Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.
Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance.
Using data from four UK adult cohorts (ages 53–80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2).
Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p = 0.08) after further adjustment.
Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.
The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability.
We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score = −0.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability.
Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability.
Physical capability in later life is influenced by factors occurring across the life course, yet exposures to area conditions have only been examined cross-sectionally. Data from the National Survey of Health and Development, a longitudinal study of a 1946 British birth cohort, were used to estimate associations of area deprivation (defined as percentage of employed people working in partly skilled or unskilled occupations) at ages 4, 26, and 53 years (residential addresses linked to census data in 1950, 1972, and 1999) with 3 measures of physical capability at age 53 years: grip strength, standing balance, and chair-rise time. Cross-classified multilevel models with individuals nested within areas at the 3 ages showed that models assessing a single time point underestimate total area contributions to physical capability. For balance and chair-rise performance, associations with area deprivation in midlife were robust to adjustment for individual socioeconomic position and prior area deprivation (mean change for a 1-standard-deviation increase: balance, −7.4% (95% confidence interval (CI): −12.8, −2.8); chair rise, 2.1% (95% CI: −0.1, 4.3)). In addition, area deprivation in childhood was related to balance after adjustment for childhood socioeconomic position (−5.1%, 95% CI: −8.7, −1.6). Interventions aimed at reducing midlife disparities in physical capability should target the socioeconomic environment of individuals—for standing balance, as early as childhood.
geography; Great Britain; health status disparities; longitudinal studies; multilevel analysis; physical endurance; residence characteristics; socioeconomic factors
Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on Z-score for carriers vs. noncarriers: −0.05 (95% CI: −0.09, −0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D–raising allele of rs2282679 [pooled β per T allele: −0.03 (95% CI: −0.05, −0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.
To investigate the associations of body mass index (BMI) and grip strength with objective measures of physical performance (chair rise time, walking speed and balance) including an assessment of sex differences and non-linearity.
Cross-sectional data from eight UK cohort studies (total N = 16 444) participating in the Healthy Ageing across the Life Course (HALCyon) research programme, ranging in age from 50 to 90+ years at the time of physical capability assessment, were used. Regression models were fitted within each study and meta-analysis methods used to pool regression coefficients across studies and to assess the extent of heterogeneity between studies.
Higher BMI was associated with poorer performance on chair rise (N = 10 773), walking speed (N = 9 761) and standing balance (N = 13 921) tests. Higher BMI was associated with stronger grip strength in men only. Stronger grip strength was associated with better performance on all tests with a tendency for the associations to be stronger in women than men; for example, walking speed was higher by 0.43 cm/s (0.14, 0.71) more per kg in women than men. Both BMI and grip strength remained independently related with performance after mutual adjustment, but there was no evidence of effect modification. Both BMI and grip strength exhibited non-linear relations with performance; those in the lowest fifth of grip strength and highest fifth of BMI having particularly poor performance. Findings were similar when waist circumference was examined in place of BMI.
Older men and women with weak muscle strength and high BMI have considerably poorer performance than others and associations were observed even in the youngest cohort (age 53). Although causality cannot be inferred from observational cross-sectional studies, our findings suggest the likely benefit of early assessment and interventions to reduce fat mass and improve muscle strength in the prevention of future functional limitations.
Creatinine based formulae for estimating renal function developed in white populations may be less valid in other ethnic groups. We assessed the performance of various estimating formulae in an Indian population.
917 subjects were recruited from the Hyderabad arm of the Indian Migration Study. Data were collected on comorbidity, serum creatinine and body composition from DXA scans. Renal function was compared using the modified Cockcroft-Gault, MDRD and CKD-EPI formulae. 24-hour creatinine production was derived from each estimate and the agreement with measured muscle mass examined. 24-hour creatinine production estimates were compared to that derived from a formula by Rule incorporating DXA measured muscle mass. Potential systematic biases were examined by age and eGFR. We assessed the association of renal function by each formula with hypertension and self-reported measures of vascular disease.
Mean modified Cockcroft-Gault eCCl was 98.8 ml/min/1.73 m2, MDRD eGFR 91.2 ml/min/1.73 m2 and CKD-EPI eGFR 96.3 ml/min/1.73 m2. MDRD derived 24-hour creatinine production showed the least age-related underestimation compared to the Rule formula. CKD-EPI showed a marked bias at higher eGFRs. All formulae showed similar strength associations with vascular disease and hypertension.
