting macrophages from excessive lipid accumulation. Conversely, macrophages deficient in functional MC1-R displayed a phenotype with impaired efflux and enhanced uptake of cholesterol. Pharmacological targeting of MC1-R in atherosclerotic apolipoprotein E-deficient mice reduced plasma cholesterol levels and aortic CD36 expression and increased plaque ABCG1 expression and signs of plaque stability. CONCLUSIONS: Our findings identify a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R confers protection against macrophage foam cell formation through a dual mechanism: It prevents cholesterol uptake while concomitantly promoting ABCA1- and ABCG1-mediated reverse cholesterol transport.
Assuntos
Colesterol/metabolismo , Macrófagos/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo , Transdução de Sinais/fisiologia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Feminino , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células HEK293 , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Receptor Tipo 1 de Melanocortina/agonistas , Transdução de Sinais/efeitos dos fármacos , alfa-MSH/metabolismo , alfa-MSH/farmacologiaRESUMO
BACKGROUND: Prediabetes often occurs together with dyslipidaemia, which is paradoxically treated with statins predisposing to type 2 diabetes mellitus. We examined peripheral blood pathway profiles in prediabetic subjects with (PRD ) and without dyslipidaemia (PR0 ) and compared these to nonprediabetic controls without dyslipidaemia (C0 ). METHODS: The participants were from the Cardiovascular Risk in Young Finns Study, including 1240 subjects aged 34 to 49 years. Genome-wide expression data of peripheral blood and gene set enrichment analysis were used to investigate the differentially expressed genes and enriched pathways between different subtypes of prediabetes. RESULTS: Pathways for cholesterol synthesis, interleukin-12-mediated signalling events, and downstream signalling in naïve CD8+ T-cells were upregulated in the PR0 group in comparison with controls (C0 ). The upregulation of these pathways was independent of waist circumference, blood pressure, smoking status, and insulin. Adjustment for CRP left the CD8+ T-cell signalling and interleukin-12-mediated signalling event pathway upregulated. The cholesterol synthesis pathway was also upregulated when all prediabetic subjects (PR0 and PRD ) were compared with the nonprediabetic control group. No pathways were upregulated or downregulated when the PRD group was compared with the C0 group. Five genes in the PR0 group and 1 in the PRD group were significantly differentially expressed in comparison with the C0 group. CONCLUSIONS: Blood cell gene expression profiles differ significantly between prediabetic subjects with and without dyslipidaemia. Whether this classification may be used in detection of prediabetic individuals at a high risk of cardiovascular complications remains to be examined.
Assuntos
Doenças Cardiovasculares/etiologia , Colesterol/biossíntese , Dislipidemias/genética , Expressão Gênica , Estado Pré-Diabético/genética , Transdução de Sinais/genética , Adulto , Glicemia , Doenças Cardiovasculares/genética , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Finlândia , Perfilação da Expressão Gênica , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Estado Pré-Diabético/complicações , Regulação para Cima , Circunferência da CinturaRESUMO
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; pâ=â2.5×10â»7), with independent replication in a second population (pâ=â0.0048, OR(95% CI)â=â1.18(1.05-1.32); meta-analysis pâ=â2.6×10â»8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (pâ=â1.2×10⻹5; fold changeâ=â335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
Assuntos
Idade de Início , Doença da Artéria Coronariana/genética , Metaloproteinase 12 da Matriz/genética , Infarto do Miocárdio/genética , Adulto , Idoso , Artérias/patologia , Doença da Artéria Coronariana/classificação , Doença da Artéria Coronariana/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Glicosaminoglicanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant (p < 5 × 10(-8)) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic (p = 0.012) and systolic (p = 0.035) BP levels, as well as peripheral vascular resistance (p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease.
Assuntos
Pressão Sanguínea , Furina , Regulação Enzimológica da Expressão Gênica , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Feminino , Furina/biossíntese , Furina/genética , Humanos , Masculino , Pró-Proteína Convertases/biossíntese , Pró-Proteína Convertases/genética , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Subtilisinas/biossíntese , Subtilisinas/genética , Resistência Vascular/genéticaRESUMO
Non-coding 886 (nc886, vtRNA2-1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability and consequences of the methylation pattern, as well as the nature and function of the nc886 RNAs transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 RNA(s) has been redefined multiple times, and in carcinogenesis, these RNAs have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of the nc886 locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets. Herein, we aim to summarize the existing literature regarding nc886, discuss how the characteristics of nc886 give rise to contradictory results, as well as to reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how the distribution of the nc886 methylation pattern is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and RNA, we aim to highlight issues in the analysis of DNA methylation and non-coding RNAs in general and offer our suggestions for what should be taken into consideration in future analyses.
