Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and morning void urinary 6-sulfatoxymelatonin levels.
We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across twelve circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n=24 cases), the Health Professionals Follow-Up Study (HPFS) (n=40 cases), and the Physicians’ Health Study (PHS) (n=105 cases). We used linear regression to evaluate the association between SNPs and morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP-sets in the pathway (gene based) were associated with our outcomes.
None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p-values = 0.01, 0.01, 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPS in TIMELESS (4 SNPs), NPAS2 (6 SNPs), PER3 (2 SNPs) and CSNK1E (1 SNP) were nominally associated with 6-sulfatoxymelatonin levels.
We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.
Circadian genes; prostate cancer; genetic polymorphisms
Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.
VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4–13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.
Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36–2.80; Health ABC) and 1.88 (1.31–2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35–2.28; Health ABC) and 1.56 (1.15–2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12–2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21–2.07), and AGES-Reykjavik, 1.43 (1.07–1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.
VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
Obesity; Aging; Leptin; Adiponectin.
Objective: to examine the relationships between impairments in hearing and vision and mortality from all-causes and cardiovascular disease (CVD) among older people.
Design: population-based cohort study.
Participants: the study population included 4,926 Icelandic individuals, aged ≥67 years, 43.4% male, who completed vision and hearing examinations between 2002 and 2006 in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS) and were followed prospectively for mortality through 2009.
Methods: participants were classified as having ‘moderate or greater’ degree of impairment for vision only (VI), hearing only (HI), and both vision and hearing (dual sensory impairment, DSI). Cox proportional hazard regression, with age as the time scale, was used to calculate hazard ratios (HR) associated with impairment and mortality due to all-causes and specifically CVD after a median follow-up of 5.3 years.
Results: the prevalence of HI, VI and DSI were 25.4, 9.2 and 7.0%, respectively. After adjusting for age, significantly (P < 0.01) increased mortality from all causes, and CVD was observed for HI and DSI, especially among men. After further adjustment for established mortality risk factors, people with HI remained at higher risk for CVD mortality [HR: 1.70 (1.27–2.27)], whereas people with DSI remained at higher risk of all-cause mortality [HR: 1.43 (1.11–1.85)] and CVD mortality [HR: 1.78 (1.18–2.69)]. Mortality rates were significantly higher in men with HI and DSI and were elevated, although not significantly, among women with HI.
Conclusions: older men with HI or DSI had a greater risk of dying from any cause and particularly cardiovascular causes within a median 5-year follow-up. Women with hearing impairment had a non-significantly elevated risk. Vision impairment alone was not associated with increased mortality.
AGES-Reykjavik study; hearing; vision; dual sensory impairment; all-cause mortality; cardiovascular disease mortality; older people
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
Atrophy of medial temporal lobe (MTL) and basal ganglia (BG) are characteristic of various neurodegenerative diseases in older people. In search of potentially modifiable factors that lead to atrophy in these structures, we studied the association of vascular risk factors to atrophy of MTL and BG in 368 non-demented men and women [b. 1907–1935] who participated in the Age, Gene/Environment, Susceptibility - Reykjavik Study. A fully automated segmentation pipeline estimated volumes of MTL and BG from whole brain MRI performed at baseline and 2.4 years later. Linear regression models showed higher systolic and diastolic blood pressures and the presence of Apo E ε4 were independently associated with increased atrophy of MTL but no association of vascular risk factors with atrophy of BG. The different susceptibility of MTL and BG atrophy to the presence of vascular risk factors suggests the relatively preserved perfusion of BG when vascular risk factors are present.
Medial temporal lobe; hippocampus; basal ganglia; thalamus; atrophy; aging; vascular risk factors
It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person’s risk of death by 1.57%.
This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0159-7) contains supplementary material, which is available to authorized users.
Heterozygosity; Human; Survival; GWAS
To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia.
Within the population-based AGES-Reykjavik Study 4,354 persons (mean age 76±5 years, 58% women) without dementia had a 1.5Tesla brain MRI. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the MINI International Neuropsychiatric Interview.
Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy (B=−1.25%; 95%CI −2.05 to −0.44%), including more gray and white matter atrophy in most lobes as well as more atrophy of the hippocampus and thalamus. Participants with current, first onset, MDD also had more brain atrophy (B=−1.62%; 95%CI −3.30 to 0.05%), while those remitted did not (B=0.06%; 95%CI −0.54 to 0.66%).
In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD, was associated with widespread gray and white matter brain atrophy. Prospective studies should examine whether MDD is a consequence of or contributes to brain volume loss and development of dementia.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
Fractures of the proximal femur are the most devastating outcome of osteoporosis. It is generally understood that age-related changes in hip structure confer increased risk, but there have been few explicit comparisons of such changes in healthy subjects to those with hip fracture. In this study, we used quantitative computed tomography and tensor-based morphometry (TBM) to identify three-dimensional internal structural patterns of the proximal femur associated with age and with incident hip fracture. A population-based cohort of 349 women representing a broad age range (21–97 years) were included in this study, along with a cohort of 222 older women (mean age 79±7 years) with (n=74) and without (n=148) incident hip fracture. Images were spatially normalized to a standardized space, and age- and fracture-specific morphometric features were identified based on statistical maps of shape features described as local changes of bone volume. Morphometric features were visualized as maps of local contractions and expansions, and significance was displayed as Student’s t-test statistical maps. Significant age-related changes included local expansions of regions low in volumetric bone mineral density (vBMD) and local contractions of regions high in vBMD. Some significant fracture-related features resembled an accentuated aging process, including local expansion of the superior aspect of the trabecular bone compartment in the femoral neck, with contraction of the adjoining cortical bone. However, other features were observed only in the comparison of hip fracture subjects with age-matched controls including focal contractions of the cortical bone at the superior aspect of the femoral neck, the lateral cortical bone just inferior to the greater trochanter, and the anterior intertrochanteric region. Results of this study support the idea that the spatial distribution of morphometric features is relevant to age-related changes in bone and independently to fracture risk. In women, the identification by TBM of fracture-specific morphometric alterations of the proximal femur, in conjunction with vBMD and clinical risk factors, may improve hip fracture prediction.
Osteoporosis; proximal femur; statistical parametric mapping; tensor-based morphometry (TBM); age; fracture
To examine the long-term association between mid-life physical activity (PA) and lower extremity function (LEF) in late-life.
A longitudinal study with an average of 25 years of follow up.
A large community-based population of 4753 men and women (mean age 76±6 yrs) residing in Reykjavik, Iceland.
On the basis of weekly hours of regular PA reported at the mid-life examination, participants were classified as “Active” and “Inactive”. Measures of LEF in late-life included gait speed from 6m walk (meter per second, m/s), Timed Up and Go (TUG, second), and Knee Extension (KE) strength (kg) tests. Linear regression analysis was used to examine the association.
Participants who were active in mid-life had significantly better LEF (faster gait speed,, β = 0.05, p ≤ 0.001; faster TUG time, β = −0.53, p ≤ 0.001; stronger KE strength, β = 1.3, p ≤ 0.001) in late-life compared with those who were not active in mid-life, after adjusting for socio-demographic and cardiovascular risk factors. After adjustment for cognitive function in late life (speed of processing, memory, and executive function), participants who were active in mid-life still had significantly faster gait speed (β = 0.04, p ≤ 0.001), faster TUG time (β = −0.34, p ≤ 0.001), and greater KE strength (β = 0.87, p ≤ 0.001) in old age compared with those who were not active in mid-life.
Regular PA reported in mid-life is associated with better performance of LEF in later life, even after controlling for late life cognitive function.
mid-life physical activity; mobility; aging; cognitive function; lower extremity function
Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10−8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.
Stroke is a leading cause of mortality with a major effect on health-related quality of life (HRQoL). There are no previous studies exploring HRQoL among stroke survivors in Ghana, despite the increasing public health significance of the disease in this country. Here we describe the profile of and factors associated with HRQoL among stroke survivors in Ghana.
This was a cross-sectional study involving 156 stroke survivors and 156 age- and sex-matched, apparently healthy controls. A robust HRQoL questionnaire involving seven domains was used to collect data from the study participants. Clinical epidemiology data were also collected from stroke survivors on parameters such as stroke severity and risk factors. Statistical analyses were performed on the interrelationships among the study variables.