Our analyses support the use of MDRD for estimating renal function in Indian populations. Further work is required to assess the predictive value of formulae for incident disease and complications of CKD.
Creatinine; Ethnicity; Muscle mass; Renal function
Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (β = 0.13, p = 0.001) and (β = 0.09, p = 0.002), respectively and weight (β = 0.13, p = 0.001) and (β = 0.09, p = 0.001), respectively. CXCR4 variant was also strongly associated with body fat (β = 0.10, p = 0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR = 1.6, p = 0.003) and (OR = 1.4, p = 0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ3970 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.
Interpreting information on diagnostic accuracy is an area that health professionals struggle with. In this paper, we use the example of Mr Samways, a 45-year-old man with joint symptoms, to illustrate how to apply the results of a diagnostic accuracy study in clinical practice. We consider the various measures used to quantify diagnostic accuracy and discuss their clinical utility. We provide an overview of potential biases to consider when evaluating a diagnostic accuracy study and consider how to determine whether the results can be applied to a particular patient.
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50–92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n = 2146 for associations between morning Cortisol Awakening Response and balance to n = 8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p < 0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase −0.075, 95% CI −0.116, −0.034, p < 0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance.
HPA axis; Physical capability; Healthy ageing
Abdominal adiposity is an important risk factor for diabetes and cardiovascular disease in Indians. Dual energy X-ray absorptiometry (DXA) can be used to determine abdominal fat depots, being more accessible and less costly than gold standard measures such as magnetic resonance imaging (MRI). DXA has not been fully validated for use in South Asians. Here, we determined the accuracy of DXA for measurement of abdominal fat in an Indian population by comparison with MRI.
146 males and females (age range 18–74, BMI range 15–46 kg/m2) from Hyderabad, India underwent whole body DXA scans on a Hologic Discovery A scanner, from which fat mass in two abdominal regions was calculated, from the L1 to L4 vertebrae (L1L4) and from the L2 to L4 vertebrae (L2L4). Abdominal MRI scans (axial T1-weighted spin echo images) were taken, from which adipose tissue volumes were calculated for the same regions.
Intra-class correlation coefficients between DXA and MRI measures of abdominal fat were high (0.98 for both regions). Although at the level of the individual, differences between DXA and MRI could be large (95% of DXA measures were between 0.8 and 1.4 times MRI measures), at the sample level, DXA only slightly overestimated MRI measures of abdominal fat mass (mean difference in L1L4 region: 2% (95% CI:0%, 5%), mean difference in L2L4 region:4% (95% CI: 1%, 7%)). There was evidence of a proportional bias in the association between DXA and MRI (correlation between difference and mean −0.3), with overestimation by DXA greater in individuals with less abdominal fat (mean bias in leaner half of sample was 6% for L1L4 (95%CI: 2, 11%) and 7% for L2L4 (95% CI:3,12%).
DXA measures of abdominal fat are suitable for use in Indian populations and provide a good indication of abdominal adiposity at the population level.
Vitamin B-12 is essential for the development and maintenance of a healthy nervous system. Brain development occurs primarily in utero and early infancy, but the role of maternal vitamin B-12 status during pregnancy on offspring cognitive function is unclear. In this study we assessed the effect of vitamin B-12 status in well-nourished pregnant women on the cognitive ability of their offspring in a UK birth cohort (ALSPAC). We then examined the association of SNPs in maternal genes FUT2 (rs492602) and TCN2 (rs1801198, rs9606756) that are related to plasma vitamin B-12, with offspring IQ. Observationally, there was a positive association between maternal vitamin B-12 intake and child’s IQ that was markedly attenuated after adjustment for potential confounders (mean difference in offspring IQ score per doubling of maternal B-12 intake, before adjustment: 2.0 (95% CI 1.3, 2.8); after adjustment: 0.7 (95% CI −0.04, 1.4)). Maternal FUT2 was weakly associated with offspring IQ: mean difference in IQ per allele was 0.9 (95% CI 0.1, 1.6). The expected effect of maternal vitamin B-12 on offspring IQ, given the relationships between SNPs and vitamin B-12, and SNPs and IQ was consistent with the observational result. Our findings suggest that maternal vitamin B-12 may not have an important effect on offspring cognitive ability. However, further examination of this issue is warranted.
