Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of ...variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10
) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
Background
Twin studies show moderate heritability of sleep traits: 40% for insomnia symptoms and 46% for sleep duration. Genome‐wide association studies (GWAS) have identified genetic variants ...involved in insomnia and sleep duration in adults, but it is unknown whether these variants affect sleep during early development. We assessed whether polygenic risk scores for insomnia (PRS‐I) and sleep duration (PRS‐SD) affect sleep throughout early childhood to adolescence.
Methods
We included 2,458 children of European ancestry (51% girls). Insomnia‐related items of the Child Behavior Checklist were reported by mothers at child's age 1.5, 3, and 6 years. At 10–15 years, the Sleep Disturbance Scale for Children and actigraphy were assessed in a subsample (N = 975). Standardized PRS‐I and PRS‐SD (higher scores indicate genetic susceptibility for insomnia and longer sleep duration, respectively) were computed at multiple p‐value thresholds based on largest GWAS to date.
Results
Children with higher PRS‐I had more insomnia‐related sleep problems between 1.5 and 15 years (BPRS‐I < 0.001 = .09, 95% CI: 0.05; 0.14). PRS‐SD was not associated with mother‐reported sleep problems. A higher PRS‐SD was in turn associated with longer actigraphically estimated sleep duration (BPRS‐SD < 5e08 = .05, 95% CI: 0.001; 0.09) and more wake after sleep onset (BPRS‐SD < 0.005 = .25, 95% CI: 0.04; 0.47) at 10–15 years, but these associations did not survive multiple testing correction.
Conclusions
Children who are genetically predisposed to insomnia have more insomnia‐like sleep problems, whereas those who are genetically predisposed to longer sleep have longer sleep duration, but are also more awake during the night in adolescence. This indicates that polygenic risk for sleep traits, based on GWAS in adults, affects sleep already in children.
Fracture incidence needs to be evaluated over time to assess the impact of the enlarging population burden of fractures (due to increase in lifespan) and the efficacy of fracture prevention ...strategies. Therefore, we aimed to evaluate the association of femoral neck bone mineral density (FN-BMD) measured using dual-energy X-ray absorptiometry (DXA) at baseline with fracture risk over a long follow-up time period. Incident non-vertebral fractures were assessed in 14,613 individuals participating in the Rotterdam Study with up to 20 years of follow-up. During a mean follow-up of 10.7 ± 6.2 years, 2971 (20.3%) participants had at least one incident non-vertebral fracture. The risk for any non-vertebral fracture was 1.37 (95% Confidence Interval (CI): 1.25–1.49) and 1.42 (95%CI: 1.35–1.50) for men and women, respectively. The majority (79% in men and 75% in women) of all fractures occurred among participants a normal or osteopenic T-score. The incidence rates per 1000 person-years for the most common fractures were 5.3 95%CI: 5.0–5.7 for hip, 4.9 95%CI: 4.6–5.3 for wrist and 2.3 95%CI: 2.0–2.5 for humerus. To examine the predictive ability of BMD through follow-up time we determined fracture hazard ratios (HR) per standard deviation decrease in femoral neck BMD across five year bins. No differences were observed, with a HR of 2.5 (95%CI: 2.0–3.1) after the first 5 years, and of 1.9 (95%CI: 1.1–3.3) after 20 years. To assess secular trends in fracture incidence at all skeletal sites we compared participants at an age of 70–80 years across two time periods: 1989–2001 (n = 2481, 60% women) and 2001–2013 (n = 2936, 58% women) and found no statistically significant difference (p < 0.05) between fracture incidence rates (i.e., incidence of non-vertebral fractures of 26.4 per 1000 PY 95%CI: 24.4–28.5) between 1989 and 2001, and of 25.4 per 1000 PY 95%CI: 23.0–28.0 between 2001 and 2013. In conclusion, BMD is still predictive of future fracture over a long period of time. While no secular changes in fractures rates seem to be observed after a decade, the majority of fractures still occur above the osteoporosis threshold, emphasizing the need to improve the screening of osteopenic patients.
•Age is the most important determinant of fracture with those of the hip, wrist and proximal humerus having the highest rates•Bone mineral density is still predictive of fractures for up to 20 years•No secular trend differences in fracture incidence rates were observed between the 1989-2001 and 2001-2013 periods
Previous studies have suggested that insufficient concentrations of vitamin D are associated with dental caries in primary teeth, but evidence remains inconclusive.
We assessed the longitudinal ...associations between prenatal, perinatal, and early childhood serum 25-hydroxyvitamin D concentrations 25(OH)D and the risk of dental caries in 6-year-old children.