The mean ages of the stroke survivors and healthy controls were 58.0 (standard deviation, 11.4) and 57.6 (standard deviation, 12.0) years, respectively. Fifty-three percent (86) of the stroke survivors had mild stroke and 35.3% (55) had moderate stroke, whereas 12.2% (19) had severe stroke. Ischemic infarction was the prevalent stroke subtype (78.1%). Hypertension was the most common risk factor (89%) among the stroke survivors, followed by diabetes (29%). HRQoL scores ranged from 57.7% (cognitive domain) to 80.0% (spirit domain) for stroke survivors, whereas HRQoL scores of the control group ranged from 65.6% (cognitive domain) to 85.2% (soul domain). For each HRQoL domain, significantly higher scores were observed for the control group compared with the stroke survivors, at P<0.05. Determinants of HRQoL of stroke survivors in multivariate analysis included age, stroke severity, poststroke duration, stroke recurrence, frequency of laughter, and negative emotions.
The most affected HRQoL domains are of the physical, psychoemotional, and cognitive domains. Rehabilitation of stroke patients in this region should include interventions targeted at these domains and modifying the statistical determinants of HRQoL where possible.
quality of life; stroke; domain; Ghana
Coronary artery calcium (CAC) and physical performance have been shown to be associated with mortality, but it is not clear whether one of them modifies the association. We investigated the association between the extent of CAC and physical performance among older individuals and explored these individual and combined effects on cardiovascular disease (CVD) and non-CVD mortality.
We studied 4074 participants of the AGES-Reykjavik Study who were free from coronary heart disease, had a CAC score calculated from computed tomography scans and had data on mobility limitations and gait speed at baseline in 2002-2006 at a mean age of 76 years. Register-based mortality was available until 2009.
Odds for mobility limitation and slow gait increased according to the extent of CAC. Altogether 645 persons died during the follow-up. High CAC, mobility limitation and slow gait were independent predictors of CVD and non-CVD mortality. The joint effect of CAC and gait speed on non-CVD mortality was synergistic, i.e. compared to those with low CAC and normal gait, the joint effect of high CAC and slow gait exceeded the additive effect of these individual exposures on non-CVD mortality. For CVD mortality, the effect was additive i.e. the joint effect of high CAC and slow gait did not exceed the sum of the individual exposures.
The extent of CAC and decreased physical performance were independent predictors of mortality and the joint presence of these risk factors increased the risk of non-CVD mortality above and beyond the individual effects.
atherosclerosis; coronary artery calcification; cardiovascular disease risk factors; aging; mortality; epidemiology
The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we have carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density to investigate changes in regional cortical thickness, as well as cortical and trabecular bone mineral density at the mid-femoral neck. Segmental QCT analysis was used to assess bone measurements in two anatomic sub-regions, the supero-lateral (superior) and infero-medial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66–90 years) who were participants in the AGES-Reykjavik study, were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 yr. (mean baseline age 74 yr.). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical vBMD inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck DXA-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men.
Cortical thickness; proximal end of femur; aging; longitudinal; QCT
Unrecognized myocardial infarction (MI) is prognostically important but electrocardiography (ECG), the main epidemiology tool for detection, is insensitive to MI.
Determine prevalence and mortality risk for unrecognized MI (UMI) detected by cardiac magnetic resonance (CMR) or ECG.
ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004–January 2007) using ECG or CMR to detect UMI.
Community dwelling participants in Iceland over age 67.
936 participants (ages 67–93 years) including 670 who were randomly selected and 266 with diabetes.
Main Outcome Measures
MI prevalence and mortality through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI).
Of 936 participants, 91 had recognized MI (RMI; 9.7% CI 8–12%), and 157 had UMI by CMR (17%; CI 14–19%) which was more prevalent than the 46 UMI by ECG (5%; CI 4–6%, p<0.001). Diabetic participants had more UMI by CMR than UMI by ECG (n=72; 21%; CI 17–26% vs. n=15; 4%; CI 2–7%, p<0.001). UMI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 33% (CI 23–43%) of individuals with RMI died (30 of 91) and 28% (CI 21–35%) with UMI died (44 of 157), both higher rates than the 17% (CI 15–20%) with no MI that died (119 of 688). UMI by CMR improved risk stratification for mortality over RMI (NRI: 0.34; CI 0.16–0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (HR 1.45 CI 1.02–2.06, absolute risk increase (ARI) 8%) and significantly improved risk stratification for mortality, NRI 0.16 (CI 0.01–0.31)) but UMI by ECG did not (HR 0.88, CI 0.45–1.73 ARI −2%; NRI: −0.05; CI −0.17–0.05). Compared to those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; CI, 28–43% or 56/157 vs.73%; CI 63–82% or 66/91; p<0.001).