Genome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations is important since it would suggest wider relevance for these findings. Given the rising prevalence of metabolic disorders and heart disease in the Indian sub-continent, these studies could be of future clinical relevance.
We studied seven common variants associated with a variety of lipid traits in previous GWASs. The study sample comprised of 3178 sib-pairs recruited as participants for the Indian Migration Study (IMS). Associations with various lipid parameters and quantitative traits were analyzed using the Fulker genetic association model.
We replicated five of the 7 main effect associations with p-values ranging from 0.03 to 1.97x10-7. We identified particularly strong association signals at rs662799 in APOA5 (beta=0.18 s.d, p=1.97 x 10-7), rs10503669 in LPL (beta =−0.18 s.d, p=1.0 x 10-4) and rs780094 in GCKR (beta=0.11 s.d, p=0.001) loci in relation to triglycerides. In addition, the GCKR variant was also associated with total cholesterol (beta=0.11 s.d, p=3.9x10-4). We also replicated the association of rs562338 in APOB (p=0.03) and rs4775041 in LIPC (p=0.007) with LDL-cholesterol and HDL-cholesterol respectively.
We report associations of five loci with various lipid traits with the effect size consistent with the same reported in Europeans. These results indicate an overlap of genetic effects pertaining to lipid traits across the European and Indian populations.
SNP; Fulker’s Association model and Lipid traits
Socioeconomic influences over a lifetime impact on health and may contribute to poor physical functioning in old age.
We examined the impact of both childhood and adulthood socioeconomic factors on locomotor function at 63-86 years (measured with the get up and go timed walk and flamingo balance test), in the UK-based Boyd Orr (n=405) and Caerphilly (n=1,196) prospective cohorts.
There was a marked reduction in walking speed and balance time with increasing age. Each year of age was associated with a 1.7% slower walk time and a 14% increased odds of poor balance. Participants who moved from a low socioeconomic position in childhood to a high socioeconomic position in adulthood had walking times 3% slower (95% CI: -2%, 8%) than people with high socioeconomic position in both periods. Participants who moved from a high socioeconomic position in childhood to a low adulthood socioeconomic position had walking times 5% slower (95% CI: -2%, 12%). Participants with a low socioeconomic position in both periods had walking times 10% slower (95% CI: 5%, 16%; P for trend <0.001).
In Boyd Orr, low socioeconomic position in childhood was associated with poor balance in old age (OR per worsening category = 1.26; 95% CI 1.01, 1.57; P=0.043), as was socioeconomic position in adulthood (OR = 1.71; 95% CI 1.20, 2.45; P=0.003). Similar associations were not observed in Caerphilly.
Accumulating socioeconomic disadvantage from childhood to adulthood is associated with slower walking time in old age, with mixed results for balance ability.
Aged; Gait; Physical performance; Social Class; Socioeconomic Factors
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
The ACTN3 R577X (rs1815739) genotype has been associated with
athletic status and muscle phenotypes, although not consistently. Our objective
was to conduct a meta-analysis of the published literature on athletic status
and investigate its associations with physical capability in several new
population-based studies. Relevant data were extracted from studies in the
literature, comparing genotype frequencies between controls and sprint/power and
endurance athletes. For life course physical capability, data were used from two
studies of adolescents and seven studies in the Healthy Ageing across the Life
Course (HALCyon) collaborative research program, involving individuals aged
between 53 and 90+ years. We found evidence from the published literature
to support the hypothesis that in Europeans the RR genotype is more common among
sprint/power athletes compared with their controls. There is currently no
evidence that the X allele is advantageous to endurance athleticism. We found no
association between R577X and grip strength (P = 0.09,
n = 7,672 in males; P =
0.90, n = 7,839 in females), standing balance, timed get
up and go, or chair rises in our studies of physical capability. The
ACTN3 R577X genotype is associated with sprint/power
athletic status in Europeans, but does not appear to be associated with
objective measures of physical capability in the general population. Hum Mutat
32:1–11, 2011. © 2011 Wiley-Liss, Inc.
