Biology subjects

Kuh, D.

Publications and source records attributed to Kuh, D..

7 recordsLinked to original sources

bioRxiv2023

Genetic impacts on DNA methylation help elucidate regulatory genomic processes

Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2,358 blood samples from three UK cohorts, with replication. Methylation levels at 34.2% of CpGs were affected by SNPs, and 98% of effects were cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both meQTL SNPs and CpGs with meQTLs were overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identified 1,520 co-localisations across 1,325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such ICOSLG (inflammatory bowel disease), and USP1 and DOCK7 (total cholesterol levels). Enrichment analysis of meQTLs and integration with expression QTLs gave insights into mechanisms underlying cis-meQTLs, for example through disruption of transcription factor binding sites for CTCF and SMC3, and trans-meQTLs, for example through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites. Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. A results database and viewer are available online.

genomics↗

bioRxiv2019

Age at period cessation and trajectories of cardiovascular risk factors across mid and later life: a prospective cohort study

What is already known about this topicAge at period cessation is associated with cardiovascular disease. Whether age at period cessation adversely affects change in conventional cardiovascular intermediates from mid to later life is not well understood.\n\nWhat this study addsWomen and clinicians concerned about the impact of type and timing of period cessation on conventional cardiovascular intermediates from midlife should be reassured that the impacts over the long term are small.\n\nAbstractO_ST_ABSObjectiveC_ST_ABSTo examine the association between age at period cessation (by type of period cessation) and trajectories of anthropometry, blood pressure, lipids and HBA1c from midlife.\n\nDesignProspective cohort study of women recruited to the Medical Research Council National Survey of Health and Development (NSHD).\n\nSettingPopulation based prospective cohort study.\n\nParticipantsWomen participating in NSHD with a known date of period cessation and at least one measure of each intermediate cardiovascular risk factor.\n\nExposuresAge at period cessation and type of period cessation (hysterectomy compared with natural menopause).\n\nOutcomesRepeated measures of systolic blood pressure, diastolic blood pressure, body mass index (BMI) and waist circumference (WC) from 36 to 69 years and repeated measures of triglyceride, low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and glycated haemoglobin (HBA1c) from 53 to 69 years.\n\nResultsWe found no evidence that age at period cessation was associated with trajectories of log triglyceride, LDL-c and HDL-c from 53 to 69 years and trajectories of blood pressure from 36 to 69 years, regardless of whether period cessation occurred naturally or due to hysterectomy. While we found some evidence of associations of age at period cessation with log BMI, log WC and log HBA1C, patterns were not consistent and differences were small at age 69 years, with confidence intervals that spanned the null. For instance, the difference in log WC at age 69 per year increase in age at natural menopause was 0.003 (95% confidence interval, -0.0002, 0.01) while the difference per year increase in age at hysterectomy was -0.002 (95% CI, -0.005, 0.001).\n\nConclusionHow and when women experience period cessation is unlikely to adversely affect conventional cardiovascular risk factors across mid and later life. Women and clinicians concerned about the impact of type and timing of period cessation on conventional cardiovascular intermediates from midlife should be reassured that the impacts over the long term are small.

epidemiology↗

bioRxiv2018

Developmental factors associated with decline in grip strength from midlife to old age: a British birth cohort study

Maintenance of muscle strength is important for healthy ageing, protecting against chronic disease and enabling independent living. We tested whether developmental factors were associated with grip strength trajectories between 53 and 69 years, and operated independently or on the same pathway/s as adult factors, in 3058 participants from a British birth cohort. Grip strength (kg) at ages 53, 60-64 and 69, was analysed using multilevel models, testing for age and sex interactions, to estimate associations with developmental factors (birthweight, growth parameters, motor and cognitive development) and childhood socioeconomic position (SEP) and investigate potential adult mediators. Heavier birthweight, beginning to walk on time, later puberty and greater weight 0-26 years in men, and earlier age at first standing in women, were associated with stronger grip but not with its decline; these associations were independent of adult factors. The slower decline in grip strength (by 0.068kg/year, 95% confidence interval (CI) 0.024,0.11 per 1SD, p=.003) in men with higher childhood cognition was attenuated by adult verbal memory which became increasingly positively associated with grip strength at older ages. Thus grip strength may increasingly reflect neural ageing processes. Targeting developmental factors to promote muscle development should increase the chance of independence in old age.

epidemiology↗

bioRxiv2018

The Delirium and Population Health Informatics Cohort study protocol: ascertaining the determinants and outcomes from delirium in a whole population.

