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1.
Hum Brain Mapp ; 45(4): e26641, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38488470

RESUMO

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.


Assuntos
Encéfalo , Transtornos Mentais , Humanos , Encéfalo/fisiologia , Cognição/fisiologia , Mapeamento Encefálico , Transtornos Mentais/metabolismo , Expressão Gênica , Imageamento por Ressonância Magnética
2.
Eur Respir J ; 63(1)2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38097206

RESUMO

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.


Assuntos
Diabetes Mellitus Tipo 2 , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Diabetes Mellitus Tipo 2/genética , Pulmão , Volume Expiratório Forçado/genética , Espirometria , Capacidade Vital
3.
Mol Psychiatry ; 28(3): 1256-1271, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36481934

RESUMO

Discovering why some people's cognitive abilities decline more than others is a key challenge for cognitive ageing research. The most effective strategy may be to address multiple risk factors from across the life-course simultaneously in relation to robust longitudinal cognitive data. We conducted a 12-year follow-up of 1091 (at age 70) men and women from the longitudinal Lothian Birth Cohort 1936 study. Comprehensive repeated cognitive measures of visuospatial ability, processing speed, memory, verbal ability, and a general cognitive factor were collected over five assessments (age 70, 73, 76, 79, and 82 years) and analysed using multivariate latent growth curve modelling. Fifteen life-course variables were used to predict variation in cognitive ability levels at age 70 and cognitive slopes from age 70 to 82. Only APOE e4 carrier status was found to be reliably informative of general- and domain-specific cognitive decline, despite there being many life-course correlates of cognitive level at age 70. APOE e4 carriers had significantly steeper slopes across all three fluid cognitive domains compared with non-carriers, especially for memory (ß = -0.234, p < 0.001) and general cognitive function (ß = -0.246, p < 0.001), denoting a widening gap in cognitive functioning with increasing age. Our findings suggest that when many other candidate predictors of cognitive ageing slope are entered en masse, their unique contributions account for relatively small proportions of variance, beyond variation in APOE e4 status. We conclude that APOE e4 status is important for identifying those at greater risk for accelerated cognitive ageing, even among ostensibly healthy individuals.


Assuntos
Envelhecimento Cognitivo , Disfunção Cognitiva , Masculino , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Coorte de Nascimento , Cognição , Apolipoproteínas E , Estilo de Vida , Apolipoproteína E4 , Testes Neuropsicológicos , Estudos Longitudinais
4.
Int J Geriatr Psychiatry ; 39(9): e6151, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39297868

RESUMO

OBJECTIVES: To explore the strength of the association between cognitive functioning and depression and anxiety in older people without dementia. METHODS: An exploratory, cross-sectional analysis of Wave 1 (2004-2007) data from the Lothian Birth Cohort 1936 dataset. Three subgroups were based on Hospital Anxiety and Depression Scale (HADS) subscales: no probable anxiety or depression (N = 592), probable anxiety no depression (N = 122), probable depression with/without anxiety (depression) (N = 30). Regression analyses determined relationships between subgroups and identified cognitive test variables. RESULTS: Participants were 744 individuals (male = 385 [51.5%]; mean [M] age = 69.5 years [Standard deviation = 0.83]); characteristics for subgroups were similar. Participants with probable depression had slower simple reaction time scores than those with no anxiety or depression (regression slope [ß] on the log10 scale = 0.05, 95% Confidence Interval [0.03, 0.08], p ≤ 0.001). Those with probable anxiety had significantly worse scores on other tests: Spatial span (ß = -0.80 [-1.36, -0.25], p ≤ 0.005), Symbol Search (ß = -1.67 [-2.90, -0.45], p ≤ 0.01), Matrix Reasoning (ß = -1.58 [-2.55, -0.60], p ≤ 0.005) and Block Design (ß = -3.33 [-5.29, -1.37], p ≤ 0.001), than those without probable anxiety or depression. CONCLUSION: Probable depression and anxiety were found to be associated with lower cognitive function in those without evidence of dementia. People with probable anxiety showed poorer performance in tests that concerned making decisions. People with probable depression showed slower processing speed.