In a community-based cohort, the prevalence of UMI by CMR was higher than the prevalence of recognized MI or UMI by ECG, and was associated with increased mortality risk.
We studied the effect of birth size on glucose and insulin metabolism among old non-diabetic individuals. We also explored the combined effect of birth size and midlife body mass index (BMI) on type 2 diabetes in old age. Our study comprised 1,682 Icelanders whose birth records included anthropometrical data. The same individuals had participated in the prospective population-based Reykjavik Study, where BMI was assessed at a mean age of 47 years, and in the AGES-Reykjavik Study during 2002 to 2006, where fasting glucose, insulin and HbA1c were measured and homeostasis model assessment for the degree of insulin resistance (HOMA-IR) calculated at a mean age of 75.5 years. Type 2 diabetes was determined as having a history of diabetes, using glucose-modifying medication or fasting glucose of >7.0 mmol/l. Of the participants, 249 had prevalent type 2 diabetes in old age. Lower birth weight and body length were associated with higher fasting glucose, insulin, HOMA-IR and HbA1c among old non-diabetic individuals. Higher birth weight and ponderal index at birth decreased the risk for type 2 diabetes in old age, odds ratio (OR), 0.61 [95 % confidence interval (CI), 0.48–0.79] and 0.96 (95 % CI, 0.92–1.00), respectively. Compared with those with high birth weight and low BMI in midlife, the odds of diabetes was almost five-fold for individuals with low birth weight and high BMI (OR, 4.93; 95 % CI, 2.14–11.37). Excessive weight gain in adulthood might be particularly detrimental to the health of old individuals with low birth weight.
Aging; Birth size; Type 2 diabetes; Dysglycaemia; Birth weight; AGES-Reykjavik Study
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%), and QT prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-SNP interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0×10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
QT interval; pharmacogenomics; gene-environment interaction
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970–2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9–17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
adiposity; body mass index; genetic association studies; menarche; obesity; waist circumference; waist:hip ratio; women's health
The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.
We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.
After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.
In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.)
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
To examine the joint association of migraine headache and major depressive disorder on brain volume in older persons without dementia.
Participants (n = 4,296, 58% women) from the population-based Age, Gene/Environment Susceptibility–Reykjavik Study were assessed for migraine headache in 1967–1991 (age 51 years [range 33–65]) according to modified International Classification of Headache Disorders–II criteria. In 2002–2006 (age 76 years [range 66–96]), lifetime history of major depressive disorder (depression) was diagnosed according to DSM-IV criteria, and full-brain MRI was acquired, which was computer postprocessed into total brain volume (TBV) (gray matter [GM], white matter [WM], white matter hyperintensities) and CSF volume for each study subject. We compared brain tissue volumes by headache categories with or without depression using linear regression, adjusting for intracranial volume and other factors.
Compared with the reference group (no headache, no depression) TBV and WM and GM volumes were smaller in those with both migraine and depression (TBV −19.2 mL, 95% confidence interval [CI] −35.3, −3.1, p = 0.02; WM −12.8 mL, CI −21.3, −4.3, p = 0.003; GM −13.0 mL, CI −26.0, 0.1, p = 0.05) but not for those with migraine alone (TBV 0.4 mL, WM 0.2 mL, GM 0.6 mL) or depression alone (TBV −3.9 mL, WM −0.9 mL, GM −2.9 mL).
Reporting both migraine and major depressive disorder was associated with smaller brain tissue volumes than having one or neither of these conditions. Migraineurs with depression may represent a distinct clinical phenotype with different long-term sequelae. Nonetheless, the number of subjects in the current study is relatively small and these findings need to be confirmed in future studies.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.