BackgroundDelirium affects 25% of older inpatients and is associated with long-term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline?\n\nMethodsThe Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged [≥]70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years.\n\nDiscussionDELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged [≥]70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes.

epidemiology↗

bioRxiv2018

Vascular risk factors for male and female urgency urinary incontinence at age 68 from a British birth cohort study

ObjectiveTo investigate the prevalence of UUI at age 68 and the contribution of vascular risk factors to male and female UUI pathogenesis in addition to the associations with raised BMI\n\nSubjects and methods1762 participants were from the MRC National Survey for Health and Development (NSHD) birth cohort, who answered the International Consultation on Incontinence Questionnaire short form (ICIQ-SF) at age 68. Logistic regression was used to estimate associations between UUI and earlier life vascular risk factors including: lipid status, diabetes, hypertension, body mass index (BMI), previous stroke or transient ischaemic attack (TIA) diagnosis; adjusting for smoking status, physical activity, co-presentation of SUI symptoms, educational attainment and in women only, type of menopause, age at period cessation and use of hormone replacement therapy.\n\nResultsUUI was reported by 12% of men and 19% of women at 68. Female sex, previous stroke or TIA diagnosis, increased BMI and hypertension (in men only) at age 60-64 were independent risk factors for UUI. Female sex, increased BMI and a previous diagnosis of stroke/ TIA increased the relative risk of more severe UUI symptoms. Type and timing of menopause and HRT use did not alter the estimated associations between UUI and vascular risk factors in women.\n\nConclusionMultifactorial mechanisms lead to UUI and vascular risk factors may contribute to pathogenesis of bladder overactivity in addition to higher BMI. Severe UUI appears to be a distinct presentation with more specific contributory mechanisms than milder UUI.

epidemiology↗

bioRxiv2017

Delirium symptoms are associated with decline in cognitive function between ages 53 to 69: findings from a British birth cohort study.

INTRODUCTIONFew population studies have investigated whether longitudinal decline after delirium in mid-to-late life might affect specific cognitive domains.\n\nMETHODSParticipants from a birth cohort completing assessments of search speed, verbal memory and the Addenbrookes Cognitive Examination at age 69 were asked about delirium symptoms between ages 60-69. Linear regression models estimated associations between delirium symptoms and cognitive outcomes.\n\nRESULTSPeriod prevalence of delirium between 60 and 69 was 4% (95% CI 3.2%,4.9%). Self-reported symptoms of delirium over the seventh decade were associated with worse scores in the Addenbrookes Cognitive Examination (-1.7 points, 95% CI -3.2, -0.1, p=0.04). In association with delirium symptoms, verbal memory scores were initially lower, with subsequent decline in search speed by age 69. These effects were independent of other Alzheimers risk factors.\n\nDISCUSSIONDelirium symptoms may be common even at relatively younger ages, and their presence may herald cognitive decline, particularly in search speed, over this time period.

epidemiology↗

bioRxiv2017

Apolipoprotein-E (ApoE) ϵ4 and cognitive decline over the adult life course

We tested the association between APOE-{varepsilon}4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and the rate of decline in these cognitive scores from age 43 to 69. Model fit was assessed with the Bayesian Information Criterion. A cross-sectional association between APOE-{varepsilon}4 and memory scores was detected at age 69 for both heterozygotes and homozygotes ({beta}=-0.68 & {beta}=-1.38 respectively, p=.03) with stronger associations in homozygotes; no associations were observed before this age. Homozygous carriers of APOE-{varepsilon}4 had a faster rate of decline in memory between ages 43 and 69, when compared to noncarriers, after adjusting for gender and childhood cognition ({beta}=-0.05, p=.04). There were no cross-sectional or longitudinal associations between APOE-{varepsilon}4 and processing speed. We conclude that APOE-{varepsilon}4 is associated with a subtly faster rate of memory decline from midlife to early old age; this may be due to effects of APOE-{varepsilon}4 becoming manifest around the latter stage of life. Continuing follow-up will determine what proportion of this increase will become clinically significant.

epidemiology↗