Assuntos
Transtorno Depressivo , Humanos , Feminino , Masculino , Idoso , Estudos Transversais , Escócia/epidemiologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Cognição/fisiologia , Testes Neuropsicológicos , Depressão/epidemiologia , Depressão/psicologia , Idoso de 80 Anos ou mais , Ansiedade/epidemiologia , Ansiedade/psicologia , Escalas de Graduação Psiquiátrica , Análise de Regressão , Estudos de Coortes , Tempo de Reação
5.
Alzheimers Dement ; 19(6): 2560-2574, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36547260

RESUMO

INTRODUCTION: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS: We examined post-mortem brain tissue from people in mid-life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer's brain homogenate. RESULTS: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid-life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline. DISCUSSION: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.


Assuntos
Doença de Alzheimer , Envelhecimento Cognitivo , Envelhecimento Saudável , Sinapses , Cognição , Sinapses/metabolismo , Sinapses/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Análise de Sequência de RNA , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Transmissão Sináptica , Mudanças Depois da Morte , Envelhecimento Saudável/metabolismo , Envelhecimento Saudável/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Gliose/patologia
6.
Am J Epidemiol ; 191(11): 1856-1866, 2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-35882379

RESUMO

Neighborhood features have been postulated to be key predictors of frailty. However, evidence is mainly limited to cross-sectional studies without indication of long-term impact. We explored how neighborhood social deprivation (NSD) across the life course is associated with frailty and frailty progression among older Scottish adults. Participants (n = 323) were persons selected from the Lothian Birth Cohort 1936 with historical measures of NSD in childhood (1936-1955), young adulthood (1956-1975), and mid- to late adulthood (1976-2014). Frailty was measured 5 times between the ages of 70 and 82 years using the Frailty Index. Confounder-adjusted life-course models were assessed using a structured modeling approach; associations were estimated for frailty at baseline using linear regression and for frailty progression using linear mixed-effects models. Accumulation was the most appropriate life-course model for males; greater accumulated NSD was associated with higher frailty at baseline (b = 0.017, 95% confidence interval: 0.005, 0.029). Among females, the mid- to late adulthood sensitive period was the best-fitting life-course model, and higher NSD in this period was associated with widening frailty trajectories (b = 0.005, 95% confidence interval: 0.0004, 0.009). To our knowledge, this is the first investigation of the life-course impact of NSD on frailty in a cohort of older adults. Policies designed to address deprivation and inequalities across the full life course may support healthy aging.


Assuntos
Fragilidade , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Idoso , Idoso de 80 Anos ou mais , Acontecimentos que Mudam a Vida , Estudos Transversais , Coorte de Nascimento , Características de Residência
7.
Eur J Neurosci ; 56(9): 5637-5649, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35362642

RESUMO

Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers ('epigenetic clocks'), and two inflammatory biomarkers (methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent associations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (ß range = 0.83-1.14, p ≤ 0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (ß = 1.32, p = 5 × 10-4 ); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (ß = 0.40, p = 0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.


Assuntos
Metilação de DNA , Doenças Neurodegenerativas , Humanos , Microglia , Epigênese Genética , Encéfalo , Inflamação/genética , Biomarcadores
8.
Psychol Sci ; 33(11): 1803-1817, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36113037

RESUMO

Identifying predictors of cognitive decline in old age helps us understand its mechanisms and identify those at greater risk. Here, we examined how cognitive change from ages 11 to 70 is associated with cognitive change at older ages (70 to 82 years) in the Lothian Birth Cohort 1936 longitudinal study (N = 1,091 at recruitment). Using latent-growth-curve models, we estimated rates of change from ages 70 to 82 in general cognitive ability (g) and in three cognitive domains: visuospatial, memory, and processing speed. We found that g accounted for 71.3% of interindividual change variance. Greater cognitive gain from ages 11 to 70 predicted slower decline in g over 12 subsequent years (ß = 0.163, p = .001), independently of cognitive level in childhood and at age 70, and domain-specific change beyond g. These results contribute to the goal of identifying people at higher risk of age-related cognitive decline.


Assuntos
Envelhecimento , Cognição , Humanos , Idoso , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Estudos Longitudinais , Estudos de Coortes , Envelhecimento/psicologia , Testes Neuropsicológicos
9.
Mol Psychiatry ; 26(8): 3806-3816, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-31796892

RESUMO

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm). A novel epigenetic clock, termed 'DNAm GrimAge' has outperformed its predecessors in predicting the risk of mortality as well as many age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n = 709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over the eighth decade (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 × 10-16). Higher DNAm GrimAge was associated with lower age 11 IQ (ß = -0.11), lower age 73 general cognitive ability (ß = -0.18), decreased brain volume (ß = -0.25) and increased brain white matter hyperintensities (ß = 0.17). There was tentative evidence for a longitudinal association between DNAm GrimAge and cognitive decline from age 70 to 79. Sixty-nine of 137 health- and brain-related phenotypes tested were significantly associated with GrimAge. Adjusting all models for childhood intelligence attenuated to non-significance a small number of associations (12/69 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge associates with lower cognitive ability and brain vascular lesions in older age, independently of early-life cognitive ability. This epigenetic predictor of mortality associates with different measures of brain health and may aid in the prediction of age-related cognitive decline.


Assuntos
Coorte de Nascimento , Epigênese Genética , Idoso , Envelhecimento/genética , Encéfalo/diagnóstico por imagem , Criança , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Humanos
10.
Mol Psychiatry ; 26(6): 2663-2676, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33414497

RESUMO

Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.


Assuntos
Variações do Número de Cópias de DNA , Genoma , Cognição , Variações do Número de Cópias de DNA/genética , Dosagem de Genes , Humanos , Testes de Inteligência
11.
Pediatr Emerg Care ; 38(1): e34-e36, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34653088

RESUMO

BACKGROUND: Jet injection of 1% lidocaine (J-Tip) has been used in the pediatric emergency department (PED) to reduce pain associated with venipuncture, but there are limited data on the effect of J-Tip on first-attempt venous access success rates. We sought to determine if using a J-Tip altered the first-attempt venous access success rate in the PED. Then, we examined the effect of J-Tip use on pain scores and resource utilization during peripheral venous access. METHODS: We prospectively evaluated children over 6 months of age who required peripheral venous access in the PED. The exposure group received 0.25 mL of 1% buffered lidocaine via jet injection 90 seconds before peripheral venous access. The control group received no local anesthesia. Parent and nurse surveys were completed during the visit. RESULTS: There was no difference in first attempt success rate between the exposure (n = 136) and control (n = 90) groups (87% vs 88%, P = 0.82). J-Tip use was associated with improved pain scores based on child report (median 1 vs 3; P < 0.001), parent report (median 1 vs 3; P < 0.001), and nurse assessment (median 0 vs 3; P < 0.001). CONCLUSIONS: Use of J-Tip in the PED to reduce pain associated with peripheral venous access did not lead to a reduction in first-attempt success rates for peripheral venous access. J-Tip was well received among nurses and parents and was associated with improved pain scores.


Assuntos
Anestésicos Locais , Lidocaína , Criança , Serviço Hospitalar de Emergência , Humanos , Injeções a Jato , Medição da Dor
12.
Mol Psychiatry ; 25(10): 2584-2598, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-30760887

RESUMO

Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within older age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initial n = 1091 age 70; final n = 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We ran additional analyses using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardized ß-values = -0.178 to 0.302), and the polygenic score for education was associated with cognitive change from childhood to age 70 (standardized ß = 0.100). No polygenic scores were statistically significantly associated with variation in cognitive change between ages 70 and 79, and effect sizes were small. However, APOE e4 status made a significant prediction of the rate of cognitive decline from age 70 to 79 (standardized ß = -0.319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par with APOE e4, a better-established predictor.


Assuntos
Cognição , Envelhecimento Cognitivo , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Idoso , Feminino , Humanos , Testes de Inteligência , Masculino , Testes Neuropsicológicos , Escócia
13.
Int J Obes (Lond) ; 43(9): 1795-1802, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30842548