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
Background Weight gain during infancy may programme later health outcomes, but examination of this hypothesis requires appropriate lifecourse methods and detailed weight gain measures during childhood. We examined associations between weight gain in infancy and early childhood and blood pressure at the age of 6.5 years in healthy children born at term.
Methods We carried out an observational analysis of data from a cluster-randomized breastfeeding promotion trial in Belarus. Of 17 046 infants enrolled between June 1996 and December 1997, 13 889 (81.5%) had systolic and diastolic blood pressure measured at 6.5 years; 10 495 children with complete data were analysed. A random-effects linear spline model with three knot points was used to estimate each individual's birthweight and weight gain from birth to 3 months, 3 months to 1 year and 1–5 years. Path analysis was used to separate direct effects from those mediated through subsequent weight gain.
Results In boys, after controlling for confounders and prior weight gain, the change in systolic blood pressure per z-score increase in weight gain was 0.09 mmHg [95% confidence interval (95% CI) −0.14 to 0.31] for birthweight; 0.41 mmHg (95% CI 0.19–0.64) for birth to 3 months; 0.69 mmHg (95% CI 0.47–0.92) for 3 months to 1 year and 0.82 mmHg (95% CI 0.58–1.06) for 1–5 years. Most of the associations between weight gain and blood pressure were mediated through weight at the age of 6.5 years. Findings for girls and diastolic blood pressure were similar.
Conclusions Children who gained weight faster than their peers, particularly at later ages, had higher blood pressure at the age of 6.5 years, with no association between birthweight and blood pressure.
Birthweight; blood pressure; lifetime; multi-level model; path analysis; weight gain
In observational epidemiological studies type 2 diabetes (T2D) and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding.
In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child’s intelligence quotient (IQ) scores in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We generated a fasting glucose (FGGRS) and a T2D (T2DGRS) genetic risk score and used them in a Mendelian randomization approach.
We found a strong correlation between the FGGRS and fasting glucose plasma measurements that were available for a subset of children, but no association of either the maternal or the offspring FGGRS with child’s IQ was observed. In contrast, the maternal T2DGRS was positively associated with offspring IQ.
Maternal and offspring genetic variants which are associated with glucose levels are not associated with offspring IQ, suggesting that there is unlikely to be a causal link between glucose exposure in utero and IQ in childhood. Further exploration in even larger cohorts is required to exclude the possibility that our null findings were due to a lack of statistical power.
Mendelian randomization; Fasting glucose; Type 2 diabetes; IQ; ALSPAC
Identification of causes of dementia soon after symptom onset is important, because appropriate treatment of some causes of dementia can slow or halt its progression or enable symptomatic treatment where appropriate. The accuracy of MRI and CT, and whether MRI is superior to CT, in detecting a vascular component to dementia in autopsy confirmed and clinical cohorts of patients with VaD, combined AD and VaD (“mixed dementia”), and AD remain unclear. We conducted a systematic review and meta-analysis to investigate this question.
We searched eight databases and screened reference lists to identify studies addressing the review question. We assessed study quality using QUADAS. We estimated summary diagnostic accuracy according to imaging finding, and ratios of diagnostic odds ratios (RDORs) for MRI versus CT and high versus low risk of bias.
We included 7 autopsy and 31 non-autopsy studies. There was little evidence that selective patient enrolment and risk of incorporation bias impacted on diagnostic accuracy (p = 0.12 to 0.95). The most widely reported imaging finding was white matter hyperintensities. For CT (11 studies) summary sensitivity and specificity were 71% (95% CI 53%-85%) and 55% (44%-66%). Corresponding figures for MRI (6 studies) were 95% (87%-98%) and 26% (12%-50%). General infarcts was the most specific imaging finding on MRI (96%; 95% CI 94%-97%) and CT (96%; 93%-98%). However, sensitivity was low for both MRI (53%; 36%-70%) and CT (52%; 22% to 80%). No imaging finding had consistently high sensitivity. Based on non-autopsy studies, MRI was more accurate than CT for six of seven imaging findings, but confidence intervals were wide.
There is insufficient evidence to suggest that MRI is superior to CT with respect to identifying cerebrovascular changes in autopsy-confirmed and clinical cohorts of VaD, AD, and ‘mixed dementia’.
