[Show abstract][Hide abstract] ABSTRACT: Background:
-There is increasing evidence that retinal microvascular diameters are associated with cardio- and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.
Methods and results:
-This study extends previous genome-wide association study results using 24,000+ multi-ethnic participants from 7 discovery and 5,000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single nucleotide polymorphisms (SNPs) and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent (CRVE) and the central retinal arteriole equivalent (CRAE). We report 4 new loci associated with CRVE, one of which is also associated with CRAE. The 4 SNPs are rs7926971 in TEAD1 (p=3.1×10(-11), minor allele frequency (MAF)=0.43), rs201259422 in TSPAN10 (p=4.4×10(-9), MAF=0.27), rs5442 in GNB3 (p=7.0×10(-10), MAF=0.05) and rs1800407 in OCA2 (p=3.4×10(-8), MAF=0.05). The latter SNP, rs1800407, was also associated with CRAE (p=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, SNP rs201255422 was associated with both systolic (p=0.001) and diastolic blood pressure (p=8.3×10(-04)).
-Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
[Show abstract][Hide abstract] ABSTRACT: Background/objectives:
The Dutch guidelines for a healthy diet aim to reduce major chronic diseases. However, supporting evidence on their overall association with all-cause and cause-specific mortality is limited. Recently, the Dutch Healthy Diet-index (DHD-index) has been developed to assess adherence to these guidelines. The aim was to examine the association between the DHD-index and all-cause mortality and deaths from cardiovascular disease (CVD), coronary heart disease (CHD), stroke and cancer.
We followed 3593 men and women aged 55 years and older enrolled in the Rotterdam Study, a population-based prospective cohort study, from baseline in 1990-1993 to 2011. A validated 170-item food frequency questionnaire at baseline was used to calculate the DHD-index score (maximum 90 points). Cox proportional hazard models were used to estimate hazard ratios (HRs) adjusting for age, sex, total energy intake, smoking and educational level.
During the 20-year follow-up, 1831 (51%) deaths were reported. Mean DHD-index score was 60.6 (s.d. 10.6). The score was inversely associated with all-cause mortality (highest vs lowest quartile HR 0.77; 95% confidence interval (CI) 0.67, 0.89). Inverse but non-significant associations were observed for mortality due to CVD (HR 0.74; 95% CI 0.55, 1.01), CHD (HR 0.60; 95% CI 0.34, 1.06) and stroke (HR 0.67; 95% CI 0.36, 1.22), whereas no association was observed with cancer mortality (HR 0.99; 95% CI 0.90, 1.11).
A higher level of adherence to the Dutch dietary guidelines, as assessed with the DHD-index, was associated with a lower risk of all-cause mortality, probably due to an inverse association with cardiovascular causes of death.European Journal of Clinical Nutrition advance online publication, 21 October 2015; doi:10.1038/ejcn.2015.163.
European journal of clinical nutrition 10/2015; DOI:10.1038/ejcn.2015.163 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/objectives:
High vitamin A intake may be associated with a decreased bone mineral density (BMD) and increased risk of fractures. Our objectives were to study whether dietary intake of vitamin A (total, retinol or beta-carotene) is associated with BMD and fracture risk and if associations are modified by body mass index (BMI) and vitamin D.
Participants were aged 55 years and older (n=5288) from the Rotterdam Study, a population-based prospective cohort. Baseline vitamin A and D intake was measured by a food frequency questionnaire. BMD was measured by dual-energy X-ray absorptiometry at four visits between baseline (1989-1993) and 2004. Serum vitamin D was assessed in a subgroup (n=3161). Fracture incidence data were derived from medical records with a mean follow-up time of 13.9 years.
Median intake of vitamin A ranged from 684 retinol equivalents (REs)/day (quintile 1) to 2000 REs/day (quintile 5). After adjustment for confounders related to lifestyle and socioeconomic status, BMD was significantly higher in subjects in the highest quintile of total vitamin A (mean difference in BMD (95% confidence interval (CI))=11.53 (0.37-22.7) mg/cm(2)) and retinol intake (mean difference in BMD (95% CI)=12.57 (1.10-24.05) mg/cm(2)) than in the middle quintile. Additional adjustment for BMI diluted these associations. Fracture risk was reduced in these subjects. Significant interaction was present between intake of retinol and overweight (BMI >25 kg/m(2)) in relation to fractures (P for interaction =0.05), but not BMD. Stratified analysis showed that these favourable associations with fracture risk were only present in overweight subjects (BMI >25 kg/m(2)). No effect modification by vitamin D intake or serum levels was observed.
Our results suggest a plausible favourable relation between high vitamin A intake from the diet and fracture risk in overweight subjects, whereas the association between vitamin A and BMD is mainly explained by BMI.European Journal of Clinical Nutrition advance online publication, 16 September 2015; doi:10.1038/ejcn.2015.154.
European journal of clinical nutrition 09/2015; DOI:10.1038/ejcn.2015.154 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Higher levels of vitamin D have been associated with lower rates of cardiovascular disease perhaps through improved lipid profiles. However, results are inconsistent and the direction of the association between vitamin D and lipid levels remains unknown. We examined bidirectional associations between serum 25-hydroxyvitamin D (25(OH)D) and cholesterol concentrations.
We used data from 1165 participants aged 55 to 88 years from the Rotterdam Study, a population-based prospective cohort study.
Main outcome measures:
Serum concentrations of 25(OH)D, total cholesterol (TC) and HDL cholesterol (HDL-C) were measured at two time points with a median time difference of 6 years. Bidirectional associations between 25(OH)D and each of the blood lipids was examined with path analyses in cross-lagged models. All models were adjusted for baseline age, sex, BMI, smoking status, and diet quality.