RESUMO

BACKGROUND: The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. This study tests associations between an epigenetic score for body mass index (BMI) and health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian Birth Cohort 1936. This study also tests whether these associations are independent of phenotypic BMI. METHOD: Analyses were conducted using data from the Lothian Birth Cohort 1936 (n = 892). Weights for the epigenetic BMI score were derived using penalised regression on methylation data from unrelated Generation Scotland participants (n = 2562). Associations were tested for replication in an independent sample: the Lothian Birth Cohort 1921 (n = 433). RESULTS: A higher epigenetic BMI score was associated with higher BMI (R2 = 0.1), greater body weight (R2 = 0.06), greater time taken to walk 6 m, poorer lung function and poorer general physical health (all R2 = 0.02), greater levels of triglycerides (R2 = 0.09), greater %total HbA1c (R2 = 0.06), lower levels of high-density lipoprotein cholesterol (HDL; R2 = 0.08), higher HDL ratio (HDL/total cholesterol; R2 = 0.03), lower health-related quality of life, physical inactivity, and greater social deprivation (all R2 = 0.02). The epigenetic BMI score (per SD) was also associated with type 2 diabetes (OR 2.17, 95% CI 1.67, 2.84), cardiovascular disease (OR 1.45, 95% CI 1.24, 1.71) and high blood pressure (OR 1.30, 95% CI 1.13, 1.49; all p < 0.00026 after Bonferroni correction). Associations were replicated for BMI (R2 = 0.06), body weight (R2 = 0.04), health-related quality of life (R2 = 0.02), HbA1c (R2 = 0.07) and triglycerides (R2 = 0.07; all p < 0.0045 after Bonferroni correction). CONCLUSIONS: We observed and replicated associations between an epigenetic score for BMI and variables related to poor physical health and metabolic syndrome. Regression models with both epigenetic and phenotypic BMI scores as predictors accounted for a greater proportion of variance in all outcome variables than either predictor alone, demonstrating independent and additive effects of epigenetic and phenotypic BMI scores.


Assuntos
Índice de Massa Corporal , Metilação de DNA/genética , Aptidão Física/fisiologia , Idoso , Peso Corporal/genética , Peso Corporal/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Epigenômica , Feminino , Humanos , Masculino , Qualidade de Vida , Escócia
14.
Nature ; 482(7384): 212-5, 2012 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-22258510

RESUMO

Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change.


Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Inteligência/genética , Inteligência/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Idoso , Envelhecimento/fisiologia , Criança , Cognição/fisiologia , Interação Gene-Ambiente , Estudos de Associação Genética , Genoma Humano/genética , Genótipo , Humanos , Testes de Inteligência , Modelos Genéticos , Fenótipo
15.
Breast J ; 24(6): 981-985, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29802656

RESUMO

Fibroadenomas (FA) are the most common benign tumor in the female breast. Most are managed conservatively provided there is clinical, radiologic, and pathologic concordance. However, surgical excision is typically recommended for cellular fibroepithelial lesions or those lesions with clinical, radiologic, or pathologic features concerning for phyllodes tumor (PT). Some studies have suggested surgical excision in all FA >30 mm to reduce core needle biopsy (CNB) sampling errors. The aim of our study was to evaluate, in the absence of any other concerning clinicopathologic features, whether surgical excision of FA was warranted based on size criteria alone. Cork University Hospital is a large academic center in Southern Ireland. Its breast cancer center provides both a screening and symptomatic service and diagnoses approximately 600 cancers per year. The breast histopathological data base was reviewed for all CNBs from January 1, 2010, to June 30, 2015, with a diagnosis of FA that went on to have excision at our institution. We excluded all cellular fibroepithelial lesions and those cases with co-existent lobular neoplasia, ductal carcinoma in situ, invasive carcinoma, atypical ductal hyperplasia, or lesions which would require excision in their own right. Cases in which the radiologic targeted mass was discordant with a diagnosis of FA were also excluded. Patient demographics and preoperative radiologic size and the radiologic target were recorded in each case. All radiology was reviewed by a breast radiologist prior to inclusion in the study, and there was histologic radiologic concordance with a diagnosis of FA in all cases. A total of 12,109 consecutive radiologically guided CNB were performed January 2010-June 2015; 3438 with a diagnosis of FA were identified of which 290 cases went on to have surgical excision. Of those 290 cases; 98.28% (n = 285) were confirmed as FA on excision. The remaining 1.72% (n = 5) had atypical features-FA with LCIS (n = 1), benign PT (n = 3), and invasive ductal carcinoma (n = 1). Our study suggests that, excision based solely on size is not warranted in clinical and radiologically concordant cases with a diagnosis of FA on CNB.


Assuntos
Biópsia com Agulha de Grande Calibre/métodos , Neoplasias da Mama/patologia , Fibroadenoma/patologia , Adulto , Neoplasias da Mama/cirurgia , Feminino , Fibroadenoma/cirurgia , Humanos , Biópsia Guiada por Imagem , Pessoa de Meia-Idade
16.
PLoS Med ; 14(1): e1002215, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28095459

RESUMO

BACKGROUND: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. CONCLUSIONS: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.


Assuntos
Índice de Massa Corporal , Doença da Artéria Coronariana/genética , Metilação de DNA , Regulação da Expressão Gênica , Leucócitos/metabolismo , Metabolismo dos Lipídeos , Idoso , Doença da Artéria Coronariana/etiologia , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Análise da Randomização Mendeliana , Obesidade/complicações , Análise de Sequência com Séries de Oligonucleotídeos
17.
Genome Res ; 24(11): 1725-33, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25249537

RESUMO

Epigenetic mechanisms such as DNA methylation (DNAm) are essential for regulation of gene expression. DNAm is dynamic, influenced by both environmental and genetic factors. Epigenetic drift is the divergence of the epigenome as a function of age due to stochastic changes in methylation. Here we show that epigenetic drift may be constrained at many CpGs across the human genome by DNA sequence variation and by lifetime environmental exposures. We estimate repeatability of DNAm at 234,811 autosomal CpGs in whole blood using longitudinal data (2-3 repeated measurements) on 478 older people from two Scottish birth cohorts--the Lothian Birth Cohorts of 1921 and 1936. Median age was 79 yr and 70 yr, and the follow-up period was ∼10 yr and ∼6 yr, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13 yr; parent median age 46 yr). CpG repeatability in older people was highly correlated (0.68) with heritability estimated in younger people. Highly heritable sites had strong underlying cis-genetic effects. Thirty-seven and 1687 autosomal CpGs were associated with smoking and sex, respectively. Both sets were strongly enriched for high repeatability. Sex-associated CpGs were also strongly enriched for high heritability. Our results show that a large number of CpGs across the genome, as a result of environmental and/or genetic constraints, have stable DNAm variation over the human lifetime. Moreover, at a number of CpGs, most variation in the population is due to genetic factors, despite some sites being highly modifiable by the environment.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Genética Populacional/métodos , Genoma Humano/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Criança , Estudos de Coortes , Estudos Transversais , Saúde da Família , Feminino , Interação Gene-Ambiente , Humanos , Padrões de Herança/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Fumar , Adulto Jovem
18.
Intelligence ; 59: 115-126, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27932854

RESUMO

It is critical to discover why some people's cognitive abilities age better than others'. We applied multivariate growth curve models to data from a narrow-age cohort measured on a multi-domain IQ measure at age 11 years and a comprehensive battery of thirteen measures of visuospatial, memory, crystallized, and processing speed abilities at ages 70, 73, and 76 years (n = 1091 at age 70). We found that 48% of the variance in change in performance on the thirteen cognitive measures was shared across all measures, an additional 26% was specific to the four ability domains, and 26% was test-specific. We tested the association of a wide variety of sociodemographic, fitness, health, and genetic variables with each of these cognitive change factors. Models that simultaneously included all covariates accounted for appreciable proportions of variance in the cognitive change factors (e.g. approximately one third of the variance in general cognitive change). However, beyond physical fitness and possession of the APOE e4 allele, very few predictors were incrementally associated with cognitive change at statistically significant levels. The results highlight a small number of factors that predict differences in cognitive ageing, and underscore that correlates of cognitive level are not necessarily predictors of decline. Even larger samples will likely be required to identify additional variables with more modest associations with normal-range heterogeneity in aging-related cognitive declines.

19.
Hum Brain Mapp ; 36(12): 4910-25, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26769551

RESUMO

Later-life changes in brain tissue volumes--decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)--are strong candidates to explain some of the variation in ageing-related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow-age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow-up). We used latent variable modeling to extract error-free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r-values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life.


Assuntos
Encéfalo/patologia , Cognição/fisiologia , Envelhecimento Cognitivo , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Modelos Neurológicos , Testes Neuropsicológicos , Fatores Sexuais , Estatística como Assunto
20.
Pediatr Emerg Care ; 31(10): 717-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26427946

RESUMO

A 9-year-old boy presented with acute onset of abdominal pain and vomiting. History, physical examination, and initial laboratory testing failed to provide a diagnosis. A computed tomography scan revealed the rare finding of epiploic appendagitis. We review the literature of this rare, but increasingly recognized, condition that mimics appendicitis and needs to be considered in the child with acute abdominal pain.


Assuntos
Abdome Agudo/etiologia , Apendicite/diagnóstico , Abdome Agudo/patologia , Apendicite/patologia , Criança , Diagnóstico Diferencial , Humanos , Masculino , Tomografia Computadorizada por Raios X
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