Dementia; CT; MRI; Diagnosis; Systematic review
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.
No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.
The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.
Aging; ageing; middle-aged; telomere; cognition; physical
Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance.
To assess the association of breast milk and quantity of infant formula and cows' milk intake during infancy with insulin resistance measures in early adulthood.
Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972–1974, to receive milk supplementation or not. Participants were the offspring, aged 23–27 years at follow-up (n = 679). Breastfeeding and formula/cows' milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI0) and insulin secretion (CIR30).
573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows' milk feeding or of increasing quartiles of formula/cows' milk consumption during infancy (<3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows' milk feeding at 3 months were: fasting glucose (−0.07 mmol/l; 95% CI: −0.19, 0.05); fasting insulin (8.0%; −8.7, 27.6); ISI0 (−6.1%; −11.3, 12.1) and CIR30 (3.8%; −19.0, 32.8). There was also little evidence that increasing intakes of formula/cows' milk at 3 months were associated with fasting glucose (increase per quartile of formula/cows' milk intake = 0.00 mmol/l; −0.03, 0.03); fasting insulin (0.8%; −3.2, 5.1); ISI 0 (−0.9%; −5.1, 3.5) and CIR30 (−2.6%; −8.4, 3.6).
We found no evidence that increasing consumption of formula/cows' milk in early infancy was associated with insulin resistance in young adulthood.
A major limitation of past work linking area socioeconomic conditions to health in mid-life has been the reliance on single point in time measurement of area. Using the MRC National Survey of Health and Development, this study for the first time linked place of residence at three major life periods of childhood (1950), young adulthood (1972), and mid-life (1999) to area-socioeconomic data from the nearest census years. Using objective measures of physical capability as the outcome, the purpose of this study was to highlight four methodological challenges of attrition bias, secular changes in socio-economic measures, historical data availability, and changing reporting units over time. In general, standing balance and chair rise time showed clear cross-sectional associations with residing in areas with high deprivation. However, it was the process of overcoming the methodological challenges, which led to the conclusion that in this example percent low social class occupations was the most appropriate measure to use when extending cross-sectional analysis of standing balance and chair rise to life course investigation.
Life course; Area; Capability; Methodology; Deprivation
Recent epidemiologic studies have demonstrated that Tourette syndrome (TS) and chronic tic disorder (CT) are more common than previously recognized. However, few population-based studies have examined the prevalence of co-occurring neuropsychiatric conditions such as obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). We evaluated the prevalence of TS, CT, and their overlap with OCD and ADHD in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.
A total of 6,768 children were evaluated using longitudinal data from mother-completed questionnaires. DSM-IV-TR diagnoses of TS and CT were derived using three levels of diagnostic stringency (Narrow, Intermediate, and Broad). Validity of the case definitions was assessed by comparing gender ratios and rates of co-occurring OCD and ADHD using heterogeneity analyses.
Age 13 prevalence rates for TS (0.3% for Narrow; 0.7% for Intermediate) and CT (0.5% for Narrow; 1.1% for Intermediate) were consistent with rates from other population-based studies. Rates of co-occurring OCD and ADHD were higher in TS and CT Narrow and Intermediate groups compared with controls but lower than has been previously reported. Only 8.2% of TS Intermediate cases had both OCD and ADHD; 69% of TS Intermediate cases did not have either co-occurring OCD or ADHD.
This study suggests that co-occurring OCD and ADHD is markedly lower in TS cases derived from population-based samples than has been reported in clinically ascertained TS cases. Further examination of the range of co-occurring neuropsychiatric disorders in population-based TS samples may shed new perspective on the underlying shared pathophysiology of these three neurodevelopmental conditions.
Tourette syndrome; prevalence; ALSPAC; obsessive-compulsive disorder; attention-deficit/hyperactivity disorder
Insulin and the insulin-like growth factor (IGF) system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age.
Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63–86 years. We examined prospective associations of insulin, IGF-I, IGF-II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men); and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women).
In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD) increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: −0.2%, 3.2%; p = 0.08), but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08), although associations were attenuated after controlling for body mass index (BMI) and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02), but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance.
There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings.