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1.
Neuroimage ; : 116443, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31927129

RESUMO

Whole-brain structural networks can be constructed using diffusion MRI and probabilistic tractography. However, measurement noise and the probabilistic nature of the tracking procedure result in an unknown proportion of spurious white matter connections. Faithful disentanglement of spurious and genuine connections is hindered by a lack of comprehensive anatomical information at the network-level. Therefore, network thresholding methods are widely used to remove ostensibly false connections, but it is not yet clear how different thresholding strategies affect basic network properties and their associations with meaningful demographic variables, such as age. In a sample of 3153 generally healthy volunteers from the UK Biobank Imaging Study (aged 44-77 years), we constructed whole-brain structural networks and applied two principled network thresholding approaches (consistency and proportional thresholding). These were applied over a broad range of threshold levels across six alternative network weightings (streamline count, fractional anisotropy, mean diffusivity and three novel weightings from neurite orientation dispersion and density imaging) and for four common network measures (mean edge weight, characteristic path length, network efficiency and network clustering coefficient). We compared network measures against age associations and found that: 1) measures derived from unthresholded matrices yielded the weakest age-associations (0.033 ≤ |ß| ≤ 0.409); and 2) the most commonly-used level of proportional-thresholding from the literature (retaining 68.7% of all possible connections) yielded significantly weaker age-associations (0.070 ≤ |ß| ≤ 0.406) than the consistency-based approach which retained only 30% of connections (0.140 ≤ |ß| ≤ 0.409). However, we determined that the stringency of the threshold was a stronger determinant of the network-age association than the choice of threshold method and the two thresholding approaches identified a highly overlapping set of connections (ICC = 0.84), when matched at 70% network sparsity. Generally, more stringent thresholding resulted in more age-sensitive network measures in five of the six network weightings, except at the highest levels of sparsity (>90%), where crucial connections were then removed. At two commonly-used threshold levels, the age-associations of the connections that were discarded (mean ß ≤ |0.068|) were significantly smaller in magnitude than the corresponding age-associations of the connections that were retained (mean ß ≤ |0.219|, p < 0.001, uncorrected). Given histological evidence of widespread degeneration of structural brain connectivity with increasing age, these results indicate that stringent thresholding methods may be most accurate in identifying true white matter connections.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31957799

RESUMO

BACKGROUND: The ageing process is characterised by declines in physical and cognitive function. However, the relationship between these trajectories remains a topic of investigation. METHODS: Using four data waves collected triennially between ages 70 and 79, we tested for associations between multiple cognitive ability domains (verbal memory, processing speed, and visuospatial ability) and physical functions (walking speed, grip strength, and lung function). We firstly tested for associations between linear declines in physical and cognitive functions over the entire 9-year study period, and then, for lead-lag coupling effects between 3-year changes in cognitive and physical functions. RESULTS: Steeper linear decline in walking speed was moderately correlated with steeper linear declines in each cognitive domain. Steeper linear decline in grip strength was moderately correlated with steeper linear declines in verbal memory and processing speed. Lead-lag coupling models showed that decline in verbal memory was preceded by declines in walking speed and grip strength. By contrast, decline in grip strength was preceded by declines in processing speed and visuospatial ability, and decline in walking speed was preceded by decline in visuospatial ability. Following additional adjustment for covariates, only coupling effects from earlier decline in processing speed to later decline in grip strength remained significant (ß = 0.545, p = 0.006). CONCLUSION: Our findings provide further evidence of an association between cognitive and physical declines and point to the potential order in which these changes occur. Decline in processing speed in particular may serve as a unique early marker of declining upper body strength.

3.
Mol Psychiatry ; 2019 Dec 03.
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.

4.
J Bone Miner Res ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31793067

RESUMO

Hypophosphatasia (HPP) is a rare inherited disorder characterised by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic-based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10-year period and performed mutation screening of ALPL in those with low ALP (≤40U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had pathogenic variants in ALPL. Ten of these individuals were heterozygous for mutations previously described in HPP and two were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including four with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss-of-function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. This article is protected by copyright. All rights reserved.