The best-fit model for 25(OH)D and TC indicated that higher baseline TC concentrations were associated with lower 25(OH)D concentrations (standardized regression coefficient -0.05 (SE 0.02)), but 25(OH)D at baseline did not predict TC. For HDL-C, the best-fit model suggested a bidirectional inverse association between HDL-C and 25(OH)D (standardized regression coefficients of -0.03 (SE 0.02)) for both directions.
Our results from path analyses on repeatedly measured 25(OH)D and lipid levels suggest that total cholesterol may be associated with decreased in 25(OH)D concentrations, but not the other way around, whereas the observed inverse association between HDL-C and 25(OH)D may be bidirectional.
[Show abstract][Hide abstract] ABSTRACT: The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.Molecular Psychiatry advance online publication, 4 August 2015; doi:10.1038/mp.2015.105.
[Show abstract][Hide abstract] ABSTRACT: Background/objectives:
Gait is an important health indicator, relating strongly to the risk of falling, morbidity and mortality. In a community-dwelling population, we investigated associations of alcohol, coffee and tobacco consumption with gait.
Two thousand forty-six non-demented participants from the Rotterdam Study underwent gait assessment by electronic walkway. We measured gait velocity and Global Gait, which is the average of seven gait domains: Rhythm, Phases, Variability, Pace, Tandem, Turning and Base of Support. Alcohol, coffee and tobacco consumption was assessed by questionnaires. With analysis of covariance, we investigated associations of consumption of alcoholic beverages, coffee consumption and smoking with Global Gait, gait velocity and the seven individual gait domains.
In all, 81.9% of participants drank alcohol, 92.4% drank coffee, 17.3% were current smokers and 50.9% were past smokers. Moderate alcohol consumption (1-3 glasses per day) associated with better gait, as measured by Global Gait (0.20 standard deviations (s.d.) (95% confidence interval: 0.10; 0.31)), gait velocity (2.65 cm/s (0.80; 4.50)), Rhythm and Variability. Consuming high amounts of coffee (>3 cups per day) associated with better Global Gait (0.18 s.d. (0.08; 0.28)), gait velocity (2.63 cm/s (0.80; 4.45)), Pace, Turning and Variability. Current smoking associated with worse Global Gait (-0.11 s.d. (-0.21; 0.00)), gait velocity (-3.47 cm/s (-5.33; -1.60)), Rhythm and Pace, compared with non-smokers.
In a community-dwelling population, consuming >1 cup of coffee and 1-3 glasses of alcohol relate to better gait, whereas smoking is related to worse gait. Further studies are required to evaluate whether interventions targeting substance consumption may aid to prevent or reduce gait deterioration and thereby related health problems.European Journal of Clinical Nutrition advance online publication, 29 July 2015; doi:10.1038/ejcn.2015.120.
European journal of clinical nutrition 07/2015; DOI:10.1038/ejcn.2015.120 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.Molecular Psychiatry advance online publication, 30 June 2015; doi:10.1038/mp.2015.69.
[Show abstract][Hide abstract] ABSTRACT: To examine the associations of body fatness, metabolic and inflammatory markers with retinal vessel calibers among children.
We performed a population-based cohort study among 4,145 school-age children. At the median age of 6.0 years (95% range 5.8, 8.0 years), we measured body mass index, total and abdominal fat mass, metabolic and inflammatory markers (blood levels of lipids, insulin and C-peptide and C-reactive protein) and retinal vascular calibers from retinal photographs.
We observed that compared to normal weight children, obese children had narrower retinal arteriolar caliber (difference -0.21 SDS (95% Confidence Interval (CI) -0.35, -0.06)), but not venular caliber. Continuous analyses showed that higher body mass index and total body fat mass, but not android/gynoid fat mass ratio and pre-peritoneal fat mass, were associated with narrower retinal arteriolar caliber (P-values <0.05 for body mass index and total body fat mass), but not with retinal venular caliber. Lipid and insulin levels were not associated with retinal vessel calibers. Higher C-reactive protein was associated with only wider retinal venular caliber (difference 0.10 SDS (95% CI 0.06, 0.14) per SDS increase in C-reactive protein). This latter association was not influenced by body mass index.
Higher body fatness is associated with narrower retinal arteriolar caliber, whereas increased C-reactive protein levels are associated with wider retinal venular caliber. Increased fat mass and inflammation correlate with microvascular development from school-age onwards.International Journal of Obesity accepted article preview online, 01 June 2015. doi:10.1038/ijo.2015.99.
International journal of obesity (2005) 06/2015; 39(10). DOI:10.1038/ijo.2015.99 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: High body mass index is associated with increased C-reactive protein levels in childhood and adulthood. Little is known about the associations of detailed adiposity measures with C-reactive protein levels in childhood. We examined the associations of general and abdominal adiposity measures with C-reactive protein levels at school age. To gain insight into the direction of causality, we used genetic risk scores based on known genetic variants in adults as proxies for child adiposity measures and C-reactive protein levels.
International journal of obesity (2005) 04/2015; 39(7). DOI:10.1038/ijo.2015.73 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts.
Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism.
We performed nested case-control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800-829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961).
Meta-analysis of the two nested case-control studies showed pooled odds ratios of 0.98 (0.91-1.05, p = 0.52), 1.04 (0.97-1.12, p = 0.28), and 1.16 (0.83-1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS.
In conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD.
Osteoporosis International 04/2015; 26(7). DOI:10.1007/s00198-015-3087-0 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20bp) and 0.16 SVs (>20bp) per generation. De novo structural changes affect on average 4.1kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a non-uniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.
Published by Cold Spring Harbor Laboratory Press.
Genome Research 04/2015; 25(6). DOI:10.1101/gr.185041.114 · 14.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.