Assuntos
Metilação de DNA , Neoplasias , Humanos , Epigênese Genética , RNARESUMO
Biological age (BA) captures detrimental age-related changes. The best-known and most-used BA indicators include DNA methylation-based epigenetic clocks and telomere length (TL). The most common biological sample material for epidemiological aging studies, whole blood, is composed of different cell types. We aimed to compare differences in BAs between blood cell types and assessed the BA indicators' cell type-specific associations with chronological age (CA). An analysis of DNA methylation-based BA indicators, including TL, methylation level at cg16867657 in ELOVL2, as well as the Hannum, Horvath, DNAmPhenoAge, and DunedinPACE epigenetic clocks, was performed on 428 biological samples of 12 blood cell types. BA values were different in the majority of the pairwise comparisons between cell types, as well as in comparison to whole blood (p < 0.05). DNAmPhenoAge showed the largest cell type differences, up to 44.5 years and DNA methylation-based TL showed the lowest differences. T cells generally had the "youngest" BA values, with differences across subsets, whereas monocytes had the "oldest" values. All BA indicators, except DunedinPACE, strongly correlated with CA within a cell type. Some differences such as DNAmPhenoAge-difference between naïve CD4 + T cells and monocytes were constant regardless of the blood donor's CA (range 20-80 years), while for DunedinPACE they were not. In conclusion, DNA methylation-based indicators of BA exhibit cell type-specific characteristics. Our results have implications for understanding the molecular mechanisms underlying epigenetic clocks and underscore the importance of considering cell composition when utilizing them as indicators for the success of aging interventions.
RESUMO
Schizophrenia is often regarded as a disorder of premature aging. We investigated (a) whether polygenic risk for schizophrenia (PRSsch ) relates to pace of epigenetic aging and (b) whether personal dispositions toward active and emotionally close relationships protect against accelerated epigenetic aging in individuals with high PRSsch . The sample came from the population-based Young Finns Study (n = 1348). Epigenetic aging was measured with DNA methylation aging algorithms such as AgeAccelHannum , EEAAHannum , IEAAHannum , IEAAHorvath , AgeAccelHorvath , AgeAccelPheno , AgeAccelGrim , and DunedinPACE. A PRSsch was calculated using summary statistics from the most comprehensive genome-wide association study of schizophrenia to date. Social dispositions were assessed in terms of extraversion, sociability, reward dependence, cooperativeness, and attachment security. We found that PRSsch did not have a statistically significant effect on any studied indicator of epigenetic aging. Instead, PRSsch had a significant interaction with reward dependence (p = 0.001-0.004), cooperation (p = 0.009-0.020), extraversion (p = 0.019-0.041), sociability (p = 0.003-0.016), and attachment security (p = 0.007-0.014) in predicting AgeAccelHannum , EEAAHannum , or IEAAHannum . Specifically, participants with high PRSsch appeared to display accelerated epigenetic aging at higher (vs. lower) levels of extraversion, sociability, attachment security, reward dependence, and cooperativeness. A rather opposite pattern was evident for those with low PRSsch . No such interactions were evident when predicting the other indicators of epigenetic aging. In conclusion, against our hypothesis, frequent social interactions may relate to accelerated epigenetic aging in individuals at risk for psychosis. We speculate that this may be explained by social-cognitive impairments (perceiving social situations as overwhelming or excessively arousing) or ending up in less supportive or deviant social groups.