5.
Wellcome Open Res ; 4: 97, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824989

RESUMO

Background: There is growing interest in using routinely collected data for research purposes. Following the success of research using routinely collected healthcare data, attention has turned to leveraging administrative data derived from systems providing other services to the population (e.g., education, social security) to conduct research on important social problems. In Scotland, specialised organisations have been set up to support researchers in their pursuit of using and linking administrative data. The landscape of administrative data in Scotland, however, is complex and changeable, and is often difficult for researchers to navigate. Purpose: This paper provides a researcher's narrative of the steps required to gain the various approvals necessary to access and link administrative data for research in social and cognitive epidemiology. Findings: This paper highlights the problems, particularly regarding the length and complexity of the process, which researchers typically face, and which result in a challenging research environment. The causes of these problems are discussed, as are potential solutions. Conclusions: Whereas the potential of administrative data is great, more work and investment are needed on the part of all those concerned - from researchers to data controllers - in order to realise this potential.

6.
BMJ Open ; 9(12): e033011, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31852706

RESUMO

OBJECTIVES: We investigated how youth cognitive and sociodemographic factors are associated with the aetiology of overweight and obesity. We examined both onset (who is at early risk for overweight and obesity) and development (who gains weight and when). DESIGN: Prospective cohort study. SETTING: We used data from the US National Longitudinal Study of Youth 1979 (NLSY) and the UK National Child Development Study (NCDS); most of both studies completed a cognitive function test in youth. PARTICIPANTS: 12 686 and 18 558 members of the NLSY and NCDS, respectively, with data on validated measures of youth cognitive function, youth socioeconomic disadvantage (eg, parental occupational class and time spent in school) and educational attainment. Height, weight and income data were available from across adulthood, from individuals' 20s into their 50s. PRIMARY AND SECONDARY OUTCOME MEASURES: Body mass index (BMI) for four time points in adulthood. We modelled gain in BMI using latent growth curve models to capture linear and quadratic components of change in BMI over time. RESULTS: Across cohorts, higher cognitive function was associated with lower overall BMI. In the UK, 1 SD higher score in cognitive function was associated with lower BMI (ß=-0.20, 95% CI -0.33 to -0.06 kg/m²). In America, this was true only for women (ß=-0.53, 95% CI -0.90 to -0.15 kg/m²), for whom higher cognitive function was associated with lower BMI. In British participants only, we found limited evidence for negative and positive associations, respectively, between education (ß=-0.15, 95% CI -0.26 to -0.04 kg/m²) and socioeconomic disadvantage (ß=0.33, 95% CI 0.23 to 0.43 kg/m²) and higher BMI. Overall, no cognitive or socioeconomic factors in youth were associated with longitudinal changes in BMI. CONCLUSIONS: While sociodemographic and particularly cognitive factors can explain some patterns in individuals' overall weight levels, differences in who gains weight in adulthood could not be explained by any of these factors.

7.
Nat Commun ; 10(1): 5741, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844048

RESUMO

Socioeconomic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. In a sample of 286,301 participants from UK Biobank, we identify 30 (29 previously unreported) independent-loci associated with income. Using a method to meta-analyze data from genetically-correlated traits, we identify an additional 120 income-associated loci. These loci show clear evidence of functionality, with transcriptional differences identified across multiple cortical tissues, and links to GABAergic and serotonergic neurotransmission. By combining our genome wide association study on income with data from eQTL studies and chromatin interactions, 24 genes are prioritized for follow up, 18 of which were previously associated with intelligence. We identify intelligence as one of the likely causal, partly-heritable phenotypes that might bridge the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities.

8.
Neuroimage Clin ; 25: 102120, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31887717

RESUMO

BACKGROUND AND PURPOSE: Perivascular Spaces (PVS), also known as Virchow-Robin spaces, seen on structural brain MRI, are important fluid drainage conduits and are associated with small vessel disease (SVD). Computational quantification of visible PVS may enable efficient analyses in large datasets and increase sensitivity to detect associations with brain disorders. We assessed the associations of computationally-derived PVS parameters with vascular factors and white matter hyperintensities (WMH), a marker of SVD. PARTICIPANTS: Community dwelling individuals (n = 700) from the Lothian Birth Cohort 1936 who had multimodal brain MRI at age 72.6 years (SD = 0.7). METHODS: We assessed PVS computationally in the centrum semiovale and deep corona radiata on T2-weighted images. The computationally calculated measures were the total PVS volume and count per subject, and the mean individual PVS length, width and size, per subject. We assessed WMH by volume and visual Fazekas scores. We compared PVS visual rating to PVS computational metrics, and tested associations between each PVS measure and vascular risk factors (hypertension, diabetes, cholesterol), vascular history (cardiovascular disease and stroke), and WMH burden, using generalized linear models, which we compared using coefficients, confidence intervals and model fit. RESULTS: In 533 subjects, the computational PVS measures correlated positively with visual PVS ratings (PVS count r = 0.59; PVS volume r = 0.61; PVS mean length r = 0.55; PVS mean width r = 0.52; PVS mean size r = 0.47). PVS size and width were associated with hypertension (OR 1.22, 95% CI [1.03 to 1.46] and 1.20, 95% CI [1.01 to 1.43], respectively), and stroke (OR 1.34, 95% CI [1.08 to 1.65] and 1.36, 95% CI [1.08 to 1.71], respectively). We found no association between other PVS measures and diabetes, hypercholesterolemia or cardiovascular disease history. Computational PVS volume, length, width and size were more strongly associated with WMH (PVS mean size versus WMH Fazekas score ß = 0.66, 95% CI [0.59 to 0.74] and versus WMH volume ß = 0.43, 95% CI [0.38 to 0.48]) than computational PVS count (WMH Fazekas score ß = 0.21, 95% CI [0.11 to 0.3]; WMH volume ß = 0.14, 95% CI [0.09 to 0.19]) or visual score. Individual PVS size showed the strongest association with WMH. CONCLUSIONS: Computational measures reflecting individual PVS size, length and width were more strongly associated with WMH, stroke and hypertension than computational count or visual PVS score. Multidimensional computational PVS metrics may increase sensitivity to detect associations of PVS with risk exposures, brain lesions and neurological disease, provide greater anatomic detail and accelerate understanding of disorders of brain fluid and waste clearance.

9.
Psychol Aging ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682139

RESUMO

It is unclear how scores on self-report resilience scales relate to key ageing-related domains in older age and if they truly measure resilience. We examined antecedents and outcomes of age-76 Brief Resilience Scale (BRS) scores in participants of the Lothian Birth Cohort 1936 (n = 655). We found bivariate associations between age-76 BRS scores and ageing-relevant antecedent variables measured at least 3 years earlier, from domains of cognitive ability, physical fitness, and wellbeing and, additionally, sociodemographics and personality (absolute r's from .082 to .49). Biological health variables were not associated with BRS scores. Age-73 cognitive ability (largest ß = 0.14), physical fitness (largest ß = 0.084), and wellbeing variables (largest ß = 0.26) made positive independent contributions to age-76 BRS scores in multivariate models. In a conservative model including all variables as covariates, corrected for multiple comparisons, only emotional stability (neuroticism) significantly independently contributed to BRS score (ß = 0.33). An exploratory backward elimination model indicated more wellbeing and personality associates of BRS scores (ßs from .087 to .32). We used latent difference score modeling to assess outcomes of BRS scores; we examined associations between age-76 BRS and change in latent factors of age-related domains between age 76 and 79. Whereas BRS scores were related cross-sectionally to levels of latent cognitive ability (r = .19), physical fitness (r = .20), and wellbeing (r = .60) factors, they were not related to declines in these domains. The independence of the BRS construct from established wellbeing and personality factors is unclear. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

10.
Artigo em Inglês | MEDLINE | ID: mdl-31690586

RESUMO

BACKGROUND: Physical frailty is associated with many adverse outcomes including disability, chronic disease, hospitalisation, institutionalisation and death. It is unclear what impact it might have on the rate of normal cognitive ageing. We investigated whether physical frailty was related to initial level of, and change in, cognitive abilities from age 70 to 79 years. METHOD: Participants were 950 members of the Lothian Birth Cohort 1936. Physical frailty was assessed at age 70 years using the Fried criteria. Cognitive function was assessed at ages 70, 73, 76 and 79 years. We used linear regression to examine cross-sectional and prospective associations between physical frailty status at age 70 years and factor score estimates for baseline level of and change in four cognitive domains (visuospatial ability, memory, processing speed and crystallised ability) and in general cognitive ability. RESULTS: Physical frailty, but not prefrailty, was associated with lower baseline levels of visuospatial ability, memory, processing speed and general cognitive ability after control for age, sex, education, depressive symptoms, smoking and number of chronic illnesses. Physical frailty was associated with greater decline in each cognitive domain: age-adjusted and sex-adjusted standardised regression coefficients (95% CIs) were: -0.45 (-0.70 to -0.20) for visuospatial ability, -0.32 (-0.56 to -0.07) for memory, -0.47 (-0.72 to -0.22) for processing speed, -0.43 (-0.68 to -0.18) for crystallised ability and -0.45 (-0.70 to -0.21) for general cognitive ability. These associations were only slightly attenuated after additional control for other covariates. CONCLUSION: Physical frailty may be an important indicator of age-related decline across multiple cognitive domains.

11.
Psychol Aging ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31714099

RESUMO

We examined associations between personality traits measured in 1958 and both all-cause and cause-specific mortality assessed 45 years later in 2003. Participants were 1,862 middle-aged men employed by the Western Electric Company. Outcomes were days to death from all causes, coronary heart disease, stroke, cancer, and causes other than circulatory diseases, cancer, accidents/homicide/suicides, or injuries (other causes). Measures in 1958 included age, education, health behaviors, biomedical risk factors, and nine content factors identified in the Minnesota Multiphasic Personality Inventory (MMPI). Four content factors-neuroticism, cynicism, extraversion, and intellectual interests-were related to the five-factor model domains of neuroticism, agreeableness, extraversion, and openness, respectively. The remaining five-psychoticism, masculinity versus femininity, religious orthodoxy, somatic complaints, and inadequacy-corresponded to the five-factor model's facets and styles (combinations of two domains) or were unrelated to the five-factor model. In age-adjusted and fully adjusted models, cynicism was associated with greater all-cause and cancer mortality. In fully adjusted models, inadequacy was associated with lower all-cause mortality and lower mortality from other causes. In age-adjusted models, religious orthodoxy was associated with lower cancer mortality. Further analyses revealed that the association between cynicism and all-cause mortality waned over time. Exploratory analyses of death from any disease of the circulatory system revealed no further associations. These findings reveal the importance of cynicism (disagreeableness) as a mortality risk factor, show that associations between cynicism and all-cause mortality are limited to certain periods of the lifespan, and highlight the need to study personality styles or types, such as inadequacy, that involve high neuroticism, low extraversion, and low conscientiousness. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

12.
Transl Psychiatry ; 9(1): 323, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31780646

RESUMO

The identification of biomarkers that discriminate individual ageing trajectories is a principal target of ageing research. Some of the most promising predictors of biological ageing have been developed using DNA methylation. One recent candidate, which tracks age-related phenotypes in addition to chronological age, is 'DNAm PhenoAge'. Here, we performed a phenome-wide association analysis of this biomarker in a cohort of older adults to assess its relationship with a comprehensive set of both historical, and contemporaneously-measured, phenotypes. Higher than expected DNAm PhenoAge compared with chronological age, known as epigenetic age acceleration, was found to associate with a number of blood, cognitive, physical fitness and lifestyle variables, and with mortality. Notably, DNAm PhenoAge, assessed at age 70, was associated with cognitive ability at age 11, and with educational attainment. Adjusting for age 11 cognitive ability attenuated the majority of the cross-sectional later-life associations between DNAm PhenoAge and health outcomes. These results highlight the importance of early life factors on healthy older ageing.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31738418

RESUMO

OBJECTIVES: Playing analog games may be associated with better cognitive function but, to date, these studies have not had extensive longitudinal follow-up. Our goal was to examine the association between playing games and change in cognitive function from age 11 to age 70, and from age 70 to 79. METHOD: Participants were 1091 non-clinical, independent, community dwelling individuals all born in 1936 and residing in Scotland. General cognitive function was assessed at ages 11 and 70, and hierarchical domains were assessed at ages 70, 73, 76, and 79 using a comprehensive cognitive battery of 14 tests. Games playing behaviours were assessed at ages 70 and 76. All models controlled for early-life cognitive function, education, social class, sex, activity levels, and health issues. All analyses were pre-registered. RESULTS: Higher frequency of playing games was associated with higher cognitive function at age 70, controlling for age 11 cognitive function, and the majority of this association could not be explained by control variables. Playing more games was also associated with less general cognitive decline from age 70 to age 79, and in particularly, less decline in memory ability. Increased games playing between 70 and 76 was associated with less decline in cognitive speed. DISCUSSION: Playing games was associated with less relative cognitive decline from age 11 to age 70, and less cognitive decline from age 70 to 79. Controlling for age 11 cognitive function and other confounders, these findings suggest that playing more games is linked to reduced lifetime decline in cognitive function.

14.
PLoS Genet ; 15(11): e1008480, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31765389

RESUMO

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates.

15.
Mol Psychiatry ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767999

RESUMO

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18 and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use associations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). No significant association between partner polygenic risk scores were observed. Associations between an individual's alcohol PRS (b = 0.05, S.E. = 0.006, p < 2 × 10-16) and smoking status PRS (b = 0.05, S.E. = 0.005, p < 2 × 10-16) were found with their partner's phenotype. In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.

16.
BMC Geriatr ; 19(1): 302, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707991

RESUMO

BACKGROUND: While the associations between personality traits and self-reported physical activity are well replicated, few studies have examined the associations between personality and device-based measures of both physical activity and sedentary behaviour. Low levels of physical activity and high levels of sedentary behaviour are known risk factors for poorer health outcomes in older age. METHODS: We used device-based measures of physical activity and sedentary behaviour recorded over 7 days in 271 79-year-old participants of the Lothian Birth Cohort 1936. Linear regression models were used to assess whether personality traits were cross-sectionally associated with step count, sedentary time, and the number of sit-to-stand transitions. Personality traits were entered one at a time, and all-together, controlling for age and sex in Model 1 and additionally for BMI and limiting long-term illness in Model 2. RESULTS: None of the associations between personality traits and measures of physical activity and sedentary behaviours remained significant after controlling for multiple-comparisons using the False Discovery Rate test (all ps > .07). CONCLUSIONS: We found no evidence that personality traits are associated with device-based measures of physical activity or sedentary behaviour in older age. More studies are needed to replicate and examine the nature of these relationships.

17.
Alzheimers Dement ; 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31619348

RESUMO

INTRODUCTION: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. METHODS: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three- to eight-year follow-up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. RESULTS: We found associations of cognitive task performance with all-cause and cause-specific dementia (P <  .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. DISCUSSION: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.

18.
Transl Psychiatry ; 9(1): 248, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591380

RESUMO

Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n = 532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P < 0.001, eta-squared ɳ2 = 0.63) and smoking pack years (r = 0.69, P < 0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P < 0.001, partial eta-squared ɳp2 = 0.022) and processing speed (P < 0.001, ɳp2 = 0.030); inflammatory markers (all P < 0.001, ranges from ɳp2 = 0.021 to 0.030); dietary patterns (healthy diet (P < 0.001, ɳp2 = 0.052) and traditional diet (P < 0.001, ɳp2 = 0.032); stroke (P = 0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P < 0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P < 0.001, ranges from ɳp2 = 0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.

19.
Psychol Med ; : 1-10, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31576797

RESUMO

BACKGROUND: Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression. METHODS: We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu. RESULTS: We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education. CONCLUSION: Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.

20.
Arterioscler Thromb Vasc Biol ; 39(12): 2542-2552, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31597446

RESUMO

OBJECTIVE: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (ßs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (ßs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation. CONCLUSIONS: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.

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