This research was conducted within the Generation R Study, a large, multi-ethnic, prospective cohort study located in Rotterdam, the Netherlands. Dental caries were assessed in children using the decayed-missing-filled-primary teeth index at a mean age of 6.1 years (90% range, 4.8–9.1). We measured serum total 25(OH)D concentrations at 3 time points: prenatally (at 18–24 weeks of gestation), perinatally (at birth), and during early childhood (at age 6 years). We performed logistic regression analyses to determine the longitudinal association of serum 25(OH)D concentrations with caries risks in 5257 children. Additionally, we constructed a Genetic Risk Score (GRS) for the genetic predispositions to serum total 25(OH)D concentrations based on 6 vitamin D–related single nucleotide polymorphisms in a subsample of 3385 children.
Children with severe prenatal and early childhood serum 25(OH)D deficiencies (<25 nmol/L) were more likely to be diagnosed with caries OR, 1.56 (95% CI, 1.18–2.06) and 1.58 (95% CI, 1.10–2.25), respectively than children with optimal concentrations (≥75 nmol/L). After adjustment for residuals of serum 25(OH)D concentrations at other time points, only the early childhood serum 25(OH)D concentration was inversely associated with the caries risk at 6 years (OR, 0.97; 95% CI, 0.95–0.98). However, our GRS analysis showed that children who are genetically predisposed to have lower serum 25(OH)D concentrations do not have a higher risk of developing caries in primary teeth.
Our study suggests a weak association between serum 25(OH)D concentrations and risks of caries in primary teeth. Based on our results, we do not recommend vitamin D supplementation for the prevention of dental caries in children.
Objective
The role of vitamin D in OA is unclear and previous epidemiological studies have provided inconsistent results. We conducted a two-sample Mendelian randomization (MR) study to investigate ...the causal relationship between genetically determined serum vitamin D levels and hip/knee OA.
Methods
Six single-nucleotide polymorphisms (SNPs) associated with vitamin D levels in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits Consortium were selected as instrumental variables. Summary statistics of the SNPs effects on OA were derived from the Iceland and UK Biobank, comprising 23 877 knee OA cases, 17 151 hip OA cases and >562 000 controls. The control samples match the OA cases in age, sex and county of origin.
Results
The MR analyses showed no causal association between genetically determined vitamin D levels and knee OA odds ratio (OR) 1.03 (95% CI 0.84, 1.26) or hip OA OR 1.06 (95% CI 0.83, 1.35).
Conclusion
Genetic variations associated with low vitamin D serum levels are not associated with increased risk of hip or knee OA in community-dwelling older adults, suggesting that vitamin D levels are not causally linked to OA. It is therefore unlikely that vitamin D supplementation protects against hip or knee OA.
Fracture rate in childhood is increasing and its consequences may affect health and developmental processes and cause school absence and restricted activity days. There are scarce epidemiologic ...studies regarding fractures in children. The aim of this study was to evaluate if pediatric fractures show disparities across sexes and ethnic groups. This study was conducted based on data from 3632 participants of the Generation R Study. Prevalent fractures were assessed using a questionnaire at a mean age of 9.7 years. Child's ethnicity was determined based on country of birth of the parents using questionnaires (geographic ancestry) or admixture analysis (genetic ancestry). Associations between fracture occurrence and sex or ethnicity were evaluated using logistic regression models adjusted for age, weight, lean mass fraction, bone mineral density (BMD) and sex/ethnicity. Fracture was reported for 525 (14.5%) children. The great majority of these children were classified as European (N = 3164), followed by African (N = 283) and Asian (N = 185) based on geographic ancestry. Similarly, the highest proportion of Europeans was observed based on genetic ancestry. Prevalence of fractures was not different between boys and girls, even after adjustment for possible confounders (OR: 1.03, 95% CI 0.84–1.27, p-value = 0.8). However, odds of prevalent fractures were two times higher in European when compared to Asian children (OR: 2.01, 95% CI 1.17–3.45, p-value = 0.01), and 1.5 times higher when compared to African children (OR: 1.50, 95% CI 1.00–2.26, p-value = 0.05). Overall, in this study, European children showed a highest risk of prevalent fractures independently of factors such as body composition and BMD, while no difference in the prevalence of fractures between boys and girls was observed.
•No differences in the risk of prevalent fracture were observed between boys and girls.•European children are more prone to fractures as compared to children from other ethnic backgrounds.•Higher risk of prevalent fracture in European children is independent of factors such as body composition and BMD.
Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, ...suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10-2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.
Abstract
Background
Looking older for one’s chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which ...facial ageing reflects systemic ageing of the human body.
Objectives
To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age.
Methods
We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5–87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2).
Results
We observed 5-year higher ΔPA (i.e. looking younger by 5 years for one’s age) to be associated with less osteoporosis odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62–0.93, less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77–0.95), less age-related hearing loss (model 2; B = −0.76, 95% CI −1.35 to −0.17) and fewer cataracts (OR 0.84, 95% CI 0.73–0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04–0.10).
Conclusions
PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.
Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on ...the activities of several B vitamin–dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine β-synthase (CBS).
We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin–related measures with bone mineral density (BMD) and strength.
We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5’-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing.
The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified.
Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength. These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
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