Assuntos
Esquizofrenia , Humanos , Esquizofrenia/genética , Estudo de Associação Genômica Ampla , Finlândia , Epigênese Genética/genética , Envelhecimento/genética , Metilação de DNA/genéticaRESUMO
Background: Studies have shown that cardiovascular health (CVH) is related to depression. We aimed to identify gene networks jointly associated with depressive symptoms and cardiovascular health metrics using the whole blood transcriptome. Materials and methods: We analyzed human blood transcriptomic data to identify gene co-expression networks, termed gene modules, shared by Beck's depression inventory (BDI-II) scores and cardiovascular health (CVH) metrics as markers of depression and cardiovascular health, respectively. The BDI-II scores were derived from Beck's Depression Inventory, a 21-item self-report inventory that measures the characteristics and symptoms of depression. CVH metrics were defined according to the American Heart Association criteria using seven indices: smoking, diet, physical activity, body mass index (BMI), blood pressure, total cholesterol, and fasting glucose. Joint association of the modules, identified with weighted co-expression analysis, as well as the member genes of the modules with the markers of depression and CVH were tested with multivariate analysis of variance (MANOVA). Results: We identified a gene module with 256 genes that were significantly correlated with both the BDI-II score and CVH metrics. Based on the MANOVA test results adjusted for age and sex, the module was associated with both depression and CVH markers. The three most significant member genes in the module were YOD1, RBX1, and LEPR. Genes in the module were enriched with biological pathways involved in brain diseases such as Alzheimer's, Parkinson's, and Huntington's. Conclusions: The identified gene module and its members can provide new joint biomarkers for depression and CVH.
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BACKGROUND AND PURPOSE: A novel association between a single nucleotide polymorphism on chromosome 7p21.1 and large-vessel ischemic stroke was recently identified. The most likely underlying gene is histone deacetylase 9 (HDAC9). The mechanism by which HDAC9 increases stroke risk is not clear; both vascular and neuronal mechanisms have been proposed. METHODS: We determined whether the lead single nucleotide polymorphisms were associated with asymptomatic carotid plaque (N=25 179) and carotid intima-media thickness (N=31 210) detected by carotid ultrasound in a meta-analysis of population-based and community cohorts. Immunohistochemistry was used to determine whether HDAC9 was expressed in healthy human cerebral and systemic arteries. In the Tampere Vascular Study, we determined whether HDAC9 mRNA expression was altered in carotid (N=29), abdominal aortic (N=15), and femoral (N=24) atherosclerotic plaques compared with control (left internal thoracic, N=28) arteries. RESULTS: Both single nucleotide polymorphisms (rs11984041 and rs2107595) were associated with common carotid intima-media thickness (rs2107595; P=0.0018) and with presence of carotid plaque (rs2107595; P=0.0022). In both cerebral and systemic arteries, HDAC9 labeling was seen in nuclei and cytoplasm of vascular smooth muscle cells, and in endothelial cells. HDAC9 expression was upregulated in carotid plaques compared with left internal thoracic controls (P=0.00000103). It was also upregulated in aortic and femoral plaques compared with controls, with mRNA expression increased in carotid compared with femoral plaques (P=0.0038). CONCLUSIONS: Our results are consistent with the 7p21.1 association acting via promoting atherosclerosis, and consistent with alterations in HDAC9 expression mediating this increased risk. Further studies in experimental models are required to confirm this link.
Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença , Histona Desacetilases/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Aterosclerose/genética , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/genética , Espessura Intima-Media Carotídea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
BACKGROUND: MicroRNAs (miRNA, miR) are noncoding RNAs that regulate gene expression by hindering translation. miRNA expression profiles have been shown to differ in vivo and in vitro in many cellular processes associated with cardiovascular diseases (CVDs). The progression of CVDs has also been shown to alter the blood miRNA profile in humans. CONTENT: We summarize the results of animal and cell experiments concerning the miRNA profile in the atherosclerotic process and the changes which occur in the blood miRNA profile of individuals with CVD. We also survey the relationship of these CVD-related miRNAs and their expression in the human advanced atherosclerotic plaque, thereby providing more insight into miRNA function in human atherosclerotic lesions. The miRNAs miR-126, -134, -145, -146a, -198, -210, -340*, and -92a were found to be expressed differently in the blood of individuals affected and unaffected by CVD. These differences paralleled those seen in tissue comparisons of miRNA expression in advanced atherosclerotic plaques and healthy arteries. Furthermore, several miRNAs associated with atherosclerosis in in vitro studies (such as miR-10a, -126, -145, -146a/b, -185, -210, and -326) were expressed in plaques in a similar pattern as was predicted by the in vitro experiments. The clinical implications of miRNAs in atherosclerosis as biomarkers and as possible drug targets are also reviewed. SUMMARY: miRNA profiles in in vitro and in vivo studies as well as in human peripheral blood are quite representative of the miRNA expression in human atherosclerotic plaques. miRNAs appear promising in terms of future clinical applications.